Ted Bosworth

TORONTO — There is little consistency in the elements and types of information captured in preparticipation physical evaluations (PPE) for sports among school-aged children, which is complicating efforts to determine if they have value, according to a study presented at the Pediatric Academic Societies annual meeting.

The study concept developed when Tammy Ng, MD, a third-year resident in pediatrics at the University of California, Davis, School of Medicine in Sacramento, was surprised to learn that the American Academy of Pediatrics (AAP) had been issuing a standard-of-care PPE for decades.

Dr. Ng had a long-standing interest in pediatric sports medicine and thought that if she was unfamiliar with this form, which was first developed by the AAP in the 1990s in collaboration with other professional organizations, there must be others who were unaware of this resource.

Assuming that this collaborative effort led by the AAP could serve as a standard of care, Dr. Ng evaluated whether PPEs at her own institution were capturing similar information.

In the most recent (5th) edition of the PPE, which was released in 2019 and is available online, medical history is elicited for numerous organ systems relevant to risk. The questions are not directed to any specific sport; the form does not even provide a question about which sports are being considered.
 

Little Consistency

In evaluating whether PPEs completed at her institution in the previous year elicited similar information, Dr. Ng sought to match 25 elements of patient history from the AAP form to questions posed in the PPEs completed at her institution, some of which had been supplied by school or sports organizations.

Of the 365 PPE forms completed at Dr. Ng’s institution that met study criteria, only 28.6% addressed all 25 elements in the AAP form (range, 0%-78%). Although more than half asked specifically about a history of respiratory symptoms, fewer than half included inquiries about cardiovascular history. There was also little consistency in the capture of information about other relevant medical history.

According to Dr. Ng, these low percentages were observed even when liberally awarding credit. For one example, she said forms that asked any question about syncope with exercise were credited with seeking information about cardiovascular health even though a yes-or-no response might not be helpful.

“We did not distinguish between syncope before or after exercise and this is relevant,” Dr. Ng said. “Syncope during exercise is more likely to be a predictor of sudden cardiac death, whereas syncope after exercise is more likely to be a vasovagal response to exertion.”

Of the 365 PPEs evaluated, about half were completed by pediatricians and half by family medicine clinicians. The average age of the children was about 14 years. Sixty-three percent were male. Only one third of the forms documented the sport for which a pre-participation screen was being submitted.

While almost all states now require PPEs for children considering participation in sports, few specify what information should be elicited, according to Dr. Ng. She further noted that no major study has shown that PPEs have any role in preventing morbidity or mortality related to sports participation.
 

Does Heterogeneity Negate Worth?

With such diversity across PPEs, evaluating their role is difficult. For example, with such heterogeneity among forms for the information elicited, there is no reasonable approach for testing their sensitivity in predicting medical complications.

Dr. Ng noted that school-created forms were just as likely as forms from other sources to diverge from the AAP-endorsed PPE and ignore organ systems relevant to risk of medical complications. Yet, if the answer is to use the AAP form, Dr. Ng noted that the first sentence on the form reads, “This form should be placed in the athlete’s medical file and should not be shared with schools or sports organizations.”

Although Dr. Ng acknowledged that providing completed PPEs to third parties raises questions about privacy, she questioned how the information should be used by children, parents, and sports organization administrators for discussing risks if not shared.

This concern was seconded in the discussion following Dr. Ng’s presentation.

“You might be signing off on sports participation, but is this for cheerleading or for football?” asked Daniel C. Worthington, MD, a pediatrician in private practice who has a clinical appointment at Case Western Reserve University School of Medicine, Cleveland. “This makes a huge difference when evaluating if participation is safe.”

He has no issue with completing PPEs for the goal of keeping children safe, but he focused on the inconsistency of how information is collected and distributed.

“The major question is: Does it make any difference?” said Dr. Worthington, referring to the completion of PPEs.

Another participant in the discussion that followed Dr. Ng’s presentation pointed out that the urgent care office in a mall near to his office offers a completed PPE form for a price of $20. In their recommendations, the AAP suggests PPEs be completed by the individual’s primary care physician during a well visit, according to Dr. Ng.

Dr. Ng indicated that PPEs and their purpose deserve a closer look. Based on her data, it is reasonable to assume that the priority for some – whether those requiring or those completing the form — is completing the task rather than meaningful screening of risk.

Dr. Ng and Dr. Worthington report no potential conflicts of interest.

TORONTO — There is little consistency in the elements and types of information captured in preparticipation physical evaluations (PPE) for sports among school-aged children, which is complicating efforts to determine if they have value, according to a study presented at the Pediatric Academic Societies annual meeting.

The study concept developed when Tammy Ng, MD, a third-year resident in pediatrics at the University of California, Davis, School of Medicine in Sacramento, was surprised to learn that the American Academy of Pediatrics (AAP) had been issuing a standard-of-care PPE for decades.

Dr. Ng had a long-standing interest in pediatric sports medicine and thought that if she was unfamiliar with this form, which was first developed by the AAP in the 1990s in collaboration with other professional organizations, there must be others who were unaware of this resource.

Assuming that this collaborative effort led by the AAP could serve as a standard of care, Dr. Ng evaluated whether PPEs at her own institution were capturing similar information.

In the most recent (5th) edition of the PPE, which was released in 2019 and is available online, medical history is elicited for numerous organ systems relevant to risk. The questions are not directed to any specific sport; the form does not even provide a question about which sports are being considered.
 

Little Consistency

In evaluating whether PPEs completed at her institution in the previous year elicited similar information, Dr. Ng sought to match 25 elements of patient history from the AAP form to questions posed in the PPEs completed at her institution, some of which had been supplied by school or sports organizations.

Of the 365 PPE forms completed at Dr. Ng’s institution that met study criteria, only 28.6% addressed all 25 elements in the AAP form (range, 0%-78%). Although more than half asked specifically about a history of respiratory symptoms, fewer than half included inquiries about cardiovascular history. There was also little consistency in the capture of information about other relevant medical history.

According to Dr. Ng, these low percentages were observed even when liberally awarding credit. For one example, she said forms that asked any question about syncope with exercise were credited with seeking information about cardiovascular health even though a yes-or-no response might not be helpful.

“We did not distinguish between syncope before or after exercise and this is relevant,” Dr. Ng said. “Syncope during exercise is more likely to be a predictor of sudden cardiac death, whereas syncope after exercise is more likely to be a vasovagal response to exertion.”

Of the 365 PPEs evaluated, about half were completed by pediatricians and half by family medicine clinicians. The average age of the children was about 14 years. Sixty-three percent were male. Only one third of the forms documented the sport for which a pre-participation screen was being submitted.

While almost all states now require PPEs for children considering participation in sports, few specify what information should be elicited, according to Dr. Ng. She further noted that no major study has shown that PPEs have any role in preventing morbidity or mortality related to sports participation.
 

Does Heterogeneity Negate Worth?

With such diversity across PPEs, evaluating their role is difficult. For example, with such heterogeneity among forms for the information elicited, there is no reasonable approach for testing their sensitivity in predicting medical complications.

Dr. Ng noted that school-created forms were just as likely as forms from other sources to diverge from the AAP-endorsed PPE and ignore organ systems relevant to risk of medical complications. Yet, if the answer is to use the AAP form, Dr. Ng noted that the first sentence on the form reads, “This form should be placed in the athlete’s medical file and should not be shared with schools or sports organizations.”

Although Dr. Ng acknowledged that providing completed PPEs to third parties raises questions about privacy, she questioned how the information should be used by children, parents, and sports organization administrators for discussing risks if not shared.

This concern was seconded in the discussion following Dr. Ng’s presentation.

“You might be signing off on sports participation, but is this for cheerleading or for football?” asked Daniel C. Worthington, MD, a pediatrician in private practice who has a clinical appointment at Case Western Reserve University School of Medicine, Cleveland. “This makes a huge difference when evaluating if participation is safe.”

He has no issue with completing PPEs for the goal of keeping children safe, but he focused on the inconsistency of how information is collected and distributed.

“The major question is: Does it make any difference?” said Dr. Worthington, referring to the completion of PPEs.

Another participant in the discussion that followed Dr. Ng’s presentation pointed out that the urgent care office in a mall near to his office offers a completed PPE form for a price of $20. In their recommendations, the AAP suggests PPEs be completed by the individual’s primary care physician during a well visit, according to Dr. Ng.

Dr. Ng indicated that PPEs and their purpose deserve a closer look. Based on her data, it is reasonable to assume that the priority for some – whether those requiring or those completing the form — is completing the task rather than meaningful screening of risk.

Dr. Ng and Dr. Worthington report no potential conflicts of interest.

TORONTO — There is little consistency in the elements and types of information captured in preparticipation physical evaluations (PPE) for sports among school-aged children, which is complicating efforts to determine if they have value, according to a study presented at the Pediatric Academic Societies annual meeting.

The study concept developed when Tammy Ng, MD, a third-year resident in pediatrics at the University of California, Davis, School of Medicine in Sacramento, was surprised to learn that the American Academy of Pediatrics (AAP) had been issuing a standard-of-care PPE for decades.

Dr. Ng had a long-standing interest in pediatric sports medicine and thought that if she was unfamiliar with this form, which was first developed by the AAP in the 1990s in collaboration with other professional organizations, there must be others who were unaware of this resource.

Assuming that this collaborative effort led by the AAP could serve as a standard of care, Dr. Ng evaluated whether PPEs at her own institution were capturing similar information.

In the most recent (5th) edition of the PPE, which was released in 2019 and is available online, medical history is elicited for numerous organ systems relevant to risk. The questions are not directed to any specific sport; the form does not even provide a question about which sports are being considered.
 

Little Consistency

In evaluating whether PPEs completed at her institution in the previous year elicited similar information, Dr. Ng sought to match 25 elements of patient history from the AAP form to questions posed in the PPEs completed at her institution, some of which had been supplied by school or sports organizations.

Of the 365 PPE forms completed at Dr. Ng’s institution that met study criteria, only 28.6% addressed all 25 elements in the AAP form (range, 0%-78%). Although more than half asked specifically about a history of respiratory symptoms, fewer than half included inquiries about cardiovascular history. There was also little consistency in the capture of information about other relevant medical history.

According to Dr. Ng, these low percentages were observed even when liberally awarding credit. For one example, she said forms that asked any question about syncope with exercise were credited with seeking information about cardiovascular health even though a yes-or-no response might not be helpful.

“We did not distinguish between syncope before or after exercise and this is relevant,” Dr. Ng said. “Syncope during exercise is more likely to be a predictor of sudden cardiac death, whereas syncope after exercise is more likely to be a vasovagal response to exertion.”

Of the 365 PPEs evaluated, about half were completed by pediatricians and half by family medicine clinicians. The average age of the children was about 14 years. Sixty-three percent were male. Only one third of the forms documented the sport for which a pre-participation screen was being submitted.

While almost all states now require PPEs for children considering participation in sports, few specify what information should be elicited, according to Dr. Ng. She further noted that no major study has shown that PPEs have any role in preventing morbidity or mortality related to sports participation.
 

Does Heterogeneity Negate Worth?

With such diversity across PPEs, evaluating their role is difficult. For example, with such heterogeneity among forms for the information elicited, there is no reasonable approach for testing their sensitivity in predicting medical complications.

Dr. Ng noted that school-created forms were just as likely as forms from other sources to diverge from the AAP-endorsed PPE and ignore organ systems relevant to risk of medical complications. Yet, if the answer is to use the AAP form, Dr. Ng noted that the first sentence on the form reads, “This form should be placed in the athlete’s medical file and should not be shared with schools or sports organizations.”

Although Dr. Ng acknowledged that providing completed PPEs to third parties raises questions about privacy, she questioned how the information should be used by children, parents, and sports organization administrators for discussing risks if not shared.

This concern was seconded in the discussion following Dr. Ng’s presentation.

“You might be signing off on sports participation, but is this for cheerleading or for football?” asked Daniel C. Worthington, MD, a pediatrician in private practice who has a clinical appointment at Case Western Reserve University School of Medicine, Cleveland. “This makes a huge difference when evaluating if participation is safe.”

He has no issue with completing PPEs for the goal of keeping children safe, but he focused on the inconsistency of how information is collected and distributed.

“The major question is: Does it make any difference?” said Dr. Worthington, referring to the completion of PPEs.

Another participant in the discussion that followed Dr. Ng’s presentation pointed out that the urgent care office in a mall near to his office offers a completed PPE form for a price of $20. In their recommendations, the AAP suggests PPEs be completed by the individual’s primary care physician during a well visit, according to Dr. Ng.

Dr. Ng indicated that PPEs and their purpose deserve a closer look. Based on her data, it is reasonable to assume that the priority for some – whether those requiring or those completing the form — is completing the task rather than meaningful screening of risk.

Dr. Ng and Dr. Worthington report no potential conflicts of interest.

DENVER — Two new drugs are headed toward pivotal trials after making their endpoints in phase 2 treatment-resistant epilepsy studies, while a first-in-man study of an implantable product suggests a new direction for this disease , according to new data presented at the 2024 annual meeting of the American Academy of Neurology.

Of the two drugs evaluated in phase 2 trials, one is a highly targeted TARP-8–dependent AMPA receptor antagonist known as ES-481. The other is XEN1101, a novel potassium channel opener that was well tolerated as well as effective.

TARP inhibitors, which act on transmembrane AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) receptor regulatory proteins, are already available for the control of epilepsy, but ES-481 might be different, according to Terrence J. O’Brien, MD, department of neuroscience, Monash University, Melbourne, Australia.
 

First-in-Class TARP Inhibitor Is Tested

As a “first-in-class, potent and selective antagonist of the TARP-γ8 AMPA receptor,” ES-481 is “predicted to effectively suppress focal seizures arising from the hippocampus and limbic system,” he said. Dr. O’Brien claims that this specificity of action appears to circumvent central nervous system side effects in studies so far.

In the phase 2a multicenter, randomized trial, 22 patients with drug-resistant epilepsy of any type (focal, generalized, or mixed) were randomized to ES-481 or placebo. In the ES-481 arm, the dose was escalated each week, climbing from 25 mg once-daily, to 25 mg twice-daily, 50 mg twice-daily, and then to 75 mg twice daily. At the end of 4 weeks and after a 7-day washout, the randomized groups were crossed over to the opposite therapy for another 4 weeks.

When data were confined to the first treatment period to avoid a carry-over effect, there was a consistent advantage for active treatment over placebo. At the highest 75-mg twice-daily dose of ES-481, the reduction in seizure frequency was 80% vs 49% on placebo ( P < .05).

The rate of complete remission at the end of the study was not greater for ES-481, but higher proportions of patients on active therapy achieved reductions from baseline in seizure activity when defined as greater than 30% (72.77% vs 36.4%) or greater than 50% (36.4% vs 18.2%). P values for these differences were not provided.

Differences in EEG were not observed, but Dr. O’Brien reported that 18 of the subjects had no EEG activity at baseline, diminishing the opportunity to show a difference.
 

Open-Label Study Supports Controlled Data

Sixteen patients have entered an open-label extension with sustained suppression of seizure activity relative to baseline observed so far, Dr. O’Brien reported.

ES-481 was well tolerated. There were no significant changes in lab values, and all four of the adverse events leading to discontinuation occurred on placebo. There were higher rates of dizziness, insomnia, gait disturbance, and dysarthria associated with ES-481 than placebo, but the rate of serious adverse events was lower (4.8% vs 14.3%).

These response rates are noteworthy because patients had severe disease with diminishing therapeutic options, according to Dr. O’Brien. For entry, patients were required to be taking one to four antiseizure medications while still experiencing seizure activity. The patients averaged one interictal epileptiform discharge and/or seizure per hour on EEG.

Large-scale, double-blind, controlled studies are planned and warranted on the basis of these data, according to Dr. O’Brien, who emphasized that benefit was achieved with a low relative risk of significant adverse events.
 

New Potassium Channel Opener Shows Promise

Data with the selective potassium channel opener XEN1101 from the previously published phase 2b X-TOLE trial were reported in two parts. The first set of data involved an analysis of response by baseline activity. The other set of data were generated by an ongoing open-label extension (OLE) of X-TOLE.

In X-TOLE, which randomized 325 patients with treatment-resistant focal-onset seizures (FOS) to one of three doses of XEN-1011 or placebo, the median reduction in FOS at the highest dose of 25 mg once-daily XEN-1011 was 52.8% vs placebo (P < .001).

In the new analysis, the goal was to look at efficacy of the 25-mg dose across differences in baseline severity, reported Roger J. Porter, MD, adjunct professor of neurology, University of Pennsylvania, Philadelphia.

Generally, a greater response was observed for those with less severe disease. For example, the response rate defined as greater than 50% reduction in seizure frequency on XEN1101 was higher for those with a baseline seizure activity of 8.5 seizures/month or fewer relative to more (65.5% vs 50.6%) and six or fewer antiseizure medications relative to more (64.2% vs 40.0%).

Pointing out that the study enrolled a challenging group of patients, Dr. Porter said that the data do not rule out efficacy “across the spectrum of epilepsy severity,” but he did suggest that these data will provide context for the coming phase 3 trials.

In the OLE data presented by Jacqueline French, MD, professor of neurology at the Langone School of Medicine of New York University, the efficacy and safety of XEN1101 taken with food has been consistent with what was observed in the double-blind trial. With up to 2 years of follow-up in the planned 5-year OLE, which is evaluating 20 mg once-daily taken with food, 60% are still on therapy,

For those followed for 24 months, 23.6% are completely seizure free, according to Dr. French. For those followed at least 12 months, 31.5% have achieved a median percent reduction in monthly seizure activity of 90% or more; 41.8% a reduction of 75% or more; and 69.7% a reduction of 50% or more.

The side-effect profile has also been consistent with that seen in the phase 2b trial. Dizziness and other mild to moderate side effects that often accompany antiseizure medications have been observed, along with modest weight gain, but there have been no new safety signals over long-term use.

If a planned phase 3 study enrolling patients with localized and general epilepsy confirms these phase 2 data, Dr. French indicated that it has the potential to advance a potassium channel opener that is both efficacious and well tolerated.
 

First-in-Man Study Performed With Stem Cell Product

The investigational product for treatment-resistant epilepsy has data on just five patients. Yet, the two patients followed the longest, both of which had highly treatment-resistant epilepsy, have had reductions in seizure activity exceeding 95%, according to Cory Nicholas, PhD, the chief executive officer of Neurona Therapeutics.

NRTX-100 is a GABAergic interneuron product derived from human pluripotent stem cells. The NRTX cells are surgically transplanted into the head and body of the hippocampus in patients with unilateral temporal lobe epilepsy with hippocampal sclerosis. The procedure is performed with MRI guidance, and patients are placed on immunosuppression that starts 1 week before surgery and is tapered 1 year later.

In this first-in-man study, the primary outcome of interest was safety. There have been no adverse events associated with this stem cell product in follow-up so far, according to Dr. Nicholas, who presented data on the first 5 of 10 procedures that have been completed so far.

Consistent with the prior work in animal models, it takes several months for the reduction in seizures to be achieved and, in animal models, to see improved functionality. It is notable that the reductions in seizure activity observed over time in those patients followed the longest have been accompanied by evidence of neurocognitive improvement, Dr. Nicholas reported.

“The efficacy has seemed durable so far, and we expect incremental improvement in clinical response over time,” said Dr. Nicholas, who reported that the Food and Drug Administration has already approved a second clinical study.
 

