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Polio: The unwanted sequel
Summer, since 1975, is traditionally a time for the BIG blockbusters to hit theaters. Some are new, others are sequels in successful franchises. Some anticipated, some not as much.
And, in summer 2022, we have the least-wanted sequel in modern history – Polio II: The Return.
Of course, this sequel isn’t in the theaters (unless the concessions staff isn’t washing their hands), definitely isn’t funny, and could potentially cost a lot more money than the latest Marvel Cinematic Universe flick.
Personally and professionally, I’m in the middle generation on the disease. I’m young enough that I never had to worry about catching it or having afflicted classmates. But, as a doctor, I’m old enough to still see the consequences. Like most neurologists, I have a handful of patients who had childhood polio, and still deal with the chronic weakness (and consequent pain and orthopedic issues it brings). Signing off on braces and other mobility aids for them is still commonplace.
One of my attendings in residency was the renowned Parkinson’s disease expert Abraham Lieberman. On rounds it was impossible not to notice his marked limp, a consequence of childhood polio, and he’d tell us what it was like, being a 6-year-old boy and dealing with the disease. You learn as much from hearing firsthand experiences as you do from textbooks.
And now the virus is showing up again. A few victims, a lot of virions circulating in waste water, but it shouldn’t be there at all.
We aren’t in the era when schoolchildren died or were crippled by it. Elementary school kids today don’t see classmates catch polio and never return to school, or see their grieving parents.
To take 1 year: More than 3,000 American children died of polio in 1952, and more than 21,000 were left with lifelong paralysis – many of them still among us.
When you think of an iron lung, you think of polio.
Those were the casualties in a war to save future generations from this, along with smallpox and other horrors.
But today, that war is mostly forgotten. And now scientific evidence is drowned out by whatever’s on Facebook and the hard-earned miracle of vaccination is ignored in favor of a nonmedical “social influencer” on YouTube.
So The majority of the population likely has nothing to worry about. But there may be segments that are hit hard, and when they are they will never accept the obvious reasons why. It will be part of a cover-up, or a conspiracy, or whatever the guy on Parler told them it was.
As doctors, we’re in the middle. We have to give patients the best recommendations we can, based on learning, evidence, and experience, but at the same time have to recognize their autonomy. I’m not following someone around to make sure they get vaccinated, or take the medication I prescribed.
But we’re also the ones who can be held legally responsible for bad outcomes, regardless of the actual facts of the matter. On the flip side, you don’t hear about someone suing a Facebook “influencer” for doling out inaccurate, potentially fatal, medical advice.
So cracks appear in herd immunity, and leaks will happen.
A few generations of neurologists, including mine, have completed training without considering polio in a differential diagnosis. It would, of course, get bandied about in grand rounds or at the conference table, but none of us really took it seriously. To us residents it was more of historical note. “Gone with the Wind” and the “Wizard of Oz” both came out in 1939, and while we all knew of them, none of us were going to be watching them at the theaters.
Unlike them, though, polio is trying make it back to prime time. It’s a sequel nobody wanted.
But here it is.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Summer, since 1975, is traditionally a time for the BIG blockbusters to hit theaters. Some are new, others are sequels in successful franchises. Some anticipated, some not as much.
And, in summer 2022, we have the least-wanted sequel in modern history – Polio II: The Return.
Of course, this sequel isn’t in the theaters (unless the concessions staff isn’t washing their hands), definitely isn’t funny, and could potentially cost a lot more money than the latest Marvel Cinematic Universe flick.
Personally and professionally, I’m in the middle generation on the disease. I’m young enough that I never had to worry about catching it or having afflicted classmates. But, as a doctor, I’m old enough to still see the consequences. Like most neurologists, I have a handful of patients who had childhood polio, and still deal with the chronic weakness (and consequent pain and orthopedic issues it brings). Signing off on braces and other mobility aids for them is still commonplace.
One of my attendings in residency was the renowned Parkinson’s disease expert Abraham Lieberman. On rounds it was impossible not to notice his marked limp, a consequence of childhood polio, and he’d tell us what it was like, being a 6-year-old boy and dealing with the disease. You learn as much from hearing firsthand experiences as you do from textbooks.
And now the virus is showing up again. A few victims, a lot of virions circulating in waste water, but it shouldn’t be there at all.
We aren’t in the era when schoolchildren died or were crippled by it. Elementary school kids today don’t see classmates catch polio and never return to school, or see their grieving parents.
To take 1 year: More than 3,000 American children died of polio in 1952, and more than 21,000 were left with lifelong paralysis – many of them still among us.
When you think of an iron lung, you think of polio.
Those were the casualties in a war to save future generations from this, along with smallpox and other horrors.
But today, that war is mostly forgotten. And now scientific evidence is drowned out by whatever’s on Facebook and the hard-earned miracle of vaccination is ignored in favor of a nonmedical “social influencer” on YouTube.
So The majority of the population likely has nothing to worry about. But there may be segments that are hit hard, and when they are they will never accept the obvious reasons why. It will be part of a cover-up, or a conspiracy, or whatever the guy on Parler told them it was.
As doctors, we’re in the middle. We have to give patients the best recommendations we can, based on learning, evidence, and experience, but at the same time have to recognize their autonomy. I’m not following someone around to make sure they get vaccinated, or take the medication I prescribed.
But we’re also the ones who can be held legally responsible for bad outcomes, regardless of the actual facts of the matter. On the flip side, you don’t hear about someone suing a Facebook “influencer” for doling out inaccurate, potentially fatal, medical advice.
So cracks appear in herd immunity, and leaks will happen.
A few generations of neurologists, including mine, have completed training without considering polio in a differential diagnosis. It would, of course, get bandied about in grand rounds or at the conference table, but none of us really took it seriously. To us residents it was more of historical note. “Gone with the Wind” and the “Wizard of Oz” both came out in 1939, and while we all knew of them, none of us were going to be watching them at the theaters.
Unlike them, though, polio is trying make it back to prime time. It’s a sequel nobody wanted.
But here it is.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Summer, since 1975, is traditionally a time for the BIG blockbusters to hit theaters. Some are new, others are sequels in successful franchises. Some anticipated, some not as much.
And, in summer 2022, we have the least-wanted sequel in modern history – Polio II: The Return.
Of course, this sequel isn’t in the theaters (unless the concessions staff isn’t washing their hands), definitely isn’t funny, and could potentially cost a lot more money than the latest Marvel Cinematic Universe flick.
Personally and professionally, I’m in the middle generation on the disease. I’m young enough that I never had to worry about catching it or having afflicted classmates. But, as a doctor, I’m old enough to still see the consequences. Like most neurologists, I have a handful of patients who had childhood polio, and still deal with the chronic weakness (and consequent pain and orthopedic issues it brings). Signing off on braces and other mobility aids for them is still commonplace.
One of my attendings in residency was the renowned Parkinson’s disease expert Abraham Lieberman. On rounds it was impossible not to notice his marked limp, a consequence of childhood polio, and he’d tell us what it was like, being a 6-year-old boy and dealing with the disease. You learn as much from hearing firsthand experiences as you do from textbooks.
And now the virus is showing up again. A few victims, a lot of virions circulating in waste water, but it shouldn’t be there at all.
We aren’t in the era when schoolchildren died or were crippled by it. Elementary school kids today don’t see classmates catch polio and never return to school, or see their grieving parents.
To take 1 year: More than 3,000 American children died of polio in 1952, and more than 21,000 were left with lifelong paralysis – many of them still among us.
When you think of an iron lung, you think of polio.
Those were the casualties in a war to save future generations from this, along with smallpox and other horrors.
But today, that war is mostly forgotten. And now scientific evidence is drowned out by whatever’s on Facebook and the hard-earned miracle of vaccination is ignored in favor of a nonmedical “social influencer” on YouTube.
So The majority of the population likely has nothing to worry about. But there may be segments that are hit hard, and when they are they will never accept the obvious reasons why. It will be part of a cover-up, or a conspiracy, or whatever the guy on Parler told them it was.
As doctors, we’re in the middle. We have to give patients the best recommendations we can, based on learning, evidence, and experience, but at the same time have to recognize their autonomy. I’m not following someone around to make sure they get vaccinated, or take the medication I prescribed.
But we’re also the ones who can be held legally responsible for bad outcomes, regardless of the actual facts of the matter. On the flip side, you don’t hear about someone suing a Facebook “influencer” for doling out inaccurate, potentially fatal, medical advice.
So cracks appear in herd immunity, and leaks will happen.
A few generations of neurologists, including mine, have completed training without considering polio in a differential diagnosis. It would, of course, get bandied about in grand rounds or at the conference table, but none of us really took it seriously. To us residents it was more of historical note. “Gone with the Wind” and the “Wizard of Oz” both came out in 1939, and while we all knew of them, none of us were going to be watching them at the theaters.
Unlike them, though, polio is trying make it back to prime time. It’s a sequel nobody wanted.
But here it is.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
First-ever Huntington staging system may jump-start drug development for early-stage disease
Researchers liken the Huntington’s disease Integrated Staging System (HD-ISS) to the system currently used to stage cancer. It groups patients according to their underlying biological, clinical, and functional characteristics.
It also includes criteria to biologically define Huntington’s disease stages across the entire disease spectrum, from birth to death, which is something that has not been done before. For now, the HD-ISS is only intended for research, but it could one day be modified for use in the clinic, investigators wrote.
“This systematization is of critical importance to select the most appropriate target population for clinical trials and studies,” said co-investigator Cristina Sampaio, MD, chief medical officer at the CHDI Foundation, Princeton, N.J.
“By providing a methodology to precisely define cases early in the neurodegenerative process, the HD-ISS will be instrumental in conducting trials in the very early disease stages,” Dr. Sampaio added.
The position paper was published in the July issue of the Lancet Neurology.
