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No benefit of three commonly used medications for MS fatigue
The TRIUMPHANT study found no difference between the effects of amantadine, modafinil, methylphenidate, and placebo in the Modified Fatigue Impact Scale (MFIS) in a study involving 141 patients with MS.
There was also no difference between any of the drugs and placebo in any of the preplanned subgroups which included different Expanded Disability Status Scale scores, depressive scores, use of disease-modifying therapy, or type of MS (relapsing remitting or progressive).
The research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
“These three drugs are used very commonly used for MS fatigue by neurologists, psychiatrists, and primary care doctors, but they don’t seem to be any better than placebo. They were all associated with increased side effects compared with placebo even with short-term use,” said lead investigator Bardia Nourbakhsh, MD, assistant professor of neurology at Johns Hopkins University, Baltimore.
However, in a post hoc analysis there was an improvement in daytime sleepiness with two of the drugs – methylphenidate and modafinil. “These two agents reduced daytime sleepiness in patients with high daytime sleepiness scores at baseline, with about a 4-point difference versus placebo, which was significant. But as this was not a preplanned analysis, we have to be cautious in its interpretation,” Dr. Nourbakhsh said. “However, this finding may not be too surprising as both these drugs are licensed as stimulants for use in narcolepsy patients with excessive daytime sleepiness.”
“Our recommendations are that as amantadine was not better than placebo in any subgroup its use should be discouraged in MS fatigue,” Dr. Nourbakhsh commented. “Modafinil and methylphenidate may possibly be considered for MS patients with excessive daytime sleepiness, but this should really be confirmed in further studies.”
Fatigue is a common and debilitating symptom of MS, occurring in about 70%-80% of patients with MS. There is no approved drug treatment. However nonpharmacologic therapies have shown some success: studies of exercise and cognitive-behavioral therapy (CBT) have shown these may be effective without causing side effects, Dr. Nourbakhsh noted. “So we should be getting patients to try exercise and CBT before jumping to medication.”
Dr. Nourbakhsh said he was disappointed with the results of the study but not terribly surprised. “We use these three medications frequently in the clinic and we have not been seeing great benefits so we wondered whether they were actually effective.”
He said that the trial was adequately powered and the question has been answered. “These are valuable results – they will hopefully encourage doctors to think twice before prescribing these medications that could be harmful and have no clear benefit,” Dr. Nourbakhsh concluded.
For the randomized, double-blind, placebo-controlled, four-sequence, four-period crossover trial, 141 patients with MS and fatigue received twice-daily oral amantadine (maximum 200 mg/day), modafinil (maximum 200 mg/day), methylphenidate (maximum 20 mg/day), or placebo, each given for up to 6 weeks with a 2-week washout between each medication.
Patients had a mean baseline MFIS score of 51.3 and were randomly assigned to one of four medication administration sequences. Data from 136 participants were available for the analysis of the primary outcome (change in MFIS score), and 111 participants completed all four medication periods.
In the intent-to-treat analysis, the least-squares means of total MFIS scores at the maximally tolerated dose were as follows: 40.7 with placebo, 41.2 with amantadine, 39.0 with modafinil, and 38.7 with methylphenidate (P = .20 for the overall medication effect; P > .05 for all pairwise comparisons). “All medications and placebo reduced the MS fatigue score by 10-12 points from baseline, so there was quite a substantial placebo effect,” Dr. Nourbakhsh noted. There was no statistically significant difference in the physical and cognitive subscales of MFIS and quality of life measures between any of the study medications and placebo. All three drugs were associated with an increase in adverse effects versus placebo.
Dr. Nourbakhsh says he is hopeful that this negative study may stimulate further research into new targets and medications for MS fatigue.
His group has recently conducted a pilot study of intravenous ketamine in MS fatigue with some encouraging results, but he stressed it needs to be tested in a larger study before it can be recommended for use in clinical practice. “While an IV medication is not ideal, the effect did seem to be quite long-lived with a difference still evident at 28 days, so it could perhaps be dosed once a month, which could be feasible,” he said.
Commenting on the TRIUMPHANT study, Jeffrey Cohen, MD, of the Cleveland Clinic, said that “fatigue is a common, often disabling, symptom of MS. It is poorly understood and probably encompasses several mechanisms. There currently is no generally effective treatment for MS-related fatigue.”
“These results are not surprising and confirm previous studies,” Dr. Cohen said. “Despite no benefit from these medicines for patients as a group, they are occasionally helpful for individual patients, so they are frequently tried empirically.
“It also is important to address any factors besides MS that may be causing or contributing to fatigue, for example, sleep disruption, medication side effects, depression, other medical conditions such as anemia or hypothyroidism,” he added.
Dr. Nourbakhsh has reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities for Jazz Pharmaceuticals.
A version of this article originally appeared on Medscape.com.
The TRIUMPHANT study found no difference between the effects of amantadine, modafinil, methylphenidate, and placebo in the Modified Fatigue Impact Scale (MFIS) in a study involving 141 patients with MS.
There was also no difference between any of the drugs and placebo in any of the preplanned subgroups which included different Expanded Disability Status Scale scores, depressive scores, use of disease-modifying therapy, or type of MS (relapsing remitting or progressive).
The research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
“These three drugs are used very commonly used for MS fatigue by neurologists, psychiatrists, and primary care doctors, but they don’t seem to be any better than placebo. They were all associated with increased side effects compared with placebo even with short-term use,” said lead investigator Bardia Nourbakhsh, MD, assistant professor of neurology at Johns Hopkins University, Baltimore.
However, in a post hoc analysis there was an improvement in daytime sleepiness with two of the drugs – methylphenidate and modafinil. “These two agents reduced daytime sleepiness in patients with high daytime sleepiness scores at baseline, with about a 4-point difference versus placebo, which was significant. But as this was not a preplanned analysis, we have to be cautious in its interpretation,” Dr. Nourbakhsh said. “However, this finding may not be too surprising as both these drugs are licensed as stimulants for use in narcolepsy patients with excessive daytime sleepiness.”
“Our recommendations are that as amantadine was not better than placebo in any subgroup its use should be discouraged in MS fatigue,” Dr. Nourbakhsh commented. “Modafinil and methylphenidate may possibly be considered for MS patients with excessive daytime sleepiness, but this should really be confirmed in further studies.”
Fatigue is a common and debilitating symptom of MS, occurring in about 70%-80% of patients with MS. There is no approved drug treatment. However nonpharmacologic therapies have shown some success: studies of exercise and cognitive-behavioral therapy (CBT) have shown these may be effective without causing side effects, Dr. Nourbakhsh noted. “So we should be getting patients to try exercise and CBT before jumping to medication.”
Dr. Nourbakhsh said he was disappointed with the results of the study but not terribly surprised. “We use these three medications frequently in the clinic and we have not been seeing great benefits so we wondered whether they were actually effective.”
He said that the trial was adequately powered and the question has been answered. “These are valuable results – they will hopefully encourage doctors to think twice before prescribing these medications that could be harmful and have no clear benefit,” Dr. Nourbakhsh concluded.
For the randomized, double-blind, placebo-controlled, four-sequence, four-period crossover trial, 141 patients with MS and fatigue received twice-daily oral amantadine (maximum 200 mg/day), modafinil (maximum 200 mg/day), methylphenidate (maximum 20 mg/day), or placebo, each given for up to 6 weeks with a 2-week washout between each medication.
Patients had a mean baseline MFIS score of 51.3 and were randomly assigned to one of four medication administration sequences. Data from 136 participants were available for the analysis of the primary outcome (change in MFIS score), and 111 participants completed all four medication periods.
In the intent-to-treat analysis, the least-squares means of total MFIS scores at the maximally tolerated dose were as follows: 40.7 with placebo, 41.2 with amantadine, 39.0 with modafinil, and 38.7 with methylphenidate (P = .20 for the overall medication effect; P > .05 for all pairwise comparisons). “All medications and placebo reduced the MS fatigue score by 10-12 points from baseline, so there was quite a substantial placebo effect,” Dr. Nourbakhsh noted. There was no statistically significant difference in the physical and cognitive subscales of MFIS and quality of life measures between any of the study medications and placebo. All three drugs were associated with an increase in adverse effects versus placebo.
Dr. Nourbakhsh says he is hopeful that this negative study may stimulate further research into new targets and medications for MS fatigue.
His group has recently conducted a pilot study of intravenous ketamine in MS fatigue with some encouraging results, but he stressed it needs to be tested in a larger study before it can be recommended for use in clinical practice. “While an IV medication is not ideal, the effect did seem to be quite long-lived with a difference still evident at 28 days, so it could perhaps be dosed once a month, which could be feasible,” he said.
Commenting on the TRIUMPHANT study, Jeffrey Cohen, MD, of the Cleveland Clinic, said that “fatigue is a common, often disabling, symptom of MS. It is poorly understood and probably encompasses several mechanisms. There currently is no generally effective treatment for MS-related fatigue.”
“These results are not surprising and confirm previous studies,” Dr. Cohen said. “Despite no benefit from these medicines for patients as a group, they are occasionally helpful for individual patients, so they are frequently tried empirically.
“It also is important to address any factors besides MS that may be causing or contributing to fatigue, for example, sleep disruption, medication side effects, depression, other medical conditions such as anemia or hypothyroidism,” he added.
Dr. Nourbakhsh has reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities for Jazz Pharmaceuticals.
A version of this article originally appeared on Medscape.com.
The TRIUMPHANT study found no difference between the effects of amantadine, modafinil, methylphenidate, and placebo in the Modified Fatigue Impact Scale (MFIS) in a study involving 141 patients with MS.
There was also no difference between any of the drugs and placebo in any of the preplanned subgroups which included different Expanded Disability Status Scale scores, depressive scores, use of disease-modifying therapy, or type of MS (relapsing remitting or progressive).
The research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
“These three drugs are used very commonly used for MS fatigue by neurologists, psychiatrists, and primary care doctors, but they don’t seem to be any better than placebo. They were all associated with increased side effects compared with placebo even with short-term use,” said lead investigator Bardia Nourbakhsh, MD, assistant professor of neurology at Johns Hopkins University, Baltimore.
However, in a post hoc analysis there was an improvement in daytime sleepiness with two of the drugs – methylphenidate and modafinil. “These two agents reduced daytime sleepiness in patients with high daytime sleepiness scores at baseline, with about a 4-point difference versus placebo, which was significant. But as this was not a preplanned analysis, we have to be cautious in its interpretation,” Dr. Nourbakhsh said. “However, this finding may not be too surprising as both these drugs are licensed as stimulants for use in narcolepsy patients with excessive daytime sleepiness.”
“Our recommendations are that as amantadine was not better than placebo in any subgroup its use should be discouraged in MS fatigue,” Dr. Nourbakhsh commented. “Modafinil and methylphenidate may possibly be considered for MS patients with excessive daytime sleepiness, but this should really be confirmed in further studies.”
Fatigue is a common and debilitating symptom of MS, occurring in about 70%-80% of patients with MS. There is no approved drug treatment. However nonpharmacologic therapies have shown some success: studies of exercise and cognitive-behavioral therapy (CBT) have shown these may be effective without causing side effects, Dr. Nourbakhsh noted. “So we should be getting patients to try exercise and CBT before jumping to medication.”
Dr. Nourbakhsh said he was disappointed with the results of the study but not terribly surprised. “We use these three medications frequently in the clinic and we have not been seeing great benefits so we wondered whether they were actually effective.”
He said that the trial was adequately powered and the question has been answered. “These are valuable results – they will hopefully encourage doctors to think twice before prescribing these medications that could be harmful and have no clear benefit,” Dr. Nourbakhsh concluded.
For the randomized, double-blind, placebo-controlled, four-sequence, four-period crossover trial, 141 patients with MS and fatigue received twice-daily oral amantadine (maximum 200 mg/day), modafinil (maximum 200 mg/day), methylphenidate (maximum 20 mg/day), or placebo, each given for up to 6 weeks with a 2-week washout between each medication.
Patients had a mean baseline MFIS score of 51.3 and were randomly assigned to one of four medication administration sequences. Data from 136 participants were available for the analysis of the primary outcome (change in MFIS score), and 111 participants completed all four medication periods.
In the intent-to-treat analysis, the least-squares means of total MFIS scores at the maximally tolerated dose were as follows: 40.7 with placebo, 41.2 with amantadine, 39.0 with modafinil, and 38.7 with methylphenidate (P = .20 for the overall medication effect; P > .05 for all pairwise comparisons). “All medications and placebo reduced the MS fatigue score by 10-12 points from baseline, so there was quite a substantial placebo effect,” Dr. Nourbakhsh noted. There was no statistically significant difference in the physical and cognitive subscales of MFIS and quality of life measures between any of the study medications and placebo. All three drugs were associated with an increase in adverse effects versus placebo.
Dr. Nourbakhsh says he is hopeful that this negative study may stimulate further research into new targets and medications for MS fatigue.
His group has recently conducted a pilot study of intravenous ketamine in MS fatigue with some encouraging results, but he stressed it needs to be tested in a larger study before it can be recommended for use in clinical practice. “While an IV medication is not ideal, the effect did seem to be quite long-lived with a difference still evident at 28 days, so it could perhaps be dosed once a month, which could be feasible,” he said.
Commenting on the TRIUMPHANT study, Jeffrey Cohen, MD, of the Cleveland Clinic, said that “fatigue is a common, often disabling, symptom of MS. It is poorly understood and probably encompasses several mechanisms. There currently is no generally effective treatment for MS-related fatigue.”
“These results are not surprising and confirm previous studies,” Dr. Cohen said. “Despite no benefit from these medicines for patients as a group, they are occasionally helpful for individual patients, so they are frequently tried empirically.
“It also is important to address any factors besides MS that may be causing or contributing to fatigue, for example, sleep disruption, medication side effects, depression, other medical conditions such as anemia or hypothyroidism,” he added.
Dr. Nourbakhsh has reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities for Jazz Pharmaceuticals.
A version of this article originally appeared on Medscape.com.
Nilotinib is safe in moderate and advanced Parkinson’s disease
according to investigators. Nevertheless, other drugs that – like nilotinib – inhibit tyrosine kinase (c-Abl) may have a neuroprotective effect, they added. The study was presented online as part of the American Academy of Neurology’s 2020 Science Highlights.
Research using preclinical models of Parkinson’s disease has indicated that nilotinib offers neuroprotection. Tanya Simuni, MD, the Arthur C. Nielsen Jr., Research Professor of Parkinson’s Disease and Movement Disorders at Northwestern University in Chicago, and colleagues conducted a prospective study to evaluate the safety and tolerability of oral nilotinib in patients with moderate or advanced Parkinson’s disease. The investigators also sought to examine nilotinib’s symptomatic effect, as measured by the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III. In addition, Dr. Simuni and colleagues analyzed the drug’s effect on progression of disability, as measured by various other Parkinson’s disease scales. The study’s exploratory outcomes included cognitive function, quality of life, pharmacokinetic profile, and a battery of serum and spinal fluid biomarkers.
The researchers conducted their randomized, double-blind, placebo-controlled, parallel-group study at 25 sites in the United States. They randomized 76 patients with Parkinson’s disease in approximately equal groups to a daily dose of placebo, 150 mg of nilotinib, or 300 mg of nilotinib. Safety visits occurred monthly. Patient assessments occurred at 3 months and at 6 months, which was the end of the treatment period. Patients presented off study medication at 1 month and 2 months after the end of the treatment period.
Treatment did not change dopamine levels
Baseline demographics and disease characteristics were balanced between groups. Mean age was about 66 years in the placebo group, 61 years in the 150-mg group, and 67 years in the 300-mg group. The proportion of male participants was 64% in the placebo group, 60% in the 150-mg group, and 81% in the 300-mg group. Disease duration was 9 years in the placebo group, approximately 9 years in the 150-mg group, and approximately 12 years in the 300-mg group. Mean MDS-UPDRS total on score was 46 in the placebo group, 47 in the 150-mg group, and 52 in the 300-mg group.
Tolerability was 84% in the placebo group, 76% in the in the 150-mg group, and 77% in the 300-mg group. The sole treatment-related serious adverse event, arrhythmia, occurred in one patient in the 300-mg group. The rate of any adverse event was 88% in the placebo group, 92% in the 150-mg group, and 88% in the 300-mg group. The rate of any serious adverse event was 8% in the placebo group and 4% in each nilotinib group.
From baseline to 1 month, MDS-UPDRS part III on scores decreased by 0.49 points in the placebo group, increased by 2.08 in the 150-mg group, and increased by 4.67 in the 300-mg group. Differences in other secondary measures (e.g., change in MDS-UPDRS part III on scores from baseline to 6 months and change in MDS-UPDRS part III off score from baseline to 6 months) were not statistically significant.
At 3 months, CSF levels of nilotinib were well below the threshold for c-Abl inhibition (approximately 11 ng/mL). The arithmetic mean levels were 0.91 ng/mL in the 150-mg group and 1.69 ng/mL in the 300-mg group. Nilotinib also failed to alter CSF levels of dopamine or its metabolites at 3 months. Dr. Simuni and colleagues did not see significant differences between treatment groups in the exploratory outcomes of cognitive function and quality of life.
“Nilotinib is not an optimal molecule to assess the therapeutic potential of c-Abl inhibition for Parkinson’s disease,” the investigators concluded.