Are New Antiseizure Therapies Needed?

The value of this and the other emerging therapies is that “no treatment for epilepsy works well in every patient. We continue to need a wide array of treatments to find the one right for the patient in front of us,” said Nassim Zecavati, MD, director of Epilepsy, Children’s Hospital, Virginia Commonwealth University, Richmond.

Asked to comment on the promise of these three therapies, Dr. Zecavati suggested each is intriguing for different reasons. AMPA receptor antagonists have proven to be a promising drug class so far, suggesting that “another could be helpful.” Potassium channel openers appear to have “a great mechanism of action,” but Dr. Zecavati said drugs in this class with a more favorable safety profile are needed.

As for NRTX-1001, she was intrigued with its novelty. She speculated that it might have particular promise for intractable drug-resistant epilepsy in patients who are not candidates for standard surgical strategies but might tolerate a less invasive procedure.

“My question might be who is going to perform this procedure,” Dr. Zecavati said. Noting that experience and skill might be needed to achieve an optimal result with cell transplantation into the brain, she said she will be waiting for more studies that might answer this question and to determine where, if effective, it would fit among current options.

Dr. O’Brien reported financial relationships with Eisai, Kinoxis, Livanova, Supernus, and UCB Pharma. Dr. Porter reported financial relationships with Axonis, Engrail, Longboard, Neurocrine, and Xenon, which provided funding for the study he discussed. Dr. French has financial relationships with more than 20 pharmaceutical companies, including Xenon, which provided funding for the study she discussed. Dr. Nicholas is chief executive officer of Neurona Therapeutics. Dr. Zecavati reported no potential conflicts of interest.

DENVER — Two new drugs are headed toward pivotal trials after making their endpoints in phase 2 treatment-resistant epilepsy studies, while a first-in-man study of an implantable product suggests a new direction for this disease , according to new data presented at the 2024 annual meeting of the American Academy of Neurology.

Of the two drugs evaluated in phase 2 trials, one is a highly targeted TARP-8–dependent AMPA receptor antagonist known as ES-481. The other is XEN1101, a novel potassium channel opener that was well tolerated as well as effective.

TARP inhibitors, which act on transmembrane AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) receptor regulatory proteins, are already available for the control of epilepsy, but ES-481 might be different, according to Terrence J. O’Brien, MD, department of neuroscience, Monash University, Melbourne, Australia.
 

First-in-Class TARP Inhibitor Is Tested

As a “first-in-class, potent and selective antagonist of the TARP-γ8 AMPA receptor,” ES-481 is “predicted to effectively suppress focal seizures arising from the hippocampus and limbic system,” he said. Dr. O’Brien claims that this specificity of action appears to circumvent central nervous system side effects in studies so far.

In the phase 2a multicenter, randomized trial, 22 patients with drug-resistant epilepsy of any type (focal, generalized, or mixed) were randomized to ES-481 or placebo. In the ES-481 arm, the dose was escalated each week, climbing from 25 mg once-daily, to 25 mg twice-daily, 50 mg twice-daily, and then to 75 mg twice daily. At the end of 4 weeks and after a 7-day washout, the randomized groups were crossed over to the opposite therapy for another 4 weeks.

When data were confined to the first treatment period to avoid a carry-over effect, there was a consistent advantage for active treatment over placebo. At the highest 75-mg twice-daily dose of ES-481, the reduction in seizure frequency was 80% vs 49% on placebo ( P < .05).

The rate of complete remission at the end of the study was not greater for ES-481, but higher proportions of patients on active therapy achieved reductions from baseline in seizure activity when defined as greater than 30% (72.77% vs 36.4%) or greater than 50% (36.4% vs 18.2%). P values for these differences were not provided.

Differences in EEG were not observed, but Dr. O’Brien reported that 18 of the subjects had no EEG activity at baseline, diminishing the opportunity to show a difference.
 

Open-Label Study Supports Controlled Data

Sixteen patients have entered an open-label extension with sustained suppression of seizure activity relative to baseline observed so far, Dr. O’Brien reported.

ES-481 was well tolerated. There were no significant changes in lab values, and all four of the adverse events leading to discontinuation occurred on placebo. There were higher rates of dizziness, insomnia, gait disturbance, and dysarthria associated with ES-481 than placebo, but the rate of serious adverse events was lower (4.8% vs 14.3%).

These response rates are noteworthy because patients had severe disease with diminishing therapeutic options, according to Dr. O’Brien. For entry, patients were required to be taking one to four antiseizure medications while still experiencing seizure activity. The patients averaged one interictal epileptiform discharge and/or seizure per hour on EEG.

Large-scale, double-blind, controlled studies are planned and warranted on the basis of these data, according to Dr. O’Brien, who emphasized that benefit was achieved with a low relative risk of significant adverse events.
 

New Potassium Channel Opener Shows Promise

Data with the selective potassium channel opener XEN1101 from the previously published phase 2b X-TOLE trial were reported in two parts. The first set of data involved an analysis of response by baseline activity. The other set of data were generated by an ongoing open-label extension (OLE) of X-TOLE.

In X-TOLE, which randomized 325 patients with treatment-resistant focal-onset seizures (FOS) to one of three doses of XEN-1011 or placebo, the median reduction in FOS at the highest dose of 25 mg once-daily XEN-1011 was 52.8% vs placebo (P < .001).

In the new analysis, the goal was to look at efficacy of the 25-mg dose across differences in baseline severity, reported Roger J. Porter, MD, adjunct professor of neurology, University of Pennsylvania, Philadelphia.

Generally, a greater response was observed for those with less severe disease. For example, the response rate defined as greater than 50% reduction in seizure frequency on XEN1101 was higher for those with a baseline seizure activity of 8.5 seizures/month or fewer relative to more (65.5% vs 50.6%) and six or fewer antiseizure medications relative to more (64.2% vs 40.0%).

Pointing out that the study enrolled a challenging group of patients, Dr. Porter said that the data do not rule out efficacy “across the spectrum of epilepsy severity,” but he did suggest that these data will provide context for the coming phase 3 trials.

In the OLE data presented by Jacqueline French, MD, professor of neurology at the Langone School of Medicine of New York University, the efficacy and safety of XEN1101 taken with food has been consistent with what was observed in the double-blind trial. With up to 2 years of follow-up in the planned 5-year OLE, which is evaluating 20 mg once-daily taken with food, 60% are still on therapy,

For those followed for 24 months, 23.6% are completely seizure free, according to Dr. French. For those followed at least 12 months, 31.5% have achieved a median percent reduction in monthly seizure activity of 90% or more; 41.8% a reduction of 75% or more; and 69.7% a reduction of 50% or more.

The side-effect profile has also been consistent with that seen in the phase 2b trial. Dizziness and other mild to moderate side effects that often accompany antiseizure medications have been observed, along with modest weight gain, but there have been no new safety signals over long-term use.

If a planned phase 3 study enrolling patients with localized and general epilepsy confirms these phase 2 data, Dr. French indicated that it has the potential to advance a potassium channel opener that is both efficacious and well tolerated.
 

First-in-Man Study Performed With Stem Cell Product

The investigational product for treatment-resistant epilepsy has data on just five patients. Yet, the two patients followed the longest, both of which had highly treatment-resistant epilepsy, have had reductions in seizure activity exceeding 95%, according to Cory Nicholas, PhD, the chief executive officer of Neurona Therapeutics.

NRTX-100 is a GABAergic interneuron product derived from human pluripotent stem cells. The NRTX cells are surgically transplanted into the head and body of the hippocampus in patients with unilateral temporal lobe epilepsy with hippocampal sclerosis. The procedure is performed with MRI guidance, and patients are placed on immunosuppression that starts 1 week before surgery and is tapered 1 year later.

In this first-in-man study, the primary outcome of interest was safety. There have been no adverse events associated with this stem cell product in follow-up so far, according to Dr. Nicholas, who presented data on the first 5 of 10 procedures that have been completed so far.

Consistent with the prior work in animal models, it takes several months for the reduction in seizures to be achieved and, in animal models, to see improved functionality. It is notable that the reductions in seizure activity observed over time in those patients followed the longest have been accompanied by evidence of neurocognitive improvement, Dr. Nicholas reported.

“The efficacy has seemed durable so far, and we expect incremental improvement in clinical response over time,” said Dr. Nicholas, who reported that the Food and Drug Administration has already approved a second clinical study.
 

Are New Antiseizure Therapies Needed?

The value of this and the other emerging therapies is that “no treatment for epilepsy works well in every patient. We continue to need a wide array of treatments to find the one right for the patient in front of us,” said Nassim Zecavati, MD, director of Epilepsy, Children’s Hospital, Virginia Commonwealth University, Richmond.

Asked to comment on the promise of these three therapies, Dr. Zecavati suggested each is intriguing for different reasons. AMPA receptor antagonists have proven to be a promising drug class so far, suggesting that “another could be helpful.” Potassium channel openers appear to have “a great mechanism of action,” but Dr. Zecavati said drugs in this class with a more favorable safety profile are needed.

As for NRTX-1001, she was intrigued with its novelty. She speculated that it might have particular promise for intractable drug-resistant epilepsy in patients who are not candidates for standard surgical strategies but might tolerate a less invasive procedure.

“My question might be who is going to perform this procedure,” Dr. Zecavati said. Noting that experience and skill might be needed to achieve an optimal result with cell transplantation into the brain, she said she will be waiting for more studies that might answer this question and to determine where, if effective, it would fit among current options.

Dr. O’Brien reported financial relationships with Eisai, Kinoxis, Livanova, Supernus, and UCB Pharma. Dr. Porter reported financial relationships with Axonis, Engrail, Longboard, Neurocrine, and Xenon, which provided funding for the study he discussed. Dr. French has financial relationships with more than 20 pharmaceutical companies, including Xenon, which provided funding for the study she discussed. Dr. Nicholas is chief executive officer of Neurona Therapeutics. Dr. Zecavati reported no potential conflicts of interest.

DENVER — Two new drugs are headed toward pivotal trials after making their endpoints in phase 2 treatment-resistant epilepsy studies, while a first-in-man study of an implantable product suggests a new direction for this disease , according to new data presented at the 2024 annual meeting of the American Academy of Neurology.

Of the two drugs evaluated in phase 2 trials, one is a highly targeted TARP-8–dependent AMPA receptor antagonist known as ES-481. The other is XEN1101, a novel potassium channel opener that was well tolerated as well as effective.

TARP inhibitors, which act on transmembrane AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) receptor regulatory proteins, are already available for the control of epilepsy, but ES-481 might be different, according to Terrence J. O’Brien, MD, department of neuroscience, Monash University, Melbourne, Australia.
 

First-in-Class TARP Inhibitor Is Tested

As a “first-in-class, potent and selective antagonist of the TARP-γ8 AMPA receptor,” ES-481 is “predicted to effectively suppress focal seizures arising from the hippocampus and limbic system,” he said. Dr. O’Brien claims that this specificity of action appears to circumvent central nervous system side effects in studies so far.

In the phase 2a multicenter, randomized trial, 22 patients with drug-resistant epilepsy of any type (focal, generalized, or mixed) were randomized to ES-481 or placebo. In the ES-481 arm, the dose was escalated each week, climbing from 25 mg once-daily, to 25 mg twice-daily, 50 mg twice-daily, and then to 75 mg twice daily. At the end of 4 weeks and after a 7-day washout, the randomized groups were crossed over to the opposite therapy for another 4 weeks.

When data were confined to the first treatment period to avoid a carry-over effect, there was a consistent advantage for active treatment over placebo. At the highest 75-mg twice-daily dose of ES-481, the reduction in seizure frequency was 80% vs 49% on placebo ( P < .05).

The rate of complete remission at the end of the study was not greater for ES-481, but higher proportions of patients on active therapy achieved reductions from baseline in seizure activity when defined as greater than 30% (72.77% vs 36.4%) or greater than 50% (36.4% vs 18.2%). P values for these differences were not provided.

Differences in EEG were not observed, but Dr. O’Brien reported that 18 of the subjects had no EEG activity at baseline, diminishing the opportunity to show a difference.
 

Open-Label Study Supports Controlled Data

Sixteen patients have entered an open-label extension with sustained suppression of seizure activity relative to baseline observed so far, Dr. O’Brien reported.

ES-481 was well tolerated. There were no significant changes in lab values, and all four of the adverse events leading to discontinuation occurred on placebo. There were higher rates of dizziness, insomnia, gait disturbance, and dysarthria associated with ES-481 than placebo, but the rate of serious adverse events was lower (4.8% vs 14.3%).

These response rates are noteworthy because patients had severe disease with diminishing therapeutic options, according to Dr. O’Brien. For entry, patients were required to be taking one to four antiseizure medications while still experiencing seizure activity. The patients averaged one interictal epileptiform discharge and/or seizure per hour on EEG.

Large-scale, double-blind, controlled studies are planned and warranted on the basis of these data, according to Dr. O’Brien, who emphasized that benefit was achieved with a low relative risk of significant adverse events.
 

New Potassium Channel Opener Shows Promise

Data with the selective potassium channel opener XEN1101 from the previously published phase 2b X-TOLE trial were reported in two parts. The first set of data involved an analysis of response by baseline activity. The other set of data were generated by an ongoing open-label extension (OLE) of X-TOLE.

In X-TOLE, which randomized 325 patients with treatment-resistant focal-onset seizures (FOS) to one of three doses of XEN-1011 or placebo, the median reduction in FOS at the highest dose of 25 mg once-daily XEN-1011 was 52.8% vs placebo (P < .001).

In the new analysis, the goal was to look at efficacy of the 25-mg dose across differences in baseline severity, reported Roger J. Porter, MD, adjunct professor of neurology, University of Pennsylvania, Philadelphia.

Generally, a greater response was observed for those with less severe disease. For example, the response rate defined as greater than 50% reduction in seizure frequency on XEN1101 was higher for those with a baseline seizure activity of 8.5 seizures/month or fewer relative to more (65.5% vs 50.6%) and six or fewer antiseizure medications relative to more (64.2% vs 40.0%).

Pointing out that the study enrolled a challenging group of patients, Dr. Porter said that the data do not rule out efficacy “across the spectrum of epilepsy severity,” but he did suggest that these data will provide context for the coming phase 3 trials.

In the OLE data presented by Jacqueline French, MD, professor of neurology at the Langone School of Medicine of New York University, the efficacy and safety of XEN1101 taken with food has been consistent with what was observed in the double-blind trial. With up to 2 years of follow-up in the planned 5-year OLE, which is evaluating 20 mg once-daily taken with food, 60% are still on therapy,

For those followed for 24 months, 23.6% are completely seizure free, according to Dr. French. For those followed at least 12 months, 31.5% have achieved a median percent reduction in monthly seizure activity of 90% or more; 41.8% a reduction of 75% or more; and 69.7% a reduction of 50% or more.

The side-effect profile has also been consistent with that seen in the phase 2b trial. Dizziness and other mild to moderate side effects that often accompany antiseizure medications have been observed, along with modest weight gain, but there have been no new safety signals over long-term use.

If a planned phase 3 study enrolling patients with localized and general epilepsy confirms these phase 2 data, Dr. French indicated that it has the potential to advance a potassium channel opener that is both efficacious and well tolerated.
 

First-in-Man Study Performed With Stem Cell Product

The investigational product for treatment-resistant epilepsy has data on just five patients. Yet, the two patients followed the longest, both of which had highly treatment-resistant epilepsy, have had reductions in seizure activity exceeding 95%, according to Cory Nicholas, PhD, the chief executive officer of Neurona Therapeutics.

NRTX-100 is a GABAergic interneuron product derived from human pluripotent stem cells. The NRTX cells are surgically transplanted into the head and body of the hippocampus in patients with unilateral temporal lobe epilepsy with hippocampal sclerosis. The procedure is performed with MRI guidance, and patients are placed on immunosuppression that starts 1 week before surgery and is tapered 1 year later.

In this first-in-man study, the primary outcome of interest was safety. There have been no adverse events associated with this stem cell product in follow-up so far, according to Dr. Nicholas, who presented data on the first 5 of 10 procedures that have been completed so far.

Consistent with the prior work in animal models, it takes several months for the reduction in seizures to be achieved and, in animal models, to see improved functionality. It is notable that the reductions in seizure activity observed over time in those patients followed the longest have been accompanied by evidence of neurocognitive improvement, Dr. Nicholas reported.

“The efficacy has seemed durable so far, and we expect incremental improvement in clinical response over time,” said Dr. Nicholas, who reported that the Food and Drug Administration has already approved a second clinical study.
 

Are New Antiseizure Therapies Needed?

The value of this and the other emerging therapies is that “no treatment for epilepsy works well in every patient. We continue to need a wide array of treatments to find the one right for the patient in front of us,” said Nassim Zecavati, MD, director of Epilepsy, Children’s Hospital, Virginia Commonwealth University, Richmond.

Asked to comment on the promise of these three therapies, Dr. Zecavati suggested each is intriguing for different reasons. AMPA receptor antagonists have proven to be a promising drug class so far, suggesting that “another could be helpful.” Potassium channel openers appear to have “a great mechanism of action,” but Dr. Zecavati said drugs in this class with a more favorable safety profile are needed.

As for NRTX-1001, she was intrigued with its novelty. She speculated that it might have particular promise for intractable drug-resistant epilepsy in patients who are not candidates for standard surgical strategies but might tolerate a less invasive procedure.

“My question might be who is going to perform this procedure,” Dr. Zecavati said. Noting that experience and skill might be needed to achieve an optimal result with cell transplantation into the brain, she said she will be waiting for more studies that might answer this question and to determine where, if effective, it would fit among current options.

Dr. O’Brien reported financial relationships with Eisai, Kinoxis, Livanova, Supernus, and UCB Pharma. Dr. Porter reported financial relationships with Axonis, Engrail, Longboard, Neurocrine, and Xenon, which provided funding for the study he discussed. Dr. French has financial relationships with more than 20 pharmaceutical companies, including Xenon, which provided funding for the study she discussed. Dr. Nicholas is chief executive officer of Neurona Therapeutics. Dr. Zecavati reported no potential conflicts of interest.

TORONTO — When electronic completion of screening questionnaires replaced manually completed paper forms at a busy academic pediatric clinic, complete data capture was almost doubled without increasing the duration of the clinic visit, and, of course, it eliminated the work associated with managing paper records.

Due to the efficacy of the pre-visit capture, “all of the information — including individual responses and total scores — is available to the provider at a glance” by the time of the examination encounter, according to Brian T. Ketterman, MD, a third-year resident in pediatrics at the Monroe Carell Jr. Children’s Hospital, Vanderbilt University, Nashville, Tennessee.

Urgent issues, such as suicidality risk, “are flagged so that they are seen first,” he added.

The goal of going paperless was to improve the amount and the consistency of data captured with each well visit, according to Dr. Ketterman. He described a major undertaking involving fundamental changes in the electronic medical record (EMR) system to accommodate the new approach.

Characterizing screening at well visits as “one of the most important jobs of a pediatrician” when he presented these data at the Pediatric Academic Societies annual meeting, he added that a paperless approach comes with many advantages.
 

Raising the Rate of Complete Data Capture

The American Academy of Pediatrics (AAP) has identified more than 30 screening elements at well-child visits. At his institution several additional screening elements have been added. Prior to going paperless, about 45.6% on average of this well-visit data was being captured in any specific patient encounter, even if the institution was doing well overall in capturing essential information, such as key laboratory values and immunizations.