New approach needed
There is no approved therapy to slow Huntington’s disease progression. Clinical trials currently enroll patients with demonstrable symptoms, which limits the ability to test therapeutics that could delay or prevent neurodegeneration.
Huntington’s disease is rare, occurring in about 2.7 per 100,000 individuals worldwide. It is caused by a mutation in the HTT gene involving a DNA segment known as a CAG trinucleotide repeat.
Currently, Huntington’s disease is diagnosed on the basis of clinical signs that emerge late in the disease course, an approach developed before the discovery of the HTT gene and the development of the genetic test for the CAG mutation.
The disease phase prior to diagnosis has been described as presymptomatic, premanifest, or prodromal. However, the three terms have varying definitions that make it difficult to compare study results across trials.
Because drug development had focused on the overt motor sign phase of the disease, there was no real need for an evidence-based staging system that classified disease phases from birth, the investigators noted.
“Now, the research community and regulators recognize that it is critical to conduct trials early in the disease when no signs or overt symptoms are measurable,” Dr. Sampaio said.
Defining disease stages
Work on the staging system was done through the Huntington’s Disease Regulatory Science Consortium, an international project begun in 2018 among biotech and pharma companies, academic institutions, and nonprofit research and advocacy organizations.
Overall, more than 50 clinicians and researchers were involved in developing the HD-ISS.
Using modeling data from four large observational studies that included patients with Huntington’s disease and control groups, researchers identified four different stages of Huntington’s disease:
- Stage 0: Begins at birth with identification of HTT gene mutations but no detectable pathologic changes.
- Stage 1: Begins when biomarker changes are detected via MRI by a volume decrease in six brain areas.
- Stage 2: Begins when clinical signs of Huntington’s disease are present, as determined through motor and cognitive assessments.
- Stage 3: Begins when functional decline is evident, with worsening on the Independence Scale and the Total Functional Capacity of the Unified Huntington’s Disease Rating Scale.
Applying the HD-ISS to clinical trials requires the collection of information routinely recorded in Huntington’s disease research, as well as some additional data, but researchers say its application is straightforward.
The HD-ISS uses a numerical staging system similar to that used in the U.S. Food and Drug Administration’s guidance for Alzheimer’s disease (AD) and integrates the prodromal, presymptomatic, or premanifest phase of the disease. This distinguishes it from earlier classification systems.
The HD-ISS can be adapted if new Huntington’s disease biomarkers are identified.
“As research results are generated, this will further validate the HD-ISS and potentially lead to the development of a derivative, and possibly simplified, system for clinical practice,” Dr. Sampaio said.
The new system goes further than a more recent proposal from the Movement Disorder Society task force, which addresses earlier stages in Huntington’s disease but doesn’t consider objective biomarker data.
Question of timing
Commenting on the findings, Erin Furr-Stimming, MD, neurologist and director of the Huntington’s Disease Society of America Center of Excellence with McGovern Medical School, UTHealth, Houston, said targeting early-stage disease will be key.
“Similar to more common neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, there is a period of at least a decade when changes are occurring in the nervous system, prior to the manifestation of clinical symptoms and signs significant enough to warrant a clinical diagnosis,” Dr. Furr-Stimming said.
She noted that multiple trials of disease-modifying agents for Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease have failed for a multitude of reasons, “but one consistent question that is relevant to all these diseases is that of timing: Should we intervene and test these therapies earlier?
“The premanifest or prodromal period may be the ideal time to intervene with a disease-modifying therapy, prior to onset of any neurodegeneration,” Dr. Furr-Stimming said.
The CHDI Foundation provided financial support to the Critical Path Institute for the Huntington’s Disease Regulatory Science Consortium, including all working group efforts. Dr. Sampio is an employee of and receives salary from CHDI Management. She has also received consultancy honorariums (unrelated to HD) from Pfizer, Kyowa Kirin, vTv Therapeutics, GW Pharmaceuticals, Neuraly, Neuroderm, Green Valley Pharmaceuticals, and Pinteon Pharmaceuticals. A full list of disclosures for the other researchers is in the original article. Dr. Furr-Stimming reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Researchers liken the Huntington’s disease Integrated Staging System (HD-ISS) to the system currently used to stage cancer. It groups patients according to their underlying biological, clinical, and functional characteristics.
It also includes criteria to biologically define Huntington’s disease stages across the entire disease spectrum, from birth to death, which is something that has not been done before. For now, the HD-ISS is only intended for research, but it could one day be modified for use in the clinic, investigators wrote.
“This systematization is of critical importance to select the most appropriate target population for clinical trials and studies,” said co-investigator Cristina Sampaio, MD, chief medical officer at the CHDI Foundation, Princeton, N.J.
“By providing a methodology to precisely define cases early in the neurodegenerative process, the HD-ISS will be instrumental in conducting trials in the very early disease stages,” Dr. Sampaio added.
The position paper was published in the July issue of the Lancet Neurology.
New approach needed
There is no approved therapy to slow Huntington’s disease progression. Clinical trials currently enroll patients with demonstrable symptoms, which limits the ability to test therapeutics that could delay or prevent neurodegeneration.
Huntington’s disease is rare, occurring in about 2.7 per 100,000 individuals worldwide. It is caused by a mutation in the HTT gene involving a DNA segment known as a CAG trinucleotide repeat.
Currently, Huntington’s disease is diagnosed on the basis of clinical signs that emerge late in the disease course, an approach developed before the discovery of the HTT gene and the development of the genetic test for the CAG mutation.
The disease phase prior to diagnosis has been described as presymptomatic, premanifest, or prodromal. However, the three terms have varying definitions that make it difficult to compare study results across trials.
Because drug development had focused on the overt motor sign phase of the disease, there was no real need for an evidence-based staging system that classified disease phases from birth, the investigators noted.
“Now, the research community and regulators recognize that it is critical to conduct trials early in the disease when no signs or overt symptoms are measurable,” Dr. Sampaio said.
Defining disease stages
Work on the staging system was done through the Huntington’s Disease Regulatory Science Consortium, an international project begun in 2018 among biotech and pharma companies, academic institutions, and nonprofit research and advocacy organizations.
Overall, more than 50 clinicians and researchers were involved in developing the HD-ISS.
Using modeling data from four large observational studies that included patients with Huntington’s disease and control groups, researchers identified four different stages of Huntington’s disease:
- Stage 0: Begins at birth with identification of HTT gene mutations but no detectable pathologic changes.
- Stage 1: Begins when biomarker changes are detected via MRI by a volume decrease in six brain areas.
- Stage 2: Begins when clinical signs of Huntington’s disease are present, as determined through motor and cognitive assessments.
- Stage 3: Begins when functional decline is evident, with worsening on the Independence Scale and the Total Functional Capacity of the Unified Huntington’s Disease Rating Scale.
Applying the HD-ISS to clinical trials requires the collection of information routinely recorded in Huntington’s disease research, as well as some additional data, but researchers say its application is straightforward.
The HD-ISS uses a numerical staging system similar to that used in the U.S. Food and Drug Administration’s guidance for Alzheimer’s disease (AD) and integrates the prodromal, presymptomatic, or premanifest phase of the disease. This distinguishes it from earlier classification systems.
The HD-ISS can be adapted if new Huntington’s disease biomarkers are identified.
“As research results are generated, this will further validate the HD-ISS and potentially lead to the development of a derivative, and possibly simplified, system for clinical practice,” Dr. Sampaio said.
The new system goes further than a more recent proposal from the Movement Disorder Society task force, which addresses earlier stages in Huntington’s disease but doesn’t consider objective biomarker data.
Question of timing
Commenting on the findings, Erin Furr-Stimming, MD, neurologist and director of the Huntington’s Disease Society of America Center of Excellence with McGovern Medical School, UTHealth, Houston, said targeting early-stage disease will be key.
“Similar to more common neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, there is a period of at least a decade when changes are occurring in the nervous system, prior to the manifestation of clinical symptoms and signs significant enough to warrant a clinical diagnosis,” Dr. Furr-Stimming said.
She noted that multiple trials of disease-modifying agents for Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease have failed for a multitude of reasons, “but one consistent question that is relevant to all these diseases is that of timing: Should we intervene and test these therapies earlier?
“The premanifest or prodromal period may be the ideal time to intervene with a disease-modifying therapy, prior to onset of any neurodegeneration,” Dr. Furr-Stimming said.
The CHDI Foundation provided financial support to the Critical Path Institute for the Huntington’s Disease Regulatory Science Consortium, including all working group efforts. Dr. Sampio is an employee of and receives salary from CHDI Management. She has also received consultancy honorariums (unrelated to HD) from Pfizer, Kyowa Kirin, vTv Therapeutics, GW Pharmaceuticals, Neuraly, Neuroderm, Green Valley Pharmaceuticals, and Pinteon Pharmaceuticals. A full list of disclosures for the other researchers is in the original article. Dr. Furr-Stimming reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Researchers liken the Huntington’s disease Integrated Staging System (HD-ISS) to the system currently used to stage cancer. It groups patients according to their underlying biological, clinical, and functional characteristics.
It also includes criteria to biologically define Huntington’s disease stages across the entire disease spectrum, from birth to death, which is something that has not been done before. For now, the HD-ISS is only intended for research, but it could one day be modified for use in the clinic, investigators wrote.
“This systematization is of critical importance to select the most appropriate target population for clinical trials and studies,” said co-investigator Cristina Sampaio, MD, chief medical officer at the CHDI Foundation, Princeton, N.J.
“By providing a methodology to precisely define cases early in the neurodegenerative process, the HD-ISS will be instrumental in conducting trials in the very early disease stages,” Dr. Sampaio added.
The position paper was published in the July issue of the Lancet Neurology.
New approach needed
There is no approved therapy to slow Huntington’s disease progression. Clinical trials currently enroll patients with demonstrable symptoms, which limits the ability to test therapeutics that could delay or prevent neurodegeneration.