Nilotinib may be an inappropriate candidate
The data “suggest that the hypothesis wasn’t tested, since the CSF and serum concentration of the drug were insufficient for enzyme inhibition,” said Peter LeWitt, MD, Sastry Foundation Endowed Chair in Neurology and professor of neurology at Wayne State University, Detroit. “A higher dose or a more CNS-penetrant drug would be needed for adequate testing of the hypothesis that c-Abl inhibition could provide disease modification.”
Nilotinib might not be an appropriate drug for this investigation, he continued. “There may be better choices among c-Abl inhibitors for penetration into the CNS, such as dasatinib, or for increased potency of effect, such as imatinib.”
Sun Pharma Advanced Research Company is conducting a clinical trial of KO706, another c-Abl inhibitor, added Dr. LeWitt, who is a researcher in that trial and an editorial adviser to Neurology Reviews. “The studies published recently in JAMA Neurology by Pagan et al. claiming target engagement with nilotinib in Parkinson’s disease patients need to be contrasted with the results of the current investigation. Disease modification with c-Abl inhibition continues to be a promising therapeutic avenue, but both positive and negative study results need careful reassessment and validation.”
The Michael J. Fox Foundation, the Cure Parkinson’s Trust, and Van Andel Research Institute funded the study. Novartis provided the study drug and placebo. The investigators reported no conflicts of interest.
SOURCE: Simuni T et al. AAN 2020. Abstract 43617.
according to investigators. Nevertheless, other drugs that – like nilotinib – inhibit tyrosine kinase (c-Abl) may have a neuroprotective effect, they added. The study was presented online as part of the American Academy of Neurology’s 2020 Science Highlights.
Research using preclinical models of Parkinson’s disease has indicated that nilotinib offers neuroprotection. Tanya Simuni, MD, the Arthur C. Nielsen Jr., Research Professor of Parkinson’s Disease and Movement Disorders at Northwestern University in Chicago, and colleagues conducted a prospective study to evaluate the safety and tolerability of oral nilotinib in patients with moderate or advanced Parkinson’s disease. The investigators also sought to examine nilotinib’s symptomatic effect, as measured by the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III. In addition, Dr. Simuni and colleagues analyzed the drug’s effect on progression of disability, as measured by various other Parkinson’s disease scales. The study’s exploratory outcomes included cognitive function, quality of life, pharmacokinetic profile, and a battery of serum and spinal fluid biomarkers.
The researchers conducted their randomized, double-blind, placebo-controlled, parallel-group study at 25 sites in the United States. They randomized 76 patients with Parkinson’s disease in approximately equal groups to a daily dose of placebo, 150 mg of nilotinib, or 300 mg of nilotinib. Safety visits occurred monthly. Patient assessments occurred at 3 months and at 6 months, which was the end of the treatment period. Patients presented off study medication at 1 month and 2 months after the end of the treatment period.
Treatment did not change dopamine levels
Baseline demographics and disease characteristics were balanced between groups. Mean age was about 66 years in the placebo group, 61 years in the 150-mg group, and 67 years in the 300-mg group. The proportion of male participants was 64% in the placebo group, 60% in the 150-mg group, and 81% in the 300-mg group. Disease duration was 9 years in the placebo group, approximately 9 years in the 150-mg group, and approximately 12 years in the 300-mg group. Mean MDS-UPDRS total on score was 46 in the placebo group, 47 in the 150-mg group, and 52 in the 300-mg group.
Tolerability was 84% in the placebo group, 76% in the in the 150-mg group, and 77% in the 300-mg group. The sole treatment-related serious adverse event, arrhythmia, occurred in one patient in the 300-mg group. The rate of any adverse event was 88% in the placebo group, 92% in the 150-mg group, and 88% in the 300-mg group. The rate of any serious adverse event was 8% in the placebo group and 4% in each nilotinib group.
From baseline to 1 month, MDS-UPDRS part III on scores decreased by 0.49 points in the placebo group, increased by 2.08 in the 150-mg group, and increased by 4.67 in the 300-mg group. Differences in other secondary measures (e.g., change in MDS-UPDRS part III on scores from baseline to 6 months and change in MDS-UPDRS part III off score from baseline to 6 months) were not statistically significant.
At 3 months, CSF levels of nilotinib were well below the threshold for c-Abl inhibition (approximately 11 ng/mL). The arithmetic mean levels were 0.91 ng/mL in the 150-mg group and 1.69 ng/mL in the 300-mg group. Nilotinib also failed to alter CSF levels of dopamine or its metabolites at 3 months. Dr. Simuni and colleagues did not see significant differences between treatment groups in the exploratory outcomes of cognitive function and quality of life.
“Nilotinib is not an optimal molecule to assess the therapeutic potential of c-Abl inhibition for Parkinson’s disease,” the investigators concluded.
Nilotinib may be an inappropriate candidate
The data “suggest that the hypothesis wasn’t tested, since the CSF and serum concentration of the drug were insufficient for enzyme inhibition,” said Peter LeWitt, MD, Sastry Foundation Endowed Chair in Neurology and professor of neurology at Wayne State University, Detroit. “A higher dose or a more CNS-penetrant drug would be needed for adequate testing of the hypothesis that c-Abl inhibition could provide disease modification.”
Nilotinib might not be an appropriate drug for this investigation, he continued. “There may be better choices among c-Abl inhibitors for penetration into the CNS, such as dasatinib, or for increased potency of effect, such as imatinib.”
Sun Pharma Advanced Research Company is conducting a clinical trial of KO706, another c-Abl inhibitor, added Dr. LeWitt, who is a researcher in that trial and an editorial adviser to Neurology Reviews. “The studies published recently in JAMA Neurology by Pagan et al. claiming target engagement with nilotinib in Parkinson’s disease patients need to be contrasted with the results of the current investigation. Disease modification with c-Abl inhibition continues to be a promising therapeutic avenue, but both positive and negative study results need careful reassessment and validation.”
The Michael J. Fox Foundation, the Cure Parkinson’s Trust, and Van Andel Research Institute funded the study. Novartis provided the study drug and placebo. The investigators reported no conflicts of interest.
SOURCE: Simuni T et al. AAN 2020. Abstract 43617.
according to investigators. Nevertheless, other drugs that – like nilotinib – inhibit tyrosine kinase (c-Abl) may have a neuroprotective effect, they added. The study was presented online as part of the American Academy of Neurology’s 2020 Science Highlights.
Research using preclinical models of Parkinson’s disease has indicated that nilotinib offers neuroprotection. Tanya Simuni, MD, the Arthur C. Nielsen Jr., Research Professor of Parkinson’s Disease and Movement Disorders at Northwestern University in Chicago, and colleagues conducted a prospective study to evaluate the safety and tolerability of oral nilotinib in patients with moderate or advanced Parkinson’s disease. The investigators also sought to examine nilotinib’s symptomatic effect, as measured by the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III. In addition, Dr. Simuni and colleagues analyzed the drug’s effect on progression of disability, as measured by various other Parkinson’s disease scales. The study’s exploratory outcomes included cognitive function, quality of life, pharmacokinetic profile, and a battery of serum and spinal fluid biomarkers.
The researchers conducted their randomized, double-blind, placebo-controlled, parallel-group study at 25 sites in the United States. They randomized 76 patients with Parkinson’s disease in approximately equal groups to a daily dose of placebo, 150 mg of nilotinib, or 300 mg of nilotinib. Safety visits occurred monthly. Patient assessments occurred at 3 months and at 6 months, which was the end of the treatment period. Patients presented off study medication at 1 month and 2 months after the end of the treatment period.
Treatment did not change dopamine levels
Baseline demographics and disease characteristics were balanced between groups. Mean age was about 66 years in the placebo group, 61 years in the 150-mg group, and 67 years in the 300-mg group. The proportion of male participants was 64% in the placebo group, 60% in the 150-mg group, and 81% in the 300-mg group. Disease duration was 9 years in the placebo group, approximately 9 years in the 150-mg group, and approximately 12 years in the 300-mg group. Mean MDS-UPDRS total on score was 46 in the placebo group, 47 in the 150-mg group, and 52 in the 300-mg group.
Tolerability was 84% in the placebo group, 76% in the in the 150-mg group, and 77% in the 300-mg group. The sole treatment-related serious adverse event, arrhythmia, occurred in one patient in the 300-mg group. The rate of any adverse event was 88% in the placebo group, 92% in the 150-mg group, and 88% in the 300-mg group. The rate of any serious adverse event was 8% in the placebo group and 4% in each nilotinib group.
From baseline to 1 month, MDS-UPDRS part III on scores decreased by 0.49 points in the placebo group, increased by 2.08 in the 150-mg group, and increased by 4.67 in the 300-mg group. Differences in other secondary measures (e.g., change in MDS-UPDRS part III on scores from baseline to 6 months and change in MDS-UPDRS part III off score from baseline to 6 months) were not statistically significant.
At 3 months, CSF levels of nilotinib were well below the threshold for c-Abl inhibition (approximately 11 ng/mL). The arithmetic mean levels were 0.91 ng/mL in the 150-mg group and 1.69 ng/mL in the 300-mg group. Nilotinib also failed to alter CSF levels of dopamine or its metabolites at 3 months. Dr. Simuni and colleagues did not see significant differences between treatment groups in the exploratory outcomes of cognitive function and quality of life.
“Nilotinib is not an optimal molecule to assess the therapeutic potential of c-Abl inhibition for Parkinson’s disease,” the investigators concluded.
Nilotinib may be an inappropriate candidate
The data “suggest that the hypothesis wasn’t tested, since the CSF and serum concentration of the drug were insufficient for enzyme inhibition,” said Peter LeWitt, MD, Sastry Foundation Endowed Chair in Neurology and professor of neurology at Wayne State University, Detroit. “A higher dose or a more CNS-penetrant drug would be needed for adequate testing of the hypothesis that c-Abl inhibition could provide disease modification.”
Nilotinib might not be an appropriate drug for this investigation, he continued. “There may be better choices among c-Abl inhibitors for penetration into the CNS, such as dasatinib, or for increased potency of effect, such as imatinib.”
Sun Pharma Advanced Research Company is conducting a clinical trial of KO706, another c-Abl inhibitor, added Dr. LeWitt, who is a researcher in that trial and an editorial adviser to Neurology Reviews. “The studies published recently in JAMA Neurology by Pagan et al. claiming target engagement with nilotinib in Parkinson’s disease patients need to be contrasted with the results of the current investigation. Disease modification with c-Abl inhibition continues to be a promising therapeutic avenue, but both positive and negative study results need careful reassessment and validation.”
The Michael J. Fox Foundation, the Cure Parkinson’s Trust, and Van Andel Research Institute funded the study. Novartis provided the study drug and placebo. The investigators reported no conflicts of interest.
SOURCE: Simuni T et al. AAN 2020. Abstract 43617.
FROM AAN 2020
Mixed results for aducanumab in two phase 3 trials for Alzheimer’s disease
Aducanumab was associated with favorable changes in activities of daily living and in Alzheimer’s disease biomarkers.
The EMERGE and ENGAGE studies compared low-dose and high-dose aducanumab and placebo over 78 weeks. The high-dose EMERGE cohort experienced a 22% improvement in the primary outcome – adjusted mean Clinical Dementia Rating Sum of Box (CDR-SB) scores – compared with baseline.
“We have with EMERGE, in the high-dose group, a positive result,” said lead author Samantha Budd Haeberlein, PhD, who presented this research online as part of the 2020 American Academy of Neurology Science Highlights.
In contrast, the low-dose EMERGE group, as well as the low-dose and high-dose cohorts in the ENGAGE study, experienced no statistically significant change in CDR-SB outcomes.
Clinical benefit was associated with the degree of exposure to aducanumab. For example, a protocol adjustment during the study increased the mean dose of aducanumab, a move associated with better outcomes.
“We believe that the difference between the results was largely due to patients’ greater exposure to the high dose of aducanumab,” Dr. Haerberlein, senior vice president and head of the neurodegeneration development unit at Biogen in Cambridge, Mass., said in an interview.
Although the studies shared an identical design, “because ENGAGE began enrolling first and recruitment remained ahead of EMERGE, more patients in EMERGE were impacted by the protocol amendments, which we believe resulted in a higher number of patients exposed to the highest dose in EMERGE versus ENGAGE,” Dr. Haerberlein added.
The EMERGE and ENGAGE studies were conducted at 348 sites in 20 countries. The research included a total of 3,285 participants with mild cognitive impairment caused by Alzheimer’s disease or mild Alzheimer’s disease dementia.
The mean age was 70 years, about 52% were women, and slightly more than half had a history of taking medication for Alzheimer’s disease. The mean Mini-Mental State Exam (MMSE) score was 26 at baseline.
Key findings
Dr. Haerberlein and colleagues reported that the 22% decrease in CDR-SB scores in the high-dose EMERGE participants was significant (P = .01). No significant difference emerged, however, in the ENGAGE study, where high-dose participants had a 2% decrease at 78 weeks in CDR-SB scores (P = .83).
The high-dose EMERGE regimen was also associated with an 18% improvement in MMSE scores (P < .05). In the ENGAGE study, the high-dose MMSE scores increased a nonsignificant 3% (P = .81).
The researchers reported no significant differences in the low-dose cohorts in both studies regarding CDR-SB or MMSE scores at week 78, compared with baseline.
They also assessed amyloid using PET scans. Levels remained essentially the same throughout both studies in the placebo participants. In contrast, there was a statistically significant, dose- and time-dependent reduction associated with both low- and high-dose aducanumab.
Aducanumab treatment was associated with significant benefits on measures of cognition and function such as memory, orientation, and language, Dr. Haeberlein said. “Patients also experienced benefits on activities of daily living including conducting personal finances; performing household chores such as cleaning, shopping, and doing laundry; and independently traveling out of the home.”
Furthermore, reductions in the CSF biomarker phospho-tau in the high-dose EMERGE and ENGAGE cohorts were statistically significant. In contrast, changes in total tau were not significant.
The proportion of patients who experienced an adverse event during EMERGE was similar across groups – 92% of the high-dose group, 88% of the low-dose group, and 87% of the placebo cohort. Similar rates were reported in the ENGAGE high-dose, 90%; low-dose, 90%; and placebo cohorts, 86%.
Adverse events reported in more than 10% of participants included headache, nasopharyngitis, and two forms of amyloid-related imaging abnormalities (ARIA), one of which related to edema (ARIA-E) and the other to hemosiderosis (ARIA-H).
Future plans
Going forward, the researchers are conducting a redosing study to offer aducanumab to all participants in the clinical trials. Also, Biogen is completing the filing of a Biologics License Application with the Food and Drug Administration and with regulatory agencies in other countries.
Early identification and treatment of Alzheimer’s disease remains a priority, Dr. Haeberlein said, because it offers an opportunity to begin health measures like exercise, mental activity, and social engagement; allows people more time to plan for the future; and gives families and loved ones’ time to prepare and support each other. From a research perspective, early identification of this population can maximize chances of participation in a clinical trial as well.
Unanswered questions
“Briefly, while both [studies] were looking at aducanumab’s effect on rate of decline across a variety of measures, one statistically showed a positive impact in a subset and the other did not,” Richard J. Caselli, MD, said when asked to comment on the EMERGE and ENGAGE findings. “The subset were the mildest affected patients on the highest dose for the longest time.”
The main difference between the two studies was that one was adequately powered for this subanalysis and the other was not. Even the underpowered subanalysis showed a beneficial trend, added Dr. Caselli, a neurologist at the Mayo Clinic in Phoenix, Arizona.
Dr. Caselli said these findings raise a number of unanswered questions. For example, is a subanalysis valid? Is the degree of improvement clinically meaningful or meaningful enough to justify the anticipated cost of the drug itself – “likely to be very expensive” plus the “cost and hassle” of monthly IV infusions? Is there enough provider and infusion center capacity going forward? What will the reimbursement from third party payers be like?
Biogen sponsored the EMERGE and ENGAGE studies. Dr. Haeberlein is a Biogen employee. Dr. Caselli had no relevant disclosures.
SOURCE: Haeberlein SB et al. AAN 2020, Abstract 46977.
Aducanumab was associated with favorable changes in activities of daily living and in Alzheimer’s disease biomarkers.
The EMERGE and ENGAGE studies compared low-dose and high-dose aducanumab and placebo over 78 weeks. The high-dose EMERGE cohort experienced a 22% improvement in the primary outcome – adjusted mean Clinical Dementia Rating Sum of Box (CDR-SB) scores – compared with baseline.
“We have with EMERGE, in the high-dose group, a positive result,” said lead author Samantha Budd Haeberlein, PhD, who presented this research online as part of the 2020 American Academy of Neurology Science Highlights.
In contrast, the low-dose EMERGE group, as well as the low-dose and high-dose cohorts in the ENGAGE study, experienced no statistically significant change in CDR-SB outcomes.
Clinical benefit was associated with the degree of exposure to aducanumab. For example, a protocol adjustment during the study increased the mean dose of aducanumab, a move associated with better outcomes.
“We believe that the difference between the results was largely due to patients’ greater exposure to the high dose of aducanumab,” Dr. Haerberlein, senior vice president and head of the neurodegeneration development unit at Biogen in Cambridge, Mass., said in an interview.
Although the studies shared an identical design, “because ENGAGE began enrolling first and recruitment remained ahead of EMERGE, more patients in EMERGE were impacted by the protocol amendments, which we believe resulted in a higher number of patients exposed to the highest dose in EMERGE versus ENGAGE,” Dr. Haerberlein added.