The vast majority of the information that was missing depended on patient or family input, such as social determinants of health (SDoH), which includes the aspects of home environment, such as nutrition and safety. Dr. Ketterman said that going paperless was inspired by positive experiences reported elsewhere.

“We wanted to build on this work,” he said.

The goal of the program was to raise the rate of complete data capture at well visits to at least 80% and do this across all languages. The first step was to create digital forms in English and Spanish for completion unique to each milestone well-child visit defined by age. For those who speak English or Spanish, these forms were supplied through the patient portal several days before the visit.

For those who spoke one of the more than 40 other languages encountered among patients at Dr. Ketterman’s institution, an interpreter was supplied. If patients arrived at the clinic without completing the digital entry, they completed it on a tablet with the help of an interpreter if one was needed.

Prior to going paperless, all screening data were captured on paper forms completed in the waiting room. The provider then manually reviewed and scored the forms before they were then scanned into the medical records. The paperless approach has eliminated all of these steps and the information is already available for review by the time the pediatrician enters the examination room.

With more than 50,000 well-child checkups captured over a recent 15-month period of paperless questionnaires, the proportion with 100% data capture using what Dr. Ketterman characterized as “strict criteria” was 84%, surpassing the goal at the initiation of the program.

“We improved in almost every screening measure,” Dr. Ketterman said, providing P values that were mostly < .001 for a range of standard tests such as M-CHAT-R (Modified Checklist for Autism in Toddlers), QPA (Quick Parenting Assessment), and PSC-17 (Pediatric Symptom Checklist) when compared to the baseline period.
 

Additional Advantages

The improvement in well-visit data capture was the goal, but the list of other advantages of the paperless system is long. For one, the EMR system now automatically uses the data to offer guidance that might improve patient outcomes. For example, if the family reports that the child does not see a dentist or does not know how to swim, these lead prompt the EMR to provide resources, such as the names of dentists of swim programs, to address the problem.

As another example, screening questions that reveal food insecurity automatically trigger guidance for enrolling in the U.S. Department of Agriculture’s WIC (Women, Infants, and Children) food program. According to Dr. Ketterman, the proportion of children now enrolled in WIC has increased 10-fold from baseline. He also reported there was a twofold increase in the proportion of patients enrolled in a free book program as a result of a screening questions that ask about reading at home.

The improvement in well-visit data capture was seen across all languages. Even if the gains were not quite as good in languages other than English or Spanish, they were still highly significant relative to baseline.
 

A ‘Life-Changing’ Improvement

The discussion following his talk made it clear that similar approaches are being actively pursued nationwide. Several in the audience working on similar programs identified such challenges as getting electronic medical record (EMR) systems to cooperate, ensuring patient enrollment in the portals, and avoiding form completion fatigue, but the comments were uniformly supportive of the benefits of this approach.

“This has been life-changing for us,” said Katie E. McPeak, MD, a primary care pediatrician and Medical Director for Health Equity at the Children’s Hospital of Philadelphia. “The information is more accurate in the digital format and it reduces time for the clinician reviewing the data in the exam room.” She also agreed that paperless completion of screen captures better information on more topics, like sleep, nutrition, and mood disorders.

However, Dr. McPeak was one of those who was concerned about form fatigue. Patients have to enter extensive information over multiple screens for each well-child visit. She said this problem might need to be addressed if the success of paperless screening leads to even greater expansion of data requested.

In addressing the work behind creating a system of the depth and scope of the one he described, Dr. Ketterman acknowledged that it involved a daunting development process with substantial coding and testing. Referring to the EMR system used at his hospital, he said the preparation required an “epic guru,” but he said that input fatigue has not yet arisen as a major issue.

“Many of the screens are mandatory, so you cannot advance without completing them, but some are optional,” he noted. “However, we are seeing a high rate of response even on the screens they could click past.”

Dr. Ketterman and Dr. McPeak report no potential conflicts of interest.

TORONTO — When electronic completion of screening questionnaires replaced manually completed paper forms at a busy academic pediatric clinic, complete data capture was almost doubled without increasing the duration of the clinic visit, and, of course, it eliminated the work associated with managing paper records.

Due to the efficacy of the pre-visit capture, “all of the information — including individual responses and total scores — is available to the provider at a glance” by the time of the examination encounter, according to Brian T. Ketterman, MD, a third-year resident in pediatrics at the Monroe Carell Jr. Children’s Hospital, Vanderbilt University, Nashville, Tennessee.

Urgent issues, such as suicidality risk, “are flagged so that they are seen first,” he added.

The goal of going paperless was to improve the amount and the consistency of data captured with each well visit, according to Dr. Ketterman. He described a major undertaking involving fundamental changes in the electronic medical record (EMR) system to accommodate the new approach.

Characterizing screening at well visits as “one of the most important jobs of a pediatrician” when he presented these data at the Pediatric Academic Societies annual meeting, he added that a paperless approach comes with many advantages.
 

Raising the Rate of Complete Data Capture

The American Academy of Pediatrics (AAP) has identified more than 30 screening elements at well-child visits. At his institution several additional screening elements have been added. Prior to going paperless, about 45.6% on average of this well-visit data was being captured in any specific patient encounter, even if the institution was doing well overall in capturing essential information, such as key laboratory values and immunizations.

The vast majority of the information that was missing depended on patient or family input, such as social determinants of health (SDoH), which includes the aspects of home environment, such as nutrition and safety. Dr. Ketterman said that going paperless was inspired by positive experiences reported elsewhere.

“We wanted to build on this work,” he said.

The goal of the program was to raise the rate of complete data capture at well visits to at least 80% and do this across all languages. The first step was to create digital forms in English and Spanish for completion unique to each milestone well-child visit defined by age. For those who speak English or Spanish, these forms were supplied through the patient portal several days before the visit.

For those who spoke one of the more than 40 other languages encountered among patients at Dr. Ketterman’s institution, an interpreter was supplied. If patients arrived at the clinic without completing the digital entry, they completed it on a tablet with the help of an interpreter if one was needed.

Prior to going paperless, all screening data were captured on paper forms completed in the waiting room. The provider then manually reviewed and scored the forms before they were then scanned into the medical records. The paperless approach has eliminated all of these steps and the information is already available for review by the time the pediatrician enters the examination room.

With more than 50,000 well-child checkups captured over a recent 15-month period of paperless questionnaires, the proportion with 100% data capture using what Dr. Ketterman characterized as “strict criteria” was 84%, surpassing the goal at the initiation of the program.

“We improved in almost every screening measure,” Dr. Ketterman said, providing P values that were mostly < .001 for a range of standard tests such as M-CHAT-R (Modified Checklist for Autism in Toddlers), QPA (Quick Parenting Assessment), and PSC-17 (Pediatric Symptom Checklist) when compared to the baseline period.
 

Additional Advantages

The improvement in well-visit data capture was the goal, but the list of other advantages of the paperless system is long. For one, the EMR system now automatically uses the data to offer guidance that might improve patient outcomes. For example, if the family reports that the child does not see a dentist or does not know how to swim, these lead prompt the EMR to provide resources, such as the names of dentists of swim programs, to address the problem.

As another example, screening questions that reveal food insecurity automatically trigger guidance for enrolling in the U.S. Department of Agriculture’s WIC (Women, Infants, and Children) food program. According to Dr. Ketterman, the proportion of children now enrolled in WIC has increased 10-fold from baseline. He also reported there was a twofold increase in the proportion of patients enrolled in a free book program as a result of a screening questions that ask about reading at home.

The improvement in well-visit data capture was seen across all languages. Even if the gains were not quite as good in languages other than English or Spanish, they were still highly significant relative to baseline.
 

A ‘Life-Changing’ Improvement

The discussion following his talk made it clear that similar approaches are being actively pursued nationwide. Several in the audience working on similar programs identified such challenges as getting electronic medical record (EMR) systems to cooperate, ensuring patient enrollment in the portals, and avoiding form completion fatigue, but the comments were uniformly supportive of the benefits of this approach.

“This has been life-changing for us,” said Katie E. McPeak, MD, a primary care pediatrician and Medical Director for Health Equity at the Children’s Hospital of Philadelphia. “The information is more accurate in the digital format and it reduces time for the clinician reviewing the data in the exam room.” She also agreed that paperless completion of screen captures better information on more topics, like sleep, nutrition, and mood disorders.

However, Dr. McPeak was one of those who was concerned about form fatigue. Patients have to enter extensive information over multiple screens for each well-child visit. She said this problem might need to be addressed if the success of paperless screening leads to even greater expansion of data requested.

In addressing the work behind creating a system of the depth and scope of the one he described, Dr. Ketterman acknowledged that it involved a daunting development process with substantial coding and testing. Referring to the EMR system used at his hospital, he said the preparation required an “epic guru,” but he said that input fatigue has not yet arisen as a major issue.

“Many of the screens are mandatory, so you cannot advance without completing them, but some are optional,” he noted. “However, we are seeing a high rate of response even on the screens they could click past.”

Dr. Ketterman and Dr. McPeak report no potential conflicts of interest.

TORONTO — When electronic completion of screening questionnaires replaced manually completed paper forms at a busy academic pediatric clinic, complete data capture was almost doubled without increasing the duration of the clinic visit, and, of course, it eliminated the work associated with managing paper records.

Due to the efficacy of the pre-visit capture, “all of the information — including individual responses and total scores — is available to the provider at a glance” by the time of the examination encounter, according to Brian T. Ketterman, MD, a third-year resident in pediatrics at the Monroe Carell Jr. Children’s Hospital, Vanderbilt University, Nashville, Tennessee.

Urgent issues, such as suicidality risk, “are flagged so that they are seen first,” he added.

The goal of going paperless was to improve the amount and the consistency of data captured with each well visit, according to Dr. Ketterman. He described a major undertaking involving fundamental changes in the electronic medical record (EMR) system to accommodate the new approach.

Characterizing screening at well visits as “one of the most important jobs of a pediatrician” when he presented these data at the Pediatric Academic Societies annual meeting, he added that a paperless approach comes with many advantages.
 

Raising the Rate of Complete Data Capture

The American Academy of Pediatrics (AAP) has identified more than 30 screening elements at well-child visits. At his institution several additional screening elements have been added. Prior to going paperless, about 45.6% on average of this well-visit data was being captured in any specific patient encounter, even if the institution was doing well overall in capturing essential information, such as key laboratory values and immunizations.

The vast majority of the information that was missing depended on patient or family input, such as social determinants of health (SDoH), which includes the aspects of home environment, such as nutrition and safety. Dr. Ketterman said that going paperless was inspired by positive experiences reported elsewhere.

“We wanted to build on this work,” he said.

The goal of the program was to raise the rate of complete data capture at well visits to at least 80% and do this across all languages. The first step was to create digital forms in English and Spanish for completion unique to each milestone well-child visit defined by age. For those who speak English or Spanish, these forms were supplied through the patient portal several days before the visit.

For those who spoke one of the more than 40 other languages encountered among patients at Dr. Ketterman’s institution, an interpreter was supplied. If patients arrived at the clinic without completing the digital entry, they completed it on a tablet with the help of an interpreter if one was needed.

Prior to going paperless, all screening data were captured on paper forms completed in the waiting room. The provider then manually reviewed and scored the forms before they were then scanned into the medical records. The paperless approach has eliminated all of these steps and the information is already available for review by the time the pediatrician enters the examination room.

With more than 50,000 well-child checkups captured over a recent 15-month period of paperless questionnaires, the proportion with 100% data capture using what Dr. Ketterman characterized as “strict criteria” was 84%, surpassing the goal at the initiation of the program.

“We improved in almost every screening measure,” Dr. Ketterman said, providing P values that were mostly < .001 for a range of standard tests such as M-CHAT-R (Modified Checklist for Autism in Toddlers), QPA (Quick Parenting Assessment), and PSC-17 (Pediatric Symptom Checklist) when compared to the baseline period.
 

Additional Advantages

The improvement in well-visit data capture was the goal, but the list of other advantages of the paperless system is long. For one, the EMR system now automatically uses the data to offer guidance that might improve patient outcomes. For example, if the family reports that the child does not see a dentist or does not know how to swim, these lead prompt the EMR to provide resources, such as the names of dentists of swim programs, to address the problem.

As another example, screening questions that reveal food insecurity automatically trigger guidance for enrolling in the U.S. Department of Agriculture’s WIC (Women, Infants, and Children) food program. According to Dr. Ketterman, the proportion of children now enrolled in WIC has increased 10-fold from baseline. He also reported there was a twofold increase in the proportion of patients enrolled in a free book program as a result of a screening questions that ask about reading at home.

The improvement in well-visit data capture was seen across all languages. Even if the gains were not quite as good in languages other than English or Spanish, they were still highly significant relative to baseline.
 

A ‘Life-Changing’ Improvement

The discussion following his talk made it clear that similar approaches are being actively pursued nationwide. Several in the audience working on similar programs identified such challenges as getting electronic medical record (EMR) systems to cooperate, ensuring patient enrollment in the portals, and avoiding form completion fatigue, but the comments were uniformly supportive of the benefits of this approach.

“This has been life-changing for us,” said Katie E. McPeak, MD, a primary care pediatrician and Medical Director for Health Equity at the Children’s Hospital of Philadelphia. “The information is more accurate in the digital format and it reduces time for the clinician reviewing the data in the exam room.” She also agreed that paperless completion of screen captures better information on more topics, like sleep, nutrition, and mood disorders.

However, Dr. McPeak was one of those who was concerned about form fatigue. Patients have to enter extensive information over multiple screens for each well-child visit. She said this problem might need to be addressed if the success of paperless screening leads to even greater expansion of data requested.

In addressing the work behind creating a system of the depth and scope of the one he described, Dr. Ketterman acknowledged that it involved a daunting development process with substantial coding and testing. Referring to the EMR system used at his hospital, he said the preparation required an “epic guru,” but he said that input fatigue has not yet arisen as a major issue.

“Many of the screens are mandatory, so you cannot advance without completing them, but some are optional,” he noted. “However, we are seeing a high rate of response even on the screens they could click past.”

Dr. Ketterman and Dr. McPeak report no potential conflicts of interest.

SAN DIEGO — Approximately 10 years ago in France, high throughput screening in a series of cases suggested that vaccine-derived rubella virus was the surprising cause of persistent cutaneous granulomas, but an update at the annual meeting of the American Academy of Dermatology suggests this phenomenon is not as rare as once supposed.

Based on accumulating evidence, the Centers for Disease Control and Prevention (CDC) through collaborations with others also recognized this in pediatric patients with inborn errors of immunity, and it is now appropriate for clinicians to consider this etiology when no other infectious agents can be identified, according to Karolyn A. Wanat, MD, professor of dermatology, Medical College of Wisconsin, Milwaukee, who spoke about rubella as a trigger in granulomatous disease at the meeting. “This is a huge evolving area of interest,” said Dr. Wanat, who has been the first author or coauthor on several published papers, including a review article published earlier this year.

In the earliest cases, including those reported in 2014, the cutaneous granulomas presumed to be causally related to vaccine-derived rubella virus were found only in those with a primary immunodeficiency. This is no longer the case. In a collaboration among US clinics, granulomas that had persisted for years in immunocompetent adults were identified, according to Dr. Wanat, the first author of a report on these findings in four adults in 2022. In addition, it now appears that wild-type rubella virus, like vaccine-derived rubella virus, can be the source of the antigenic response that underlies the development of rubella-associated cutaneous granulomas.

The phenotype of these granulomas is comparable to granulomas associated with other infectious agents. On dermatopathology, these commonly feature a robust granulomatous inflammation with multinucleated giant cells and lymphocytic infiltrate. Necrosis and fibrosis are also common.

“These are the types of granulomas that we would be thinking infection. If tissue cultures are negative, we would probably repeat them,” she said, suggesting that suspicion of an infectious etiology would probably remain high even after multiple negative tests.

Of the cases accruing in the United States and elsewhere, most but not all have been linked to inborn errors of immunity. In a 2020 CDC review, the risk of granulomas caused by compromised immunity, such as defects in T cell function, was estimated to be in the range of 0.6% to 2.5%, Dr. Wanat said.

It is now known that primary immunodeficiency is not a prerequisite, but this should not change the perception that the rubella vaccine, which was introduced in 1979, is effective and safe, according to Dr. Wanat. The vaccine is associated with few serious adverse events and is so effective that rubella was eliminated from the United States in 2004 and from the Americas in 2015.

This makes cases of granuloma associated with wild-type rubella virus surprising, but they appear to be exceedingly rare. Whether caused by vaccine exposure or another source, the mechanism of latent development of cutaneous granulomas is consistent with other infectious sources, and is not well understood.

“Rubella is a sneaky virus that can persist in some immunoprivileged sites indefinitely,” Dr. Wanat said. These sites include the eyes, joints, and placenta.

Many initial cases of rubella-associated granulomas occurred on the arms, presumably where the vaccine was administered, despite long intervals between exposure and lesion growth. This interval is often measured in years.

With more cases, it is now understood that involvement of other organs does occur even if the skin is the most common site of antigenic response in patients with immunodeficiency. The liver and lymph nodes represent other tissues that have been affected. Even lesions in the brain have been seen on autopsy.

Based on the benefit-to-risk ratio of a highly effective and successful vaccine, however, the association with a risk of granulomas “should not raise questions” about the value of the vaccine itself, Dr. Wanat noted.

“The proportion of patients who develop these granulomas is very, very low. Yet, the vaccine provides life-long immunity,” she said.

The discovery of granulomas associated with wild type rubella infection was “shocking” based on the supposition that the rubella virus had been eliminated, but this is just one of the unexpected discoveries as the still-evolving science has traced the story of rubella-associated granulomas over the past 10 years.

Cases now include children and adults through advanced ages.

Shedding of the virus and risk of infection to others has been studied but so far, the risk — if it exists — is very low. The evidence includes the many patients who have lived with the granulomas for years, even decades, without any known spread to others.

As for ongoing work in this area, Dr. Wanat said that a histopathological case definition for rubella-associated granulomas is being developed, and she and other investigators are actively seeking new cases to better characterize the disease.

So far, optimal treatment is not well defined. A number of strategies have had limited success or are considered impractical for routine use. One example is a stem cell transplant. In a case Dr. Wanat cited, complete resolution of the skin lesions was achieved with a transplant.

“I am not suggesting that those with localized disease in the skin should undergo a transplant, but it does support the role of the immune system and the potential for a reboot to clear the skin,” she said.

Other therapies associated with benefit in at least some patients include tumor necrosis factor (TNF) inhibitors with dapsone and ribavirin. The risk of adverse events for the latter might again limit its use, Dr. Wanat said.

With awareness, the number of granulomas found to be associated with rubella virus is expected to grow. Dr. Wanat speculated that those areas of the country that not yet have documented a case will do so over time. For idiopathic cases of cutaneous granulomas, rubella should be kept in mind, she said.

Characterizing rubella-associated cutaneous granulomas as “a public health concern,” Dr. Wanat urged clinicians to consider this etiology in lesions that match the phenotype, particularly when other more common infectious agents cannot be identified.

Asked for his perspective, Jeffrey P. North, MD, managing director of the UCSF Dermatopathology, and professor of dermatology and pathology at the University of California, San Francisco, agreed that rubella should be considered as a source of granulomas with a suspected infectious etiology when a pathogen cannot be found.