Huntington’s disease is rare, occurring in about 2.7 per 100,000 individuals worldwide. It is caused by a mutation in the HTT gene involving a DNA segment known as a CAG trinucleotide repeat.
Currently, Huntington’s disease is diagnosed on the basis of clinical signs that emerge late in the disease course, an approach developed before the discovery of the HTT gene and the development of the genetic test for the CAG mutation.
The disease phase prior to diagnosis has been described as presymptomatic, premanifest, or prodromal. However, the three terms have varying definitions that make it difficult to compare study results across trials.
Because drug development had focused on the overt motor sign phase of the disease, there was no real need for an evidence-based staging system that classified disease phases from birth, the investigators noted.
“Now, the research community and regulators recognize that it is critical to conduct trials early in the disease when no signs or overt symptoms are measurable,” Dr. Sampaio said.
Defining disease stages
Work on the staging system was done through the Huntington’s Disease Regulatory Science Consortium, an international project begun in 2018 among biotech and pharma companies, academic institutions, and nonprofit research and advocacy organizations.
Overall, more than 50 clinicians and researchers were involved in developing the HD-ISS.
Using modeling data from four large observational studies that included patients with Huntington’s disease and control groups, researchers identified four different stages of Huntington’s disease:
- Stage 0: Begins at birth with identification of HTT gene mutations but no detectable pathologic changes.
- Stage 1: Begins when biomarker changes are detected via MRI by a volume decrease in six brain areas.
- Stage 2: Begins when clinical signs of Huntington’s disease are present, as determined through motor and cognitive assessments.
- Stage 3: Begins when functional decline is evident, with worsening on the Independence Scale and the Total Functional Capacity of the Unified Huntington’s Disease Rating Scale.
Applying the HD-ISS to clinical trials requires the collection of information routinely recorded in Huntington’s disease research, as well as some additional data, but researchers say its application is straightforward.
The HD-ISS uses a numerical staging system similar to that used in the U.S. Food and Drug Administration’s guidance for Alzheimer’s disease (AD) and integrates the prodromal, presymptomatic, or premanifest phase of the disease. This distinguishes it from earlier classification systems.
The HD-ISS can be adapted if new Huntington’s disease biomarkers are identified.
“As research results are generated, this will further validate the HD-ISS and potentially lead to the development of a derivative, and possibly simplified, system for clinical practice,” Dr. Sampaio said.
The new system goes further than a more recent proposal from the Movement Disorder Society task force, which addresses earlier stages in Huntington’s disease but doesn’t consider objective biomarker data.
Question of timing
Commenting on the findings, Erin Furr-Stimming, MD, neurologist and director of the Huntington’s Disease Society of America Center of Excellence with McGovern Medical School, UTHealth, Houston, said targeting early-stage disease will be key.
“Similar to more common neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, there is a period of at least a decade when changes are occurring in the nervous system, prior to the manifestation of clinical symptoms and signs significant enough to warrant a clinical diagnosis,” Dr. Furr-Stimming said.
She noted that multiple trials of disease-modifying agents for Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease have failed for a multitude of reasons, “but one consistent question that is relevant to all these diseases is that of timing: Should we intervene and test these therapies earlier?
“The premanifest or prodromal period may be the ideal time to intervene with a disease-modifying therapy, prior to onset of any neurodegeneration,” Dr. Furr-Stimming said.
The CHDI Foundation provided financial support to the Critical Path Institute for the Huntington’s Disease Regulatory Science Consortium, including all working group efforts. Dr. Sampio is an employee of and receives salary from CHDI Management. She has also received consultancy honorariums (unrelated to HD) from Pfizer, Kyowa Kirin, vTv Therapeutics, GW Pharmaceuticals, Neuraly, Neuroderm, Green Valley Pharmaceuticals, and Pinteon Pharmaceuticals. A full list of disclosures for the other researchers is in the original article. Dr. Furr-Stimming reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE LANCET NEUROLOGY
FDA unveils 5-year plan for ALS and other neurodegenerative diseases
The agency’s Action Plan for Rare Neurodegenerative Diseases including Amyotrophic Lateral Sclerosis (ALS) aims to advance the development of safe and effective medical products and facilitate patient access to novel treatments.
“The effects of rare neurodegenerative diseases are devastating, with very few effective therapeutic options available to patients. We recognize the urgent need for new treatments that can both improve and extend the lives of people diagnosed with these diseases,” FDA Commissioner Robert M. Califf, MD, said in a news release.
“To face that challenge and to accelerate drug development, we need innovative approaches to better understand these diseases while also building on current scientific and research capabilities,” Dr. Califf acknowledged.
“This action plan, especially including the use of public-private partnerships and direct involvement of patients, will ensure the FDA is working toward meeting the task set forth by Congress to enhance the quality of life for those suffering by facilitating access to new therapies,” Dr. Califf added.
Blueprint to ‘aggressively’ move forward
The action plan represents a “blueprint” for how the agency will “aggressively” move forward to address challenges in drug development for rare neurodegenerative diseases to improve patient health, the FDA said.
The plan was created in accordance with provisions in the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) that President Biden signed into law in late 2021.
Targeted activities include establishing the FDA Rare Neurodegenerative Diseases Task Force and the public-private partnership for rare neurodegenerative diseases, developing disease-specific science strategies over the next 5 years, and leveraging ongoing FDA regulatory science efforts.
The ALS Science Strategy is part of the plan focused specifically on ALS. It provides a “forward-leaning” framework for FDA activities, which include efforts to improve characterization of disease pathogenesis and natural history, boost clinical trial infrastructure and agility to enable early selection of promising therapeutic candidates for further development, optimize clinical trial design, improve access to the trials, streamline clinical trial operations, and reduce the time and cost of drug development.
The FDA says patient engagement, public workshops, research projects, coordination across FDA centers and offices, and collaboration with the National Institutes of Health will be key to the success of implementation of the ALS Science Strategy.
A version of this article first appeared on Medscape.com.
The agency’s Action Plan for Rare Neurodegenerative Diseases including Amyotrophic Lateral Sclerosis (ALS) aims to advance the development of safe and effective medical products and facilitate patient access to novel treatments.
“The effects of rare neurodegenerative diseases are devastating, with very few effective therapeutic options available to patients. We recognize the urgent need for new treatments that can both improve and extend the lives of people diagnosed with these diseases,” FDA Commissioner Robert M. Califf, MD, said in a news release.
“To face that challenge and to accelerate drug development, we need innovative approaches to better understand these diseases while also building on current scientific and research capabilities,” Dr. Califf acknowledged.
“This action plan, especially including the use of public-private partnerships and direct involvement of patients, will ensure the FDA is working toward meeting the task set forth by Congress to enhance the quality of life for those suffering by facilitating access to new therapies,” Dr. Califf added.
Blueprint to ‘aggressively’ move forward
The action plan represents a “blueprint” for how the agency will “aggressively” move forward to address challenges in drug development for rare neurodegenerative diseases to improve patient health, the FDA said.
The plan was created in accordance with provisions in the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) that President Biden signed into law in late 2021.
Targeted activities include establishing the FDA Rare Neurodegenerative Diseases Task Force and the public-private partnership for rare neurodegenerative diseases, developing disease-specific science strategies over the next 5 years, and leveraging ongoing FDA regulatory science efforts.
The ALS Science Strategy is part of the plan focused specifically on ALS. It provides a “forward-leaning” framework for FDA activities, which include efforts to improve characterization of disease pathogenesis and natural history, boost clinical trial infrastructure and agility to enable early selection of promising therapeutic candidates for further development, optimize clinical trial design, improve access to the trials, streamline clinical trial operations, and reduce the time and cost of drug development.
The FDA says patient engagement, public workshops, research projects, coordination across FDA centers and offices, and collaboration with the National Institutes of Health will be key to the success of implementation of the ALS Science Strategy.
A version of this article first appeared on Medscape.com.
The agency’s Action Plan for Rare Neurodegenerative Diseases including Amyotrophic Lateral Sclerosis (ALS) aims to advance the development of safe and effective medical products and facilitate patient access to novel treatments.
“The effects of rare neurodegenerative diseases are devastating, with very few effective therapeutic options available to patients. We recognize the urgent need for new treatments that can both improve and extend the lives of people diagnosed with these diseases,” FDA Commissioner Robert M. Califf, MD, said in a news release.
“To face that challenge and to accelerate drug development, we need innovative approaches to better understand these diseases while also building on current scientific and research capabilities,” Dr. Califf acknowledged.
“This action plan, especially including the use of public-private partnerships and direct involvement of patients, will ensure the FDA is working toward meeting the task set forth by Congress to enhance the quality of life for those suffering by facilitating access to new therapies,” Dr. Califf added.
Blueprint to ‘aggressively’ move forward
The action plan represents a “blueprint” for how the agency will “aggressively” move forward to address challenges in drug development for rare neurodegenerative diseases to improve patient health, the FDA said.
The plan was created in accordance with provisions in the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) that President Biden signed into law in late 2021.
Targeted activities include establishing the FDA Rare Neurodegenerative Diseases Task Force and the public-private partnership for rare neurodegenerative diseases, developing disease-specific science strategies over the next 5 years, and leveraging ongoing FDA regulatory science efforts.
The ALS Science Strategy is part of the plan focused specifically on ALS. It provides a “forward-leaning” framework for FDA activities, which include efforts to improve characterization of disease pathogenesis and natural history, boost clinical trial infrastructure and agility to enable early selection of promising therapeutic candidates for further development, optimize clinical trial design, improve access to the trials, streamline clinical trial operations, and reduce the time and cost of drug development.
The FDA says patient engagement, public workshops, research projects, coordination across FDA centers and offices, and collaboration with the National Institutes of Health will be key to the success of implementation of the ALS Science Strategy.
A version of this article first appeared on Medscape.com.
Tofersen linked to slow, positive effects in ALS
caused by superoxide dismutase 1 (SOD1) gene mutations.