The EMERGE and ENGAGE studies were conducted at 348 sites in 20 countries. The research included a total of 3,285 participants with mild cognitive impairment caused by Alzheimer’s disease or mild Alzheimer’s disease dementia.
The mean age was 70 years, about 52% were women, and slightly more than half had a history of taking medication for Alzheimer’s disease. The mean Mini-Mental State Exam (MMSE) score was 26 at baseline.
Key findings
Dr. Haerberlein and colleagues reported that the 22% decrease in CDR-SB scores in the high-dose EMERGE participants was significant (P = .01). No significant difference emerged, however, in the ENGAGE study, where high-dose participants had a 2% decrease at 78 weeks in CDR-SB scores (P = .83).
The high-dose EMERGE regimen was also associated with an 18% improvement in MMSE scores (P < .05). In the ENGAGE study, the high-dose MMSE scores increased a nonsignificant 3% (P = .81).
The researchers reported no significant differences in the low-dose cohorts in both studies regarding CDR-SB or MMSE scores at week 78, compared with baseline.
They also assessed amyloid using PET scans. Levels remained essentially the same throughout both studies in the placebo participants. In contrast, there was a statistically significant, dose- and time-dependent reduction associated with both low- and high-dose aducanumab.
Aducanumab treatment was associated with significant benefits on measures of cognition and function such as memory, orientation, and language, Dr. Haeberlein said. “Patients also experienced benefits on activities of daily living including conducting personal finances; performing household chores such as cleaning, shopping, and doing laundry; and independently traveling out of the home.”
Furthermore, reductions in the CSF biomarker phospho-tau in the high-dose EMERGE and ENGAGE cohorts were statistically significant. In contrast, changes in total tau were not significant.
The proportion of patients who experienced an adverse event during EMERGE was similar across groups – 92% of the high-dose group, 88% of the low-dose group, and 87% of the placebo cohort. Similar rates were reported in the ENGAGE high-dose, 90%; low-dose, 90%; and placebo cohorts, 86%.
Adverse events reported in more than 10% of participants included headache, nasopharyngitis, and two forms of amyloid-related imaging abnormalities (ARIA), one of which related to edema (ARIA-E) and the other to hemosiderosis (ARIA-H).
Future plans
Going forward, the researchers are conducting a redosing study to offer aducanumab to all participants in the clinical trials. Also, Biogen is completing the filing of a Biologics License Application with the Food and Drug Administration and with regulatory agencies in other countries.
Early identification and treatment of Alzheimer’s disease remains a priority, Dr. Haeberlein said, because it offers an opportunity to begin health measures like exercise, mental activity, and social engagement; allows people more time to plan for the future; and gives families and loved ones’ time to prepare and support each other. From a research perspective, early identification of this population can maximize chances of participation in a clinical trial as well.
Unanswered questions
“Briefly, while both [studies] were looking at aducanumab’s effect on rate of decline across a variety of measures, one statistically showed a positive impact in a subset and the other did not,” Richard J. Caselli, MD, said when asked to comment on the EMERGE and ENGAGE findings. “The subset were the mildest affected patients on the highest dose for the longest time.”
The main difference between the two studies was that one was adequately powered for this subanalysis and the other was not. Even the underpowered subanalysis showed a beneficial trend, added Dr. Caselli, a neurologist at the Mayo Clinic in Phoenix, Arizona.
Dr. Caselli said these findings raise a number of unanswered questions. For example, is a subanalysis valid? Is the degree of improvement clinically meaningful or meaningful enough to justify the anticipated cost of the drug itself – “likely to be very expensive” plus the “cost and hassle” of monthly IV infusions? Is there enough provider and infusion center capacity going forward? What will the reimbursement from third party payers be like?
Biogen sponsored the EMERGE and ENGAGE studies. Dr. Haeberlein is a Biogen employee. Dr. Caselli had no relevant disclosures.
SOURCE: Haeberlein SB et al. AAN 2020, Abstract 46977.
Aducanumab was associated with favorable changes in activities of daily living and in Alzheimer’s disease biomarkers.
The EMERGE and ENGAGE studies compared low-dose and high-dose aducanumab and placebo over 78 weeks. The high-dose EMERGE cohort experienced a 22% improvement in the primary outcome – adjusted mean Clinical Dementia Rating Sum of Box (CDR-SB) scores – compared with baseline.
“We have with EMERGE, in the high-dose group, a positive result,” said lead author Samantha Budd Haeberlein, PhD, who presented this research online as part of the 2020 American Academy of Neurology Science Highlights.
In contrast, the low-dose EMERGE group, as well as the low-dose and high-dose cohorts in the ENGAGE study, experienced no statistically significant change in CDR-SB outcomes.
Clinical benefit was associated with the degree of exposure to aducanumab. For example, a protocol adjustment during the study increased the mean dose of aducanumab, a move associated with better outcomes.
“We believe that the difference between the results was largely due to patients’ greater exposure to the high dose of aducanumab,” Dr. Haerberlein, senior vice president and head of the neurodegeneration development unit at Biogen in Cambridge, Mass., said in an interview.
Although the studies shared an identical design, “because ENGAGE began enrolling first and recruitment remained ahead of EMERGE, more patients in EMERGE were impacted by the protocol amendments, which we believe resulted in a higher number of patients exposed to the highest dose in EMERGE versus ENGAGE,” Dr. Haerberlein added.
The EMERGE and ENGAGE studies were conducted at 348 sites in 20 countries. The research included a total of 3,285 participants with mild cognitive impairment caused by Alzheimer’s disease or mild Alzheimer’s disease dementia.
The mean age was 70 years, about 52% were women, and slightly more than half had a history of taking medication for Alzheimer’s disease. The mean Mini-Mental State Exam (MMSE) score was 26 at baseline.
Key findings
Dr. Haerberlein and colleagues reported that the 22% decrease in CDR-SB scores in the high-dose EMERGE participants was significant (P = .01). No significant difference emerged, however, in the ENGAGE study, where high-dose participants had a 2% decrease at 78 weeks in CDR-SB scores (P = .83).
The high-dose EMERGE regimen was also associated with an 18% improvement in MMSE scores (P < .05). In the ENGAGE study, the high-dose MMSE scores increased a nonsignificant 3% (P = .81).
The researchers reported no significant differences in the low-dose cohorts in both studies regarding CDR-SB or MMSE scores at week 78, compared with baseline.
They also assessed amyloid using PET scans. Levels remained essentially the same throughout both studies in the placebo participants. In contrast, there was a statistically significant, dose- and time-dependent reduction associated with both low- and high-dose aducanumab.
Aducanumab treatment was associated with significant benefits on measures of cognition and function such as memory, orientation, and language, Dr. Haeberlein said. “Patients also experienced benefits on activities of daily living including conducting personal finances; performing household chores such as cleaning, shopping, and doing laundry; and independently traveling out of the home.”
Furthermore, reductions in the CSF biomarker phospho-tau in the high-dose EMERGE and ENGAGE cohorts were statistically significant. In contrast, changes in total tau were not significant.
The proportion of patients who experienced an adverse event during EMERGE was similar across groups – 92% of the high-dose group, 88% of the low-dose group, and 87% of the placebo cohort. Similar rates were reported in the ENGAGE high-dose, 90%; low-dose, 90%; and placebo cohorts, 86%.
Adverse events reported in more than 10% of participants included headache, nasopharyngitis, and two forms of amyloid-related imaging abnormalities (ARIA), one of which related to edema (ARIA-E) and the other to hemosiderosis (ARIA-H).
Future plans
Going forward, the researchers are conducting a redosing study to offer aducanumab to all participants in the clinical trials. Also, Biogen is completing the filing of a Biologics License Application with the Food and Drug Administration and with regulatory agencies in other countries.
Early identification and treatment of Alzheimer’s disease remains a priority, Dr. Haeberlein said, because it offers an opportunity to begin health measures like exercise, mental activity, and social engagement; allows people more time to plan for the future; and gives families and loved ones’ time to prepare and support each other. From a research perspective, early identification of this population can maximize chances of participation in a clinical trial as well.
Unanswered questions
“Briefly, while both [studies] were looking at aducanumab’s effect on rate of decline across a variety of measures, one statistically showed a positive impact in a subset and the other did not,” Richard J. Caselli, MD, said when asked to comment on the EMERGE and ENGAGE findings. “The subset were the mildest affected patients on the highest dose for the longest time.”
The main difference between the two studies was that one was adequately powered for this subanalysis and the other was not. Even the underpowered subanalysis showed a beneficial trend, added Dr. Caselli, a neurologist at the Mayo Clinic in Phoenix, Arizona.
Dr. Caselli said these findings raise a number of unanswered questions. For example, is a subanalysis valid? Is the degree of improvement clinically meaningful or meaningful enough to justify the anticipated cost of the drug itself – “likely to be very expensive” plus the “cost and hassle” of monthly IV infusions? Is there enough provider and infusion center capacity going forward? What will the reimbursement from third party payers be like?
Biogen sponsored the EMERGE and ENGAGE studies. Dr. Haeberlein is a Biogen employee. Dr. Caselli had no relevant disclosures.
SOURCE: Haeberlein SB et al. AAN 2020, Abstract 46977.
FROM AAN 2020
Galcanezumab looks promising for treatment-resistant migraine
“The patients included in our study had previously tried multiple migraine preventive treatments that didn’t work for them. These patients are left with limited treatment options to help with the debilitating pain of migraine,” said lead author Holland C. Detke, PhD, senior clinical research advisor at Eli Lilly and Company Biomedicines.
Participants who took the drug experienced “a rapid reduction in migraine days starting as early as month 1, and continuing through the 6 months of the study,” Dr. Detke said.
The treatment group reported an average 4.0 fewer monthly migraine days at 3 months, for example, compared with a baseline of 13.4 days, whereas the placebo group decreased an average 1.29 days from a similar baseline of 13.0 migraine days.
Dr. Detke presented these and other results of the open-label phase of the CONQUER phase 3 trial online as part of the 2020 American Academy of Neurology Science Highlights.
The investigators enrolled 462 adults with episodic or chronic migraine. All participants previously failed two to four migraine treatments because of insufficient efficacy or issues around tolerability or safety. At month 0, 232 people were randomly assigned to galcanezumab and another 230 to placebo injections. At 3 months, 449 participants received a galcanezumab injection as part of the open-label treatment phase.
Participants were an average 48 years old, approximately 86% were women, and 82% were white. At baseline, mean Migraine Specific Quality of Life Role Function Restrictive (MSQ RFR) domain score was 45, “indicating significant impairment in functioning,” Dr. Detke said. At the same time, mean Migraine Disability Assessment Test (MIDAS) total score was 51, “indicating quite severe disability.”
Significant outcomes
The decrease in migraine days at 3 months – 4.0 days with treatment versus 1.29 with placebo – was statistically significant (P < .0001). During the open-label phase, participants who switched from placebo “essentially catch up to where the previously treated people were,” Dr. Detke said. At 6 months, the decrease in average monthly headache days was 5.60 in the initial galcanezumab group versus 5.24 in the initial placebo group.
Significant differences at 3 months versus baseline were observed in participants who received galcanezumab when investigators assessed reduction in 50% or more, 75% or more, or 100% of mean monthly migraine days. No such significant decreases were seen in the placebo group.
Treatment-emergent adverse events reported in the open-label phase included nasopharyngitis in 4.2%, injection site pain in 3.8%, and injection site erythema in 2.7%. Five participants discontinued during the open-label phase because of adverse events.
The results of the study suggest galcanezumab “should be considered as a treatment option for patients who have not had success with previous treatments,” Dr. Detke said.
Multiple strengths of study
“It is encouraging that galcanezumab works in patients who have failed prior reduction strategies,” A. Laine Green, MD, a neurologist at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., said when asked to comment.
This study did not look at patients who have failed more than four previous reduction strategies, he added. “Clinically we see many of these patients. To be fair, no one has studied this group using the monoclonal antibodies.”
Dr. Green noted several strengths of the study. The groups were similar, there were few dropouts during the open-label extension, and there were no unexpected side effects or adverse events. “Those who got placebo caught up to those who received active treatment in the double-blind phase,” he said. “It is also nice to see patient reported outcomes improved as headaches improve. This adds consistency to the results.”
One caveat, Dr. Green noted, is “with open-label extensions, there is always the potential for bias because patients know what treatment they are receiving.”
Overall [the study] gives hope that patients who have failed previous reduction strategies may respond to the newer monoclonal antibodies.”
Aligns with previous findings
The results are “the same as any other long-term extension study of a drug for migraine,” Stephen Silberstein, MD, said when asked to comment. “The longer one takes it, the better you get.”
The research also confirms that if you switch patients taking placebo to an active treatment, they get better, added Dr. Silberstein, director of the Headache Center at Jefferson Health in Philadelphia.
Because they are injections, agents such as galcanezumab, other monoclonal antibodies, and botulinum toxin offer better compliance for headache compared with small molecule medications that require daily oral dosing, he added.
Eli Lilly and Company funded the study. Dr. Holland Detke is a Lilly employee. Dr. Green collaborated with Lilly on a poster for the AHS scientific meeting on a similar topic but did not receive compensation. Up until August 2019, he served as a consultant for Lilly, Novartis, Teva and Allergan. Dr. Green is also a member of the Medscape and American Headache Society Migraine Steering Committee. Dr. Silberstein is a member of the advisory board and consultant for Lilly.
Source: Detke HC et al. AAN 2020. Abstract 43625.
“The patients included in our study had previously tried multiple migraine preventive treatments that didn’t work for them. These patients are left with limited treatment options to help with the debilitating pain of migraine,” said lead author Holland C. Detke, PhD, senior clinical research advisor at Eli Lilly and Company Biomedicines.
Participants who took the drug experienced “a rapid reduction in migraine days starting as early as month 1, and continuing through the 6 months of the study,” Dr. Detke said.
The treatment group reported an average 4.0 fewer monthly migraine days at 3 months, for example, compared with a baseline of 13.4 days, whereas the placebo group decreased an average 1.29 days from a similar baseline of 13.0 migraine days.
Dr. Detke presented these and other results of the open-label phase of the CONQUER phase 3 trial online as part of the 2020 American Academy of Neurology Science Highlights.
The investigators enrolled 462 adults with episodic or chronic migraine. All participants previously failed two to four migraine treatments because of insufficient efficacy or issues around tolerability or safety. At month 0, 232 people were randomly assigned to galcanezumab and another 230 to placebo injections. At 3 months, 449 participants received a galcanezumab injection as part of the open-label treatment phase.
Participants were an average 48 years old, approximately 86% were women, and 82% were white. At baseline, mean Migraine Specific Quality of Life Role Function Restrictive (MSQ RFR) domain score was 45, “indicating significant impairment in functioning,” Dr. Detke said. At the same time, mean Migraine Disability Assessment Test (MIDAS) total score was 51, “indicating quite severe disability.”
Significant outcomes
The decrease in migraine days at 3 months – 4.0 days with treatment versus 1.29 with placebo – was statistically significant (P < .0001). During the open-label phase, participants who switched from placebo “essentially catch up to where the previously treated people were,” Dr. Detke said. At 6 months, the decrease in average monthly headache days was 5.60 in the initial galcanezumab group versus 5.24 in the initial placebo group.
Significant differences at 3 months versus baseline were observed in participants who received galcanezumab when investigators assessed reduction in 50% or more, 75% or more, or 100% of mean monthly migraine days. No such significant decreases were seen in the placebo group.
Treatment-emergent adverse events reported in the open-label phase included nasopharyngitis in 4.2%, injection site pain in 3.8%, and injection site erythema in 2.7%. Five participants discontinued during the open-label phase because of adverse events.
The results of the study suggest galcanezumab “should be considered as a treatment option for patients who have not had success with previous treatments,” Dr. Detke said.
Multiple strengths of study
“It is encouraging that galcanezumab works in patients who have failed prior reduction strategies,” A. Laine Green, MD, a neurologist at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., said when asked to comment.
This study did not look at patients who have failed more than four previous reduction strategies, he added. “Clinically we see many of these patients. To be fair, no one has studied this group using the monoclonal antibodies.”
Dr. Green noted several strengths of the study. The groups were similar, there were few dropouts during the open-label extension, and there were no unexpected side effects or adverse events. “Those who got placebo caught up to those who received active treatment in the double-blind phase,” he said. “It is also nice to see patient reported outcomes improved as headaches improve. This adds consistency to the results.”
One caveat, Dr. Green noted, is “with open-label extensions, there is always the potential for bias because patients know what treatment they are receiving.”
Overall [the study] gives hope that patients who have failed previous reduction strategies may respond to the newer monoclonal antibodies.”
Aligns with previous findings
The results are “the same as any other long-term extension study of a drug for migraine,” Stephen Silberstein, MD, said when asked to comment. “The longer one takes it, the better you get.”
The research also confirms that if you switch patients taking placebo to an active treatment, they get better, added Dr. Silberstein, director of the Headache Center at Jefferson Health in Philadelphia.
Because they are injections, agents such as galcanezumab, other monoclonal antibodies, and botulinum toxin offer better compliance for headache compared with small molecule medications that require daily oral dosing, he added.