“It is likely much more common than we know as it has only been recently described and testing for it is limited. I suspected there are a lot of undiagnosed patients suffering from this disease,” Dr. North said in an interview.

“One of the important points for clinicians to consider is that while this has been reported mostly in patients with some form of immunodeficiency, there have also been patients reported to have this condition with no immunodeficiency,” he added. Even though the association between rubella and granulomas was made 10 years ago, awareness is only now spreading, which means the frequency with which rubella leads to granulomas remains uncertain.

“I think we will start to get a better idea of how common this is as more people learn about and testing for it expands,” Dr. North said.

Dr. Wanat reports no potential conflicts of interest. Dr. North reports financial relationships with AdviNow and Kiniksa Pharmaceuticals.

SAN DIEGO — Approximately 10 years ago in France, high throughput screening in a series of cases suggested that vaccine-derived rubella virus was the surprising cause of persistent cutaneous granulomas, but an update at the annual meeting of the American Academy of Dermatology suggests this phenomenon is not as rare as once supposed.

Based on accumulating evidence, the Centers for Disease Control and Prevention (CDC) through collaborations with others also recognized this in pediatric patients with inborn errors of immunity, and it is now appropriate for clinicians to consider this etiology when no other infectious agents can be identified, according to Karolyn A. Wanat, MD, professor of dermatology, Medical College of Wisconsin, Milwaukee, who spoke about rubella as a trigger in granulomatous disease at the meeting. “This is a huge evolving area of interest,” said Dr. Wanat, who has been the first author or coauthor on several published papers, including a review article published earlier this year.

In the earliest cases, including those reported in 2014, the cutaneous granulomas presumed to be causally related to vaccine-derived rubella virus were found only in those with a primary immunodeficiency. This is no longer the case. In a collaboration among US clinics, granulomas that had persisted for years in immunocompetent adults were identified, according to Dr. Wanat, the first author of a report on these findings in four adults in 2022. In addition, it now appears that wild-type rubella virus, like vaccine-derived rubella virus, can be the source of the antigenic response that underlies the development of rubella-associated cutaneous granulomas.

The phenotype of these granulomas is comparable to granulomas associated with other infectious agents. On dermatopathology, these commonly feature a robust granulomatous inflammation with multinucleated giant cells and lymphocytic infiltrate. Necrosis and fibrosis are also common.

“These are the types of granulomas that we would be thinking infection. If tissue cultures are negative, we would probably repeat them,” she said, suggesting that suspicion of an infectious etiology would probably remain high even after multiple negative tests.

Of the cases accruing in the United States and elsewhere, most but not all have been linked to inborn errors of immunity. In a 2020 CDC review, the risk of granulomas caused by compromised immunity, such as defects in T cell function, was estimated to be in the range of 0.6% to 2.5%, Dr. Wanat said.

It is now known that primary immunodeficiency is not a prerequisite, but this should not change the perception that the rubella vaccine, which was introduced in 1979, is effective and safe, according to Dr. Wanat. The vaccine is associated with few serious adverse events and is so effective that rubella was eliminated from the United States in 2004 and from the Americas in 2015.

This makes cases of granuloma associated with wild-type rubella virus surprising, but they appear to be exceedingly rare. Whether caused by vaccine exposure or another source, the mechanism of latent development of cutaneous granulomas is consistent with other infectious sources, and is not well understood.

“Rubella is a sneaky virus that can persist in some immunoprivileged sites indefinitely,” Dr. Wanat said. These sites include the eyes, joints, and placenta.

Many initial cases of rubella-associated granulomas occurred on the arms, presumably where the vaccine was administered, despite long intervals between exposure and lesion growth. This interval is often measured in years.

With more cases, it is now understood that involvement of other organs does occur even if the skin is the most common site of antigenic response in patients with immunodeficiency. The liver and lymph nodes represent other tissues that have been affected. Even lesions in the brain have been seen on autopsy.

Based on the benefit-to-risk ratio of a highly effective and successful vaccine, however, the association with a risk of granulomas “should not raise questions” about the value of the vaccine itself, Dr. Wanat noted.

“The proportion of patients who develop these granulomas is very, very low. Yet, the vaccine provides life-long immunity,” she said.

The discovery of granulomas associated with wild type rubella infection was “shocking” based on the supposition that the rubella virus had been eliminated, but this is just one of the unexpected discoveries as the still-evolving science has traced the story of rubella-associated granulomas over the past 10 years.

Cases now include children and adults through advanced ages.

Shedding of the virus and risk of infection to others has been studied but so far, the risk — if it exists — is very low. The evidence includes the many patients who have lived with the granulomas for years, even decades, without any known spread to others.

As for ongoing work in this area, Dr. Wanat said that a histopathological case definition for rubella-associated granulomas is being developed, and she and other investigators are actively seeking new cases to better characterize the disease.

So far, optimal treatment is not well defined. A number of strategies have had limited success or are considered impractical for routine use. One example is a stem cell transplant. In a case Dr. Wanat cited, complete resolution of the skin lesions was achieved with a transplant.

“I am not suggesting that those with localized disease in the skin should undergo a transplant, but it does support the role of the immune system and the potential for a reboot to clear the skin,” she said.

Other therapies associated with benefit in at least some patients include tumor necrosis factor (TNF) inhibitors with dapsone and ribavirin. The risk of adverse events for the latter might again limit its use, Dr. Wanat said.

With awareness, the number of granulomas found to be associated with rubella virus is expected to grow. Dr. Wanat speculated that those areas of the country that not yet have documented a case will do so over time. For idiopathic cases of cutaneous granulomas, rubella should be kept in mind, she said.

Characterizing rubella-associated cutaneous granulomas as “a public health concern,” Dr. Wanat urged clinicians to consider this etiology in lesions that match the phenotype, particularly when other more common infectious agents cannot be identified.

Asked for his perspective, Jeffrey P. North, MD, managing director of the UCSF Dermatopathology, and professor of dermatology and pathology at the University of California, San Francisco, agreed that rubella should be considered as a source of granulomas with a suspected infectious etiology when a pathogen cannot be found.

“It is likely much more common than we know as it has only been recently described and testing for it is limited. I suspected there are a lot of undiagnosed patients suffering from this disease,” Dr. North said in an interview.

“One of the important points for clinicians to consider is that while this has been reported mostly in patients with some form of immunodeficiency, there have also been patients reported to have this condition with no immunodeficiency,” he added. Even though the association between rubella and granulomas was made 10 years ago, awareness is only now spreading, which means the frequency with which rubella leads to granulomas remains uncertain.

“I think we will start to get a better idea of how common this is as more people learn about and testing for it expands,” Dr. North said.

Dr. Wanat reports no potential conflicts of interest. Dr. North reports financial relationships with AdviNow and Kiniksa Pharmaceuticals.

SAN DIEGO — Approximately 10 years ago in France, high throughput screening in a series of cases suggested that vaccine-derived rubella virus was the surprising cause of persistent cutaneous granulomas, but an update at the annual meeting of the American Academy of Dermatology suggests this phenomenon is not as rare as once supposed.

Based on accumulating evidence, the Centers for Disease Control and Prevention (CDC) through collaborations with others also recognized this in pediatric patients with inborn errors of immunity, and it is now appropriate for clinicians to consider this etiology when no other infectious agents can be identified, according to Karolyn A. Wanat, MD, professor of dermatology, Medical College of Wisconsin, Milwaukee, who spoke about rubella as a trigger in granulomatous disease at the meeting. “This is a huge evolving area of interest,” said Dr. Wanat, who has been the first author or coauthor on several published papers, including a review article published earlier this year.

In the earliest cases, including those reported in 2014, the cutaneous granulomas presumed to be causally related to vaccine-derived rubella virus were found only in those with a primary immunodeficiency. This is no longer the case. In a collaboration among US clinics, granulomas that had persisted for years in immunocompetent adults were identified, according to Dr. Wanat, the first author of a report on these findings in four adults in 2022. In addition, it now appears that wild-type rubella virus, like vaccine-derived rubella virus, can be the source of the antigenic response that underlies the development of rubella-associated cutaneous granulomas.

The phenotype of these granulomas is comparable to granulomas associated with other infectious agents. On dermatopathology, these commonly feature a robust granulomatous inflammation with multinucleated giant cells and lymphocytic infiltrate. Necrosis and fibrosis are also common.

“These are the types of granulomas that we would be thinking infection. If tissue cultures are negative, we would probably repeat them,” she said, suggesting that suspicion of an infectious etiology would probably remain high even after multiple negative tests.

Of the cases accruing in the United States and elsewhere, most but not all have been linked to inborn errors of immunity. In a 2020 CDC review, the risk of granulomas caused by compromised immunity, such as defects in T cell function, was estimated to be in the range of 0.6% to 2.5%, Dr. Wanat said.

It is now known that primary immunodeficiency is not a prerequisite, but this should not change the perception that the rubella vaccine, which was introduced in 1979, is effective and safe, according to Dr. Wanat. The vaccine is associated with few serious adverse events and is so effective that rubella was eliminated from the United States in 2004 and from the Americas in 2015.

This makes cases of granuloma associated with wild-type rubella virus surprising, but they appear to be exceedingly rare. Whether caused by vaccine exposure or another source, the mechanism of latent development of cutaneous granulomas is consistent with other infectious sources, and is not well understood.

“Rubella is a sneaky virus that can persist in some immunoprivileged sites indefinitely,” Dr. Wanat said. These sites include the eyes, joints, and placenta.

Many initial cases of rubella-associated granulomas occurred on the arms, presumably where the vaccine was administered, despite long intervals between exposure and lesion growth. This interval is often measured in years.

With more cases, it is now understood that involvement of other organs does occur even if the skin is the most common site of antigenic response in patients with immunodeficiency. The liver and lymph nodes represent other tissues that have been affected. Even lesions in the brain have been seen on autopsy.

Based on the benefit-to-risk ratio of a highly effective and successful vaccine, however, the association with a risk of granulomas “should not raise questions” about the value of the vaccine itself, Dr. Wanat noted.

“The proportion of patients who develop these granulomas is very, very low. Yet, the vaccine provides life-long immunity,” she said.

The discovery of granulomas associated with wild type rubella infection was “shocking” based on the supposition that the rubella virus had been eliminated, but this is just one of the unexpected discoveries as the still-evolving science has traced the story of rubella-associated granulomas over the past 10 years.

Cases now include children and adults through advanced ages.

Shedding of the virus and risk of infection to others has been studied but so far, the risk — if it exists — is very low. The evidence includes the many patients who have lived with the granulomas for years, even decades, without any known spread to others.

As for ongoing work in this area, Dr. Wanat said that a histopathological case definition for rubella-associated granulomas is being developed, and she and other investigators are actively seeking new cases to better characterize the disease.

So far, optimal treatment is not well defined. A number of strategies have had limited success or are considered impractical for routine use. One example is a stem cell transplant. In a case Dr. Wanat cited, complete resolution of the skin lesions was achieved with a transplant.

“I am not suggesting that those with localized disease in the skin should undergo a transplant, but it does support the role of the immune system and the potential for a reboot to clear the skin,” she said.

Other therapies associated with benefit in at least some patients include tumor necrosis factor (TNF) inhibitors with dapsone and ribavirin. The risk of adverse events for the latter might again limit its use, Dr. Wanat said.

With awareness, the number of granulomas found to be associated with rubella virus is expected to grow. Dr. Wanat speculated that those areas of the country that not yet have documented a case will do so over time. For idiopathic cases of cutaneous granulomas, rubella should be kept in mind, she said.

Characterizing rubella-associated cutaneous granulomas as “a public health concern,” Dr. Wanat urged clinicians to consider this etiology in lesions that match the phenotype, particularly when other more common infectious agents cannot be identified.

Asked for his perspective, Jeffrey P. North, MD, managing director of the UCSF Dermatopathology, and professor of dermatology and pathology at the University of California, San Francisco, agreed that rubella should be considered as a source of granulomas with a suspected infectious etiology when a pathogen cannot be found.

“It is likely much more common than we know as it has only been recently described and testing for it is limited. I suspected there are a lot of undiagnosed patients suffering from this disease,” Dr. North said in an interview.

“One of the important points for clinicians to consider is that while this has been reported mostly in patients with some form of immunodeficiency, there have also been patients reported to have this condition with no immunodeficiency,” he added. Even though the association between rubella and granulomas was made 10 years ago, awareness is only now spreading, which means the frequency with which rubella leads to granulomas remains uncertain.

“I think we will start to get a better idea of how common this is as more people learn about and testing for it expands,” Dr. North said.

Dr. Wanat reports no potential conflicts of interest. Dr. North reports financial relationships with AdviNow and Kiniksa Pharmaceuticals.

DENVER — Unlike a first trial of PB&TURSO, which led to regulatory approval of this combination therapy in 2022, a second larger and longer multicenter placebo-controlled study was unable to show any significant benefit on primary or secondary endpoints.

As a result, “PB&TURSO is no longer available for new patients in the United States of Canada,” reported Leonard H. van den Berg, MD, PhD, Direction of the Netherlands ALS Center, UMC Utrecht Brain Center, Utrecht, the Netherlands.

Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr. van den Berg, who presented the results of this new trial, called PHOENIX, at the 2024 annual meeting of the American Academy of Neurology.

Ted Bosworth/MDedge News

PB&TURSO, marketed as Relyvrio (Amylyx), is a combination of sodium phenylbutyrate (PB) and taurursodiol (TAURO). Having shown promise for preventing neuronal death in experimental and early human studies, it was approved on the basis of the of the double-blind multicenter CENTAUR trial published in The New England Journal of Medicine in 2022.
 

ALSFRS-R Served as Primary Endpoint in Both Trials

In CENTAUR, like the newly completed PHOENIX, the primary outcome was rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) over 24 weeks. On this endpoint, the rate of change for those randomized to PB&TAURO was –1.24 points per month versus –1.66 points per month on placebo, a difference of 0.42 points that met statistical significance (P = .02).

The CENTAUR trial, which enrolled 177 patients, also showed no differences between those in the experimental and placebo arms for any of the secondary endpoints, including time to tracheostomy, permanent ventilation, or death.

In the much larger and longer PHOENIX trial, 664 ALS patients were randomized in a 3:2 ratio to PB&TURSO or placebo. Fifty-seven percent in each group completed 48 weeks of follow-up. The proportions of patients who withdrew from the study were similar across the reasons, such as adverse events and disease progression.

For the ALSFRS-R primary endpoint at 48 weeks, the decline in both groups was essentially linear and almost completely overlapped with a final change from baseline of –14.98 points in the PB&TURSO group that was statistically indistinguishable from the –15.32 point-change (P = .667) in the placebo group, Dr. van den Berg reported.

Similarly, there were no clinically meaningful or statistically significant differences in the secondary endpoints of mean change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scores or mean change in slow vital capacity (SVC) when compared to baseline or between arms.

As in CENTAUR, the most common side effects associated with PB&TURSO were gastrointestinal, particularly diarrhea (31% vs 10%), but serious adverse events were slightly less common on PT&TURSO (26% vs 28%), and Dr. van der Berg characterized the drug as “generally well tolerated.”
 

Differences Between Two Trials Were Evaluated

The entry criteria for PHOENIX trial differed modestly from those of the CENTAUR trial. Clinically definite or probable ALS was required in only two or more body regions versus three or more in the earlier trial. Patients were also allowed entry with SVC greater than 60% versus greater than 55% for CENTAUR and have had a longer period since symptom onset (< 24 vs < 18 months). Both studies permitted use of edaravone.

When stratified, patients who entered PHOENIX with CENTAUR-like entry criteria had a similar response to PB&TURSO relative to those who did not. Similarly, there were no meaningful differences between those enrolled in European study sites versus elsewhere. Background edaravone versus no edaravone also had no apparent effect on outcomes.

An ongoing open-label extension of the PHOENIX trial is still collecting data on survival, which was a prespecified endpoint. This endpoint, which requires 70% or more of patients to have died or have been followed for 3 or more years since the last patient was randomized, is not expected until February 2026.

Although “there are further biomarker and subgroup analyses planned,” Dr. van den Berg said that the neutral results of the PHOENIX trial, which he characterized as the largest controlled trial in ALS ever conducted, do not encourage further studies with this agent.
 

‘Unfortunate’ Results

Robert Bowser, PhD, chief scientific officer and chair of the department of translational neuroscience, Barrow Neurological Institute, Phoenix, called the results “unfortunate.” Just last year, Dr. Bowser published a study showing a reduction in the concentration of biomarkers associated with ALS among patients in the CENTAUR study who were treated with PB&TURSO.

Moreover, the reduction in the serum concentrations of the biomarkers he studied, which included C-reactive protein and YKL-40, correlated with ALSFRS-R total score.

In that paper, he speculated that CRP and YKL-40 might emerge as treatment-sensitive biomarkers in ALS “pending further confirmatory studies, but Dr. Bowser indicated that the PHOENIX study has prompted the correct response from the manufacturers.

“Credit should be given to the leaders at Amylyx for following through with their promise to remove the drug from the market if the PHOENIX study did not confirm the results from the CENTAUR study,” he said.

However, he believes that the study will still have value for better understanding ALS.

“As we move forward, it will be interesting to see biomarker data generated from the biosamples collected during the PHOENIX trial to learn more about treatment impact on biomarkers within those that received the drug,” he said. “I am sure we will continue to learn more from the PHOENIX trial.”

Dr. van den Berg has financial relationships with approximately 10 pharmaceutical companies, including Amylyx, which provided funding for the PHOENIX trial. Dr. Bowser reported no potential conflicts of interest.

DENVER — Unlike a first trial of PB&TURSO, which led to regulatory approval of this combination therapy in 2022, a second larger and longer multicenter placebo-controlled study was unable to show any significant benefit on primary or secondary endpoints.

As a result, “PB&TURSO is no longer available for new patients in the United States of Canada,” reported Leonard H. van den Berg, MD, PhD, Direction of the Netherlands ALS Center, UMC Utrecht Brain Center, Utrecht, the Netherlands.

Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr. van den Berg, who presented the results of this new trial, called PHOENIX, at the 2024 annual meeting of the American Academy of Neurology.

Ted Bosworth/MDedge News

PB&TURSO, marketed as Relyvrio (Amylyx), is a combination of sodium phenylbutyrate (PB) and taurursodiol (TAURO). Having shown promise for preventing neuronal death in experimental and early human studies, it was approved on the basis of the of the double-blind multicenter CENTAUR trial published in The New England Journal of Medicine in 2022.
 

ALSFRS-R Served as Primary Endpoint in Both Trials

In CENTAUR, like the newly completed PHOENIX, the primary outcome was rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) over 24 weeks. On this endpoint, the rate of change for those randomized to PB&TAURO was –1.24 points per month versus –1.66 points per month on placebo, a difference of 0.42 points that met statistical significance (P = .02).

The CENTAUR trial, which enrolled 177 patients, also showed no differences between those in the experimental and placebo arms for any of the secondary endpoints, including time to tracheostomy, permanent ventilation, or death.

In the much larger and longer PHOENIX trial, 664 ALS patients were randomized in a 3:2 ratio to PB&TURSO or placebo. Fifty-seven percent in each group completed 48 weeks of follow-up. The proportions of patients who withdrew from the study were similar across the reasons, such as adverse events and disease progression.