The 1-year results, presented at the European Network for the Cure of Amyotrophic Lateral Sclerosis (ENCALS) 2022 meeting, show a deceleration in functional decline that is similar, but “more pronounced” than the previously reported 6-month results, which were not statistically significant, said lead investigator Timothy Miller, MD, PhD, professor of neurology and director of the ALS Center, Washington University, St. Louis.
“What I thought we saw in the first data cut is confirmed by what we saw in the longer data,” he said in an interview. “There were trends [showing] those treated with tofersen did a bit better, but it was hard to be sure. It was hard to be confident in what we were seeing at that early time point.”
Now, with 6 more months of data, Dr. Miller says he is confident that tofersen is slowing down the neurodegenerative disease process. “I see results that I’m encouraged by,” he said. “As a clinician who treats people with ALS with this mutation I would want this drug to be available to people that I see in my clinic.”
One-year VALOR study results
The primary efficacy objective of the VALOR study was to show the 28-week impact of 100 mg tofersen (three doses given about 2 weeks apart, then five doses given every 4 weeks), versus placebo, on function, measured on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R). The open-label extension switched placebo-treated patients to tofersen (delayed-start group) and continued to compare them with the early-start group up to 1 year. This open-label extension phase included 49 patients who had been on early-start tofersen and 18 patients in the delayed-start group.
For the primary endpoint, change from baseline in 48-point ALSFRS-R score, there was a statistically significant benefit for the early-start patients with these patients scoring 3.5 points higher than the delayed-start group (P = .0272, 95% confidence interval [CI], 0.4-6.7). This means that both groups declined in function, which is expected in ALS, but the early-start group declined more slowly.
There was also a benefit associated with early-start tofersen for a number of secondary endpoints, including change from baseline in total SOD1 cerebrospinal fluid concentration (CSF SOD1), plasma neurofilament light chain (NfL) levels, and respiratory function.
“This drug targets the MRNA of SOD1, so it lowers the MRNA and then the SOD1 protein falls,” explained Dr. Miller, adding that these levels dropped 21% in the delayed start group, and 33% in the early-start group. “I think the data pretty clearly show that [tofersen] does what it is supposed to do, and that is the first step.”
Neurofilament light chain, a marker of neurodegeneration, also dropped by 41% in the delayed-start group, and 51% in the early-start group.
Respiratory function, as measured by percent predicted slow vital capacity (SVC), also declined 9.2% more slowly in the early- versus delayed-start group (P = .0159).
Finally, muscle strength, as measured by handheld dynamometry (HHD) score, declined more slowly in the early-start group compared with the late-start group, with an adjusted mean difference in score of 2.8 (P = 0.0186).
Dr. Miller said that the data show that it takes time for tofersen to impact clinical function, but there are signs of benefit before that. “I think what you see is that just starting on the drug, the first thing that happens is SOD1 goes down, the next thing is that neurofilament decreases, but clinical function is not yet changing. It takes time. What I see in these data is that it takes time for us to see that effect on clinical function.”
The bigger picture
While acknowledging that tofersen acts on a genetic mutation found in only about 2% of ALS, Dr. Miller said the study findings carry significance for the wider ALS patient population.
“Assuming we agree there is a clinical effect here, assuming we agree that there is real stabilization of clinical function, I think if we agree on that point then we know that ALS is now a treatable disorder. And that’s a really important point. I’m not sure that we knew that before,” he said. “Yes, there are FDA-approved medications that slow down ALS a bit, but they don’t stabilize it, and if we get the target correct – and we have the correct genetic target here – there can be a substantial influence on slowing down the disease, so that’s one thing to learn for the whole ALS community.”
What lies ahead?
Asked to comment on the study, Richard Bedlack, MD, PhD, who was not involved in the research, said the findings are important and show “clinically meaningful” results. “Based on the new benefit-to-burden ratio, I believe most of my patients with SOD1 mutations will want to try this drug. I would like to be able to offer it to them. But I am curious to see what the FDA will do with these data,” said Dr. Bedlack, professor of neurology at Duke University in Durham, N.C., and director of the Duke ALS Clinic.
“Sometimes that open-label extension gives us time to see differences between patients who initially got drug and those who initially got placebo. That seems to be the case with tofersen here, and it was also the case with AMX0035 [Amylyx Pharmaceuticals Inc.], which did not show a survival benefit in the first 6 months but did in the open-label extension.” A recent FDA advisory board panel concluded there was insufficient evidence of benefit for AMX0035, he noted. “I wonder if the same concern will be raised here, necessitating confirmation in another trial. I hope not, but only time will tell.”
Dr. Miller added that these results “highlight how difficult ALS drug development still is. Among the many uncertainties in setting up a trial (targets, doses, inclusion criteria, outcomes), we still do not know how long we need to treat patients in order to see statistically significant changes in the clinical measures we use (ALSFRS-R, respiratory function, strength, survival, etc.). Most American studies are 6 months long and most European studies are 12 months long. Longer studies may be more likely to show benefits on certain measures (e.g., survival), but they cost more, they are challenged by dropouts as the disease progresses, and the idea of randomizing someone to a placebo for a whole year is psychologically difficult for patients, families, and many clinicians (myself included). So, we are seeing more studies like this one where the first 6 months are randomized, blinded, and placebo controlled, and then there is an open-label extension that lasts many months more.”
The study was sponsored by Biogen. Writing and editorial support was provided by Excel Scientific Solutions. Tofersen was discovered by Ionis Pharmaceuticals Inc. Dr. Miller disclosed ties with Biogen, Ionis Pharmaceuticals Inc., Cytokinetics, C2N, Disarm Therapeutics, and UCB Pharma. Dr. Bedlack disclosed ties with Biogen.
caused by superoxide dismutase 1 (SOD1) gene mutations.
The 1-year results, presented at the European Network for the Cure of Amyotrophic Lateral Sclerosis (ENCALS) 2022 meeting, show a deceleration in functional decline that is similar, but “more pronounced” than the previously reported 6-month results, which were not statistically significant, said lead investigator Timothy Miller, MD, PhD, professor of neurology and director of the ALS Center, Washington University, St. Louis.
“What I thought we saw in the first data cut is confirmed by what we saw in the longer data,” he said in an interview. “There were trends [showing] those treated with tofersen did a bit better, but it was hard to be sure. It was hard to be confident in what we were seeing at that early time point.”
Now, with 6 more months of data, Dr. Miller says he is confident that tofersen is slowing down the neurodegenerative disease process. “I see results that I’m encouraged by,” he said. “As a clinician who treats people with ALS with this mutation I would want this drug to be available to people that I see in my clinic.”
One-year VALOR study results
The primary efficacy objective of the VALOR study was to show the 28-week impact of 100 mg tofersen (three doses given about 2 weeks apart, then five doses given every 4 weeks), versus placebo, on function, measured on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R). The open-label extension switched placebo-treated patients to tofersen (delayed-start group) and continued to compare them with the early-start group up to 1 year. This open-label extension phase included 49 patients who had been on early-start tofersen and 18 patients in the delayed-start group.
For the primary endpoint, change from baseline in 48-point ALSFRS-R score, there was a statistically significant benefit for the early-start patients with these patients scoring 3.5 points higher than the delayed-start group (P = .0272, 95% confidence interval [CI], 0.4-6.7). This means that both groups declined in function, which is expected in ALS, but the early-start group declined more slowly.
There was also a benefit associated with early-start tofersen for a number of secondary endpoints, including change from baseline in total SOD1 cerebrospinal fluid concentration (CSF SOD1), plasma neurofilament light chain (NfL) levels, and respiratory function.
“This drug targets the MRNA of SOD1, so it lowers the MRNA and then the SOD1 protein falls,” explained Dr. Miller, adding that these levels dropped 21% in the delayed start group, and 33% in the early-start group. “I think the data pretty clearly show that [tofersen] does what it is supposed to do, and that is the first step.”
Neurofilament light chain, a marker of neurodegeneration, also dropped by 41% in the delayed-start group, and 51% in the early-start group.
Respiratory function, as measured by percent predicted slow vital capacity (SVC), also declined 9.2% more slowly in the early- versus delayed-start group (P = .0159).
Finally, muscle strength, as measured by handheld dynamometry (HHD) score, declined more slowly in the early-start group compared with the late-start group, with an adjusted mean difference in score of 2.8 (P = 0.0186).
Dr. Miller said that the data show that it takes time for tofersen to impact clinical function, but there are signs of benefit before that. “I think what you see is that just starting on the drug, the first thing that happens is SOD1 goes down, the next thing is that neurofilament decreases, but clinical function is not yet changing. It takes time. What I see in these data is that it takes time for us to see that effect on clinical function.”
The bigger picture
While acknowledging that tofersen acts on a genetic mutation found in only about 2% of ALS, Dr. Miller said the study findings carry significance for the wider ALS patient population.
“Assuming we agree there is a clinical effect here, assuming we agree that there is real stabilization of clinical function, I think if we agree on that point then we know that ALS is now a treatable disorder. And that’s a really important point. I’m not sure that we knew that before,” he said. “Yes, there are FDA-approved medications that slow down ALS a bit, but they don’t stabilize it, and if we get the target correct – and we have the correct genetic target here – there can be a substantial influence on slowing down the disease, so that’s one thing to learn for the whole ALS community.”
What lies ahead?
Asked to comment on the study, Richard Bedlack, MD, PhD, who was not involved in the research, said the findings are important and show “clinically meaningful” results. “Based on the new benefit-to-burden ratio, I believe most of my patients with SOD1 mutations will want to try this drug. I would like to be able to offer it to them. But I am curious to see what the FDA will do with these data,” said Dr. Bedlack, professor of neurology at Duke University in Durham, N.C., and director of the Duke ALS Clinic.