Eli Lilly and Company funded the study. Dr. Holland Detke is a Lilly employee. Dr. Green collaborated with Lilly on a poster for the AHS scientific meeting on a similar topic but did not receive compensation. Up until August 2019, he served as a consultant for Lilly, Novartis, Teva and Allergan. Dr. Green is also a member of the Medscape and American Headache Society Migraine Steering Committee. Dr. Silberstein is a member of the advisory board and consultant for Lilly.
Source: Detke HC et al. AAN 2020. Abstract 43625.
“The patients included in our study had previously tried multiple migraine preventive treatments that didn’t work for them. These patients are left with limited treatment options to help with the debilitating pain of migraine,” said lead author Holland C. Detke, PhD, senior clinical research advisor at Eli Lilly and Company Biomedicines.
Participants who took the drug experienced “a rapid reduction in migraine days starting as early as month 1, and continuing through the 6 months of the study,” Dr. Detke said.
The treatment group reported an average 4.0 fewer monthly migraine days at 3 months, for example, compared with a baseline of 13.4 days, whereas the placebo group decreased an average 1.29 days from a similar baseline of 13.0 migraine days.
Dr. Detke presented these and other results of the open-label phase of the CONQUER phase 3 trial online as part of the 2020 American Academy of Neurology Science Highlights.
The investigators enrolled 462 adults with episodic or chronic migraine. All participants previously failed two to four migraine treatments because of insufficient efficacy or issues around tolerability or safety. At month 0, 232 people were randomly assigned to galcanezumab and another 230 to placebo injections. At 3 months, 449 participants received a galcanezumab injection as part of the open-label treatment phase.
Participants were an average 48 years old, approximately 86% were women, and 82% were white. At baseline, mean Migraine Specific Quality of Life Role Function Restrictive (MSQ RFR) domain score was 45, “indicating significant impairment in functioning,” Dr. Detke said. At the same time, mean Migraine Disability Assessment Test (MIDAS) total score was 51, “indicating quite severe disability.”
Significant outcomes
The decrease in migraine days at 3 months – 4.0 days with treatment versus 1.29 with placebo – was statistically significant (P < .0001). During the open-label phase, participants who switched from placebo “essentially catch up to where the previously treated people were,” Dr. Detke said. At 6 months, the decrease in average monthly headache days was 5.60 in the initial galcanezumab group versus 5.24 in the initial placebo group.
Significant differences at 3 months versus baseline were observed in participants who received galcanezumab when investigators assessed reduction in 50% or more, 75% or more, or 100% of mean monthly migraine days. No such significant decreases were seen in the placebo group.
Treatment-emergent adverse events reported in the open-label phase included nasopharyngitis in 4.2%, injection site pain in 3.8%, and injection site erythema in 2.7%. Five participants discontinued during the open-label phase because of adverse events.
The results of the study suggest galcanezumab “should be considered as a treatment option for patients who have not had success with previous treatments,” Dr. Detke said.
Multiple strengths of study
“It is encouraging that galcanezumab works in patients who have failed prior reduction strategies,” A. Laine Green, MD, a neurologist at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., said when asked to comment.
This study did not look at patients who have failed more than four previous reduction strategies, he added. “Clinically we see many of these patients. To be fair, no one has studied this group using the monoclonal antibodies.”
Dr. Green noted several strengths of the study. The groups were similar, there were few dropouts during the open-label extension, and there were no unexpected side effects or adverse events. “Those who got placebo caught up to those who received active treatment in the double-blind phase,” he said. “It is also nice to see patient reported outcomes improved as headaches improve. This adds consistency to the results.”
One caveat, Dr. Green noted, is “with open-label extensions, there is always the potential for bias because patients know what treatment they are receiving.”
Overall [the study] gives hope that patients who have failed previous reduction strategies may respond to the newer monoclonal antibodies.”
Aligns with previous findings
The results are “the same as any other long-term extension study of a drug for migraine,” Stephen Silberstein, MD, said when asked to comment. “The longer one takes it, the better you get.”
The research also confirms that if you switch patients taking placebo to an active treatment, they get better, added Dr. Silberstein, director of the Headache Center at Jefferson Health in Philadelphia.
Because they are injections, agents such as galcanezumab, other monoclonal antibodies, and botulinum toxin offer better compliance for headache compared with small molecule medications that require daily oral dosing, he added.
Eli Lilly and Company funded the study. Dr. Holland Detke is a Lilly employee. Dr. Green collaborated with Lilly on a poster for the AHS scientific meeting on a similar topic but did not receive compensation. Up until August 2019, he served as a consultant for Lilly, Novartis, Teva and Allergan. Dr. Green is also a member of the Medscape and American Headache Society Migraine Steering Committee. Dr. Silberstein is a member of the advisory board and consultant for Lilly.
Source: Detke HC et al. AAN 2020. Abstract 43625.
FROM AAN 2020
Chronic migraine is associated with changes in the amygdala
, according to researchers. This increased connectivity is associated with clinical and affective measures. The data suggest that changes in the amygdala’s structure and function may play a role in the transformation to chronic migraine, according to the researchers. The study was presented online as part of the American Academy of Neurology’s 2020 Science Highlights.
Approximately 3% of patients with episodic migraine progress to chronic migraine each year. Chronic migraine is associated with increased headache frequency, greater disability, and increased psychiatric comorbidities. The pathophysiological mechanisms of the transformation from episodic to chronic migraine are not completely understood.
Danielle D. DeSouza, PhD, instructor in neurology at Stanford (Calif.) University, and colleagues sought to investigate the role of the amygdala in the transformation of migraine. The amygdala is involved in nociceptive processing, emotional responses, and affective states such as depression and anxiety. Researchers have suggested that alterations in the structure or function of the amygdala might contribute to the worsening of pain and mood that coincides with the transformation of migraine.
Dr. DeSouza and colleagues enrolled 88 patients with migraine, diagnosed according to International Classification of Headache Disorders–3 criteria, in their study. Forty-four patients (36 women; mean age, 37.8 years) had chronic migraine, and 44 patients (36 women; mean age, 37.5 years) had episodic migraine. Participants underwent 3T MRI scanning during which investigators acquired T1-weighted structural and resting-state images of the brain. Participants also completed self-report questionnaires to evaluate depression and somatization (Patient Health Questionnaire), anxiety (Generalized Anxiety Disorder 7-item scale), pain catastrophizing (Pain Catastrophizing Scale), headache frequency, and headache intensity.
The investigators examined resting-state functional connectivity between the amygdala and the following three brain networks: DMN, salience network (SN), and central executive network (CEN). They assessed amygdala volume with voxel-based morphometry.
Analyses indicated that connectivity between the left amygdala and the DMN (i.e., the medial prefrontal cortex and the precuneus/posterior cingulate cortex) was increased in patients with chronic migraine, compared with those with episodic migraine. In all patients, resting-state functional connectivity between the amygdala and the DMN was positively associated with headache frequency. Connectivity between the left amygdala and the SN was positively associated with headache intensity, and connectivity between the right amygdala and the CEN was positively associated with pain catastrophizing. Both of these findings held in all patients.
In addition, Dr. DeSouza and colleagues found that bilateral amygdala volumes, including the basolateral and superficial/corticoid nuclei, were increased in patients with chronic migraine, compared with those with episodic migraine. Headache intensity and depression predicted differences in right amygdala volume, and depression alone predicted differences in left amygdala volume.
Dr. DeSouza reported no disclosures. One of the investigators acts as an adviser to Alder, Allergan, Amgen, Biohaven, Curex, Teva, and Xoc about matters unrelated to this study.
SOURCE: DeSouza DD et al. AAN 2020, Abstract 46914.
, according to researchers. This increased connectivity is associated with clinical and affective measures. The data suggest that changes in the amygdala’s structure and function may play a role in the transformation to chronic migraine, according to the researchers. The study was presented online as part of the American Academy of Neurology’s 2020 Science Highlights.
Approximately 3% of patients with episodic migraine progress to chronic migraine each year. Chronic migraine is associated with increased headache frequency, greater disability, and increased psychiatric comorbidities. The pathophysiological mechanisms of the transformation from episodic to chronic migraine are not completely understood.
Danielle D. DeSouza, PhD, instructor in neurology at Stanford (Calif.) University, and colleagues sought to investigate the role of the amygdala in the transformation of migraine. The amygdala is involved in nociceptive processing, emotional responses, and affective states such as depression and anxiety. Researchers have suggested that alterations in the structure or function of the amygdala might contribute to the worsening of pain and mood that coincides with the transformation of migraine.
Dr. DeSouza and colleagues enrolled 88 patients with migraine, diagnosed according to International Classification of Headache Disorders–3 criteria, in their study. Forty-four patients (36 women; mean age, 37.8 years) had chronic migraine, and 44 patients (36 women; mean age, 37.5 years) had episodic migraine. Participants underwent 3T MRI scanning during which investigators acquired T1-weighted structural and resting-state images of the brain. Participants also completed self-report questionnaires to evaluate depression and somatization (Patient Health Questionnaire), anxiety (Generalized Anxiety Disorder 7-item scale), pain catastrophizing (Pain Catastrophizing Scale), headache frequency, and headache intensity.
The investigators examined resting-state functional connectivity between the amygdala and the following three brain networks: DMN, salience network (SN), and central executive network (CEN). They assessed amygdala volume with voxel-based morphometry.
Analyses indicated that connectivity between the left amygdala and the DMN (i.e., the medial prefrontal cortex and the precuneus/posterior cingulate cortex) was increased in patients with chronic migraine, compared with those with episodic migraine. In all patients, resting-state functional connectivity between the amygdala and the DMN was positively associated with headache frequency. Connectivity between the left amygdala and the SN was positively associated with headache intensity, and connectivity between the right amygdala and the CEN was positively associated with pain catastrophizing. Both of these findings held in all patients.
In addition, Dr. DeSouza and colleagues found that bilateral amygdala volumes, including the basolateral and superficial/corticoid nuclei, were increased in patients with chronic migraine, compared with those with episodic migraine. Headache intensity and depression predicted differences in right amygdala volume, and depression alone predicted differences in left amygdala volume.
Dr. DeSouza reported no disclosures. One of the investigators acts as an adviser to Alder, Allergan, Amgen, Biohaven, Curex, Teva, and Xoc about matters unrelated to this study.
SOURCE: DeSouza DD et al. AAN 2020, Abstract 46914.
, according to researchers. This increased connectivity is associated with clinical and affective measures. The data suggest that changes in the amygdala’s structure and function may play a role in the transformation to chronic migraine, according to the researchers. The study was presented online as part of the American Academy of Neurology’s 2020 Science Highlights.
Approximately 3% of patients with episodic migraine progress to chronic migraine each year. Chronic migraine is associated with increased headache frequency, greater disability, and increased psychiatric comorbidities. The pathophysiological mechanisms of the transformation from episodic to chronic migraine are not completely understood.
Danielle D. DeSouza, PhD, instructor in neurology at Stanford (Calif.) University, and colleagues sought to investigate the role of the amygdala in the transformation of migraine. The amygdala is involved in nociceptive processing, emotional responses, and affective states such as depression and anxiety. Researchers have suggested that alterations in the structure or function of the amygdala might contribute to the worsening of pain and mood that coincides with the transformation of migraine.
Dr. DeSouza and colleagues enrolled 88 patients with migraine, diagnosed according to International Classification of Headache Disorders–3 criteria, in their study. Forty-four patients (36 women; mean age, 37.8 years) had chronic migraine, and 44 patients (36 women; mean age, 37.5 years) had episodic migraine. Participants underwent 3T MRI scanning during which investigators acquired T1-weighted structural and resting-state images of the brain. Participants also completed self-report questionnaires to evaluate depression and somatization (Patient Health Questionnaire), anxiety (Generalized Anxiety Disorder 7-item scale), pain catastrophizing (Pain Catastrophizing Scale), headache frequency, and headache intensity.
The investigators examined resting-state functional connectivity between the amygdala and the following three brain networks: DMN, salience network (SN), and central executive network (CEN). They assessed amygdala volume with voxel-based morphometry.
Analyses indicated that connectivity between the left amygdala and the DMN (i.e., the medial prefrontal cortex and the precuneus/posterior cingulate cortex) was increased in patients with chronic migraine, compared with those with episodic migraine. In all patients, resting-state functional connectivity between the amygdala and the DMN was positively associated with headache frequency. Connectivity between the left amygdala and the SN was positively associated with headache intensity, and connectivity between the right amygdala and the CEN was positively associated with pain catastrophizing. Both of these findings held in all patients.
In addition, Dr. DeSouza and colleagues found that bilateral amygdala volumes, including the basolateral and superficial/corticoid nuclei, were increased in patients with chronic migraine, compared with those with episodic migraine. Headache intensity and depression predicted differences in right amygdala volume, and depression alone predicted differences in left amygdala volume.
Dr. DeSouza reported no disclosures. One of the investigators acts as an adviser to Alder, Allergan, Amgen, Biohaven, Curex, Teva, and Xoc about matters unrelated to this study.
SOURCE: DeSouza DD et al. AAN 2020, Abstract 46914.
FROM AAN 2020
New research confirms the efficacy and safety of onasemnogene abeparvovec for SMA
The research was presented online as part of the 2020 AAN Science Highlights.
SMA results from a mutation in SMN1, which encodes the SMN protein necessary for motor function. Deficiency of this protein causes motor neurons to die, resulting in severe muscle weakness. At 2 years of age, untreated patients with SMA type 1 generally die or require permanent ventilation.
The Food and Drug Administration approved onasemnogene abeparvovec-xioi under the brand name Zolgensma in May 2019. The gene-replacement therapy, which is administered once intravenously, delivers a fully functional copy of human SMN1 into the target motor neuron cells. It is indicated as treatment for SMA in infants younger than 2 years of age.
Preliminary STR1VE data
Preliminary data from the phase 3 STR1VE study were scheduled to be presented at the meeting. The open-label, single-arm, single-dose study enrolled symptomatic patients with SMA type 1 (SMA1) at multiple US sites. Enrollment was completed in May 2019.
The study included 10 male patients and 12 female patients. Participants’ mean age at dosing was 3.7 months. Of 19 patients who could have reached age 13.6 months at data cutoff, 17 (89.5%) were surviving without permanent ventilation, compared with a 25% survival rate among untreated patients. One of the 19 patients died, and the event was judged to be unrelated to treatment. Another of the 19 reached a respiratory endpoint or withdrew consent.
The population’s mean baseline Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score was 32. This score increased by 6.9, 11.7, and 14.3 points at months 1, 3, and 5, respectively. Half of the 22 infants sat independently for 30 or more seconds, and this milestone was achieved at a mean of 8.2 months after treatment. Five of six (83%) patients age 18 months or older sat independently for 30 or more seconds, which was one of the study’s primary endpoints. As of March 8, 2019, treatment-emergent adverse events of special interest were transient and not associated with any sequelae.
The STR1VE study was sponsored by AveXis, the maker of onasemnogene abeparvovec-xioi. Several of the investigators are employees of AveXis, and others received funding from the company.
Long-term follow-up in START
Long-term follow-up data for participants in the phase 1/2a START study also were scheduled to be presented. Patients who completed START were eligible to participate, and the trial’s primary aim was to evaluate the long-term safety of onasemnogene abeparvovec-xioi. Patients are intended to have five annual visits, followed by 10 annual phone calls, and the investigators request local physicians or neurologists to transfer patient records. Safety assessments include medical history and record review, physical examination, clinical laboratory evaluation, and pulmonary assessments. Efficacy assessments include evaluation of the maintenance of developmental milestones.
As of May 31, 2019, 13 patients in two cohorts had been enrolled and had had a baseline visit. For patients in Cohort 2, the mean age and time since dosing were 4.2 years and 3.9 years, respectively. All patients in Cohort 2 were alive and did not require permanent ventilation. Participants did not lose any developmental milestones that they had achieved at the end of START. Two patients were able to walk, and two could stand with assistance during long-term follow-up. This result suggests the durability of the treatment’s effect. No new treatment-related serious adverse events or adverse events of special interest had occurred as of March 8, 2019.
“We know from accumulating experience that treating infants by gene therapy is safe,” said Jerry R. Mendell, MD, the principal investigator and an attending neurologist at Nationwide Children’s Hospital in Columbus, Ohio. “Of the 15 patients we had in our first trial, only four adverse events related to the gene delivery were encountered, and only two of these were considered serious adverse events [i.e., liver enzymes that were 10 times greater than normal laboratory levels]. These laboratory tests occurred without accompanying clinical symptoms or signs. All were suppressed by corticosteroids and related to the liver inflammation. This pattern of safety has been seen in our very large gene therapy experience. No long-term surprises were encountered.”
The START study was sponsored by AveXis. Several of the investigators are employees of AveXis, and others received funding from the company.
Update on the SPR1NT study
Interim safety and efficacy data from the ongoing SPR1NT study, which includes presymptomatic patients, also were scheduled to be presented. The trial “was built on the basic premise that spinal motor neuron degeneration associated with SMN protein deficiency begins in utero, continues to progress rapidly during the first months of life, and is irreversible,” said Kevin Strauss, MD, medical director of the Clinic for Special Children in Strasburg, Pennsylvania. “SPR1NT leveraged the advantages conferred by carrier testing and newborn screening programs for SMA, which allowed the first 22 children enrolled to have a confirmed molecular diagnosis between 1 and 26 days of postnatal life, before the onset of dysphagia, respiratory compromise, or overt weakness.”