For the ALSFRS-R primary endpoint at 48 weeks, the decline in both groups was essentially linear and almost completely overlapped with a final change from baseline of –14.98 points in the PB&TURSO group that was statistically indistinguishable from the –15.32 point-change (P = .667) in the placebo group, Dr. van den Berg reported.

Similarly, there were no clinically meaningful or statistically significant differences in the secondary endpoints of mean change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scores or mean change in slow vital capacity (SVC) when compared to baseline or between arms.

As in CENTAUR, the most common side effects associated with PB&TURSO were gastrointestinal, particularly diarrhea (31% vs 10%), but serious adverse events were slightly less common on PT&TURSO (26% vs 28%), and Dr. van der Berg characterized the drug as “generally well tolerated.”
 

Differences Between Two Trials Were Evaluated

The entry criteria for PHOENIX trial differed modestly from those of the CENTAUR trial. Clinically definite or probable ALS was required in only two or more body regions versus three or more in the earlier trial. Patients were also allowed entry with SVC greater than 60% versus greater than 55% for CENTAUR and have had a longer period since symptom onset (< 24 vs < 18 months). Both studies permitted use of edaravone.

When stratified, patients who entered PHOENIX with CENTAUR-like entry criteria had a similar response to PB&TURSO relative to those who did not. Similarly, there were no meaningful differences between those enrolled in European study sites versus elsewhere. Background edaravone versus no edaravone also had no apparent effect on outcomes.

An ongoing open-label extension of the PHOENIX trial is still collecting data on survival, which was a prespecified endpoint. This endpoint, which requires 70% or more of patients to have died or have been followed for 3 or more years since the last patient was randomized, is not expected until February 2026.

Although “there are further biomarker and subgroup analyses planned,” Dr. van den Berg said that the neutral results of the PHOENIX trial, which he characterized as the largest controlled trial in ALS ever conducted, do not encourage further studies with this agent.
 

‘Unfortunate’ Results

Robert Bowser, PhD, chief scientific officer and chair of the department of translational neuroscience, Barrow Neurological Institute, Phoenix, called the results “unfortunate.” Just last year, Dr. Bowser published a study showing a reduction in the concentration of biomarkers associated with ALS among patients in the CENTAUR study who were treated with PB&TURSO.

Moreover, the reduction in the serum concentrations of the biomarkers he studied, which included C-reactive protein and YKL-40, correlated with ALSFRS-R total score.

In that paper, he speculated that CRP and YKL-40 might emerge as treatment-sensitive biomarkers in ALS “pending further confirmatory studies, but Dr. Bowser indicated that the PHOENIX study has prompted the correct response from the manufacturers.

“Credit should be given to the leaders at Amylyx for following through with their promise to remove the drug from the market if the PHOENIX study did not confirm the results from the CENTAUR study,” he said.

However, he believes that the study will still have value for better understanding ALS.

“As we move forward, it will be interesting to see biomarker data generated from the biosamples collected during the PHOENIX trial to learn more about treatment impact on biomarkers within those that received the drug,” he said. “I am sure we will continue to learn more from the PHOENIX trial.”

Dr. van den Berg has financial relationships with approximately 10 pharmaceutical companies, including Amylyx, which provided funding for the PHOENIX trial. Dr. Bowser reported no potential conflicts of interest.

DENVER — Unlike a first trial of PB&TURSO, which led to regulatory approval of this combination therapy in 2022, a second larger and longer multicenter placebo-controlled study was unable to show any significant benefit on primary or secondary endpoints.

As a result, “PB&TURSO is no longer available for new patients in the United States of Canada,” reported Leonard H. van den Berg, MD, PhD, Direction of the Netherlands ALS Center, UMC Utrecht Brain Center, Utrecht, the Netherlands.

Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr. van den Berg, who presented the results of this new trial, called PHOENIX, at the 2024 annual meeting of the American Academy of Neurology.

Ted Bosworth/MDedge News

PB&TURSO, marketed as Relyvrio (Amylyx), is a combination of sodium phenylbutyrate (PB) and taurursodiol (TAURO). Having shown promise for preventing neuronal death in experimental and early human studies, it was approved on the basis of the of the double-blind multicenter CENTAUR trial published in The New England Journal of Medicine in 2022.
 

ALSFRS-R Served as Primary Endpoint in Both Trials

In CENTAUR, like the newly completed PHOENIX, the primary outcome was rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) over 24 weeks. On this endpoint, the rate of change for those randomized to PB&TAURO was –1.24 points per month versus –1.66 points per month on placebo, a difference of 0.42 points that met statistical significance (P = .02).

The CENTAUR trial, which enrolled 177 patients, also showed no differences between those in the experimental and placebo arms for any of the secondary endpoints, including time to tracheostomy, permanent ventilation, or death.

In the much larger and longer PHOENIX trial, 664 ALS patients were randomized in a 3:2 ratio to PB&TURSO or placebo. Fifty-seven percent in each group completed 48 weeks of follow-up. The proportions of patients who withdrew from the study were similar across the reasons, such as adverse events and disease progression.

For the ALSFRS-R primary endpoint at 48 weeks, the decline in both groups was essentially linear and almost completely overlapped with a final change from baseline of –14.98 points in the PB&TURSO group that was statistically indistinguishable from the –15.32 point-change (P = .667) in the placebo group, Dr. van den Berg reported.

Similarly, there were no clinically meaningful or statistically significant differences in the secondary endpoints of mean change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scores or mean change in slow vital capacity (SVC) when compared to baseline or between arms.

As in CENTAUR, the most common side effects associated with PB&TURSO were gastrointestinal, particularly diarrhea (31% vs 10%), but serious adverse events were slightly less common on PT&TURSO (26% vs 28%), and Dr. van der Berg characterized the drug as “generally well tolerated.”
 

Differences Between Two Trials Were Evaluated

The entry criteria for PHOENIX trial differed modestly from those of the CENTAUR trial. Clinically definite or probable ALS was required in only two or more body regions versus three or more in the earlier trial. Patients were also allowed entry with SVC greater than 60% versus greater than 55% for CENTAUR and have had a longer period since symptom onset (< 24 vs < 18 months). Both studies permitted use of edaravone.

When stratified, patients who entered PHOENIX with CENTAUR-like entry criteria had a similar response to PB&TURSO relative to those who did not. Similarly, there were no meaningful differences between those enrolled in European study sites versus elsewhere. Background edaravone versus no edaravone also had no apparent effect on outcomes.

An ongoing open-label extension of the PHOENIX trial is still collecting data on survival, which was a prespecified endpoint. This endpoint, which requires 70% or more of patients to have died or have been followed for 3 or more years since the last patient was randomized, is not expected until February 2026.

Although “there are further biomarker and subgroup analyses planned,” Dr. van den Berg said that the neutral results of the PHOENIX trial, which he characterized as the largest controlled trial in ALS ever conducted, do not encourage further studies with this agent.
 

‘Unfortunate’ Results

Robert Bowser, PhD, chief scientific officer and chair of the department of translational neuroscience, Barrow Neurological Institute, Phoenix, called the results “unfortunate.” Just last year, Dr. Bowser published a study showing a reduction in the concentration of biomarkers associated with ALS among patients in the CENTAUR study who were treated with PB&TURSO.

Moreover, the reduction in the serum concentrations of the biomarkers he studied, which included C-reactive protein and YKL-40, correlated with ALSFRS-R total score.

In that paper, he speculated that CRP and YKL-40 might emerge as treatment-sensitive biomarkers in ALS “pending further confirmatory studies, but Dr. Bowser indicated that the PHOENIX study has prompted the correct response from the manufacturers.

“Credit should be given to the leaders at Amylyx for following through with their promise to remove the drug from the market if the PHOENIX study did not confirm the results from the CENTAUR study,” he said.

However, he believes that the study will still have value for better understanding ALS.

“As we move forward, it will be interesting to see biomarker data generated from the biosamples collected during the PHOENIX trial to learn more about treatment impact on biomarkers within those that received the drug,” he said. “I am sure we will continue to learn more from the PHOENIX trial.”

Dr. van den Berg has financial relationships with approximately 10 pharmaceutical companies, including Amylyx, which provided funding for the PHOENIX trial. Dr. Bowser reported no potential conflicts of interest.

DENVER — When combined with rHuPh20, a recombinant DNA-derived human hyaluronidase, efgartigimod, promises a new treatment option for chronic inflammatory demyelinating polyneuropathy (CIDP), according to the results of a phase 2 multinational trial, which were reported at the 2024 annual meeting of the American Academy of Neurology.

“Regardless of prior therapy for CIDP, efgartigimod PH20 was associated with a rapid clinical improvement, and clinical responses have been maintained out to 48 weeks,” said Jeffrey A. Allen, MD, an associate professor of neurology, University of Minnesota, Minneapolis.

Efgartigimod, which reduces circulating IgG immunoglobulin, has been available for the treatment of myasthenia gravis since 2021. In a new trial, called ADHERE, the combination of efgartigimod and rHuPH20 (E-PH20) was tested for CIDP, the most common of the chronic immune-mediated inflammatory polyneuropathies.

Ted Bosworth/MDedge News

ADHERE Called Largest CIDP Trial to Date

In this study, which Dr. Allen called the largest randomized controlled trial ever performed with a CIDP treatment, a run-in stage was required for those candidates who were already on treatment. When these patients went off treatment during this 12-week run-in, clinical deterioration was required to advance to the first of two stages of the trial. Patients with symptomatic CIDP but off treatment at the time of enrollment did not participate in the run-in.

After the run-in, patients who advanced to stage A received 1000 mg of E-PH20 open label for 12 weeks. Of those on treatment prior to the run-in, about half were receiving intravenous immunoglobulins (IVIg). Almost all the remainder had been receiving corticosteroids. About 30% had been off treatment and entered stage A without participating in the run in.

The primary endpoint of stage A was the percentage of patients with evidence of clinical improvement (ECI). Patients who participated in the run-in were allowed to resume their prior treatment for stage A and the subsequent blinded stage B. Stage A was event driven so that it was closed once 88 events were reached,

The ECI endpoint was met by 66.5% of the patients, who thereby met eligibility for the randomized stage B. As the study design excluded those who achieved clinical improvement after the 88-event limit was reached, they were not included among responders. Had they been included, Dr. Allen said that the primary endpoint of stage A would have been reached by 70.4%.

The patterns of improvement in stage A were similar across type of prior CIDP treatment, including no treatment, according to Dr. Allen, who noted that 39.8% of those enrolled in stage A met the primary endpoint within 4 weeks.

There were 322 patients in stage A. Of these, 211 enrolled in stage B. They were randomized in a 1:1 ratio to 1000 mg of E-PH20 or placebo administered weekly by subcutaneous injection. Of those eligible for stage B, 40% had not participated in the run-in.
 

aINCAT Provided Primary Endpoint for CIDP Trial

For stage B, the primary endpoint was time from baseline to a clinically meaningful limitation of activity. This was evaluated with the adjusted inflammatory neuropathy cause and treatment (aINCAT) disability score.

By the end of 48 weeks of treatment, 27.9% had relapsed on E-PH20 according to the aiNCAT disability score versus 53.6% on those on placebo. By hazard ratio (HR 0.39), the active treatment arm was associated with a highly significant 61% (P = .000039) greater likelihood of avoiding relapse.

When stratified by a background of no therapy, IVIg, subcutaneous immunoglobulins (SCIg), or corticosteroids, all groups in the active treatment arm did better in stage B than any group in the placebo arm, according to Dr. Allen.

In the 48-week deterioration curves, sustained control was observed among responders out to the end of controlled study. Although there appeared to be numerical advantage for those on both E-PH20 and corticosteroids, E-PH20 arms with concomitant IVIg, SCIg, or no treatment also showed sustained control without significant differences between them.

On functional aINCAT scores, 80.9% achieved at least a 1-point improvement. The improvement was at least 2 points in 42.7%, at least 3 points in 28.2%, and at least 4 points in 11.8%.
 

E-PH20 Is Characterized as Well Tolerated

Injection site erythema (5.4% vs 0%) and injection site bruising (5.4% vs 0.9%) were more common on E-PH20 than placebo, but there was no difference in serious adverse events, and events possibly related to active treatment, such as headache (3.6% vs. 1.8%) were considered to be of mild to moderate severity.

“The safety profile of efgartigimod plus PH20 was consistent with the safety profile of efgartigimod in other autoimmune diseases,” Dr. Allen said.

The weekly subcutaneous injection can be administered within 90 seconds or less, Dr. Allen said. He called this drug a potential “new therapeutic option to reduce treatment burden in patients with CIDP” if it is approved.

There is a need for new options, according to Brett M. Morrison, MD, PhD, associate professor of neurology at the Johns Hopkins School of Medicine, Baltimore, and an expert in neuromuscular disorders. Dr. Morrison was not involved in the study.

“Although there are three currently approved treatments — steroids, IVIg, and plasmapheresis, at least 20% of CIDP patients have minimal or no response” to any of these, Dr. Morrison said. He added that many of those who do respond to standard therapies have a substantial side effect burden that has created a need for alternatives.

Based on the data presented so far, which suggest substantial efficacy and a favorable safety profile, efgartigimod, if and when it becomes available, “would be an important new treatment for CIDP,” according to Dr. Morrison.

Dr. Allen has financial relationships with more than 10 pharmaceutical companies, including Argenx, which provided funding for the ACHIEVE trial. Dr. Morrison reported no potential conflicts of interest.

DENVER — When combined with rHuPh20, a recombinant DNA-derived human hyaluronidase, efgartigimod, promises a new treatment option for chronic inflammatory demyelinating polyneuropathy (CIDP), according to the results of a phase 2 multinational trial, which were reported at the 2024 annual meeting of the American Academy of Neurology.

“Regardless of prior therapy for CIDP, efgartigimod PH20 was associated with a rapid clinical improvement, and clinical responses have been maintained out to 48 weeks,” said Jeffrey A. Allen, MD, an associate professor of neurology, University of Minnesota, Minneapolis.

Efgartigimod, which reduces circulating IgG immunoglobulin, has been available for the treatment of myasthenia gravis since 2021. In a new trial, called ADHERE, the combination of efgartigimod and rHuPH20 (E-PH20) was tested for CIDP, the most common of the chronic immune-mediated inflammatory polyneuropathies.

Ted Bosworth/MDedge News

ADHERE Called Largest CIDP Trial to Date

In this study, which Dr. Allen called the largest randomized controlled trial ever performed with a CIDP treatment, a run-in stage was required for those candidates who were already on treatment. When these patients went off treatment during this 12-week run-in, clinical deterioration was required to advance to the first of two stages of the trial. Patients with symptomatic CIDP but off treatment at the time of enrollment did not participate in the run-in.

After the run-in, patients who advanced to stage A received 1000 mg of E-PH20 open label for 12 weeks. Of those on treatment prior to the run-in, about half were receiving intravenous immunoglobulins (IVIg). Almost all the remainder had been receiving corticosteroids. About 30% had been off treatment and entered stage A without participating in the run in.

The primary endpoint of stage A was the percentage of patients with evidence of clinical improvement (ECI). Patients who participated in the run-in were allowed to resume their prior treatment for stage A and the subsequent blinded stage B. Stage A was event driven so that it was closed once 88 events were reached,

The ECI endpoint was met by 66.5% of the patients, who thereby met eligibility for the randomized stage B. As the study design excluded those who achieved clinical improvement after the 88-event limit was reached, they were not included among responders. Had they been included, Dr. Allen said that the primary endpoint of stage A would have been reached by 70.4%.

The patterns of improvement in stage A were similar across type of prior CIDP treatment, including no treatment, according to Dr. Allen, who noted that 39.8% of those enrolled in stage A met the primary endpoint within 4 weeks.

There were 322 patients in stage A. Of these, 211 enrolled in stage B. They were randomized in a 1:1 ratio to 1000 mg of E-PH20 or placebo administered weekly by subcutaneous injection. Of those eligible for stage B, 40% had not participated in the run-in.
 

aINCAT Provided Primary Endpoint for CIDP Trial

For stage B, the primary endpoint was time from baseline to a clinically meaningful limitation of activity. This was evaluated with the adjusted inflammatory neuropathy cause and treatment (aINCAT) disability score.

By the end of 48 weeks of treatment, 27.9% had relapsed on E-PH20 according to the aiNCAT disability score versus 53.6% on those on placebo. By hazard ratio (HR 0.39), the active treatment arm was associated with a highly significant 61% (P = .000039) greater likelihood of avoiding relapse.

When stratified by a background of no therapy, IVIg, subcutaneous immunoglobulins (SCIg), or corticosteroids, all groups in the active treatment arm did better in stage B than any group in the placebo arm, according to Dr. Allen.

In the 48-week deterioration curves, sustained control was observed among responders out to the end of controlled study. Although there appeared to be numerical advantage for those on both E-PH20 and corticosteroids, E-PH20 arms with concomitant IVIg, SCIg, or no treatment also showed sustained control without significant differences between them.

On functional aINCAT scores, 80.9% achieved at least a 1-point improvement. The improvement was at least 2 points in 42.7%, at least 3 points in 28.2%, and at least 4 points in 11.8%.
 

E-PH20 Is Characterized as Well Tolerated

Injection site erythema (5.4% vs 0%) and injection site bruising (5.4% vs 0.9%) were more common on E-PH20 than placebo, but there was no difference in serious adverse events, and events possibly related to active treatment, such as headache (3.6% vs. 1.8%) were considered to be of mild to moderate severity.

“The safety profile of efgartigimod plus PH20 was consistent with the safety profile of efgartigimod in other autoimmune diseases,” Dr. Allen said.

The weekly subcutaneous injection can be administered within 90 seconds or less, Dr. Allen said. He called this drug a potential “new therapeutic option to reduce treatment burden in patients with CIDP” if it is approved.

There is a need for new options, according to Brett M. Morrison, MD, PhD, associate professor of neurology at the Johns Hopkins School of Medicine, Baltimore, and an expert in neuromuscular disorders. Dr. Morrison was not involved in the study.

“Although there are three currently approved treatments — steroids, IVIg, and plasmapheresis, at least 20% of CIDP patients have minimal or no response” to any of these, Dr. Morrison said. He added that many of those who do respond to standard therapies have a substantial side effect burden that has created a need for alternatives.

Based on the data presented so far, which suggest substantial efficacy and a favorable safety profile, efgartigimod, if and when it becomes available, “would be an important new treatment for CIDP,” according to Dr. Morrison.

Dr. Allen has financial relationships with more than 10 pharmaceutical companies, including Argenx, which provided funding for the ACHIEVE trial. Dr. Morrison reported no potential conflicts of interest.

DENVER — When combined with rHuPh20, a recombinant DNA-derived human hyaluronidase, efgartigimod, promises a new treatment option for chronic inflammatory demyelinating polyneuropathy (CIDP), according to the results of a phase 2 multinational trial, which were reported at the 2024 annual meeting of the American Academy of Neurology.

“Regardless of prior therapy for CIDP, efgartigimod PH20 was associated with a rapid clinical improvement, and clinical responses have been maintained out to 48 weeks,” said Jeffrey A. Allen, MD, an associate professor of neurology, University of Minnesota, Minneapolis.

Efgartigimod, which reduces circulating IgG immunoglobulin, has been available for the treatment of myasthenia gravis since 2021. In a new trial, called ADHERE, the combination of efgartigimod and rHuPH20 (E-PH20) was tested for CIDP, the most common of the chronic immune-mediated inflammatory polyneuropathies.