“Sometimes that open-label extension gives us time to see differences between patients who initially got drug and those who initially got placebo. That seems to be the case with tofersen here, and it was also the case with AMX0035 [Amylyx Pharmaceuticals Inc.], which did not show a survival benefit in the first 6 months but did in the open-label extension.” A recent FDA advisory board panel concluded there was insufficient evidence of benefit for AMX0035, he noted. “I wonder if the same concern will be raised here, necessitating confirmation in another trial. I hope not, but only time will tell.”
Dr. Miller added that these results “highlight how difficult ALS drug development still is. Among the many uncertainties in setting up a trial (targets, doses, inclusion criteria, outcomes), we still do not know how long we need to treat patients in order to see statistically significant changes in the clinical measures we use (ALSFRS-R, respiratory function, strength, survival, etc.). Most American studies are 6 months long and most European studies are 12 months long. Longer studies may be more likely to show benefits on certain measures (e.g., survival), but they cost more, they are challenged by dropouts as the disease progresses, and the idea of randomizing someone to a placebo for a whole year is psychologically difficult for patients, families, and many clinicians (myself included). So, we are seeing more studies like this one where the first 6 months are randomized, blinded, and placebo controlled, and then there is an open-label extension that lasts many months more.”
The study was sponsored by Biogen. Writing and editorial support was provided by Excel Scientific Solutions. Tofersen was discovered by Ionis Pharmaceuticals Inc. Dr. Miller disclosed ties with Biogen, Ionis Pharmaceuticals Inc., Cytokinetics, C2N, Disarm Therapeutics, and UCB Pharma. Dr. Bedlack disclosed ties with Biogen.
caused by superoxide dismutase 1 (SOD1) gene mutations.
The 1-year results, presented at the European Network for the Cure of Amyotrophic Lateral Sclerosis (ENCALS) 2022 meeting, show a deceleration in functional decline that is similar, but “more pronounced” than the previously reported 6-month results, which were not statistically significant, said lead investigator Timothy Miller, MD, PhD, professor of neurology and director of the ALS Center, Washington University, St. Louis.
“What I thought we saw in the first data cut is confirmed by what we saw in the longer data,” he said in an interview. “There were trends [showing] those treated with tofersen did a bit better, but it was hard to be sure. It was hard to be confident in what we were seeing at that early time point.”
Now, with 6 more months of data, Dr. Miller says he is confident that tofersen is slowing down the neurodegenerative disease process. “I see results that I’m encouraged by,” he said. “As a clinician who treats people with ALS with this mutation I would want this drug to be available to people that I see in my clinic.”
One-year VALOR study results
The primary efficacy objective of the VALOR study was to show the 28-week impact of 100 mg tofersen (three doses given about 2 weeks apart, then five doses given every 4 weeks), versus placebo, on function, measured on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R). The open-label extension switched placebo-treated patients to tofersen (delayed-start group) and continued to compare them with the early-start group up to 1 year. This open-label extension phase included 49 patients who had been on early-start tofersen and 18 patients in the delayed-start group.
For the primary endpoint, change from baseline in 48-point ALSFRS-R score, there was a statistically significant benefit for the early-start patients with these patients scoring 3.5 points higher than the delayed-start group (P = .0272, 95% confidence interval [CI], 0.4-6.7). This means that both groups declined in function, which is expected in ALS, but the early-start group declined more slowly.
There was also a benefit associated with early-start tofersen for a number of secondary endpoints, including change from baseline in total SOD1 cerebrospinal fluid concentration (CSF SOD1), plasma neurofilament light chain (NfL) levels, and respiratory function.
“This drug targets the MRNA of SOD1, so it lowers the MRNA and then the SOD1 protein falls,” explained Dr. Miller, adding that these levels dropped 21% in the delayed start group, and 33% in the early-start group. “I think the data pretty clearly show that [tofersen] does what it is supposed to do, and that is the first step.”
Neurofilament light chain, a marker of neurodegeneration, also dropped by 41% in the delayed-start group, and 51% in the early-start group.
Respiratory function, as measured by percent predicted slow vital capacity (SVC), also declined 9.2% more slowly in the early- versus delayed-start group (P = .0159).
Finally, muscle strength, as measured by handheld dynamometry (HHD) score, declined more slowly in the early-start group compared with the late-start group, with an adjusted mean difference in score of 2.8 (P = 0.0186).
Dr. Miller said that the data show that it takes time for tofersen to impact clinical function, but there are signs of benefit before that. “I think what you see is that just starting on the drug, the first thing that happens is SOD1 goes down, the next thing is that neurofilament decreases, but clinical function is not yet changing. It takes time. What I see in these data is that it takes time for us to see that effect on clinical function.”
The bigger picture
While acknowledging that tofersen acts on a genetic mutation found in only about 2% of ALS, Dr. Miller said the study findings carry significance for the wider ALS patient population.
“Assuming we agree there is a clinical effect here, assuming we agree that there is real stabilization of clinical function, I think if we agree on that point then we know that ALS is now a treatable disorder. And that’s a really important point. I’m not sure that we knew that before,” he said. “Yes, there are FDA-approved medications that slow down ALS a bit, but they don’t stabilize it, and if we get the target correct – and we have the correct genetic target here – there can be a substantial influence on slowing down the disease, so that’s one thing to learn for the whole ALS community.”
What lies ahead?
Asked to comment on the study, Richard Bedlack, MD, PhD, who was not involved in the research, said the findings are important and show “clinically meaningful” results. “Based on the new benefit-to-burden ratio, I believe most of my patients with SOD1 mutations will want to try this drug. I would like to be able to offer it to them. But I am curious to see what the FDA will do with these data,” said Dr. Bedlack, professor of neurology at Duke University in Durham, N.C., and director of the Duke ALS Clinic.
“Sometimes that open-label extension gives us time to see differences between patients who initially got drug and those who initially got placebo. That seems to be the case with tofersen here, and it was also the case with AMX0035 [Amylyx Pharmaceuticals Inc.], which did not show a survival benefit in the first 6 months but did in the open-label extension.” A recent FDA advisory board panel concluded there was insufficient evidence of benefit for AMX0035, he noted. “I wonder if the same concern will be raised here, necessitating confirmation in another trial. I hope not, but only time will tell.”
Dr. Miller added that these results “highlight how difficult ALS drug development still is. Among the many uncertainties in setting up a trial (targets, doses, inclusion criteria, outcomes), we still do not know how long we need to treat patients in order to see statistically significant changes in the clinical measures we use (ALSFRS-R, respiratory function, strength, survival, etc.). Most American studies are 6 months long and most European studies are 12 months long. Longer studies may be more likely to show benefits on certain measures (e.g., survival), but they cost more, they are challenged by dropouts as the disease progresses, and the idea of randomizing someone to a placebo for a whole year is psychologically difficult for patients, families, and many clinicians (myself included). So, we are seeing more studies like this one where the first 6 months are randomized, blinded, and placebo controlled, and then there is an open-label extension that lasts many months more.”
The study was sponsored by Biogen. Writing and editorial support was provided by Excel Scientific Solutions. Tofersen was discovered by Ionis Pharmaceuticals Inc. Dr. Miller disclosed ties with Biogen, Ionis Pharmaceuticals Inc., Cytokinetics, C2N, Disarm Therapeutics, and UCB Pharma. Dr. Bedlack disclosed ties with Biogen.
FROM THE ENCALS MEETING 2022
FDA expands indication for spinal muscular atrophy drug
As previously reported, the FDA first approved oral risdiplam for SMA in children older than age 2 years in 2020.
The FDA expanded the indication for risdiplam to include babies younger than 2 months old because of interim safety and efficacy data from the ongoing RAINBOWFISH study. It includes 25 babies from birth to 6 weeks of age at first dose, all of whom have genetically diagnosed SMA but are not yet presenting with symptoms.
After 12 months of risdiplam treatment, the majority of presymptomatic infants with SMA reached key motor milestones, Genentech said in a news release.
Of the six babies with two or three copies of the SMN2 gene, all were able to sit after 1 year of active treatment, roughly two-thirds could stand, and half could walk independently.
All babies were alive at 12 months without permanent ventilation.
“The approval of Evrysdi for presymptomatic babies is particularly important, as early treatment of SMA, before symptoms start to arise, can help babies to achieve motor milestones,” Richard Finkel, MD, principal investigator of the trial, said in the release.
“With the inclusion of SMA in newborn screening programs, this approval provides the opportunity to start treating at home with Evrysdi soon after the diagnosis is confirmed,” added Dr. Finkel, who is director of the experimental neuroscience program, St. Jude Children’s Research Hospital, Memphis.
From newborns to older adults?
SMA is a rare and often fatal genetic disease that causes muscle weakness and progressive loss of movement.
SMA, which affects about 1 in 10,000 babies, is caused by a mutation in the survival motor neuron 1 (SMN1) gene. The gene encodes the SMN protein, which is critical for the maintenance and function of motor neurons.
Risdiplam is an orally administered, centrally and peripherally distributed small molecule that modulates survival motor neuron 2 (SMN2) premessenger RNA splicing to increase SMN protein levels.
As part of the label extension, the prescribing information for risdiplam has also been updated to include 2-year pooled data from parts 1 and 2 of the FIREFISH study, which demonstrated long-term efficacy and safety in symptomatic infants with Type 1 SMA, the company noted.
“Because of its efficacy in multiple settings, Evrysdi is now available for people with SMA, from presymptomatic newborns to older adults,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Genentech, said in the release.
“We are proud of this achievement, which has the potential to make a real difference to those living with SMA and their caregivers,” Dr. Garraway added.
A version of this article first appeared on Medscape.com.
As previously reported, the FDA first approved oral risdiplam for SMA in children older than age 2 years in 2020.
The FDA expanded the indication for risdiplam to include babies younger than 2 months old because of interim safety and efficacy data from the ongoing RAINBOWFISH study. It includes 25 babies from birth to 6 weeks of age at first dose, all of whom have genetically diagnosed SMA but are not yet presenting with symptoms.
After 12 months of risdiplam treatment, the majority of presymptomatic infants with SMA reached key motor milestones, Genentech said in a news release.