In this multicenter, open-label, phase 3 trial, presymptomatic patients age 6 weeks or younger who are expected to develop SMA receive onasemnogene abeparvovec-xioi once and are evaluated during 18 or 24 months. The primary outcomes are sitting for 30 or more seconds for infants with two copies of SMN2 and standing unassisted for infants with three copies of SMN2.
As of December 31, 2019, 29 infants had been treated in the efficacy group at a mean age of 20.6 days among infants with two copies of SMN2 and 28.7 days among infants with three copies of SMN2. All patients are alive, and no patient in SPR1NT required ventilation support at last visit. Among 14 patients with two copies of SMN2, all achieved CHOP INTEND scores of 50 or greater, which exceeds the maximal score observed in untreated patients. Eight have achieved sitting, seven of whom achieved it within the World Health Organization sitting age range of 3.8-9.2 months. The other six patients have not yet passed the WHO developmental window. Among 15 patients with three copies of SMN2, four stood independently and three walked independently, all within the WHO developmental windows of 6.9-16.9 months and 8.2-17.6 months, respectively. The other patients have not yet passed the WHO developmental window. No patient in either cohort required a feeding tube, and most remained within the normal weight range. Treatment-emergent adverse events of special interest were reported in 16 patients. The study is ongoing, and patients continue to meet primary endpoints.
“Comparing functional and motor indices between these two groups [i.e., patients with two copies of SMN2 and those with three copies] should contribute to our understanding of how motor neuron loss during fetal development may impact long-term neurological outcomes over the arc of life and could even form a basis for considering antenatal gene therapy for severe forms of SMA,” said Dr. Strauss.
SPR1NT was funded by AveXis. Several of the investigators are employees of AveXis, and others received funding from the company.
Combination therapy may be a possibility
A benefit of onasemnogene abeparvovec-xioi is that the adeno-associated virus that delivers it does not integrate itself into the genome, said Darryl C. De Vivo, MD, Sidney Carter professor of neurology and professor of pediatrics at Columbia University in New York. “The bad news is that every time the cell divides, the gene therapy goes to one of the two daughter cells, but not to both. ... That means the effectiveness, in theory, would be reduced by 50% with each cell division, possibly affecting the durability of treatment.” The fact that brain and spinal cord neurons are presumed to be fully populated around the time of birth partly mitigates this concern, he added. “There isn’t too much additional cell division going on in neurons after birth at a time when the gene therapy would be administered.”
Furthermore, the cellular distribution of the gene therapy within the nervous system, which is unclear, might affect the therapy’s effect. “These are largely unanswered questions,” said Dr. De Vivo. “The answers to these questions only will come with continued observation of patients who have been treated.”
Considering that nusinersen, the antisense oligonucleotide also approved for SMA, targets SMN2, and the gene therapy replaces SMN1, “there may be some wisdom in thinking about combination therapy,” said Dr. De Vivo. “There’s no doubt that these therapeutic agents are effective,” and continued follow-up will clarify their comparative efficacy, he concluded.
SOURCES: Day JW, et al. AAN 2020. Abstract S27.001. Mendell JR, et al. AAN 2020. Abstract S27.002. Strauss KA, et al. AAN 2020. Abstract S27.003.
The research was presented online as part of the 2020 AAN Science Highlights.
SMA results from a mutation in SMN1, which encodes the SMN protein necessary for motor function. Deficiency of this protein causes motor neurons to die, resulting in severe muscle weakness. At 2 years of age, untreated patients with SMA type 1 generally die or require permanent ventilation.
The Food and Drug Administration approved onasemnogene abeparvovec-xioi under the brand name Zolgensma in May 2019. The gene-replacement therapy, which is administered once intravenously, delivers a fully functional copy of human SMN1 into the target motor neuron cells. It is indicated as treatment for SMA in infants younger than 2 years of age.
Preliminary STR1VE data
Preliminary data from the phase 3 STR1VE study were scheduled to be presented at the meeting. The open-label, single-arm, single-dose study enrolled symptomatic patients with SMA type 1 (SMA1) at multiple US sites. Enrollment was completed in May 2019.
The study included 10 male patients and 12 female patients. Participants’ mean age at dosing was 3.7 months. Of 19 patients who could have reached age 13.6 months at data cutoff, 17 (89.5%) were surviving without permanent ventilation, compared with a 25% survival rate among untreated patients. One of the 19 patients died, and the event was judged to be unrelated to treatment. Another of the 19 reached a respiratory endpoint or withdrew consent.
The population’s mean baseline Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score was 32. This score increased by 6.9, 11.7, and 14.3 points at months 1, 3, and 5, respectively. Half of the 22 infants sat independently for 30 or more seconds, and this milestone was achieved at a mean of 8.2 months after treatment. Five of six (83%) patients age 18 months or older sat independently for 30 or more seconds, which was one of the study’s primary endpoints. As of March 8, 2019, treatment-emergent adverse events of special interest were transient and not associated with any sequelae.
The STR1VE study was sponsored by AveXis, the maker of onasemnogene abeparvovec-xioi. Several of the investigators are employees of AveXis, and others received funding from the company.
Long-term follow-up in START
Long-term follow-up data for participants in the phase 1/2a START study also were scheduled to be presented. Patients who completed START were eligible to participate, and the trial’s primary aim was to evaluate the long-term safety of onasemnogene abeparvovec-xioi. Patients are intended to have five annual visits, followed by 10 annual phone calls, and the investigators request local physicians or neurologists to transfer patient records. Safety assessments include medical history and record review, physical examination, clinical laboratory evaluation, and pulmonary assessments. Efficacy assessments include evaluation of the maintenance of developmental milestones.
As of May 31, 2019, 13 patients in two cohorts had been enrolled and had had a baseline visit. For patients in Cohort 2, the mean age and time since dosing were 4.2 years and 3.9 years, respectively. All patients in Cohort 2 were alive and did not require permanent ventilation. Participants did not lose any developmental milestones that they had achieved at the end of START. Two patients were able to walk, and two could stand with assistance during long-term follow-up. This result suggests the durability of the treatment’s effect. No new treatment-related serious adverse events or adverse events of special interest had occurred as of March 8, 2019.
“We know from accumulating experience that treating infants by gene therapy is safe,” said Jerry R. Mendell, MD, the principal investigator and an attending neurologist at Nationwide Children’s Hospital in Columbus, Ohio. “Of the 15 patients we had in our first trial, only four adverse events related to the gene delivery were encountered, and only two of these were considered serious adverse events [i.e., liver enzymes that were 10 times greater than normal laboratory levels]. These laboratory tests occurred without accompanying clinical symptoms or signs. All were suppressed by corticosteroids and related to the liver inflammation. This pattern of safety has been seen in our very large gene therapy experience. No long-term surprises were encountered.”
The START study was sponsored by AveXis. Several of the investigators are employees of AveXis, and others received funding from the company.
Update on the SPR1NT study
Interim safety and efficacy data from the ongoing SPR1NT study, which includes presymptomatic patients, also were scheduled to be presented. The trial “was built on the basic premise that spinal motor neuron degeneration associated with SMN protein deficiency begins in utero, continues to progress rapidly during the first months of life, and is irreversible,” said Kevin Strauss, MD, medical director of the Clinic for Special Children in Strasburg, Pennsylvania. “SPR1NT leveraged the advantages conferred by carrier testing and newborn screening programs for SMA, which allowed the first 22 children enrolled to have a confirmed molecular diagnosis between 1 and 26 days of postnatal life, before the onset of dysphagia, respiratory compromise, or overt weakness.”
In this multicenter, open-label, phase 3 trial, presymptomatic patients age 6 weeks or younger who are expected to develop SMA receive onasemnogene abeparvovec-xioi once and are evaluated during 18 or 24 months. The primary outcomes are sitting for 30 or more seconds for infants with two copies of SMN2 and standing unassisted for infants with three copies of SMN2.
As of December 31, 2019, 29 infants had been treated in the efficacy group at a mean age of 20.6 days among infants with two copies of SMN2 and 28.7 days among infants with three copies of SMN2. All patients are alive, and no patient in SPR1NT required ventilation support at last visit. Among 14 patients with two copies of SMN2, all achieved CHOP INTEND scores of 50 or greater, which exceeds the maximal score observed in untreated patients. Eight have achieved sitting, seven of whom achieved it within the World Health Organization sitting age range of 3.8-9.2 months. The other six patients have not yet passed the WHO developmental window. Among 15 patients with three copies of SMN2, four stood independently and three walked independently, all within the WHO developmental windows of 6.9-16.9 months and 8.2-17.6 months, respectively. The other patients have not yet passed the WHO developmental window. No patient in either cohort required a feeding tube, and most remained within the normal weight range. Treatment-emergent adverse events of special interest were reported in 16 patients. The study is ongoing, and patients continue to meet primary endpoints.
“Comparing functional and motor indices between these two groups [i.e., patients with two copies of SMN2 and those with three copies] should contribute to our understanding of how motor neuron loss during fetal development may impact long-term neurological outcomes over the arc of life and could even form a basis for considering antenatal gene therapy for severe forms of SMA,” said Dr. Strauss.
SPR1NT was funded by AveXis. Several of the investigators are employees of AveXis, and others received funding from the company.
Combination therapy may be a possibility
A benefit of onasemnogene abeparvovec-xioi is that the adeno-associated virus that delivers it does not integrate itself into the genome, said Darryl C. De Vivo, MD, Sidney Carter professor of neurology and professor of pediatrics at Columbia University in New York. “The bad news is that every time the cell divides, the gene therapy goes to one of the two daughter cells, but not to both. ... That means the effectiveness, in theory, would be reduced by 50% with each cell division, possibly affecting the durability of treatment.” The fact that brain and spinal cord neurons are presumed to be fully populated around the time of birth partly mitigates this concern, he added. “There isn’t too much additional cell division going on in neurons after birth at a time when the gene therapy would be administered.”
Furthermore, the cellular distribution of the gene therapy within the nervous system, which is unclear, might affect the therapy’s effect. “These are largely unanswered questions,” said Dr. De Vivo. “The answers to these questions only will come with continued observation of patients who have been treated.”
Considering that nusinersen, the antisense oligonucleotide also approved for SMA, targets SMN2, and the gene therapy replaces SMN1, “there may be some wisdom in thinking about combination therapy,” said Dr. De Vivo. “There’s no doubt that these therapeutic agents are effective,” and continued follow-up will clarify their comparative efficacy, he concluded.
SOURCES: Day JW, et al. AAN 2020. Abstract S27.001. Mendell JR, et al. AAN 2020. Abstract S27.002. Strauss KA, et al. AAN 2020. Abstract S27.003.
The research was presented online as part of the 2020 AAN Science Highlights.
SMA results from a mutation in SMN1, which encodes the SMN protein necessary for motor function. Deficiency of this protein causes motor neurons to die, resulting in severe muscle weakness. At 2 years of age, untreated patients with SMA type 1 generally die or require permanent ventilation.
The Food and Drug Administration approved onasemnogene abeparvovec-xioi under the brand name Zolgensma in May 2019. The gene-replacement therapy, which is administered once intravenously, delivers a fully functional copy of human SMN1 into the target motor neuron cells. It is indicated as treatment for SMA in infants younger than 2 years of age.
Preliminary STR1VE data
Preliminary data from the phase 3 STR1VE study were scheduled to be presented at the meeting. The open-label, single-arm, single-dose study enrolled symptomatic patients with SMA type 1 (SMA1) at multiple US sites. Enrollment was completed in May 2019.
The study included 10 male patients and 12 female patients. Participants’ mean age at dosing was 3.7 months. Of 19 patients who could have reached age 13.6 months at data cutoff, 17 (89.5%) were surviving without permanent ventilation, compared with a 25% survival rate among untreated patients. One of the 19 patients died, and the event was judged to be unrelated to treatment. Another of the 19 reached a respiratory endpoint or withdrew consent.
The population’s mean baseline Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score was 32. This score increased by 6.9, 11.7, and 14.3 points at months 1, 3, and 5, respectively. Half of the 22 infants sat independently for 30 or more seconds, and this milestone was achieved at a mean of 8.2 months after treatment. Five of six (83%) patients age 18 months or older sat independently for 30 or more seconds, which was one of the study’s primary endpoints. As of March 8, 2019, treatment-emergent adverse events of special interest were transient and not associated with any sequelae.
The STR1VE study was sponsored by AveXis, the maker of onasemnogene abeparvovec-xioi. Several of the investigators are employees of AveXis, and others received funding from the company.
Long-term follow-up in START
Long-term follow-up data for participants in the phase 1/2a START study also were scheduled to be presented. Patients who completed START were eligible to participate, and the trial’s primary aim was to evaluate the long-term safety of onasemnogene abeparvovec-xioi. Patients are intended to have five annual visits, followed by 10 annual phone calls, and the investigators request local physicians or neurologists to transfer patient records. Safety assessments include medical history and record review, physical examination, clinical laboratory evaluation, and pulmonary assessments. Efficacy assessments include evaluation of the maintenance of developmental milestones.
As of May 31, 2019, 13 patients in two cohorts had been enrolled and had had a baseline visit. For patients in Cohort 2, the mean age and time since dosing were 4.2 years and 3.9 years, respectively. All patients in Cohort 2 were alive and did not require permanent ventilation. Participants did not lose any developmental milestones that they had achieved at the end of START. Two patients were able to walk, and two could stand with assistance during long-term follow-up. This result suggests the durability of the treatment’s effect. No new treatment-related serious adverse events or adverse events of special interest had occurred as of March 8, 2019.
“We know from accumulating experience that treating infants by gene therapy is safe,” said Jerry R. Mendell, MD, the principal investigator and an attending neurologist at Nationwide Children’s Hospital in Columbus, Ohio. “Of the 15 patients we had in our first trial, only four adverse events related to the gene delivery were encountered, and only two of these were considered serious adverse events [i.e., liver enzymes that were 10 times greater than normal laboratory levels]. These laboratory tests occurred without accompanying clinical symptoms or signs. All were suppressed by corticosteroids and related to the liver inflammation. This pattern of safety has been seen in our very large gene therapy experience. No long-term surprises were encountered.”
The START study was sponsored by AveXis. Several of the investigators are employees of AveXis, and others received funding from the company.
Update on the SPR1NT study
Interim safety and efficacy data from the ongoing SPR1NT study, which includes presymptomatic patients, also were scheduled to be presented. The trial “was built on the basic premise that spinal motor neuron degeneration associated with SMN protein deficiency begins in utero, continues to progress rapidly during the first months of life, and is irreversible,” said Kevin Strauss, MD, medical director of the Clinic for Special Children in Strasburg, Pennsylvania. “SPR1NT leveraged the advantages conferred by carrier testing and newborn screening programs for SMA, which allowed the first 22 children enrolled to have a confirmed molecular diagnosis between 1 and 26 days of postnatal life, before the onset of dysphagia, respiratory compromise, or overt weakness.”
In this multicenter, open-label, phase 3 trial, presymptomatic patients age 6 weeks or younger who are expected to develop SMA receive onasemnogene abeparvovec-xioi once and are evaluated during 18 or 24 months. The primary outcomes are sitting for 30 or more seconds for infants with two copies of SMN2 and standing unassisted for infants with three copies of SMN2.
As of December 31, 2019, 29 infants had been treated in the efficacy group at a mean age of 20.6 days among infants with two copies of SMN2 and 28.7 days among infants with three copies of SMN2. All patients are alive, and no patient in SPR1NT required ventilation support at last visit. Among 14 patients with two copies of SMN2, all achieved CHOP INTEND scores of 50 or greater, which exceeds the maximal score observed in untreated patients. Eight have achieved sitting, seven of whom achieved it within the World Health Organization sitting age range of 3.8-9.2 months. The other six patients have not yet passed the WHO developmental window. Among 15 patients with three copies of SMN2, four stood independently and three walked independently, all within the WHO developmental windows of 6.9-16.9 months and 8.2-17.6 months, respectively. The other patients have not yet passed the WHO developmental window. No patient in either cohort required a feeding tube, and most remained within the normal weight range. Treatment-emergent adverse events of special interest were reported in 16 patients. The study is ongoing, and patients continue to meet primary endpoints.
“Comparing functional and motor indices between these two groups [i.e., patients with two copies of SMN2 and those with three copies] should contribute to our understanding of how motor neuron loss during fetal development may impact long-term neurological outcomes over the arc of life and could even form a basis for considering antenatal gene therapy for severe forms of SMA,” said Dr. Strauss.
SPR1NT was funded by AveXis. Several of the investigators are employees of AveXis, and others received funding from the company.
Combination therapy may be a possibility
A benefit of onasemnogene abeparvovec-xioi is that the adeno-associated virus that delivers it does not integrate itself into the genome, said Darryl C. De Vivo, MD, Sidney Carter professor of neurology and professor of pediatrics at Columbia University in New York. “The bad news is that every time the cell divides, the gene therapy goes to one of the two daughter cells, but not to both. ... That means the effectiveness, in theory, would be reduced by 50% with each cell division, possibly affecting the durability of treatment.” The fact that brain and spinal cord neurons are presumed to be fully populated around the time of birth partly mitigates this concern, he added. “There isn’t too much additional cell division going on in neurons after birth at a time when the gene therapy would be administered.”
Furthermore, the cellular distribution of the gene therapy within the nervous system, which is unclear, might affect the therapy’s effect. “These are largely unanswered questions,” said Dr. De Vivo. “The answers to these questions only will come with continued observation of patients who have been treated.”