Ted Bosworth/MDedge News

ADHERE Called Largest CIDP Trial to Date

In this study, which Dr. Allen called the largest randomized controlled trial ever performed with a CIDP treatment, a run-in stage was required for those candidates who were already on treatment. When these patients went off treatment during this 12-week run-in, clinical deterioration was required to advance to the first of two stages of the trial. Patients with symptomatic CIDP but off treatment at the time of enrollment did not participate in the run-in.

After the run-in, patients who advanced to stage A received 1000 mg of E-PH20 open label for 12 weeks. Of those on treatment prior to the run-in, about half were receiving intravenous immunoglobulins (IVIg). Almost all the remainder had been receiving corticosteroids. About 30% had been off treatment and entered stage A without participating in the run in.

The primary endpoint of stage A was the percentage of patients with evidence of clinical improvement (ECI). Patients who participated in the run-in were allowed to resume their prior treatment for stage A and the subsequent blinded stage B. Stage A was event driven so that it was closed once 88 events were reached,

The ECI endpoint was met by 66.5% of the patients, who thereby met eligibility for the randomized stage B. As the study design excluded those who achieved clinical improvement after the 88-event limit was reached, they were not included among responders. Had they been included, Dr. Allen said that the primary endpoint of stage A would have been reached by 70.4%.

The patterns of improvement in stage A were similar across type of prior CIDP treatment, including no treatment, according to Dr. Allen, who noted that 39.8% of those enrolled in stage A met the primary endpoint within 4 weeks.

There were 322 patients in stage A. Of these, 211 enrolled in stage B. They were randomized in a 1:1 ratio to 1000 mg of E-PH20 or placebo administered weekly by subcutaneous injection. Of those eligible for stage B, 40% had not participated in the run-in.
 

aINCAT Provided Primary Endpoint for CIDP Trial

For stage B, the primary endpoint was time from baseline to a clinically meaningful limitation of activity. This was evaluated with the adjusted inflammatory neuropathy cause and treatment (aINCAT) disability score.

By the end of 48 weeks of treatment, 27.9% had relapsed on E-PH20 according to the aiNCAT disability score versus 53.6% on those on placebo. By hazard ratio (HR 0.39), the active treatment arm was associated with a highly significant 61% (P = .000039) greater likelihood of avoiding relapse.

When stratified by a background of no therapy, IVIg, subcutaneous immunoglobulins (SCIg), or corticosteroids, all groups in the active treatment arm did better in stage B than any group in the placebo arm, according to Dr. Allen.

In the 48-week deterioration curves, sustained control was observed among responders out to the end of controlled study. Although there appeared to be numerical advantage for those on both E-PH20 and corticosteroids, E-PH20 arms with concomitant IVIg, SCIg, or no treatment also showed sustained control without significant differences between them.

On functional aINCAT scores, 80.9% achieved at least a 1-point improvement. The improvement was at least 2 points in 42.7%, at least 3 points in 28.2%, and at least 4 points in 11.8%.
 

E-PH20 Is Characterized as Well Tolerated

Injection site erythema (5.4% vs 0%) and injection site bruising (5.4% vs 0.9%) were more common on E-PH20 than placebo, but there was no difference in serious adverse events, and events possibly related to active treatment, such as headache (3.6% vs. 1.8%) were considered to be of mild to moderate severity.

“The safety profile of efgartigimod plus PH20 was consistent with the safety profile of efgartigimod in other autoimmune diseases,” Dr. Allen said.

The weekly subcutaneous injection can be administered within 90 seconds or less, Dr. Allen said. He called this drug a potential “new therapeutic option to reduce treatment burden in patients with CIDP” if it is approved.

There is a need for new options, according to Brett M. Morrison, MD, PhD, associate professor of neurology at the Johns Hopkins School of Medicine, Baltimore, and an expert in neuromuscular disorders. Dr. Morrison was not involved in the study.

“Although there are three currently approved treatments — steroids, IVIg, and plasmapheresis, at least 20% of CIDP patients have minimal or no response” to any of these, Dr. Morrison said. He added that many of those who do respond to standard therapies have a substantial side effect burden that has created a need for alternatives.

Based on the data presented so far, which suggest substantial efficacy and a favorable safety profile, efgartigimod, if and when it becomes available, “would be an important new treatment for CIDP,” according to Dr. Morrison.

Dr. Allen has financial relationships with more than 10 pharmaceutical companies, including Argenx, which provided funding for the ACHIEVE trial. Dr. Morrison reported no potential conflicts of interest.

A head-to-head trial of minimally invasive procedures to manage benign prostatic hyperplasia found that urethral implants appear to provide more durable control of symptoms than thermal therapy. 

The ongoing CLEAR RCT study includes 68 men in the United States and the United Kingdom who have undergone one of two minimally invasive surgical techniques (MISTs). It found a procedure in which prostate tissue is lifted away from the urethra to improve urinary flow provided faster relief of symptoms, lower rates of catheterization, and higher patient satisfaction at 1 month than did an alternative approach that relies on thermal energy for tissue ablation, according to Mark Rochester, MD, a consultant urologist at the Norfolk and Norwich University Hospitals in England. 

“These results give clinicians and patients some data with which to choose between devices,” said Dr. Rochester, who presented the data at the 2024 annual meeting of the European Association of Urology.
 

CLEAR RCT Called First MIST Controlled Trial

Dr. Rochester called CLEAR RCT “the first head-to-head randomized controlled trial to compare two contemporary MISTs”: UroLift (Teleflex), known generically as a prostatic urethral lift (PUL), and Rezum (Boston Scientific), known as water vapor thermal therapy (WVTT). 

In the PUL technique, a delivery device is introduced into the urethra and advanced to the site of hyperplasia where implants are placed to lift and hold the tissue away on each side of the urethra. The implants are designed for long-term relief of the obstruction that inhibits urinary flow.

In the WVTT technique, thermal energy in the form of water vapor is introduced into the enlarged prostate tissue where it disperses through the interstices to produce denaturization of the tissue and cell death. Over time, the ablated tissue, which is eventually reabsorbed in the healing process, relieves pressure on the urethra to improve passage of urine. 

Both procedures can be performed on an outpatient basis without general anesthesia. Each typically permits discontinuation of medications commonly prescribed for lower urinary tract symptoms, and both are associated with a low risk of erectile dysfunction. Most routine activities can be resumed within a few days.

Baseline characteristics of the 35 patients randomized to PUL and 33 patients randomized to WVTT were similar in regard to body mass index, prostate volume, baseline International Prostate Symptom Score (IPSS), post-void volume test, and maximum urinary flow. 

Although this is a preliminary 3-month analysis of a study not yet completed, the primary endpoint was catheter independence on postop day 3 through 7. No patients randomized to PUL failed the primary endpoint versus nine (26%) of the patients randomized to WVTT. 

Of the nine, six failed because they were not catheter-independent by day 3; three more failed after they had initially achieved catheter independence but then required the device in order to void within 7 days, Dr. Rochester reported. Four of these patients had further recurrences within 3 months of the procedure. 

The response measured by symptoms and objective studies of such variables as peak flow (Qmax) also favored PUL over WVTT in the early postperative period, according to the analysis. By 14 days, for example, IPSS scores were superior at 14 days and 1 month, although they no longer differed statistically at the 3-month mark. Qmax was significantly greater in the PUL group at 14 days but not at 1 or 3 months, according to Dr. Rochester. 
 

QOL Advantage at 1 Month Lost at 3 Months

From baseline, more patients in the PUL than WVTT group had a meaningful improvement in quality of life (QoL) at 14 days (39.5% vs 5.6%) and 1 month (47.8% vs 19.2%), Dr. Rochester said. Again, however, the between-group differences had lost significance by 3 months.

Patients who were satisfied or very satisfied at 1 month (48% vs 25%) also favored PUL, and about the same proportion (55%) were satisfied at 3 months, Dr. Rochester said.

Adverse events attributed to these procedures were slightly higher in the PUL group (21%) than the WVTT group (17%), but none was serious. At longest follow-up to date, which is 1 year in some patients, one man in each group required an invasive retreatment.

Patients or clinicians might prefer one technique over the other in an individual case, but the goal of CLEAR RCT was to provide objective evidence when educating patients about treatment options.

“Patients typically want to know which one is preferred, and we needed data to back up this conversation,” Dr. Rochester said. 
 

Measuring the Right Endpoint?

While longer follow-up might reveal differences in the durability of symptom relief, outcomes other than the primary endpoint of CLEAR RCT should be considered when selecting between these modalities, according to Dean Elterman, MD, MSc, an associate professor in urology at the University of Toronto in Canada. He suggested that catheter-free rates on days 3-7 is “a unique primary endpoint.” 

“Patients choose different therapies for different personal reasons. For some, having a catheter for less time is an important short-term goal, while for others the long-term benefit may carry more weight,” said Dr. Elterman, who led a study in 2021 that pooled data from two sham-controlled trials to consider differences between PUL and WVTT at 3 years. In that study, WVTT was associated with fewer surgical retreatments (4.4% vs 10.7%) and better symptom relief at long-term follow-up.

Given the differences in the mechanisms of PUL and WVTT, he said it is probably inappropriate to consider just one endpoint, such as early catheter independence, in considering the differences between the two MISTs. 

“This study does show PUL patients have less interference with participation in daily activities within the first month, but the clinical improvement and quality of life are the same in each group at 3 months,” he noted.

“If short-term benefits are weighed as more important to a patient, then this study may be informative,” he said. But he thinks many patients will be at least as interested in long-term follow-up to see if early benefits are durable.

Dr. Rochester reported financial relationships with Intuitive Surgical and Teleflex, which manufactures UroLift and was the sponsor of the CLEAR RCT trial. Dr. Elterman reported financial relationships with BioRobotics and Olympus.

A version of this article appeared on Medscape.com.

A head-to-head trial of minimally invasive procedures to manage benign prostatic hyperplasia found that urethral implants appear to provide more durable control of symptoms than thermal therapy. 

The ongoing CLEAR RCT study includes 68 men in the United States and the United Kingdom who have undergone one of two minimally invasive surgical techniques (MISTs). It found a procedure in which prostate tissue is lifted away from the urethra to improve urinary flow provided faster relief of symptoms, lower rates of catheterization, and higher patient satisfaction at 1 month than did an alternative approach that relies on thermal energy for tissue ablation, according to Mark Rochester, MD, a consultant urologist at the Norfolk and Norwich University Hospitals in England. 

“These results give clinicians and patients some data with which to choose between devices,” said Dr. Rochester, who presented the data at the 2024 annual meeting of the European Association of Urology.
 

CLEAR RCT Called First MIST Controlled Trial

Dr. Rochester called CLEAR RCT “the first head-to-head randomized controlled trial to compare two contemporary MISTs”: UroLift (Teleflex), known generically as a prostatic urethral lift (PUL), and Rezum (Boston Scientific), known as water vapor thermal therapy (WVTT). 

In the PUL technique, a delivery device is introduced into the urethra and advanced to the site of hyperplasia where implants are placed to lift and hold the tissue away on each side of the urethra. The implants are designed for long-term relief of the obstruction that inhibits urinary flow.

In the WVTT technique, thermal energy in the form of water vapor is introduced into the enlarged prostate tissue where it disperses through the interstices to produce denaturization of the tissue and cell death. Over time, the ablated tissue, which is eventually reabsorbed in the healing process, relieves pressure on the urethra to improve passage of urine. 

Both procedures can be performed on an outpatient basis without general anesthesia. Each typically permits discontinuation of medications commonly prescribed for lower urinary tract symptoms, and both are associated with a low risk of erectile dysfunction. Most routine activities can be resumed within a few days.

Baseline characteristics of the 35 patients randomized to PUL and 33 patients randomized to WVTT were similar in regard to body mass index, prostate volume, baseline International Prostate Symptom Score (IPSS), post-void volume test, and maximum urinary flow. 

Although this is a preliminary 3-month analysis of a study not yet completed, the primary endpoint was catheter independence on postop day 3 through 7. No patients randomized to PUL failed the primary endpoint versus nine (26%) of the patients randomized to WVTT. 

Of the nine, six failed because they were not catheter-independent by day 3; three more failed after they had initially achieved catheter independence but then required the device in order to void within 7 days, Dr. Rochester reported. Four of these patients had further recurrences within 3 months of the procedure. 

The response measured by symptoms and objective studies of such variables as peak flow (Qmax) also favored PUL over WVTT in the early postperative period, according to the analysis. By 14 days, for example, IPSS scores were superior at 14 days and 1 month, although they no longer differed statistically at the 3-month mark. Qmax was significantly greater in the PUL group at 14 days but not at 1 or 3 months, according to Dr. Rochester. 
 

QOL Advantage at 1 Month Lost at 3 Months

From baseline, more patients in the PUL than WVTT group had a meaningful improvement in quality of life (QoL) at 14 days (39.5% vs 5.6%) and 1 month (47.8% vs 19.2%), Dr. Rochester said. Again, however, the between-group differences had lost significance by 3 months.

Patients who were satisfied or very satisfied at 1 month (48% vs 25%) also favored PUL, and about the same proportion (55%) were satisfied at 3 months, Dr. Rochester said.

Adverse events attributed to these procedures were slightly higher in the PUL group (21%) than the WVTT group (17%), but none was serious. At longest follow-up to date, which is 1 year in some patients, one man in each group required an invasive retreatment.

Patients or clinicians might prefer one technique over the other in an individual case, but the goal of CLEAR RCT was to provide objective evidence when educating patients about treatment options.

“Patients typically want to know which one is preferred, and we needed data to back up this conversation,” Dr. Rochester said. 
 

Measuring the Right Endpoint?

While longer follow-up might reveal differences in the durability of symptom relief, outcomes other than the primary endpoint of CLEAR RCT should be considered when selecting between these modalities, according to Dean Elterman, MD, MSc, an associate professor in urology at the University of Toronto in Canada. He suggested that catheter-free rates on days 3-7 is “a unique primary endpoint.” 

“Patients choose different therapies for different personal reasons. For some, having a catheter for less time is an important short-term goal, while for others the long-term benefit may carry more weight,” said Dr. Elterman, who led a study in 2021 that pooled data from two sham-controlled trials to consider differences between PUL and WVTT at 3 years. In that study, WVTT was associated with fewer surgical retreatments (4.4% vs 10.7%) and better symptom relief at long-term follow-up.

Given the differences in the mechanisms of PUL and WVTT, he said it is probably inappropriate to consider just one endpoint, such as early catheter independence, in considering the differences between the two MISTs. 

“This study does show PUL patients have less interference with participation in daily activities within the first month, but the clinical improvement and quality of life are the same in each group at 3 months,” he noted.

“If short-term benefits are weighed as more important to a patient, then this study may be informative,” he said. But he thinks many patients will be at least as interested in long-term follow-up to see if early benefits are durable.

Dr. Rochester reported financial relationships with Intuitive Surgical and Teleflex, which manufactures UroLift and was the sponsor of the CLEAR RCT trial. Dr. Elterman reported financial relationships with BioRobotics and Olympus.

A version of this article appeared on Medscape.com.

A head-to-head trial of minimally invasive procedures to manage benign prostatic hyperplasia found that urethral implants appear to provide more durable control of symptoms than thermal therapy. 

The ongoing CLEAR RCT study includes 68 men in the United States and the United Kingdom who have undergone one of two minimally invasive surgical techniques (MISTs). It found a procedure in which prostate tissue is lifted away from the urethra to improve urinary flow provided faster relief of symptoms, lower rates of catheterization, and higher patient satisfaction at 1 month than did an alternative approach that relies on thermal energy for tissue ablation, according to Mark Rochester, MD, a consultant urologist at the Norfolk and Norwich University Hospitals in England. 

“These results give clinicians and patients some data with which to choose between devices,” said Dr. Rochester, who presented the data at the 2024 annual meeting of the European Association of Urology.
 

CLEAR RCT Called First MIST Controlled Trial

Dr. Rochester called CLEAR RCT “the first head-to-head randomized controlled trial to compare two contemporary MISTs”: UroLift (Teleflex), known generically as a prostatic urethral lift (PUL), and Rezum (Boston Scientific), known as water vapor thermal therapy (WVTT). 

In the PUL technique, a delivery device is introduced into the urethra and advanced to the site of hyperplasia where implants are placed to lift and hold the tissue away on each side of the urethra. The implants are designed for long-term relief of the obstruction that inhibits urinary flow.

In the WVTT technique, thermal energy in the form of water vapor is introduced into the enlarged prostate tissue where it disperses through the interstices to produce denaturization of the tissue and cell death. Over time, the ablated tissue, which is eventually reabsorbed in the healing process, relieves pressure on the urethra to improve passage of urine. 

Both procedures can be performed on an outpatient basis without general anesthesia. Each typically permits discontinuation of medications commonly prescribed for lower urinary tract symptoms, and both are associated with a low risk of erectile dysfunction. Most routine activities can be resumed within a few days.

Baseline characteristics of the 35 patients randomized to PUL and 33 patients randomized to WVTT were similar in regard to body mass index, prostate volume, baseline International Prostate Symptom Score (IPSS), post-void volume test, and maximum urinary flow. 

Although this is a preliminary 3-month analysis of a study not yet completed, the primary endpoint was catheter independence on postop day 3 through 7. No patients randomized to PUL failed the primary endpoint versus nine (26%) of the patients randomized to WVTT. 

Of the nine, six failed because they were not catheter-independent by day 3; three more failed after they had initially achieved catheter independence but then required the device in order to void within 7 days, Dr. Rochester reported. Four of these patients had further recurrences within 3 months of the procedure. 

The response measured by symptoms and objective studies of such variables as peak flow (Qmax) also favored PUL over WVTT in the early postperative period, according to the analysis. By 14 days, for example, IPSS scores were superior at 14 days and 1 month, although they no longer differed statistically at the 3-month mark. Qmax was significantly greater in the PUL group at 14 days but not at 1 or 3 months, according to Dr. Rochester. 
 

QOL Advantage at 1 Month Lost at 3 Months

From baseline, more patients in the PUL than WVTT group had a meaningful improvement in quality of life (QoL) at 14 days (39.5% vs 5.6%) and 1 month (47.8% vs 19.2%), Dr. Rochester said. Again, however, the between-group differences had lost significance by 3 months.

Patients who were satisfied or very satisfied at 1 month (48% vs 25%) also favored PUL, and about the same proportion (55%) were satisfied at 3 months, Dr. Rochester said.

Adverse events attributed to these procedures were slightly higher in the PUL group (21%) than the WVTT group (17%), but none was serious. At longest follow-up to date, which is 1 year in some patients, one man in each group required an invasive retreatment.

Patients or clinicians might prefer one technique over the other in an individual case, but the goal of CLEAR RCT was to provide objective evidence when educating patients about treatment options.

“Patients typically want to know which one is preferred, and we needed data to back up this conversation,” Dr. Rochester said. 
 

Measuring the Right Endpoint?

While longer follow-up might reveal differences in the durability of symptom relief, outcomes other than the primary endpoint of CLEAR RCT should be considered when selecting between these modalities, according to Dean Elterman, MD, MSc, an associate professor in urology at the University of Toronto in Canada. He suggested that catheter-free rates on days 3-7 is “a unique primary endpoint.” 