Of the six babies with two or three copies of the SMN2 gene, all were able to sit after 1 year of active treatment, roughly two-thirds could stand, and half could walk independently.
All babies were alive at 12 months without permanent ventilation.
“The approval of Evrysdi for presymptomatic babies is particularly important, as early treatment of SMA, before symptoms start to arise, can help babies to achieve motor milestones,” Richard Finkel, MD, principal investigator of the trial, said in the release.
“With the inclusion of SMA in newborn screening programs, this approval provides the opportunity to start treating at home with Evrysdi soon after the diagnosis is confirmed,” added Dr. Finkel, who is director of the experimental neuroscience program, St. Jude Children’s Research Hospital, Memphis.
From newborns to older adults?
SMA is a rare and often fatal genetic disease that causes muscle weakness and progressive loss of movement.
SMA, which affects about 1 in 10,000 babies, is caused by a mutation in the survival motor neuron 1 (SMN1) gene. The gene encodes the SMN protein, which is critical for the maintenance and function of motor neurons.
Risdiplam is an orally administered, centrally and peripherally distributed small molecule that modulates survival motor neuron 2 (SMN2) premessenger RNA splicing to increase SMN protein levels.
As part of the label extension, the prescribing information for risdiplam has also been updated to include 2-year pooled data from parts 1 and 2 of the FIREFISH study, which demonstrated long-term efficacy and safety in symptomatic infants with Type 1 SMA, the company noted.
“Because of its efficacy in multiple settings, Evrysdi is now available for people with SMA, from presymptomatic newborns to older adults,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Genentech, said in the release.
“We are proud of this achievement, which has the potential to make a real difference to those living with SMA and their caregivers,” Dr. Garraway added.
A version of this article first appeared on Medscape.com.
As previously reported, the FDA first approved oral risdiplam for SMA in children older than age 2 years in 2020.
The FDA expanded the indication for risdiplam to include babies younger than 2 months old because of interim safety and efficacy data from the ongoing RAINBOWFISH study. It includes 25 babies from birth to 6 weeks of age at first dose, all of whom have genetically diagnosed SMA but are not yet presenting with symptoms.
After 12 months of risdiplam treatment, the majority of presymptomatic infants with SMA reached key motor milestones, Genentech said in a news release.
Of the six babies with two or three copies of the SMN2 gene, all were able to sit after 1 year of active treatment, roughly two-thirds could stand, and half could walk independently.
All babies were alive at 12 months without permanent ventilation.
“The approval of Evrysdi for presymptomatic babies is particularly important, as early treatment of SMA, before symptoms start to arise, can help babies to achieve motor milestones,” Richard Finkel, MD, principal investigator of the trial, said in the release.
“With the inclusion of SMA in newborn screening programs, this approval provides the opportunity to start treating at home with Evrysdi soon after the diagnosis is confirmed,” added Dr. Finkel, who is director of the experimental neuroscience program, St. Jude Children’s Research Hospital, Memphis.
From newborns to older adults?
SMA is a rare and often fatal genetic disease that causes muscle weakness and progressive loss of movement.
SMA, which affects about 1 in 10,000 babies, is caused by a mutation in the survival motor neuron 1 (SMN1) gene. The gene encodes the SMN protein, which is critical for the maintenance and function of motor neurons.
Risdiplam is an orally administered, centrally and peripherally distributed small molecule that modulates survival motor neuron 2 (SMN2) premessenger RNA splicing to increase SMN protein levels.
As part of the label extension, the prescribing information for risdiplam has also been updated to include 2-year pooled data from parts 1 and 2 of the FIREFISH study, which demonstrated long-term efficacy and safety in symptomatic infants with Type 1 SMA, the company noted.
“Because of its efficacy in multiple settings, Evrysdi is now available for people with SMA, from presymptomatic newborns to older adults,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Genentech, said in the release.
“We are proud of this achievement, which has the potential to make a real difference to those living with SMA and their caregivers,” Dr. Garraway added.
A version of this article first appeared on Medscape.com.
FDA approves oral form of ALS drug edaravone
Edaravone is a pyrazolone free-radical scavenger thought to lessen the effects of oxidative stress, which is a probable factor in ALS onset and progression. The drug was first approved in 2017 as an intravenous (IV) infusion to treat ALS.
Radicava ORS is self-administered and can be taken at home. After fasting overnight, Radicava ORS should be taken in the morning orally or through a feeding tube. The oral version has the same dosing regimen as the original IV version, with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period and subsequent treatment cycles consisting of daily dosing for 10 out of 14-day periods, followed by 14-day drug-free periods.
Compared with the IV formation of Radicava, Radicava ORS has been shown to generate comparable levels of active drug in the bloodstream, the FDA said.
The FDA determined that IV Radicava was effective based on a 6-month clinical trial in Japan involving 137 individuals who were randomly chosen to receive either the drug or a placebo. At 24 weeks, individuals receiving Radicava showed less decline on a clinical assessment of daily functioning, compared with those receiving placebo.
The most common side effects of Radicava are bruising, problems walking, and headache. Fatigue is also a possible side effect from Radicava ORS. Both formulations can have serious side effects associated with allergic reactions, including hives, rash, and shortness of breath.
Full prescribing information, including additional information on risks associated with Radicava ORS, is available online.
The FDA granted Radicava ORS orphan drug status, priority review, and Fast Track designations.
A version of this article first appeared on Medscape.com.
Edaravone is a pyrazolone free-radical scavenger thought to lessen the effects of oxidative stress, which is a probable factor in ALS onset and progression. The drug was first approved in 2017 as an intravenous (IV) infusion to treat ALS.
Radicava ORS is self-administered and can be taken at home. After fasting overnight, Radicava ORS should be taken in the morning orally or through a feeding tube. The oral version has the same dosing regimen as the original IV version, with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period and subsequent treatment cycles consisting of daily dosing for 10 out of 14-day periods, followed by 14-day drug-free periods.
Compared with the IV formation of Radicava, Radicava ORS has been shown to generate comparable levels of active drug in the bloodstream, the FDA said.
The FDA determined that IV Radicava was effective based on a 6-month clinical trial in Japan involving 137 individuals who were randomly chosen to receive either the drug or a placebo. At 24 weeks, individuals receiving Radicava showed less decline on a clinical assessment of daily functioning, compared with those receiving placebo.
The most common side effects of Radicava are bruising, problems walking, and headache. Fatigue is also a possible side effect from Radicava ORS. Both formulations can have serious side effects associated with allergic reactions, including hives, rash, and shortness of breath.
Full prescribing information, including additional information on risks associated with Radicava ORS, is available online.
The FDA granted Radicava ORS orphan drug status, priority review, and Fast Track designations.
A version of this article first appeared on Medscape.com.
Edaravone is a pyrazolone free-radical scavenger thought to lessen the effects of oxidative stress, which is a probable factor in ALS onset and progression. The drug was first approved in 2017 as an intravenous (IV) infusion to treat ALS.
Radicava ORS is self-administered and can be taken at home. After fasting overnight, Radicava ORS should be taken in the morning orally or through a feeding tube. The oral version has the same dosing regimen as the original IV version, with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period and subsequent treatment cycles consisting of daily dosing for 10 out of 14-day periods, followed by 14-day drug-free periods.
Compared with the IV formation of Radicava, Radicava ORS has been shown to generate comparable levels of active drug in the bloodstream, the FDA said.
The FDA determined that IV Radicava was effective based on a 6-month clinical trial in Japan involving 137 individuals who were randomly chosen to receive either the drug or a placebo. At 24 weeks, individuals receiving Radicava showed less decline on a clinical assessment of daily functioning, compared with those receiving placebo.
The most common side effects of Radicava are bruising, problems walking, and headache. Fatigue is also a possible side effect from Radicava ORS. Both formulations can have serious side effects associated with allergic reactions, including hives, rash, and shortness of breath.
Full prescribing information, including additional information on risks associated with Radicava ORS, is available online.
The FDA granted Radicava ORS orphan drug status, priority review, and Fast Track designations.
A version of this article first appeared on Medscape.com.
Reducing Attacks and Neuropathic Pain in NMOSD
Patients with neuromyelitis optica spectrum disorder (NMOSD) experience unpredictable episodes of inflammation involving the optic nerve, spine, or both. Debilitating neuropathic pain accompanies the healing process, which lasts anywhere from 2 to 6 months after an attack.
In this ReCAP, Dr Michael Levy, of Harvard Medical School in Boston, Massachusetts, outlines the heavy psychological and economic burdens associated with NMOSD and reports on three new targeted therapies that have been approved to prevent relapse and delay disease progression.
He then looks at current pharmaceutical treatments for NMOSD pain, before reporting promising trial data exploring transcutaneous electrical nerve stimulation as a safe and cost-effective treatment for neuropathic pain.
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Michael Levy, MD, PhD, Associate Professor, Department of Neurology, Harvard Medical School, Boston, Massachusetts
Michael Levy, MD, PhD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Alexion; Horizon; Genentech; UCB; Sanofi; Quest
Received research grant from: National Institutes of Health; Sanofi; Genentech; Horizon; Alexion
Patients with neuromyelitis optica spectrum disorder (NMOSD) experience unpredictable episodes of inflammation involving the optic nerve, spine, or both. Debilitating neuropathic pain accompanies the healing process, which lasts anywhere from 2 to 6 months after an attack.
In this ReCAP, Dr Michael Levy, of Harvard Medical School in Boston, Massachusetts, outlines the heavy psychological and economic burdens associated with NMOSD and reports on three new targeted therapies that have been approved to prevent relapse and delay disease progression.
He then looks at current pharmaceutical treatments for NMOSD pain, before reporting promising trial data exploring transcutaneous electrical nerve stimulation as a safe and cost-effective treatment for neuropathic pain.