Considering that nusinersen, the antisense oligonucleotide also approved for SMA, targets SMN2, and the gene therapy replaces SMN1, “there may be some wisdom in thinking about combination therapy,” said Dr. De Vivo. “There’s no doubt that these therapeutic agents are effective,” and continued follow-up will clarify their comparative efficacy, he concluded.
SOURCES: Day JW, et al. AAN 2020. Abstract S27.001. Mendell JR, et al. AAN 2020. Abstract S27.002. Strauss KA, et al. AAN 2020. Abstract S27.003.
FROM AAN 2020
Frontal lobe glucose abnormalities may indicate increased SUDEP risk
, new research suggests.
“The data provide initial evidence that hypometabolism in certain parts of the frontal cortex may be associated with higher SUDEP risk,” said lead author Maysaa M. Basha, MD, associate professor of neurology and director of the Adult Comprehensive Epilepsy Program, Wayne State University/Detroit Medical Center, in Michigan.
If this research is validated, “it potentially can be used to screen patients for higher SUDEP risk,” she said. The idea is to identify those at high risk and then reduce that risk with more aggressive management of seizures or closer monitoring in certain cases, she added.
The research is being presented online as part of the 2020 American Academy of Neurology (AAN) Science Highlights.
Hypometabolism
Dr. Basha and colleagues were encouraged to pursue this new line of research after a pilot [18F]fluorodeoxyglucose positron-emission tomography (FDG-PET) study revealed frontal lobe hypometabolism among patients who subsequently died.
“We wanted to determine if such a metabolic abnormality is associated with SUDEP risk,” said Dr. Basha. She noted that no PET studies have addressed this question, only MRI studies.
In this new study, researchers aimed to identify specific patterns of objectively detected brain glucose metabolic abnormalities in patients with refractory focal epilepsy who were at risk for SUDEP.
The study included 80 patients (45 female patients) aged 16 to 61 years (mean age, 37 years) who underwent FDG-PET as part of their presurgical evaluation for epilepsy surgery. Patients with large brain lesions, such as an infarct or a large tumor, were excluded from the study; such lesions can affect the accuracy of an objective PET analysis, explained Dr. Basha.
The researchers assessed risk for SUDEP using the seven-item SUDEP inventory (SUDEP-7), which was developed as a marker of clinical SUDEP risk. The 0- to 10-point scale is used to evaluate the frequency of tonic-clonic and other seizures, the duration of epilepsy, the use of antiepileptic drugs, and intellectual disability.
The researchers calculated SUDEP-7 inventory scores as closely as possible to FDG-PET assessments. The mean score in the patient population was 3.6.
The investigators divided participants into two subgroups: 22 patients had a SUDEP score of 5 or greater; and 58 had a score of less than 5 (higher scores indicate higher risk for SUDEP).
The researchers compared PET scans of each of these subgroups to PET scans from healthy adults to determine whether they showed common areas of metabolic abnormality. For this, they used an image analytic software program called Statistical Parametric Mapping, which compares group values of metabolic activity measured in small units of the brain (voxels) with statistical methods.
The analysis showed that the higher-risk group displayed a common pattern of hypometabolism in certain brain areas.
“The epilepsy patient subgroup with high SUDEP risk showed areas of decreased metabolism, as compared to the control group, in portions of the frontal cortex,” said Dr. Basha. “The statistically most significant decreases were in the right frontal lobe area—both lateral convexity and medial cortex.”
Dr. Basha added that these group abnormalities were “remarkably similar” to the individual metabolic abnormalities found in the four SUDEP patients in the previous pilot study who underwent PET scanning and who subsequently died.
A similar group analysis showed that the group at low SUDEP risk displayed no common metabolic abnormalities.
MRI findings were normal for 40 patients.
Dr. Basha and colleagues believe that “this is the first PET study assessing the metabolic correlates of SUDEP risk on the group level.”
Common feature
Interictal glucose hypometabolism is “common in and around epileptic foci,” noted Dr. Basha. However, this could extend into nonepileptic regions—for example, to remote connected regions where seizures can spread from the primary focus and into subcortical gray matter structures, such the thalamus.
Some of these metabolic abnormalities may indicate subtle, microscopic, structural abnormalities in the affected brain, said Dr. Basha.
Abnormalities that are induced by epilepsy and that result from purely metabolic changes could be partly or fully reversed if seizures are controlled on a long-term basis, she said. “Some metabolic abnormalities can be reversed after better seizure control with antiepileptic drugs, epileptic surgery, or other antiepileptic treatment,” she said.
It’s “quite possible” that the same brain pattern would be evident in children with epilepsy, although her team has not performed the same analysis in a younger pediatric group, said Dr. Basha. She noted that it would be unethical to administer PET scans, which involve radiation, to young, healthy control persons.
It’s too early to recommend that all epilepsy patients undergo FDG-PET scanning to see whether this pattern of brain glucose hypometabolism is present, said Dr. Basha. “But if this is proven to be a good biomarker, the next step would be a prospective study” to see whether this brain marker is a true signal of SUDEP risk.
“I don’t think our single study would do that, but ultimately, that would be the goal,” she added.
One more piece of the SUDEP puzzle
Commenting on the study, William Davis Gaillard, MD, president of the American Epilepsy Society and chief of neurology, Children’s National Medical Center, Chevy Chase, Maryland, said this new information provides one more piece of the SUDEP puzzle but doesn’t complete the picture.
The study authors assessed PET scans of a group of patients and found common abnormalities that implicate the right medial frontal cortex. “That’s a pretty reasonable method” of investigation, said Dr. Gaillard.
“The challenge is that they’re looking at people they believe have a risk of SUDEP as opposed to people who died,” said Dr. Gaillard.
But he agreed that the results might signal “a biomarker” that “allows you to identify who’s at high risk, and then you may be able to intervene to save them.”
It’s not clear that people with frontal lobe epilepsy are at greater risk for SUDEP than those with temporal lobe epilepsy, he said.
“What you don’t know is whether this represents people with a seizure focus in that area or this represents a common network implicated in people with diverse forms of focal epilepsy; so you need to do some more work,” he said.
Dr. Gaillard pointed out that other research has implicated regions other than the mesial frontal cortex in SUDEP risk. These regions include the insula, the amygdala, the hippocampus, and the brain stem.
He also noted that the SUDEP-7, which has not been thoroughly validated, is designed for use only in adults.
In his own practice, he asks patients about the frequency of tonic-clonic seizures and whether they occur at night. The number of antiepileptic medications a patient takes reflects the difficulty of controlling seizures and may not be “an independent variable for risk,” said Dr. Gaillard.
“It’s clear one needs a better assessment and better idea of who is at risk,” he said.
The researchers have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
SOURCE: Basha A et al. AAN 2020. Abstract P5.001.
, new research suggests.
“The data provide initial evidence that hypometabolism in certain parts of the frontal cortex may be associated with higher SUDEP risk,” said lead author Maysaa M. Basha, MD, associate professor of neurology and director of the Adult Comprehensive Epilepsy Program, Wayne State University/Detroit Medical Center, in Michigan.
If this research is validated, “it potentially can be used to screen patients for higher SUDEP risk,” she said. The idea is to identify those at high risk and then reduce that risk with more aggressive management of seizures or closer monitoring in certain cases, she added.
The research is being presented online as part of the 2020 American Academy of Neurology (AAN) Science Highlights.
Hypometabolism
Dr. Basha and colleagues were encouraged to pursue this new line of research after a pilot [18F]fluorodeoxyglucose positron-emission tomography (FDG-PET) study revealed frontal lobe hypometabolism among patients who subsequently died.
“We wanted to determine if such a metabolic abnormality is associated with SUDEP risk,” said Dr. Basha. She noted that no PET studies have addressed this question, only MRI studies.
In this new study, researchers aimed to identify specific patterns of objectively detected brain glucose metabolic abnormalities in patients with refractory focal epilepsy who were at risk for SUDEP.
The study included 80 patients (45 female patients) aged 16 to 61 years (mean age, 37 years) who underwent FDG-PET as part of their presurgical evaluation for epilepsy surgery. Patients with large brain lesions, such as an infarct or a large tumor, were excluded from the study; such lesions can affect the accuracy of an objective PET analysis, explained Dr. Basha.
The researchers assessed risk for SUDEP using the seven-item SUDEP inventory (SUDEP-7), which was developed as a marker of clinical SUDEP risk. The 0- to 10-point scale is used to evaluate the frequency of tonic-clonic and other seizures, the duration of epilepsy, the use of antiepileptic drugs, and intellectual disability.
The researchers calculated SUDEP-7 inventory scores as closely as possible to FDG-PET assessments. The mean score in the patient population was 3.6.
The investigators divided participants into two subgroups: 22 patients had a SUDEP score of 5 or greater; and 58 had a score of less than 5 (higher scores indicate higher risk for SUDEP).
The researchers compared PET scans of each of these subgroups to PET scans from healthy adults to determine whether they showed common areas of metabolic abnormality. For this, they used an image analytic software program called Statistical Parametric Mapping, which compares group values of metabolic activity measured in small units of the brain (voxels) with statistical methods.
The analysis showed that the higher-risk group displayed a common pattern of hypometabolism in certain brain areas.
“The epilepsy patient subgroup with high SUDEP risk showed areas of decreased metabolism, as compared to the control group, in portions of the frontal cortex,” said Dr. Basha. “The statistically most significant decreases were in the right frontal lobe area—both lateral convexity and medial cortex.”
Dr. Basha added that these group abnormalities were “remarkably similar” to the individual metabolic abnormalities found in the four SUDEP patients in the previous pilot study who underwent PET scanning and who subsequently died.
A similar group analysis showed that the group at low SUDEP risk displayed no common metabolic abnormalities.
MRI findings were normal for 40 patients.
Dr. Basha and colleagues believe that “this is the first PET study assessing the metabolic correlates of SUDEP risk on the group level.”
Common feature
Interictal glucose hypometabolism is “common in and around epileptic foci,” noted Dr. Basha. However, this could extend into nonepileptic regions—for example, to remote connected regions where seizures can spread from the primary focus and into subcortical gray matter structures, such the thalamus.
Some of these metabolic abnormalities may indicate subtle, microscopic, structural abnormalities in the affected brain, said Dr. Basha.
Abnormalities that are induced by epilepsy and that result from purely metabolic changes could be partly or fully reversed if seizures are controlled on a long-term basis, she said. “Some metabolic abnormalities can be reversed after better seizure control with antiepileptic drugs, epileptic surgery, or other antiepileptic treatment,” she said.
It’s “quite possible” that the same brain pattern would be evident in children with epilepsy, although her team has not performed the same analysis in a younger pediatric group, said Dr. Basha. She noted that it would be unethical to administer PET scans, which involve radiation, to young, healthy control persons.
It’s too early to recommend that all epilepsy patients undergo FDG-PET scanning to see whether this pattern of brain glucose hypometabolism is present, said Dr. Basha. “But if this is proven to be a good biomarker, the next step would be a prospective study” to see whether this brain marker is a true signal of SUDEP risk.
“I don’t think our single study would do that, but ultimately, that would be the goal,” she added.
One more piece of the SUDEP puzzle
Commenting on the study, William Davis Gaillard, MD, president of the American Epilepsy Society and chief of neurology, Children’s National Medical Center, Chevy Chase, Maryland, said this new information provides one more piece of the SUDEP puzzle but doesn’t complete the picture.
The study authors assessed PET scans of a group of patients and found common abnormalities that implicate the right medial frontal cortex. “That’s a pretty reasonable method” of investigation, said Dr. Gaillard.
“The challenge is that they’re looking at people they believe have a risk of SUDEP as opposed to people who died,” said Dr. Gaillard.
But he agreed that the results might signal “a biomarker” that “allows you to identify who’s at high risk, and then you may be able to intervene to save them.”
It’s not clear that people with frontal lobe epilepsy are at greater risk for SUDEP than those with temporal lobe epilepsy, he said.
“What you don’t know is whether this represents people with a seizure focus in that area or this represents a common network implicated in people with diverse forms of focal epilepsy; so you need to do some more work,” he said.
Dr. Gaillard pointed out that other research has implicated regions other than the mesial frontal cortex in SUDEP risk. These regions include the insula, the amygdala, the hippocampus, and the brain stem.
He also noted that the SUDEP-7, which has not been thoroughly validated, is designed for use only in adults.
In his own practice, he asks patients about the frequency of tonic-clonic seizures and whether they occur at night. The number of antiepileptic medications a patient takes reflects the difficulty of controlling seizures and may not be “an independent variable for risk,” said Dr. Gaillard.
“It’s clear one needs a better assessment and better idea of who is at risk,” he said.
The researchers have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
SOURCE: Basha A et al. AAN 2020. Abstract P5.001.
, new research suggests.
“The data provide initial evidence that hypometabolism in certain parts of the frontal cortex may be associated with higher SUDEP risk,” said lead author Maysaa M. Basha, MD, associate professor of neurology and director of the Adult Comprehensive Epilepsy Program, Wayne State University/Detroit Medical Center, in Michigan.
If this research is validated, “it potentially can be used to screen patients for higher SUDEP risk,” she said. The idea is to identify those at high risk and then reduce that risk with more aggressive management of seizures or closer monitoring in certain cases, she added.
The research is being presented online as part of the 2020 American Academy of Neurology (AAN) Science Highlights.
Hypometabolism
Dr. Basha and colleagues were encouraged to pursue this new line of research after a pilot [18F]fluorodeoxyglucose positron-emission tomography (FDG-PET) study revealed frontal lobe hypometabolism among patients who subsequently died.
“We wanted to determine if such a metabolic abnormality is associated with SUDEP risk,” said Dr. Basha. She noted that no PET studies have addressed this question, only MRI studies.
In this new study, researchers aimed to identify specific patterns of objectively detected brain glucose metabolic abnormalities in patients with refractory focal epilepsy who were at risk for SUDEP.
The study included 80 patients (45 female patients) aged 16 to 61 years (mean age, 37 years) who underwent FDG-PET as part of their presurgical evaluation for epilepsy surgery. Patients with large brain lesions, such as an infarct or a large tumor, were excluded from the study; such lesions can affect the accuracy of an objective PET analysis, explained Dr. Basha.
The researchers assessed risk for SUDEP using the seven-item SUDEP inventory (SUDEP-7), which was developed as a marker of clinical SUDEP risk. The 0- to 10-point scale is used to evaluate the frequency of tonic-clonic and other seizures, the duration of epilepsy, the use of antiepileptic drugs, and intellectual disability.
The researchers calculated SUDEP-7 inventory scores as closely as possible to FDG-PET assessments. The mean score in the patient population was 3.6.
The investigators divided participants into two subgroups: 22 patients had a SUDEP score of 5 or greater; and 58 had a score of less than 5 (higher scores indicate higher risk for SUDEP).
The researchers compared PET scans of each of these subgroups to PET scans from healthy adults to determine whether they showed common areas of metabolic abnormality. For this, they used an image analytic software program called Statistical Parametric Mapping, which compares group values of metabolic activity measured in small units of the brain (voxels) with statistical methods.
The analysis showed that the higher-risk group displayed a common pattern of hypometabolism in certain brain areas.
“The epilepsy patient subgroup with high SUDEP risk showed areas of decreased metabolism, as compared to the control group, in portions of the frontal cortex,” said Dr. Basha. “The statistically most significant decreases were in the right frontal lobe area—both lateral convexity and medial cortex.”
Dr. Basha added that these group abnormalities were “remarkably similar” to the individual metabolic abnormalities found in the four SUDEP patients in the previous pilot study who underwent PET scanning and who subsequently died.
A similar group analysis showed that the group at low SUDEP risk displayed no common metabolic abnormalities.
MRI findings were normal for 40 patients.
Dr. Basha and colleagues believe that “this is the first PET study assessing the metabolic correlates of SUDEP risk on the group level.”
Common feature
Interictal glucose hypometabolism is “common in and around epileptic foci,” noted Dr. Basha. However, this could extend into nonepileptic regions—for example, to remote connected regions where seizures can spread from the primary focus and into subcortical gray matter structures, such the thalamus.
Some of these metabolic abnormalities may indicate subtle, microscopic, structural abnormalities in the affected brain, said Dr. Basha.
Abnormalities that are induced by epilepsy and that result from purely metabolic changes could be partly or fully reversed if seizures are controlled on a long-term basis, she said. “Some metabolic abnormalities can be reversed after better seizure control with antiepileptic drugs, epileptic surgery, or other antiepileptic treatment,” she said.
It’s “quite possible” that the same brain pattern would be evident in children with epilepsy, although her team has not performed the same analysis in a younger pediatric group, said Dr. Basha. She noted that it would be unethical to administer PET scans, which involve radiation, to young, healthy control persons.
It’s too early to recommend that all epilepsy patients undergo FDG-PET scanning to see whether this pattern of brain glucose hypometabolism is present, said Dr. Basha. “But if this is proven to be a good biomarker, the next step would be a prospective study” to see whether this brain marker is a true signal of SUDEP risk.
“I don’t think our single study would do that, but ultimately, that would be the goal,” she added.
One more piece of the SUDEP puzzle
Commenting on the study, William Davis Gaillard, MD, president of the American Epilepsy Society and chief of neurology, Children’s National Medical Center, Chevy Chase, Maryland, said this new information provides one more piece of the SUDEP puzzle but doesn’t complete the picture.