“Patients choose different therapies for different personal reasons. For some, having a catheter for less time is an important short-term goal, while for others the long-term benefit may carry more weight,” said Dr. Elterman, who led a study in 2021 that pooled data from two sham-controlled trials to consider differences between PUL and WVTT at 3 years. In that study, WVTT was associated with fewer surgical retreatments (4.4% vs 10.7%) and better symptom relief at long-term follow-up.

Given the differences in the mechanisms of PUL and WVTT, he said it is probably inappropriate to consider just one endpoint, such as early catheter independence, in considering the differences between the two MISTs. 

“This study does show PUL patients have less interference with participation in daily activities within the first month, but the clinical improvement and quality of life are the same in each group at 3 months,” he noted.

“If short-term benefits are weighed as more important to a patient, then this study may be informative,” he said. But he thinks many patients will be at least as interested in long-term follow-up to see if early benefits are durable.

Dr. Rochester reported financial relationships with Intuitive Surgical and Teleflex, which manufactures UroLift and was the sponsor of the CLEAR RCT trial. Dr. Elterman reported financial relationships with BioRobotics and Olympus.

A version of this article appeared on Medscape.com.

Men with low-risk prostate cancer who go on active surveillance rather than treatment are best followed-up for more than 15 years — and perhaps indefinitely — according one of the longest studies to date to look at the issue. 

Previous studies have shown that active surveillance continued for 15 years is appropriate to identify men who progress and need treatment, but now data out to 25 years “suggest that meticulous follow-up is needed over a longer time if the chance for cure is not to be missed,” said Emmeli Palmstedt, PhD, a research student in the Department of Urology at the Sahlgrenska Academy at the University of Gothenburg, Sweden. “These data are crucial, given the long current life expectancy” of men in otherwise good health. 

Dr. Palmstedt presented the findings at the 2024 annual meeting of the European Association of Urology.

At many centers, active surveillance is a standard of care for men with low-risk prostate cancer based on a benefit-to-risk ratio that favors delayed intervention, according to Palmstedt. Several studies, including the Göteburg-1 active surveillance trial initiated at her institution, have supported follow-up for 15 years. A new set of data from Göteborg now extends to 25 years.
 

Long-Life Expectancy Justifies Extended Surveillance

The prospective Göteborg study began enrolling men with very low- or low-risk (78%) or intermediate-risk (22%) prostate cancer in 1995. In the active surveillance program, prostate-specific antigen (PSA) was measured routinely with biopsies ordered for PSA levels ≥ 2.5 ng/mL. 

In an analysis published in 2016 when 202 (43%) of 474 patients managed with active surveillance had discontinued surveillance to start treatment, the median follow-up period was 8 years. The rate of mortality associated with prostate cancer at 15 years was estimated to be 0% for men in the very low-risk group, 4% for men in the low-risk group, and 10% for those with intermediate-risk tumors. The estimates for failure-free survival at 15 years were 88%, 77%, and 40% for the very low-, low-, and intermediate-risk groups, respectively.

In the most recent follow-up, when the median age in the Göteburg-1 study was 80 years (the median age at diagnosis was 66 years), the median follow-up period was 15.1 years with a range of up to 28.1 years. In this analysis, which focused on patients with low-risk prostate cancer at baseline, discontinuations from active surveillance had climbed to 47%. Most of these men discontinued to initiate treatment, but 79 (16%) had failed acute surveillance, meaning their progression was not caught in time for curative-intent treatment, and 2% had died from prostate cancer.
 

Treatment-Free Survival Falls to 31% 

The rate of treatment-free survival, which was estimated to be 65% in the 15-year analysis published in 2016, had declined to 31%. The rate of failure-free survival was 59%, and prostate cancer-specific survival was 92%, according to the researchers. 

While Dr. Palmstedt did not separate out her data for very low- and low-risk patients, she noted that deaths from prostate cancer among all low-risk patients climbed fourfold (8% vs 2%) since the 2016 figures were published. The proportion of men no longer failure-free climbed from 10% to more than 40%. 

“These are non-negligible numbers,” said Dr. Palmstedt, who added that overall survival fell from 69% at 15 years to 37% at 25 years.

Although some men between the 15-year and 25-year timepoints were switched to watchful waiting, these data have not yet been analyzed.

The low rate of deaths from prostate cancer over the extended period is reassuring, Dr. Palmstedt said, but the main message from the new study is that active surveillance permits curative-intent treatment to be offered even after late follow-up. She emphasized that patients without progression by 15 years cannot be considered “safe.”

Based on these data, “men with a long remaining life expectancy should be informed that active surveillance is still viable after 15 years,” Dr. Palmstedt said.
 

Active Surveillance Now More Common

Over the past decade, the proportion of men with prostate cancer managed with active surveillance has been rising steadily, according to Matthew R. Cooperberg, MD, MPH, professor of urology at the University of California, San Francisco. In a study published last year in JAMA Network Open, Dr. Cooperberg and his colleagues reported that rates of active surveillance rose from 26.5% in 2014 to 59.6% in 2021. However, given the value of the approach for avoiding overtreatment of men with low-risk prostate cancers, even that increase is not enough, he said.

“The window of opportunity for cure is typically very wide,” Dr. Cooperberg said. Although many men “will never need treatment ... long-term surveillance is definitely important” for those that do, he said. The data from trials like Göteborg-1 support the principle that this strategy still preserves the option of treatment when it is needed. 

“Treatment for cure at age 70 is generally far preferable to treatment at 55, and surveillance should absolutely be preferred treatment for the vast majority of men with low-grade disease at diagnosis,” he explained.

Dr. Palmstedt reported no potential conflicts of interest. Dr. Cooperberg reported financial relationships with Astellas, AstraZeneca, Bayer, Dendreon, Exact Sciences, Janssen, Merck, Pfizer, and Verana Health. 
 

A version of this article appeared on Medscape.com.

Men with low-risk prostate cancer who go on active surveillance rather than treatment are best followed-up for more than 15 years — and perhaps indefinitely — according one of the longest studies to date to look at the issue. 

Previous studies have shown that active surveillance continued for 15 years is appropriate to identify men who progress and need treatment, but now data out to 25 years “suggest that meticulous follow-up is needed over a longer time if the chance for cure is not to be missed,” said Emmeli Palmstedt, PhD, a research student in the Department of Urology at the Sahlgrenska Academy at the University of Gothenburg, Sweden. “These data are crucial, given the long current life expectancy” of men in otherwise good health. 

Dr. Palmstedt presented the findings at the 2024 annual meeting of the European Association of Urology.

At many centers, active surveillance is a standard of care for men with low-risk prostate cancer based on a benefit-to-risk ratio that favors delayed intervention, according to Palmstedt. Several studies, including the Göteburg-1 active surveillance trial initiated at her institution, have supported follow-up for 15 years. A new set of data from Göteborg now extends to 25 years.
 

Long-Life Expectancy Justifies Extended Surveillance

The prospective Göteborg study began enrolling men with very low- or low-risk (78%) or intermediate-risk (22%) prostate cancer in 1995. In the active surveillance program, prostate-specific antigen (PSA) was measured routinely with biopsies ordered for PSA levels ≥ 2.5 ng/mL. 

In an analysis published in 2016 when 202 (43%) of 474 patients managed with active surveillance had discontinued surveillance to start treatment, the median follow-up period was 8 years. The rate of mortality associated with prostate cancer at 15 years was estimated to be 0% for men in the very low-risk group, 4% for men in the low-risk group, and 10% for those with intermediate-risk tumors. The estimates for failure-free survival at 15 years were 88%, 77%, and 40% for the very low-, low-, and intermediate-risk groups, respectively.

In the most recent follow-up, when the median age in the Göteburg-1 study was 80 years (the median age at diagnosis was 66 years), the median follow-up period was 15.1 years with a range of up to 28.1 years. In this analysis, which focused on patients with low-risk prostate cancer at baseline, discontinuations from active surveillance had climbed to 47%. Most of these men discontinued to initiate treatment, but 79 (16%) had failed acute surveillance, meaning their progression was not caught in time for curative-intent treatment, and 2% had died from prostate cancer.
 

Treatment-Free Survival Falls to 31% 

The rate of treatment-free survival, which was estimated to be 65% in the 15-year analysis published in 2016, had declined to 31%. The rate of failure-free survival was 59%, and prostate cancer-specific survival was 92%, according to the researchers. 

While Dr. Palmstedt did not separate out her data for very low- and low-risk patients, she noted that deaths from prostate cancer among all low-risk patients climbed fourfold (8% vs 2%) since the 2016 figures were published. The proportion of men no longer failure-free climbed from 10% to more than 40%. 

“These are non-negligible numbers,” said Dr. Palmstedt, who added that overall survival fell from 69% at 15 years to 37% at 25 years.

Although some men between the 15-year and 25-year timepoints were switched to watchful waiting, these data have not yet been analyzed.

The low rate of deaths from prostate cancer over the extended period is reassuring, Dr. Palmstedt said, but the main message from the new study is that active surveillance permits curative-intent treatment to be offered even after late follow-up. She emphasized that patients without progression by 15 years cannot be considered “safe.”

Based on these data, “men with a long remaining life expectancy should be informed that active surveillance is still viable after 15 years,” Dr. Palmstedt said.
 

Active Surveillance Now More Common

Over the past decade, the proportion of men with prostate cancer managed with active surveillance has been rising steadily, according to Matthew R. Cooperberg, MD, MPH, professor of urology at the University of California, San Francisco. In a study published last year in JAMA Network Open, Dr. Cooperberg and his colleagues reported that rates of active surveillance rose from 26.5% in 2014 to 59.6% in 2021. However, given the value of the approach for avoiding overtreatment of men with low-risk prostate cancers, even that increase is not enough, he said.

“The window of opportunity for cure is typically very wide,” Dr. Cooperberg said. Although many men “will never need treatment ... long-term surveillance is definitely important” for those that do, he said. The data from trials like Göteborg-1 support the principle that this strategy still preserves the option of treatment when it is needed. 

“Treatment for cure at age 70 is generally far preferable to treatment at 55, and surveillance should absolutely be preferred treatment for the vast majority of men with low-grade disease at diagnosis,” he explained.

Dr. Palmstedt reported no potential conflicts of interest. Dr. Cooperberg reported financial relationships with Astellas, AstraZeneca, Bayer, Dendreon, Exact Sciences, Janssen, Merck, Pfizer, and Verana Health. 
 

A version of this article appeared on Medscape.com.

Men with low-risk prostate cancer who go on active surveillance rather than treatment are best followed-up for more than 15 years — and perhaps indefinitely — according one of the longest studies to date to look at the issue. 

Previous studies have shown that active surveillance continued for 15 years is appropriate to identify men who progress and need treatment, but now data out to 25 years “suggest that meticulous follow-up is needed over a longer time if the chance for cure is not to be missed,” said Emmeli Palmstedt, PhD, a research student in the Department of Urology at the Sahlgrenska Academy at the University of Gothenburg, Sweden. “These data are crucial, given the long current life expectancy” of men in otherwise good health. 

Dr. Palmstedt presented the findings at the 2024 annual meeting of the European Association of Urology.

At many centers, active surveillance is a standard of care for men with low-risk prostate cancer based on a benefit-to-risk ratio that favors delayed intervention, according to Palmstedt. Several studies, including the Göteburg-1 active surveillance trial initiated at her institution, have supported follow-up for 15 years. A new set of data from Göteborg now extends to 25 years.
 

Long-Life Expectancy Justifies Extended Surveillance

The prospective Göteborg study began enrolling men with very low- or low-risk (78%) or intermediate-risk (22%) prostate cancer in 1995. In the active surveillance program, prostate-specific antigen (PSA) was measured routinely with biopsies ordered for PSA levels ≥ 2.5 ng/mL. 

In an analysis published in 2016 when 202 (43%) of 474 patients managed with active surveillance had discontinued surveillance to start treatment, the median follow-up period was 8 years. The rate of mortality associated with prostate cancer at 15 years was estimated to be 0% for men in the very low-risk group, 4% for men in the low-risk group, and 10% for those with intermediate-risk tumors. The estimates for failure-free survival at 15 years were 88%, 77%, and 40% for the very low-, low-, and intermediate-risk groups, respectively.

In the most recent follow-up, when the median age in the Göteburg-1 study was 80 years (the median age at diagnosis was 66 years), the median follow-up period was 15.1 years with a range of up to 28.1 years. In this analysis, which focused on patients with low-risk prostate cancer at baseline, discontinuations from active surveillance had climbed to 47%. Most of these men discontinued to initiate treatment, but 79 (16%) had failed acute surveillance, meaning their progression was not caught in time for curative-intent treatment, and 2% had died from prostate cancer.
 

Treatment-Free Survival Falls to 31% 

The rate of treatment-free survival, which was estimated to be 65% in the 15-year analysis published in 2016, had declined to 31%. The rate of failure-free survival was 59%, and prostate cancer-specific survival was 92%, according to the researchers. 

While Dr. Palmstedt did not separate out her data for very low- and low-risk patients, she noted that deaths from prostate cancer among all low-risk patients climbed fourfold (8% vs 2%) since the 2016 figures were published. The proportion of men no longer failure-free climbed from 10% to more than 40%. 

“These are non-negligible numbers,” said Dr. Palmstedt, who added that overall survival fell from 69% at 15 years to 37% at 25 years.

Although some men between the 15-year and 25-year timepoints were switched to watchful waiting, these data have not yet been analyzed.

The low rate of deaths from prostate cancer over the extended period is reassuring, Dr. Palmstedt said, but the main message from the new study is that active surveillance permits curative-intent treatment to be offered even after late follow-up. She emphasized that patients without progression by 15 years cannot be considered “safe.”

Based on these data, “men with a long remaining life expectancy should be informed that active surveillance is still viable after 15 years,” Dr. Palmstedt said.
 

Active Surveillance Now More Common

Over the past decade, the proportion of men with prostate cancer managed with active surveillance has been rising steadily, according to Matthew R. Cooperberg, MD, MPH, professor of urology at the University of California, San Francisco. In a study published last year in JAMA Network Open, Dr. Cooperberg and his colleagues reported that rates of active surveillance rose from 26.5% in 2014 to 59.6% in 2021. However, given the value of the approach for avoiding overtreatment of men with low-risk prostate cancers, even that increase is not enough, he said.

“The window of opportunity for cure is typically very wide,” Dr. Cooperberg said. Although many men “will never need treatment ... long-term surveillance is definitely important” for those that do, he said. The data from trials like Göteborg-1 support the principle that this strategy still preserves the option of treatment when it is needed. 

“Treatment for cure at age 70 is generally far preferable to treatment at 55, and surveillance should absolutely be preferred treatment for the vast majority of men with low-grade disease at diagnosis,” he explained.

Dr. Palmstedt reported no potential conflicts of interest. Dr. Cooperberg reported financial relationships with Astellas, AstraZeneca, Bayer, Dendreon, Exact Sciences, Janssen, Merck, Pfizer, and Verana Health. 
 

A version of this article appeared on Medscape.com.

DENVER — Upon entry into the open-label extension (OLE) of the pivotal trial that led to approval of lecanemab for Alzheimer’s disease, placebo patients failed to show any appreciable catch up to the benefit achieved in the experimental arm, according to a first report of 6-month OLE data.

Due to the steady disease progression observed after the switch of placebo to active therapy, the message of these data is that “early initiation of lecanemab is important,” according to Michael Irizarry, MD, the senior vice president of clinical research at Eisai Ltd, which markets lecanemab.

The 6-month OLE data along with data from a tau PET substudy were presented by Dr. Irizarry at the 2024 annual meeting of the American Academy of Neurology.

From the start of the OLE through the 6-month follow-up, the downward trajectory of cognitive function, as measured with the Clinical Dementia Rating – Sum of Boxes (CDR-SB), has been parallel for the lecanemab-start and switch arms. As a result, the degree of separation between active and placebo groups over the course of the OLE has remained unchanged from the end of the randomized trial.

This does not rule out any benefit in the switch arm, according to Dr. Irizarry. Although there was no discernible change in the trajectory of decline among placebo patients after they were switched to lecanemab, Dr. Irizarry postulated that this might overlook the greater likely decline over time with no treatment.

“There was no placebo group in the OLE to compare with those on active treatment,” he pointed out. He then juxtaposed data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Over the same 6-month timeframe, these data show a hypothetical separation of the curves if no treatment had been received.

The 6-month OLE data provide a preliminary look at outcomes in a planned 4-year follow-up. At the end of the randomized CLARITY trial, the mean decline from the baseline CDR-SB score of 3.2, was 1.21 in the lecanemab group, translating into a 38% decline, and 1.66 in the placebo group, translating into about a 50% decline. Over the 6 months of OLE, there has been a further mean CDR-SB reduction of approximately 0.6 in both arms, suggesting a further 18% decline from baseline.
 

Additional Data

In the pivotal CLARITY trial, which was published a few months prior to regulatory approval early last year, 1785 patients were randomized to 10 mg/kg lecanemab or placebo infused every 2 weeks. At the end of 18 months, the superiority of lecanemab for the primary endpoint of adverse change in CDR-SB was highly significant (P < .001) as were the differences in key secondary endpoints, such as Alzheimer’s Disease Composite Score (P < .001).

Of those who participated in CLARITY, 1385 patients entered the OLE. Placebo patients were switched to lecanemab which is being maintained in all patients on the trial schedule of 10 mg/kg administered by intravenous infusion every 2 weeks.

In addition to the overall OLE 6-month data, which has not raised any new safety signals, Dr. Irizarry provided a new look at the PET TAU substudy with a focus on patients who entered the study with a low relative tau burden. Of the three classifications, which also included medium and high tau, as measured with positron-emission tomography (PET), the low tau group represented 41.2% of the 342 tau PET substudy participants. With only 2.9% entering the study with a high tau burden, almost all the others fell in the medium stratification.

Due to the potential for a lower therapeutic response, “patients with low Tau are often excluded from trials,” Dr. Irizarry said. But the sizable proportion of low tau patients has permitted an assessment of relative response with lecanemab, which turned out to be substantial.

“Consistent rates of clinical stability or improvements were observed regardless of baseline tau levels with the highest rates of improvements observed for the low tau group after 24 months of follow-up,” Dr. Irizarry reported.

In previously reported results from the tau PET substudy, lecanemab was shown to slow tau spread at least numerically in every section of the brain evaluated, including the frontal, cingulate, parietal, and whole cortical gray matter areas. The reductions reached significance for the medial temporal (P = .0024), meta temporal (P = .012), and temporal (P = .16) portions.

When most recently evaluated in the OLE, the CDR-SB score declined 38% less among those treated with lecanemab than those treated with placebo in the subgroup enrolled in the tau PET substudy.

Relative to those with intermediate or high tau, patients in the low tau had an even greater reduction in cognitive decline than those with higher tau burdens. Although Dr. Irizarry cautioned that greater baseline CDR-SB scores exaggerated the treatment effect in the low tau group, the message is that “a lecanemab treatment effect is seen even when baseline tau levels are low.”

Now, with the recent market withdrawal of aducanumab, another anti-amyloid monoclonal antibody that was previously approved for Alzheimer’s disease, lecanemab is the only therapy currently available for the goal of changing disease progression, not just modifying symptoms.
 

Looking Long Term

Both sets of data provide important messages for clinicians, according to Marcelo Matiello, MD, a physician investigator at Mass General Hospital and associate professor of neurology at Harvard Medical School, Boston.