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Michael Levy, MD, PhD, Associate Professor, Department of Neurology, Harvard Medical School, Boston, Massachusetts
Michael Levy, MD, PhD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Alexion; Horizon; Genentech; UCB; Sanofi; Quest
Received research grant from: National Institutes of Health; Sanofi; Genentech; Horizon; Alexion
Patients with neuromyelitis optica spectrum disorder (NMOSD) experience unpredictable episodes of inflammation involving the optic nerve, spine, or both. Debilitating neuropathic pain accompanies the healing process, which lasts anywhere from 2 to 6 months after an attack.
In this ReCAP, Dr Michael Levy, of Harvard Medical School in Boston, Massachusetts, outlines the heavy psychological and economic burdens associated with NMOSD and reports on three new targeted therapies that have been approved to prevent relapse and delay disease progression.
He then looks at current pharmaceutical treatments for NMOSD pain, before reporting promising trial data exploring transcutaneous electrical nerve stimulation as a safe and cost-effective treatment for neuropathic pain.
--
Michael Levy, MD, PhD, Associate Professor, Department of Neurology, Harvard Medical School, Boston, Massachusetts
Michael Levy, MD, PhD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Alexion; Horizon; Genentech; UCB; Sanofi; Quest
Received research grant from: National Institutes of Health; Sanofi; Genentech; Horizon; Alexion
Steroids counter ataxia telangiectasia
SEATTLE –
The disease is an autosomal recessive disorder caused by mutations in the ATM gene, which is critical to the response to cellular insults such as DNA breaks, oxidative damage, and other forms of stress. The result is clinical manifestations that range from a suppressed immune system to organ damage and neurological symptoms that typically lead patients to be wheelchair bound by their teenage years.
“It’s really multisystem and a very, very difficult disease for people to live with,” Howard M. Lederman, MD, PhD, said in an interview. Dr. Lederman is a coauthor of the study, which was presented by Stefan Zielen, PhD, professor at the University of Goethe, at the 2022 annual meeting of the American Academy of Neurology.
Various therapies have been developed to improve immunodeficiency, lung disease, and some of the other clinical aspects of the condition, but there is no treatment for its neurological effects. “There’s not really been a good animal model, which has been a big problem in trying to test drugs and design treatment trials,” said Dr. Lederman, professor of pediatrics and medicine at Johns Hopkins University, Baltimore.
The new results may change that. “In the children under the age of 9, there was really a very clear slowdown in the neurodegeneration, and specifically the time that it took for them to lose the ability to ambulate. It’s very exciting, because it’s the first time that anybody has really shown in a double-blind, placebo-controlled, large phase 3 study that any drug has been able to do this. And there were really no steroid side effects, which is the other really remarkable thing about this study,” said Dr. Lederman.
The therapy grew out of a study by researchers in Italy who treated pediatric ataxia telangiectasia patients with corticosteroids and found some transitory improvements in gross motor function, but concerns about long-term exposure to steroids limited its application. EryDel, which specializes in encapsulating therapeutics in red blood cells, became interested and developed a formulation using the patient’s own red blood cells infused with DSP. Reinfused to the patients, the red blood cells slowly release the steroid.
It isn’t clear how dexamethasone works. There are data suggesting that it might lead to transcription of small pieces of the ATM protein, “but that has really not been nailed down in any way at this point. Corticosteroids act on all kinds of cells in all kinds of ways, and so there might be a little bit of this so-called mini-ATM that’s produced, but that may or may not be related to the way in which corticosteroids have a beneficial effect on the rate of neurodegeneration,” said Dr. Lederman.
The treatment process is not easy. Children must have 50-60 cc of blood removed. Red blood cells treated to become porous are exposed to DSP, and then resealed. Then the cells are reinfused. “The whole process takes from beginning to end probably about 3 hours, with a really experienced team of people doing it. And it’s limiting because it’s not easy to put in an IV and take 50 or 60 cc of blood out of children much younger than 5 or 6. The process is now being modified to see whether we could do it with 20 to 30 cc instead,” said Dr. Lederman.
A ‘promising and impressive’ study
The study is promising, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “They were able to show a slower rate of neurological degeneration or duration on both the lower and higher dose compared with the placebo. This is promising and impressive, in the sense that it’s a really large (trial) for a rare condition,” Dr. Johnson, vice chair of research at Virginia Commonwealth University, Richmond, said in an interview.
The study included 164 patients Europe, Australia, Israel, Tunisia, India, and the United States, who received 5-10 mg dexamethasone, 14-22 mg DSP, or placebo. Mean ages in each group ranged from 9.6 to 10.4 years.
In an intention-to-treat analysis, modified International Cooperative Ataxia Rating Scale (mICARS) scores trended toward improvement in the low-dose (–1.37; P = .0847) and high-dose groups (–1.40; P = .0765) when determined by central raters during the COVID-19 pandemic. There was also a trend toward improvement when determined by local raters in the low dose group (–1.73; P = .0720) and a statistically significant change in the high dose group (–2.11; P = .0277). The researchers noted some inconsistency between local and central raters, due to inconsistency of videography and language challenges for central raters.
An intention-to-treat analysis of a subgroup of 89 patients age 6-9, who were compared with natural history data from 245 patients, found a deterioration of mICARS of 3.7 per year, compared with 0.92 in the high-dose group, for a reduction of 75% (P = .020). In the high-dose group, 51.7% had a minimal or significant improvement compared with baseline according to the Clinical Global Impression of Change, as did 29.0% on low dose, and 27.6% in the placebo group.
SEATTLE –
The disease is an autosomal recessive disorder caused by mutations in the ATM gene, which is critical to the response to cellular insults such as DNA breaks, oxidative damage, and other forms of stress. The result is clinical manifestations that range from a suppressed immune system to organ damage and neurological symptoms that typically lead patients to be wheelchair bound by their teenage years.
“It’s really multisystem and a very, very difficult disease for people to live with,” Howard M. Lederman, MD, PhD, said in an interview. Dr. Lederman is a coauthor of the study, which was presented by Stefan Zielen, PhD, professor at the University of Goethe, at the 2022 annual meeting of the American Academy of Neurology.
Various therapies have been developed to improve immunodeficiency, lung disease, and some of the other clinical aspects of the condition, but there is no treatment for its neurological effects. “There’s not really been a good animal model, which has been a big problem in trying to test drugs and design treatment trials,” said Dr. Lederman, professor of pediatrics and medicine at Johns Hopkins University, Baltimore.
The new results may change that. “In the children under the age of 9, there was really a very clear slowdown in the neurodegeneration, and specifically the time that it took for them to lose the ability to ambulate. It’s very exciting, because it’s the first time that anybody has really shown in a double-blind, placebo-controlled, large phase 3 study that any drug has been able to do this. And there were really no steroid side effects, which is the other really remarkable thing about this study,” said Dr. Lederman.
The therapy grew out of a study by researchers in Italy who treated pediatric ataxia telangiectasia patients with corticosteroids and found some transitory improvements in gross motor function, but concerns about long-term exposure to steroids limited its application. EryDel, which specializes in encapsulating therapeutics in red blood cells, became interested and developed a formulation using the patient’s own red blood cells infused with DSP. Reinfused to the patients, the red blood cells slowly release the steroid.
It isn’t clear how dexamethasone works. There are data suggesting that it might lead to transcription of small pieces of the ATM protein, “but that has really not been nailed down in any way at this point. Corticosteroids act on all kinds of cells in all kinds of ways, and so there might be a little bit of this so-called mini-ATM that’s produced, but that may or may not be related to the way in which corticosteroids have a beneficial effect on the rate of neurodegeneration,” said Dr. Lederman.
The treatment process is not easy. Children must have 50-60 cc of blood removed. Red blood cells treated to become porous are exposed to DSP, and then resealed. Then the cells are reinfused. “The whole process takes from beginning to end probably about 3 hours, with a really experienced team of people doing it. And it’s limiting because it’s not easy to put in an IV and take 50 or 60 cc of blood out of children much younger than 5 or 6. The process is now being modified to see whether we could do it with 20 to 30 cc instead,” said Dr. Lederman.
A ‘promising and impressive’ study
The study is promising, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “They were able to show a slower rate of neurological degeneration or duration on both the lower and higher dose compared with the placebo. This is promising and impressive, in the sense that it’s a really large (trial) for a rare condition,” Dr. Johnson, vice chair of research at Virginia Commonwealth University, Richmond, said in an interview.
The study included 164 patients Europe, Australia, Israel, Tunisia, India, and the United States, who received 5-10 mg dexamethasone, 14-22 mg DSP, or placebo. Mean ages in each group ranged from 9.6 to 10.4 years.
In an intention-to-treat analysis, modified International Cooperative Ataxia Rating Scale (mICARS) scores trended toward improvement in the low-dose (–1.37; P = .0847) and high-dose groups (–1.40; P = .0765) when determined by central raters during the COVID-19 pandemic. There was also a trend toward improvement when determined by local raters in the low dose group (–1.73; P = .0720) and a statistically significant change in the high dose group (–2.11; P = .0277). The researchers noted some inconsistency between local and central raters, due to inconsistency of videography and language challenges for central raters.
An intention-to-treat analysis of a subgroup of 89 patients age 6-9, who were compared with natural history data from 245 patients, found a deterioration of mICARS of 3.7 per year, compared with 0.92 in the high-dose group, for a reduction of 75% (P = .020). In the high-dose group, 51.7% had a minimal or significant improvement compared with baseline according to the Clinical Global Impression of Change, as did 29.0% on low dose, and 27.6% in the placebo group.
SEATTLE –
The disease is an autosomal recessive disorder caused by mutations in the ATM gene, which is critical to the response to cellular insults such as DNA breaks, oxidative damage, and other forms of stress. The result is clinical manifestations that range from a suppressed immune system to organ damage and neurological symptoms that typically lead patients to be wheelchair bound by their teenage years.