The study authors assessed PET scans of a group of patients and found common abnormalities that implicate the right medial frontal cortex. “That’s a pretty reasonable method” of investigation, said Dr. Gaillard.
“The challenge is that they’re looking at people they believe have a risk of SUDEP as opposed to people who died,” said Dr. Gaillard.
But he agreed that the results might signal “a biomarker” that “allows you to identify who’s at high risk, and then you may be able to intervene to save them.”
It’s not clear that people with frontal lobe epilepsy are at greater risk for SUDEP than those with temporal lobe epilepsy, he said.
“What you don’t know is whether this represents people with a seizure focus in that area or this represents a common network implicated in people with diverse forms of focal epilepsy; so you need to do some more work,” he said.
Dr. Gaillard pointed out that other research has implicated regions other than the mesial frontal cortex in SUDEP risk. These regions include the insula, the amygdala, the hippocampus, and the brain stem.
He also noted that the SUDEP-7, which has not been thoroughly validated, is designed for use only in adults.
In his own practice, he asks patients about the frequency of tonic-clonic seizures and whether they occur at night. The number of antiepileptic medications a patient takes reflects the difficulty of controlling seizures and may not be “an independent variable for risk,” said Dr. Gaillard.
“It’s clear one needs a better assessment and better idea of who is at risk,” he said.
The researchers have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
SOURCE: Basha A et al. AAN 2020. Abstract P5.001.
Natalizumab bests fingolimod for relapsing-remitting MS
(RRMS). Use of natalizumab was associated with fewer new T2 lesions (0.7 vs 1.4 with fingolimod) and gadolinium-enhancing lesions (0.03 vs. 0.5, respectively) at 12 months, for example.
“The take-home message is that natalizumab showed significant superiority compared to fingolimod on the primary outcome, which was the proportion of patients reaching NEDA [no evidence of disease activity] at 12 months,” lead author Mikael Cohen, MD, said.
“The difference between both drugs was prominent on MRI parameters, especially regarding the number of gadolinium-enhancing lesions,” added Dr. Cohen, of the Department of Neurology at University Hospital Center in Nice, France.
This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Twelve-month results
The design of the Best Escalation Strategy in MS (BEST MS) study makes it unique, Dr. Cohen said. “It was a prospective and standardized study, unlike most other publications comparing efficacy of those two drugs that were based on retrospective analysis of data registries,” he said. Although BEST MS was an open-label, real-life analysis, the neuroradiologist who analyzed MRI images was blinded to treatment arms, he added.
The multicenter study began in France in 2013, when natalizumab and fingolimod were the two most commonly used agents for active RRMS.
Dr. Cohen and colleagues assessed 230 patients with the condition. The mean age was 38 years, and 75% were women. At the discretion of the treating physician, 113 participants received natalizumab, and 117 were treated with fingolimod.
A multivariate analysis confirmed that fingolimod was associated with a lower likelihood of achieving NEDA at 12 months.
Most relapses occurred early, and the annual relapse rate favored natalizumab, the researchers noted. In addition, the number of discontinuations due to adverse events was higher in the fingolimod group.
“We are working to submit the paper for publication,” Dr. Cohen said. It has also been submitted to the ECTRIMS/ACTRIMS Joint Congress in Washington, DC, for presentation in September 2020.
More tesearch warranted
Commenting on the study, Michelle H. Cameron, MD, said the findings are difficult to interpret because “this was not a randomized controlled trial. Treatment choice was at the discretion of the providers.
“It is hard to know what biases this approach introduced – although it is reassuring that the baseline clinical and radiographic characteristics are described as similar,” said Cameron, codirector of the MS Center of Excellence West at the VA Portland Health Care System, Oregon.
In addition, the superior MRI outcomes at 12 months with natalizumab need to be backed up by clinical outcomes, she said, preferably spanning at least 2 years.
“Overall, these results seem to be consistent with the randomized controlled trials of these individual agents,” Dr. Cameron concluded.
BEST MS was an institutional study and was not funded by any pharmaceutical firm. Dr. Cohen has disclosed no relevant financial relationships. Dr. Cameron is a consultant for Greenwich Biosciences and Adamas Pharmaceuticals.
This article first appeared on Medscape.com.
(RRMS). Use of natalizumab was associated with fewer new T2 lesions (0.7 vs 1.4 with fingolimod) and gadolinium-enhancing lesions (0.03 vs. 0.5, respectively) at 12 months, for example.
“The take-home message is that natalizumab showed significant superiority compared to fingolimod on the primary outcome, which was the proportion of patients reaching NEDA [no evidence of disease activity] at 12 months,” lead author Mikael Cohen, MD, said.
“The difference between both drugs was prominent on MRI parameters, especially regarding the number of gadolinium-enhancing lesions,” added Dr. Cohen, of the Department of Neurology at University Hospital Center in Nice, France.
This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Twelve-month results
The design of the Best Escalation Strategy in MS (BEST MS) study makes it unique, Dr. Cohen said. “It was a prospective and standardized study, unlike most other publications comparing efficacy of those two drugs that were based on retrospective analysis of data registries,” he said. Although BEST MS was an open-label, real-life analysis, the neuroradiologist who analyzed MRI images was blinded to treatment arms, he added.
The multicenter study began in France in 2013, when natalizumab and fingolimod were the two most commonly used agents for active RRMS.
Dr. Cohen and colleagues assessed 230 patients with the condition. The mean age was 38 years, and 75% were women. At the discretion of the treating physician, 113 participants received natalizumab, and 117 were treated with fingolimod.
A multivariate analysis confirmed that fingolimod was associated with a lower likelihood of achieving NEDA at 12 months.
Most relapses occurred early, and the annual relapse rate favored natalizumab, the researchers noted. In addition, the number of discontinuations due to adverse events was higher in the fingolimod group.
“We are working to submit the paper for publication,” Dr. Cohen said. It has also been submitted to the ECTRIMS/ACTRIMS Joint Congress in Washington, DC, for presentation in September 2020.
More tesearch warranted
Commenting on the study, Michelle H. Cameron, MD, said the findings are difficult to interpret because “this was not a randomized controlled trial. Treatment choice was at the discretion of the providers.
“It is hard to know what biases this approach introduced – although it is reassuring that the baseline clinical and radiographic characteristics are described as similar,” said Cameron, codirector of the MS Center of Excellence West at the VA Portland Health Care System, Oregon.
In addition, the superior MRI outcomes at 12 months with natalizumab need to be backed up by clinical outcomes, she said, preferably spanning at least 2 years.
“Overall, these results seem to be consistent with the randomized controlled trials of these individual agents,” Dr. Cameron concluded.
BEST MS was an institutional study and was not funded by any pharmaceutical firm. Dr. Cohen has disclosed no relevant financial relationships. Dr. Cameron is a consultant for Greenwich Biosciences and Adamas Pharmaceuticals.
This article first appeared on Medscape.com.
(RRMS). Use of natalizumab was associated with fewer new T2 lesions (0.7 vs 1.4 with fingolimod) and gadolinium-enhancing lesions (0.03 vs. 0.5, respectively) at 12 months, for example.
“The take-home message is that natalizumab showed significant superiority compared to fingolimod on the primary outcome, which was the proportion of patients reaching NEDA [no evidence of disease activity] at 12 months,” lead author Mikael Cohen, MD, said.
“The difference between both drugs was prominent on MRI parameters, especially regarding the number of gadolinium-enhancing lesions,” added Dr. Cohen, of the Department of Neurology at University Hospital Center in Nice, France.
This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Twelve-month results
The design of the Best Escalation Strategy in MS (BEST MS) study makes it unique, Dr. Cohen said. “It was a prospective and standardized study, unlike most other publications comparing efficacy of those two drugs that were based on retrospective analysis of data registries,” he said. Although BEST MS was an open-label, real-life analysis, the neuroradiologist who analyzed MRI images was blinded to treatment arms, he added.
The multicenter study began in France in 2013, when natalizumab and fingolimod were the two most commonly used agents for active RRMS.
Dr. Cohen and colleagues assessed 230 patients with the condition. The mean age was 38 years, and 75% were women. At the discretion of the treating physician, 113 participants received natalizumab, and 117 were treated with fingolimod.
A multivariate analysis confirmed that fingolimod was associated with a lower likelihood of achieving NEDA at 12 months.
Most relapses occurred early, and the annual relapse rate favored natalizumab, the researchers noted. In addition, the number of discontinuations due to adverse events was higher in the fingolimod group.
“We are working to submit the paper for publication,” Dr. Cohen said. It has also been submitted to the ECTRIMS/ACTRIMS Joint Congress in Washington, DC, for presentation in September 2020.
More tesearch warranted
Commenting on the study, Michelle H. Cameron, MD, said the findings are difficult to interpret because “this was not a randomized controlled trial. Treatment choice was at the discretion of the providers.
“It is hard to know what biases this approach introduced – although it is reassuring that the baseline clinical and radiographic characteristics are described as similar,” said Cameron, codirector of the MS Center of Excellence West at the VA Portland Health Care System, Oregon.
In addition, the superior MRI outcomes at 12 months with natalizumab need to be backed up by clinical outcomes, she said, preferably spanning at least 2 years.
“Overall, these results seem to be consistent with the randomized controlled trials of these individual agents,” Dr. Cameron concluded.
BEST MS was an institutional study and was not funded by any pharmaceutical firm. Dr. Cohen has disclosed no relevant financial relationships. Dr. Cameron is a consultant for Greenwich Biosciences and Adamas Pharmaceuticals.
This article first appeared on Medscape.com.
Incidental finding on brain MRI seen in 5% of older patients
New research shows that Knowing the expected prevalence of such incidental findings in the older general population is “extremely useful” for both researchers and clinicians, said study co-author Sarah Elisabeth Keuss, MBChB, clinical research associate, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.
“In research, the knowledge helps to inform study protocols regarding how to manage incidental findings and enables study participants to be appropriately informed,” said Dr. Keuss. Greater awareness also helps clinicians make decisions about whether or not to scan a patient, she said, adding that imaging is increasingly available to them. It allows clinicians to counsel patients regarding the probability of an incidental finding and balance that risk against the potential benefits of having a test.
The research is being presented online as part of the American Academy of Neurology 2020 Science Highlights. The incidental findings also were published last year in BMJ Open.
The new findings are from the first wave of data collection for the Insight 46 study, a neuroimaging substudy of the MRC National Survey of Health and Development (NSHD) 1946 British birth cohort, a broadly representative sample of the population born in mainland Britain during 1946. The research uses detailed brain imaging, cognitive testing, and blood and other biomarkers to investigate genetic and life-course factors associated with Alzheimer’s disease and cerebrovascular disease.
The current study included 502 individuals, aged about 71 years at the time of the analysis, and 49% were women. Almost all (93.8%) participants underwent 1-day MRI scans. Some 4.5% of these participants had an incidental finding of brain abnormality as per a prespecified standardized protocol.
Suspected vascular malformations were present in 1.9%, and suspected intracranial mass lesions were present in 1.5%. The single most common vascular abnormality was a suspected cerebral aneurysm, which affected 1.1% of participants.
Suspected meningiomas were the most common intracranial lesion, affecting 0.6% of study participants.
Action plan
Participants and their primary care provider were informed of findings “that were deemed to be potentially serious, or life-threatening, or could have a major impact on quality of life,” said Dr. Keuss. Relevant experts “came up with a recommended clinical action plan to help the primary care provider decide what should be the next course of action with regard to investigation or referral to another specialist,” said Dr. Keuss.
The new results are important for clinical decision-making, said Dr. Keuss. “Clinicians should consider the possibility of detecting an incidental finding whenever they’re requesting a brain scan. They should balance that risk against the possible benefits of recommending a test.”
The prevalence of incidental findings on MRI reported in the literature varies because of different methods used to review scans. “However, comparing our study with similar studies, the prevalence of the key findings with regard to aneurysms and intracranial mass lesions are very similar,” said Dr. Keuss.
Dr. Keuss and colleagues do not recommend all elderly patients get a brain scan.
“We don’t know what the long-term consequences are of being informed you have an incidental finding of an abnormality; we don’t know if it improves their outcome, and it potentially could cause anxiety,” said Dr. Keuss.
Psychological impact
The researchers have not looked at the psychological impact of negative findings on study participants, but they could do so at a later date.
“It would be very important to look into that given the potential to cause anxiety,” said Dr. Keuss. “It’s important to find out the potential negative consequences to inform researchers in future about how best to manage these findings.”
From blood tests, the analysis found that more than a third (34.6%) of participants had at least one related abnormality. The most common of these were kidney impairment (about 9%), thyroid function abnormalities (between 4% and 5%), anemia (about 4%), and low vitamin B12 levels (about 3%).
However, few of these reached the prespecified threshold for urgent action, and Dr. Keuss noted these findings were not the focus of her AAN presentation.
A strength of the study was that participants were almost the exact same age.
Important issue
Commenting on the research, David S. Liebeskind, MD, professor of neurology and director, Neurovascular Imaging Research Core, University of California, Los Angeles, said it raises “a very interesting” and “important” public health issue.
“The question is whether we do things based around individual symptomatic status, or at a larger level in terms of public health, screening the larger population to figure out who is at risk for any particular disease or disorder.”
From the standpoint of imaging technologies like MRI that show details about brain structures, experts debate whether the population should be screened “before something occurs,” said Dr. Liebeskind. “Imaging has the capacity to tell us a tremendous amount; whether this implies we should therefore image everybody is a larger public health question.”
The issue is “fraught with a lot of difficulty and complexity” as treatment paradigms tend to be “built around symptomatic status,” he said. “When we sit in the office or with a patient at the bedside, we usually focus on that individual patient and not necessarily on the larger public.”
Dr. Liebeskind noted that the question of whether to put the emphasis on the individual patient or the public at large is also being discussed during the current COVID-19 pandemic.
He wasn’t surprised that the study uncovered incidental findings in almost 5% of the sample. “If you take an 80-year-old and study their brain, a good chunk, if not half or more, will have some abnormality,” he said.
Drs. Keuss and Liebeskind have reported no relevant financial relationships.
This article first appeared on Medscape.com.
New research shows that Knowing the expected prevalence of such incidental findings in the older general population is “extremely useful” for both researchers and clinicians, said study co-author Sarah Elisabeth Keuss, MBChB, clinical research associate, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.
“In research, the knowledge helps to inform study protocols regarding how to manage incidental findings and enables study participants to be appropriately informed,” said Dr. Keuss. Greater awareness also helps clinicians make decisions about whether or not to scan a patient, she said, adding that imaging is increasingly available to them. It allows clinicians to counsel patients regarding the probability of an incidental finding and balance that risk against the potential benefits of having a test.
The research is being presented online as part of the American Academy of Neurology 2020 Science Highlights. The incidental findings also were published last year in BMJ Open.
The new findings are from the first wave of data collection for the Insight 46 study, a neuroimaging substudy of the MRC National Survey of Health and Development (NSHD) 1946 British birth cohort, a broadly representative sample of the population born in mainland Britain during 1946. The research uses detailed brain imaging, cognitive testing, and blood and other biomarkers to investigate genetic and life-course factors associated with Alzheimer’s disease and cerebrovascular disease.
The current study included 502 individuals, aged about 71 years at the time of the analysis, and 49% were women. Almost all (93.8%) participants underwent 1-day MRI scans. Some 4.5% of these participants had an incidental finding of brain abnormality as per a prespecified standardized protocol.
Suspected vascular malformations were present in 1.9%, and suspected intracranial mass lesions were present in 1.5%. The single most common vascular abnormality was a suspected cerebral aneurysm, which affected 1.1% of participants.
Suspected meningiomas were the most common intracranial lesion, affecting 0.6% of study participants.
Action plan
Participants and their primary care provider were informed of findings “that were deemed to be potentially serious, or life-threatening, or could have a major impact on quality of life,” said Dr. Keuss. Relevant experts “came up with a recommended clinical action plan to help the primary care provider decide what should be the next course of action with regard to investigation or referral to another specialist,” said Dr. Keuss.
The new results are important for clinical decision-making, said Dr. Keuss. “Clinicians should consider the possibility of detecting an incidental finding whenever they’re requesting a brain scan. They should balance that risk against the possible benefits of recommending a test.”
The prevalence of incidental findings on MRI reported in the literature varies because of different methods used to review scans. “However, comparing our study with similar studies, the prevalence of the key findings with regard to aneurysms and intracranial mass lesions are very similar,” said Dr. Keuss.
Dr. Keuss and colleagues do not recommend all elderly patients get a brain scan.
“We don’t know what the long-term consequences are of being informed you have an incidental finding of an abnormality; we don’t know if it improves their outcome, and it potentially could cause anxiety,” said Dr. Keuss.
Psychological impact
The researchers have not looked at the psychological impact of negative findings on study participants, but they could do so at a later date.
“It would be very important to look into that given the potential to cause anxiety,” said Dr. Keuss. “It’s important to find out the potential negative consequences to inform researchers in future about how best to manage these findings.”
From blood tests, the analysis found that more than a third (34.6%) of participants had at least one related abnormality. The most common of these were kidney impairment (about 9%), thyroid function abnormalities (between 4% and 5%), anemia (about 4%), and low vitamin B12 levels (about 3%).
However, few of these reached the prespecified threshold for urgent action, and Dr. Keuss noted these findings were not the focus of her AAN presentation.
A strength of the study was that participants were almost the exact same age.