“Clinicians are really looking for more data because this remains a relatively new drug,” he said. Both sets of findings presented by Dr. Irizarry “look good but the follow-up is still short, so I think everyone is still looking closely at long-term safety and efficacy.”

The need for continuous indefinite therapy is one concern that Dr. Matiello expressed. As moderator of the session in which these data were presented, Dr. Matiello specifically asked Dr. Irizarry if there are plans to explore whether periods without treatment might be a means to reduce the cost and burden of frequent infusions while preserving cognitive gains.

In response, Dr. Irizarry said that earlier studies showed rapid progression when lecanemab was stopped. On this basis, he thinks therapy must be maintained, but he did say that there are plans to look at less frequent dosing, such as once per month. He also said that a subcutaneous formulation in development might also reduce the burden of prolonged treatment.

Dr. Irizarry is an employee of Eisai Ltd., which manufacturers lecanemab. Dr. Matiello reports no potential conflicts of interest.

DENVER — Upon entry into the open-label extension (OLE) of the pivotal trial that led to approval of lecanemab for Alzheimer’s disease, placebo patients failed to show any appreciable catch up to the benefit achieved in the experimental arm, according to a first report of 6-month OLE data.

Due to the steady disease progression observed after the switch of placebo to active therapy, the message of these data is that “early initiation of lecanemab is important,” according to Michael Irizarry, MD, the senior vice president of clinical research at Eisai Ltd, which markets lecanemab.

The 6-month OLE data along with data from a tau PET substudy were presented by Dr. Irizarry at the 2024 annual meeting of the American Academy of Neurology.

From the start of the OLE through the 6-month follow-up, the downward trajectory of cognitive function, as measured with the Clinical Dementia Rating – Sum of Boxes (CDR-SB), has been parallel for the lecanemab-start and switch arms. As a result, the degree of separation between active and placebo groups over the course of the OLE has remained unchanged from the end of the randomized trial.

This does not rule out any benefit in the switch arm, according to Dr. Irizarry. Although there was no discernible change in the trajectory of decline among placebo patients after they were switched to lecanemab, Dr. Irizarry postulated that this might overlook the greater likely decline over time with no treatment.

“There was no placebo group in the OLE to compare with those on active treatment,” he pointed out. He then juxtaposed data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Over the same 6-month timeframe, these data show a hypothetical separation of the curves if no treatment had been received.

The 6-month OLE data provide a preliminary look at outcomes in a planned 4-year follow-up. At the end of the randomized CLARITY trial, the mean decline from the baseline CDR-SB score of 3.2, was 1.21 in the lecanemab group, translating into a 38% decline, and 1.66 in the placebo group, translating into about a 50% decline. Over the 6 months of OLE, there has been a further mean CDR-SB reduction of approximately 0.6 in both arms, suggesting a further 18% decline from baseline.
 

Additional Data

In the pivotal CLARITY trial, which was published a few months prior to regulatory approval early last year, 1785 patients were randomized to 10 mg/kg lecanemab or placebo infused every 2 weeks. At the end of 18 months, the superiority of lecanemab for the primary endpoint of adverse change in CDR-SB was highly significant (P < .001) as were the differences in key secondary endpoints, such as Alzheimer’s Disease Composite Score (P < .001).

Of those who participated in CLARITY, 1385 patients entered the OLE. Placebo patients were switched to lecanemab which is being maintained in all patients on the trial schedule of 10 mg/kg administered by intravenous infusion every 2 weeks.

In addition to the overall OLE 6-month data, which has not raised any new safety signals, Dr. Irizarry provided a new look at the PET TAU substudy with a focus on patients who entered the study with a low relative tau burden. Of the three classifications, which also included medium and high tau, as measured with positron-emission tomography (PET), the low tau group represented 41.2% of the 342 tau PET substudy participants. With only 2.9% entering the study with a high tau burden, almost all the others fell in the medium stratification.

Due to the potential for a lower therapeutic response, “patients with low Tau are often excluded from trials,” Dr. Irizarry said. But the sizable proportion of low tau patients has permitted an assessment of relative response with lecanemab, which turned out to be substantial.

“Consistent rates of clinical stability or improvements were observed regardless of baseline tau levels with the highest rates of improvements observed for the low tau group after 24 months of follow-up,” Dr. Irizarry reported.

In previously reported results from the tau PET substudy, lecanemab was shown to slow tau spread at least numerically in every section of the brain evaluated, including the frontal, cingulate, parietal, and whole cortical gray matter areas. The reductions reached significance for the medial temporal (P = .0024), meta temporal (P = .012), and temporal (P = .16) portions.

When most recently evaluated in the OLE, the CDR-SB score declined 38% less among those treated with lecanemab than those treated with placebo in the subgroup enrolled in the tau PET substudy.

Relative to those with intermediate or high tau, patients in the low tau had an even greater reduction in cognitive decline than those with higher tau burdens. Although Dr. Irizarry cautioned that greater baseline CDR-SB scores exaggerated the treatment effect in the low tau group, the message is that “a lecanemab treatment effect is seen even when baseline tau levels are low.”

Now, with the recent market withdrawal of aducanumab, another anti-amyloid monoclonal antibody that was previously approved for Alzheimer’s disease, lecanemab is the only therapy currently available for the goal of changing disease progression, not just modifying symptoms.
 

Looking Long Term

Both sets of data provide important messages for clinicians, according to Marcelo Matiello, MD, a physician investigator at Mass General Hospital and associate professor of neurology at Harvard Medical School, Boston.

“Clinicians are really looking for more data because this remains a relatively new drug,” he said. Both sets of findings presented by Dr. Irizarry “look good but the follow-up is still short, so I think everyone is still looking closely at long-term safety and efficacy.”

The need for continuous indefinite therapy is one concern that Dr. Matiello expressed. As moderator of the session in which these data were presented, Dr. Matiello specifically asked Dr. Irizarry if there are plans to explore whether periods without treatment might be a means to reduce the cost and burden of frequent infusions while preserving cognitive gains.

In response, Dr. Irizarry said that earlier studies showed rapid progression when lecanemab was stopped. On this basis, he thinks therapy must be maintained, but he did say that there are plans to look at less frequent dosing, such as once per month. He also said that a subcutaneous formulation in development might also reduce the burden of prolonged treatment.

Dr. Irizarry is an employee of Eisai Ltd., which manufacturers lecanemab. Dr. Matiello reports no potential conflicts of interest.

DENVER — Upon entry into the open-label extension (OLE) of the pivotal trial that led to approval of lecanemab for Alzheimer’s disease, placebo patients failed to show any appreciable catch up to the benefit achieved in the experimental arm, according to a first report of 6-month OLE data.

Due to the steady disease progression observed after the switch of placebo to active therapy, the message of these data is that “early initiation of lecanemab is important,” according to Michael Irizarry, MD, the senior vice president of clinical research at Eisai Ltd, which markets lecanemab.

The 6-month OLE data along with data from a tau PET substudy were presented by Dr. Irizarry at the 2024 annual meeting of the American Academy of Neurology.

From the start of the OLE through the 6-month follow-up, the downward trajectory of cognitive function, as measured with the Clinical Dementia Rating – Sum of Boxes (CDR-SB), has been parallel for the lecanemab-start and switch arms. As a result, the degree of separation between active and placebo groups over the course of the OLE has remained unchanged from the end of the randomized trial.

This does not rule out any benefit in the switch arm, according to Dr. Irizarry. Although there was no discernible change in the trajectory of decline among placebo patients after they were switched to lecanemab, Dr. Irizarry postulated that this might overlook the greater likely decline over time with no treatment.

“There was no placebo group in the OLE to compare with those on active treatment,” he pointed out. He then juxtaposed data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Over the same 6-month timeframe, these data show a hypothetical separation of the curves if no treatment had been received.

The 6-month OLE data provide a preliminary look at outcomes in a planned 4-year follow-up. At the end of the randomized CLARITY trial, the mean decline from the baseline CDR-SB score of 3.2, was 1.21 in the lecanemab group, translating into a 38% decline, and 1.66 in the placebo group, translating into about a 50% decline. Over the 6 months of OLE, there has been a further mean CDR-SB reduction of approximately 0.6 in both arms, suggesting a further 18% decline from baseline.
 

Additional Data

In the pivotal CLARITY trial, which was published a few months prior to regulatory approval early last year, 1785 patients were randomized to 10 mg/kg lecanemab or placebo infused every 2 weeks. At the end of 18 months, the superiority of lecanemab for the primary endpoint of adverse change in CDR-SB was highly significant (P < .001) as were the differences in key secondary endpoints, such as Alzheimer’s Disease Composite Score (P < .001).

Of those who participated in CLARITY, 1385 patients entered the OLE. Placebo patients were switched to lecanemab which is being maintained in all patients on the trial schedule of 10 mg/kg administered by intravenous infusion every 2 weeks.

In addition to the overall OLE 6-month data, which has not raised any new safety signals, Dr. Irizarry provided a new look at the PET TAU substudy with a focus on patients who entered the study with a low relative tau burden. Of the three classifications, which also included medium and high tau, as measured with positron-emission tomography (PET), the low tau group represented 41.2% of the 342 tau PET substudy participants. With only 2.9% entering the study with a high tau burden, almost all the others fell in the medium stratification.

Due to the potential for a lower therapeutic response, “patients with low Tau are often excluded from trials,” Dr. Irizarry said. But the sizable proportion of low tau patients has permitted an assessment of relative response with lecanemab, which turned out to be substantial.

“Consistent rates of clinical stability or improvements were observed regardless of baseline tau levels with the highest rates of improvements observed for the low tau group after 24 months of follow-up,” Dr. Irizarry reported.

In previously reported results from the tau PET substudy, lecanemab was shown to slow tau spread at least numerically in every section of the brain evaluated, including the frontal, cingulate, parietal, and whole cortical gray matter areas. The reductions reached significance for the medial temporal (P = .0024), meta temporal (P = .012), and temporal (P = .16) portions.

When most recently evaluated in the OLE, the CDR-SB score declined 38% less among those treated with lecanemab than those treated with placebo in the subgroup enrolled in the tau PET substudy.

Relative to those with intermediate or high tau, patients in the low tau had an even greater reduction in cognitive decline than those with higher tau burdens. Although Dr. Irizarry cautioned that greater baseline CDR-SB scores exaggerated the treatment effect in the low tau group, the message is that “a lecanemab treatment effect is seen even when baseline tau levels are low.”

Now, with the recent market withdrawal of aducanumab, another anti-amyloid monoclonal antibody that was previously approved for Alzheimer’s disease, lecanemab is the only therapy currently available for the goal of changing disease progression, not just modifying symptoms.
 

Looking Long Term

Both sets of data provide important messages for clinicians, according to Marcelo Matiello, MD, a physician investigator at Mass General Hospital and associate professor of neurology at Harvard Medical School, Boston.

“Clinicians are really looking for more data because this remains a relatively new drug,” he said. Both sets of findings presented by Dr. Irizarry “look good but the follow-up is still short, so I think everyone is still looking closely at long-term safety and efficacy.”

The need for continuous indefinite therapy is one concern that Dr. Matiello expressed. As moderator of the session in which these data were presented, Dr. Matiello specifically asked Dr. Irizarry if there are plans to explore whether periods without treatment might be a means to reduce the cost and burden of frequent infusions while preserving cognitive gains.

In response, Dr. Irizarry said that earlier studies showed rapid progression when lecanemab was stopped. On this basis, he thinks therapy must be maintained, but he did say that there are plans to look at less frequent dosing, such as once per month. He also said that a subcutaneous formulation in development might also reduce the burden of prolonged treatment.

Dr. Irizarry is an employee of Eisai Ltd., which manufacturers lecanemab. Dr. Matiello reports no potential conflicts of interest.

DENVER — After working for decades in a field littered with promising but failed clinical trials, a prominent researcher in amyotrophic lateral sclerosis (ALS) has decided to turn her attention to prevention, a direction of research that she thinks has more promise.

According to the gene-time hypothesis, duration of exposure to noxious chemicals and genetic susceptibility are key drivers of ALS risk, explained Eva Feldman, MD, PhD, director of the ALS Center of Excellence at the University of Michigan, Ann Arbor. She believes that existing research in risk modification is already promising.

“I think ALS prevention is real and attainable,” she said as this year’s recipient of the Sheila Essey Award for significant contributions in ALS research.

In describing her “pivot” to prevention from treatment at the 2024 annual meeting of the American Academy of Neurology, Dr. Feldman described her growing pessimism about treating a disease that has so consistently resisted even stabilization, let alone cure.

“I spent 10 years trying to repurpose IGF-1 as an ALS therapy. We took it from preclinical work all the way to a phase 3 multicenter trial, but in the end no effect was seen,” Dr. Feldman said,

This was followed by another 10 years spent on the promise of stem cells. In this case, she was eventually involved in two multicenter trials. In fact, trials are still ongoing in Europe, but Dr. Feldman said this strategy is “no longer going forward in the United States,” and she no longer anticipates favorable results.
 

The New Focus on Prevention

The basic concept in the prevention studies she is now working on with Stephen Goutman, MD, a frequent coauthor, and other colleagues at her center, is that the duration of exposure to persistent organic pollutants (POPs), along with some degree of genetic predisposition, determines risk for ALS. The simple idea is the reducing exposure will reduce ALS risk.

There is already substantial support for the underlying time-gene hypothesis, according to Dr. Feldman. Among several examples, she described work with 122 POPS that appear individually and in many cases collectively to correlate with ALS risk. Recent work with an environmental risk score (ERS) that permits studies of risk when accounting for exposure to families of pollutants, has supported these as potentially modifiable risks.

A high ERS “correlates with an ALS risk that is 3 to 4 times higher than a low score,” she said. In addition, those ALS patients with a high relative to a low ERS have a significant 0.6-year reduction in median survival.

Some specific POPs, such as pesticides, correlate with increased risk by themselves, but Dr. Feldman has begun focusing on occupational exposures, particularly in industries that are most likely to increase exposure POPs. Several of the POPs most implicated in ALS, such as polychlorinated biphenyls used in coolants and lubricants, organochlorine pesticides, and polybrominated diphenyl esters, are already banned or mostly banned in the United States, but they persist in the environment and remain legal elsewhere.

Dr. Feldman reported no potential conflicts of interest.

DENVER — After working for decades in a field littered with promising but failed clinical trials, a prominent researcher in amyotrophic lateral sclerosis (ALS) has decided to turn her attention to prevention, a direction of research that she thinks has more promise.

According to the gene-time hypothesis, duration of exposure to noxious chemicals and genetic susceptibility are key drivers of ALS risk, explained Eva Feldman, MD, PhD, director of the ALS Center of Excellence at the University of Michigan, Ann Arbor. She believes that existing research in risk modification is already promising.

“I think ALS prevention is real and attainable,” she said as this year’s recipient of the Sheila Essey Award for significant contributions in ALS research.

In describing her “pivot” to prevention from treatment at the 2024 annual meeting of the American Academy of Neurology, Dr. Feldman described her growing pessimism about treating a disease that has so consistently resisted even stabilization, let alone cure.

“I spent 10 years trying to repurpose IGF-1 as an ALS therapy. We took it from preclinical work all the way to a phase 3 multicenter trial, but in the end no effect was seen,” Dr. Feldman said,

This was followed by another 10 years spent on the promise of stem cells. In this case, she was eventually involved in two multicenter trials. In fact, trials are still ongoing in Europe, but Dr. Feldman said this strategy is “no longer going forward in the United States,” and she no longer anticipates favorable results.
 

The New Focus on Prevention

The basic concept in the prevention studies she is now working on with Stephen Goutman, MD, a frequent coauthor, and other colleagues at her center, is that the duration of exposure to persistent organic pollutants (POPs), along with some degree of genetic predisposition, determines risk for ALS. The simple idea is the reducing exposure will reduce ALS risk.

There is already substantial support for the underlying time-gene hypothesis, according to Dr. Feldman. Among several examples, she described work with 122 POPS that appear individually and in many cases collectively to correlate with ALS risk. Recent work with an environmental risk score (ERS) that permits studies of risk when accounting for exposure to families of pollutants, has supported these as potentially modifiable risks.

A high ERS “correlates with an ALS risk that is 3 to 4 times higher than a low score,” she said. In addition, those ALS patients with a high relative to a low ERS have a significant 0.6-year reduction in median survival.

Some specific POPs, such as pesticides, correlate with increased risk by themselves, but Dr. Feldman has begun focusing on occupational exposures, particularly in industries that are most likely to increase exposure POPs. Several of the POPs most implicated in ALS, such as polychlorinated biphenyls used in coolants and lubricants, organochlorine pesticides, and polybrominated diphenyl esters, are already banned or mostly banned in the United States, but they persist in the environment and remain legal elsewhere.

Dr. Feldman reported no potential conflicts of interest.

DENVER — After working for decades in a field littered with promising but failed clinical trials, a prominent researcher in amyotrophic lateral sclerosis (ALS) has decided to turn her attention to prevention, a direction of research that she thinks has more promise.

According to the gene-time hypothesis, duration of exposure to noxious chemicals and genetic susceptibility are key drivers of ALS risk, explained Eva Feldman, MD, PhD, director of the ALS Center of Excellence at the University of Michigan, Ann Arbor. She believes that existing research in risk modification is already promising.

“I think ALS prevention is real and attainable,” she said as this year’s recipient of the Sheila Essey Award for significant contributions in ALS research.

In describing her “pivot” to prevention from treatment at the 2024 annual meeting of the American Academy of Neurology, Dr. Feldman described her growing pessimism about treating a disease that has so consistently resisted even stabilization, let alone cure.

“I spent 10 years trying to repurpose IGF-1 as an ALS therapy. We took it from preclinical work all the way to a phase 3 multicenter trial, but in the end no effect was seen,” Dr. Feldman said,

This was followed by another 10 years spent on the promise of stem cells. In this case, she was eventually involved in two multicenter trials. In fact, trials are still ongoing in Europe, but Dr. Feldman said this strategy is “no longer going forward in the United States,” and she no longer anticipates favorable results.
 

The New Focus on Prevention

The basic concept in the prevention studies she is now working on with Stephen Goutman, MD, a frequent coauthor, and other colleagues at her center, is that the duration of exposure to persistent organic pollutants (POPs), along with some degree of genetic predisposition, determines risk for ALS. The simple idea is the reducing exposure will reduce ALS risk.

There is already substantial support for the underlying time-gene hypothesis, according to Dr. Feldman. Among several examples, she described work with 122 POPS that appear individually and in many cases collectively to correlate with ALS risk. Recent work with an environmental risk score (ERS) that permits studies of risk when accounting for exposure to families of pollutants, has supported these as potentially modifiable risks.

A high ERS “correlates with an ALS risk that is 3 to 4 times higher than a low score,” she said. In addition, those ALS patients with a high relative to a low ERS have a significant 0.6-year reduction in median survival.

Some specific POPs, such as pesticides, correlate with increased risk by themselves, but Dr. Feldman has begun focusing on occupational exposures, particularly in industries that are most likely to increase exposure POPs. Several of the POPs most implicated in ALS, such as polychlorinated biphenyls used in coolants and lubricants, organochlorine pesticides, and polybrominated diphenyl esters, are already banned or mostly banned in the United States, but they persist in the environment and remain legal elsewhere.

Dr. Feldman reported no potential conflicts of interest.