Important issue
Commenting on the research, David S. Liebeskind, MD, professor of neurology and director, Neurovascular Imaging Research Core, University of California, Los Angeles, said it raises “a very interesting” and “important” public health issue.
“The question is whether we do things based around individual symptomatic status, or at a larger level in terms of public health, screening the larger population to figure out who is at risk for any particular disease or disorder.”
From the standpoint of imaging technologies like MRI that show details about brain structures, experts debate whether the population should be screened “before something occurs,” said Dr. Liebeskind. “Imaging has the capacity to tell us a tremendous amount; whether this implies we should therefore image everybody is a larger public health question.”
The issue is “fraught with a lot of difficulty and complexity” as treatment paradigms tend to be “built around symptomatic status,” he said. “When we sit in the office or with a patient at the bedside, we usually focus on that individual patient and not necessarily on the larger public.”
Dr. Liebeskind noted that the question of whether to put the emphasis on the individual patient or the public at large is also being discussed during the current COVID-19 pandemic.
He wasn’t surprised that the study uncovered incidental findings in almost 5% of the sample. “If you take an 80-year-old and study their brain, a good chunk, if not half or more, will have some abnormality,” he said.
Drs. Keuss and Liebeskind have reported no relevant financial relationships.
This article first appeared on Medscape.com.
New research shows that Knowing the expected prevalence of such incidental findings in the older general population is “extremely useful” for both researchers and clinicians, said study co-author Sarah Elisabeth Keuss, MBChB, clinical research associate, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.
“In research, the knowledge helps to inform study protocols regarding how to manage incidental findings and enables study participants to be appropriately informed,” said Dr. Keuss. Greater awareness also helps clinicians make decisions about whether or not to scan a patient, she said, adding that imaging is increasingly available to them. It allows clinicians to counsel patients regarding the probability of an incidental finding and balance that risk against the potential benefits of having a test.
The research is being presented online as part of the American Academy of Neurology 2020 Science Highlights. The incidental findings also were published last year in BMJ Open.
The new findings are from the first wave of data collection for the Insight 46 study, a neuroimaging substudy of the MRC National Survey of Health and Development (NSHD) 1946 British birth cohort, a broadly representative sample of the population born in mainland Britain during 1946. The research uses detailed brain imaging, cognitive testing, and blood and other biomarkers to investigate genetic and life-course factors associated with Alzheimer’s disease and cerebrovascular disease.
The current study included 502 individuals, aged about 71 years at the time of the analysis, and 49% were women. Almost all (93.8%) participants underwent 1-day MRI scans. Some 4.5% of these participants had an incidental finding of brain abnormality as per a prespecified standardized protocol.
Suspected vascular malformations were present in 1.9%, and suspected intracranial mass lesions were present in 1.5%. The single most common vascular abnormality was a suspected cerebral aneurysm, which affected 1.1% of participants.
Suspected meningiomas were the most common intracranial lesion, affecting 0.6% of study participants.
Action plan
Participants and their primary care provider were informed of findings “that were deemed to be potentially serious, or life-threatening, or could have a major impact on quality of life,” said Dr. Keuss. Relevant experts “came up with a recommended clinical action plan to help the primary care provider decide what should be the next course of action with regard to investigation or referral to another specialist,” said Dr. Keuss.
The new results are important for clinical decision-making, said Dr. Keuss. “Clinicians should consider the possibility of detecting an incidental finding whenever they’re requesting a brain scan. They should balance that risk against the possible benefits of recommending a test.”
The prevalence of incidental findings on MRI reported in the literature varies because of different methods used to review scans. “However, comparing our study with similar studies, the prevalence of the key findings with regard to aneurysms and intracranial mass lesions are very similar,” said Dr. Keuss.
Dr. Keuss and colleagues do not recommend all elderly patients get a brain scan.
“We don’t know what the long-term consequences are of being informed you have an incidental finding of an abnormality; we don’t know if it improves their outcome, and it potentially could cause anxiety,” said Dr. Keuss.
Psychological impact
The researchers have not looked at the psychological impact of negative findings on study participants, but they could do so at a later date.
“It would be very important to look into that given the potential to cause anxiety,” said Dr. Keuss. “It’s important to find out the potential negative consequences to inform researchers in future about how best to manage these findings.”
From blood tests, the analysis found that more than a third (34.6%) of participants had at least one related abnormality. The most common of these were kidney impairment (about 9%), thyroid function abnormalities (between 4% and 5%), anemia (about 4%), and low vitamin B12 levels (about 3%).
However, few of these reached the prespecified threshold for urgent action, and Dr. Keuss noted these findings were not the focus of her AAN presentation.
A strength of the study was that participants were almost the exact same age.
Important issue
Commenting on the research, David S. Liebeskind, MD, professor of neurology and director, Neurovascular Imaging Research Core, University of California, Los Angeles, said it raises “a very interesting” and “important” public health issue.
“The question is whether we do things based around individual symptomatic status, or at a larger level in terms of public health, screening the larger population to figure out who is at risk for any particular disease or disorder.”
From the standpoint of imaging technologies like MRI that show details about brain structures, experts debate whether the population should be screened “before something occurs,” said Dr. Liebeskind. “Imaging has the capacity to tell us a tremendous amount; whether this implies we should therefore image everybody is a larger public health question.”
The issue is “fraught with a lot of difficulty and complexity” as treatment paradigms tend to be “built around symptomatic status,” he said. “When we sit in the office or with a patient at the bedside, we usually focus on that individual patient and not necessarily on the larger public.”
Dr. Liebeskind noted that the question of whether to put the emphasis on the individual patient or the public at large is also being discussed during the current COVID-19 pandemic.
He wasn’t surprised that the study uncovered incidental findings in almost 5% of the sample. “If you take an 80-year-old and study their brain, a good chunk, if not half or more, will have some abnormality,” he said.
Drs. Keuss and Liebeskind have reported no relevant financial relationships.
This article first appeared on Medscape.com.
Serum NfL in early MS can help predict clinical course
research suggests. The study showed that patients with higher sNfL within 5 years of MS diagnosis had a higher risk of long term-clinical disability and higher risk of developing progressive MS. The level of sNfL also predicted the rate of increase over time in the Expanded Disability Status Scale (EDSS).
Serum NfL levels can provide “useful information in both directions, adding to both an overall reassuring picture or worrying picture both at first presentation and then on subsequent visits,” said Simon Thebault, MBBCh, a neurology resident at the University of Ottawa and the Ottawa Hospital Research Institute, Canada.
This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Prognostication from day one
Many studies have shown a correlation between MS disease activity (clinical relapses, EDSS progression, MRI lesions) and elevated sNfL. Other studies have also looked at the prognostic value of NfL in serum and cerebrospinal fluid (CSF), but the data are limited by the lack of long-term biobanked samples and subsequent follow-up, Dr. Thebault explained.
The new study took advantage of the Ottawa MS biobank, which contains carefully frozen and stored samples from more than 3,000 patients with MS going back up to 25 years.
The team identified patients with serum collected within 5 years of first MS symptom onset (baseline) who were followed for a median of 18.9 years (range 15.0 to 27.0 years). They quantified levels of sNfL in 67 patients and 37 matched controls.
In patients with MS, the median baseline sNfL level was 10.1 pg/mL – 38.5% higher than the median level in controls (7.26 pg/mL, P = 0.004).
The baseline sNfL level was “most helpful as a sensitive predictive marker to rule out disease progression,” the researchers reported in their meeting abstract.
Patients with baseline sNfL levels less than 7.62 pg/mL were 4.3 times less likely to develop significant disability (EDSS score ≥ 4; P = 0.001) and 7.1 times less likely to develop progressive MS by end of follow-up (P = 0.054).
The most rapid disease progression was seen in patients with the highest baseline NfL levels (3rd-tertile, > 13.2 pg/mL). Higher baseline sNfL level was associated with faster rate of EDSS progression even after adjusting for confounders of age, sex, and disease-modifying treatment.
“We were able to show that serum neurofilament levels collected very early in the disease, usually at the time of first diagnosis, were predictive of the clinical progression [by EDSS score] and the risk of evolving to secondary progressive MS on average 19 years later,” Dr. Thebault said. A baseline level less than 7.6 pg/mL was “reassuring.”
“Prognostication in MS from day one is important,” he emphasized.
“If we know someone is on a bad trajectory, neurologists might recommend more aggressive therapies up front. Equally, if a patient has a very reassuring picture, then maybe it is more appropriate to start with safer treatments [the so called ‘platform therapies’] that may serve a patient well for many years, as they did for many in the years before higher-efficacy therapies were available,” Dr. Thebault said.
“In the hands of an expert MS neurologist who understands both the pearls and pitfalls of this test ... serum neurofilament is already a useful clinical tool, and we have implemented it in our daily practice in Ottawa,” he concluded.
Noteworthy study
Commenting on the study, Asaff Harel, MD, neurologist at Lenox Hill Hospital in New York City, said the findings in this study are “noteworthy, as there is a relative lack of effective prognostic biomarkers in the field of MS.”
“It remains to be seen whether this improves risk stratification of patients above what can be achieved by looking at other prognostic factors, such as age, gender, baseline EDSS, and severity and frequency of relapses during early disease course,” Dr. Harel cautioned.
“This was a relatively small study and further research is necessary,” Dr. Harel added. It’s also worth noting, he said, that out of the 67 patients who met criteria to be included in the study (i.e., those with blood samples taken during “early MS,” more than 15 years ago), almost half were lost to follow-up, which could potentially open the study to error.
It is also “unclear whether early NfL level is a better prognostic marker than severity of early disease course and baseline EDSS, both of which were not addressed in the study, and this will be interesting to determine in the future,” Dr. Harel commented.
Funding for the study was provided by The Ottawa Hospital Pilot Project Grant. Thebault and Harel have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
research suggests. The study showed that patients with higher sNfL within 5 years of MS diagnosis had a higher risk of long term-clinical disability and higher risk of developing progressive MS. The level of sNfL also predicted the rate of increase over time in the Expanded Disability Status Scale (EDSS).
Serum NfL levels can provide “useful information in both directions, adding to both an overall reassuring picture or worrying picture both at first presentation and then on subsequent visits,” said Simon Thebault, MBBCh, a neurology resident at the University of Ottawa and the Ottawa Hospital Research Institute, Canada.
This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Prognostication from day one
Many studies have shown a correlation between MS disease activity (clinical relapses, EDSS progression, MRI lesions) and elevated sNfL. Other studies have also looked at the prognostic value of NfL in serum and cerebrospinal fluid (CSF), but the data are limited by the lack of long-term biobanked samples and subsequent follow-up, Dr. Thebault explained.
The new study took advantage of the Ottawa MS biobank, which contains carefully frozen and stored samples from more than 3,000 patients with MS going back up to 25 years.
The team identified patients with serum collected within 5 years of first MS symptom onset (baseline) who were followed for a median of 18.9 years (range 15.0 to 27.0 years). They quantified levels of sNfL in 67 patients and 37 matched controls.
In patients with MS, the median baseline sNfL level was 10.1 pg/mL – 38.5% higher than the median level in controls (7.26 pg/mL, P = 0.004).
The baseline sNfL level was “most helpful as a sensitive predictive marker to rule out disease progression,” the researchers reported in their meeting abstract.
Patients with baseline sNfL levels less than 7.62 pg/mL were 4.3 times less likely to develop significant disability (EDSS score ≥ 4; P = 0.001) and 7.1 times less likely to develop progressive MS by end of follow-up (P = 0.054).
The most rapid disease progression was seen in patients with the highest baseline NfL levels (3rd-tertile, > 13.2 pg/mL). Higher baseline sNfL level was associated with faster rate of EDSS progression even after adjusting for confounders of age, sex, and disease-modifying treatment.
“We were able to show that serum neurofilament levels collected very early in the disease, usually at the time of first diagnosis, were predictive of the clinical progression [by EDSS score] and the risk of evolving to secondary progressive MS on average 19 years later,” Dr. Thebault said. A baseline level less than 7.6 pg/mL was “reassuring.”
“Prognostication in MS from day one is important,” he emphasized.
“If we know someone is on a bad trajectory, neurologists might recommend more aggressive therapies up front. Equally, if a patient has a very reassuring picture, then maybe it is more appropriate to start with safer treatments [the so called ‘platform therapies’] that may serve a patient well for many years, as they did for many in the years before higher-efficacy therapies were available,” Dr. Thebault said.
“In the hands of an expert MS neurologist who understands both the pearls and pitfalls of this test ... serum neurofilament is already a useful clinical tool, and we have implemented it in our daily practice in Ottawa,” he concluded.
Noteworthy study
Commenting on the study, Asaff Harel, MD, neurologist at Lenox Hill Hospital in New York City, said the findings in this study are “noteworthy, as there is a relative lack of effective prognostic biomarkers in the field of MS.”
“It remains to be seen whether this improves risk stratification of patients above what can be achieved by looking at other prognostic factors, such as age, gender, baseline EDSS, and severity and frequency of relapses during early disease course,” Dr. Harel cautioned.
“This was a relatively small study and further research is necessary,” Dr. Harel added. It’s also worth noting, he said, that out of the 67 patients who met criteria to be included in the study (i.e., those with blood samples taken during “early MS,” more than 15 years ago), almost half were lost to follow-up, which could potentially open the study to error.
It is also “unclear whether early NfL level is a better prognostic marker than severity of early disease course and baseline EDSS, both of which were not addressed in the study, and this will be interesting to determine in the future,” Dr. Harel commented.
Funding for the study was provided by The Ottawa Hospital Pilot Project Grant. Thebault and Harel have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
research suggests. The study showed that patients with higher sNfL within 5 years of MS diagnosis had a higher risk of long term-clinical disability and higher risk of developing progressive MS. The level of sNfL also predicted the rate of increase over time in the Expanded Disability Status Scale (EDSS).
Serum NfL levels can provide “useful information in both directions, adding to both an overall reassuring picture or worrying picture both at first presentation and then on subsequent visits,” said Simon Thebault, MBBCh, a neurology resident at the University of Ottawa and the Ottawa Hospital Research Institute, Canada.
This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Prognostication from day one
Many studies have shown a correlation between MS disease activity (clinical relapses, EDSS progression, MRI lesions) and elevated sNfL. Other studies have also looked at the prognostic value of NfL in serum and cerebrospinal fluid (CSF), but the data are limited by the lack of long-term biobanked samples and subsequent follow-up, Dr. Thebault explained.
The new study took advantage of the Ottawa MS biobank, which contains carefully frozen and stored samples from more than 3,000 patients with MS going back up to 25 years.
The team identified patients with serum collected within 5 years of first MS symptom onset (baseline) who were followed for a median of 18.9 years (range 15.0 to 27.0 years). They quantified levels of sNfL in 67 patients and 37 matched controls.
In patients with MS, the median baseline sNfL level was 10.1 pg/mL – 38.5% higher than the median level in controls (7.26 pg/mL, P = 0.004).
The baseline sNfL level was “most helpful as a sensitive predictive marker to rule out disease progression,” the researchers reported in their meeting abstract.
Patients with baseline sNfL levels less than 7.62 pg/mL were 4.3 times less likely to develop significant disability (EDSS score ≥ 4; P = 0.001) and 7.1 times less likely to develop progressive MS by end of follow-up (P = 0.054).
The most rapid disease progression was seen in patients with the highest baseline NfL levels (3rd-tertile, > 13.2 pg/mL). Higher baseline sNfL level was associated with faster rate of EDSS progression even after adjusting for confounders of age, sex, and disease-modifying treatment.
“We were able to show that serum neurofilament levels collected very early in the disease, usually at the time of first diagnosis, were predictive of the clinical progression [by EDSS score] and the risk of evolving to secondary progressive MS on average 19 years later,” Dr. Thebault said. A baseline level less than 7.6 pg/mL was “reassuring.”
“Prognostication in MS from day one is important,” he emphasized.
“If we know someone is on a bad trajectory, neurologists might recommend more aggressive therapies up front. Equally, if a patient has a very reassuring picture, then maybe it is more appropriate to start with safer treatments [the so called ‘platform therapies’] that may serve a patient well for many years, as they did for many in the years before higher-efficacy therapies were available,” Dr. Thebault said.
“In the hands of an expert MS neurologist who understands both the pearls and pitfalls of this test ... serum neurofilament is already a useful clinical tool, and we have implemented it in our daily practice in Ottawa,” he concluded.
Noteworthy study
Commenting on the study, Asaff Harel, MD, neurologist at Lenox Hill Hospital in New York City, said the findings in this study are “noteworthy, as there is a relative lack of effective prognostic biomarkers in the field of MS.”
“It remains to be seen whether this improves risk stratification of patients above what can be achieved by looking at other prognostic factors, such as age, gender, baseline EDSS, and severity and frequency of relapses during early disease course,” Dr. Harel cautioned.
“This was a relatively small study and further research is necessary,” Dr. Harel added. It’s also worth noting, he said, that out of the 67 patients who met criteria to be included in the study (i.e., those with blood samples taken during “early MS,” more than 15 years ago), almost half were lost to follow-up, which could potentially open the study to error.
It is also “unclear whether early NfL level is a better prognostic marker than severity of early disease course and baseline EDSS, both of which were not addressed in the study, and this will be interesting to determine in the future,” Dr. Harel commented.
Funding for the study was provided by The Ottawa Hospital Pilot Project Grant. Thebault and Harel have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.