“It’s really multisystem and a very, very difficult disease for people to live with,” Howard M. Lederman, MD, PhD, said in an interview. Dr. Lederman is a coauthor of the study, which was presented by Stefan Zielen, PhD, professor at the University of Goethe, at the 2022 annual meeting of the American Academy of Neurology.
Various therapies have been developed to improve immunodeficiency, lung disease, and some of the other clinical aspects of the condition, but there is no treatment for its neurological effects. “There’s not really been a good animal model, which has been a big problem in trying to test drugs and design treatment trials,” said Dr. Lederman, professor of pediatrics and medicine at Johns Hopkins University, Baltimore.
The new results may change that. “In the children under the age of 9, there was really a very clear slowdown in the neurodegeneration, and specifically the time that it took for them to lose the ability to ambulate. It’s very exciting, because it’s the first time that anybody has really shown in a double-blind, placebo-controlled, large phase 3 study that any drug has been able to do this. And there were really no steroid side effects, which is the other really remarkable thing about this study,” said Dr. Lederman.
The therapy grew out of a study by researchers in Italy who treated pediatric ataxia telangiectasia patients with corticosteroids and found some transitory improvements in gross motor function, but concerns about long-term exposure to steroids limited its application. EryDel, which specializes in encapsulating therapeutics in red blood cells, became interested and developed a formulation using the patient’s own red blood cells infused with DSP. Reinfused to the patients, the red blood cells slowly release the steroid.
It isn’t clear how dexamethasone works. There are data suggesting that it might lead to transcription of small pieces of the ATM protein, “but that has really not been nailed down in any way at this point. Corticosteroids act on all kinds of cells in all kinds of ways, and so there might be a little bit of this so-called mini-ATM that’s produced, but that may or may not be related to the way in which corticosteroids have a beneficial effect on the rate of neurodegeneration,” said Dr. Lederman.
The treatment process is not easy. Children must have 50-60 cc of blood removed. Red blood cells treated to become porous are exposed to DSP, and then resealed. Then the cells are reinfused. “The whole process takes from beginning to end probably about 3 hours, with a really experienced team of people doing it. And it’s limiting because it’s not easy to put in an IV and take 50 or 60 cc of blood out of children much younger than 5 or 6. The process is now being modified to see whether we could do it with 20 to 30 cc instead,” said Dr. Lederman.
A ‘promising and impressive’ study
The study is promising, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “They were able to show a slower rate of neurological degeneration or duration on both the lower and higher dose compared with the placebo. This is promising and impressive, in the sense that it’s a really large (trial) for a rare condition,” Dr. Johnson, vice chair of research at Virginia Commonwealth University, Richmond, said in an interview.
The study included 164 patients Europe, Australia, Israel, Tunisia, India, and the United States, who received 5-10 mg dexamethasone, 14-22 mg DSP, or placebo. Mean ages in each group ranged from 9.6 to 10.4 years.
In an intention-to-treat analysis, modified International Cooperative Ataxia Rating Scale (mICARS) scores trended toward improvement in the low-dose (–1.37; P = .0847) and high-dose groups (–1.40; P = .0765) when determined by central raters during the COVID-19 pandemic. There was also a trend toward improvement when determined by local raters in the low dose group (–1.73; P = .0720) and a statistically significant change in the high dose group (–2.11; P = .0277). The researchers noted some inconsistency between local and central raters, due to inconsistency of videography and language challenges for central raters.
An intention-to-treat analysis of a subgroup of 89 patients age 6-9, who were compared with natural history data from 245 patients, found a deterioration of mICARS of 3.7 per year, compared with 0.92 in the high-dose group, for a reduction of 75% (P = .020). In the high-dose group, 51.7% had a minimal or significant improvement compared with baseline according to the Clinical Global Impression of Change, as did 29.0% on low dose, and 27.6% in the placebo group.
AT AAN 2022
Nanoparticle shows promise for ALS
SEATTLE – , which was the change in the summated motor unit index (MUNIX) from baseline to week 36.
The drug, CNM-Au8, is being developed by Clene, and would represent a novel mechanism of action. “This is a brand-new approach. We used it complementary with riluzole and it was well tolerated, so I see this as an add-on therapy. I think if we can show some more positivity and longer-term results, it’s going to be a game changer for ALS,” Matthew Kiernan, MBBS, PhD, said in an interview. Dr. Kiernan presented the results at the 2022 annual meeting of the American Academy of Neurology.
Riluzole (Rilutek), which received Food and Drug Administration approval in 1995, inhibits glutamate release to counter excitotoxicity, which is believed to play a role in ALS, Huntington’s disease, ischemia, and other acute and chronic neurodegenerative diseases. The other FDA-approved agent for ALS is the neuroprotective agent and free-radical scavenger edaravone (Radicava), approved in 2017.
CNM-Au8 is made up of catalytically active gold nanocrystals that cross the blood-brain barrier, but lacks the toxicity associated with other synthetic gold compounds, according to the company. The formulation is also being investigated for the treatment of Parkinson’s disease and multiple sclerosis. Basic research has shown that it stabilizes mitochondria and reduces accumulation of the TDP-43 protein, which is linked to spread of ALS through the brain, Dr. Kiernan said during his presentation.
The treatment is well tolerated. “Normally in an ALS trial, we see about a 25% dropout rate. There were no dropouts on the active compound in the clinical trial. There are less deaths, so improved survival,” said Dr. Kiernan, the Bushell chair of neurology at the University of Sydney and codirector of the Brain and Mind Center in Sydney.
Good safety signal
The fact that the trial missed its primary endpoint isn’t too concerning, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “ALS clinical trials are incredibly difficult to conduct, especially a phase 2 learning-phase clinical trial. At this phase, I’m much more buoyed by the fact that they have a good safety signal, and that they’re willing to move forward to that phase 3 clinical trial,” Dr. Johnson said in an interview. He is vice chair of research at Virginia Commonwealth University, Richmond.
A phase 3 clinical trial is in development in the United States and Europe. The drug also is included as part of the HEALEY ALS Platform Trial, which is testing multiple ALS therapies simultaneously. “The results from that should be available by the second half of this year and it will also inform us as to what the approach should be,” said Dr. Kiernan.
Dr. Johnson also was enthusiastic. “I’m excited to see the results in terms of the primary endpoints for that next phase 3 clinical trial,” he said.
Ongoing research
In September 2021, Clene announced a second expanded access program for people with ALS.
The study included a 36-week double-blind treatment period followed by long-term, open-label follow-up. Twenty-three patients received 30 mg CNM-Au8, and 22 received placebo. In the first 36 weeks, the treatment group was more likely to have no disease progression, defined as death, tracheostomy, noninvasive ventilation, or a gastronomy tube (P = .0125). The researchers compared the probability of experiencing a less than 6-point decline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. At 12 weeks, it was about 85% in both groups. At 24 weeks, it was about 60% to 50% in favor of the CNM-Au8 group, and at 36 weeks it was about 50% to 20% (P = .0350).
At 36 weeks, quality of life as measured by the ALS Specific Quality of Life–Short Form was better in the treatment group at 36 weeks (mean change, 0.9; P = .0177).
Survival was better in the treatment group at 96 weeks than the mortality derived from a European Network for the Cure of ALS prediction model (hazard ratio [HR], 0.2974; P = .0068). This benefit also was experienced by patients who received drug throughout the study (HR, 0.36; 95% confidence interval [CI], 0.12-1.1) and those who started out on placebo and converted to active drug during the open-label period (HR, 0.24; 95% CI, 0.064-0.88).
The study was funded by Clene and FightMND. Dr. Kiernan and Dr. Johnson have no relevant financial disclosures.
SEATTLE – , which was the change in the summated motor unit index (MUNIX) from baseline to week 36.
The drug, CNM-Au8, is being developed by Clene, and would represent a novel mechanism of action. “This is a brand-new approach. We used it complementary with riluzole and it was well tolerated, so I see this as an add-on therapy. I think if we can show some more positivity and longer-term results, it’s going to be a game changer for ALS,” Matthew Kiernan, MBBS, PhD, said in an interview. Dr. Kiernan presented the results at the 2022 annual meeting of the American Academy of Neurology.
Riluzole (Rilutek), which received Food and Drug Administration approval in 1995, inhibits glutamate release to counter excitotoxicity, which is believed to play a role in ALS, Huntington’s disease, ischemia, and other acute and chronic neurodegenerative diseases. The other FDA-approved agent for ALS is the neuroprotective agent and free-radical scavenger edaravone (Radicava), approved in 2017.
CNM-Au8 is made up of catalytically active gold nanocrystals that cross the blood-brain barrier, but lacks the toxicity associated with other synthetic gold compounds, according to the company. The formulation is also being investigated for the treatment of Parkinson’s disease and multiple sclerosis. Basic research has shown that it stabilizes mitochondria and reduces accumulation of the TDP-43 protein, which is linked to spread of ALS through the brain, Dr. Kiernan said during his presentation.
The treatment is well tolerated. “Normally in an ALS trial, we see about a 25% dropout rate. There were no dropouts on the active compound in the clinical trial. There are less deaths, so improved survival,” said Dr. Kiernan, the Bushell chair of neurology at the University of Sydney and codirector of the Brain and Mind Center in Sydney.
Good safety signal
The fact that the trial missed its primary endpoint isn’t too concerning, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “ALS clinical trials are incredibly difficult to conduct, especially a phase 2 learning-phase clinical trial. At this phase, I’m much more buoyed by the fact that they have a good safety signal, and that they’re willing to move forward to that phase 3 clinical trial,” Dr. Johnson said in an interview. He is vice chair of research at Virginia Commonwealth University, Richmond.
A phase 3 clinical trial is in development in the United States and Europe. The drug also is included as part of the HEALEY ALS Platform Trial, which is testing multiple ALS therapies simultaneously. “The results from that should be available by the second half of this year and it will also inform us as to what the approach should be,” said Dr. Kiernan.
Dr. Johnson also was enthusiastic. “I’m excited to see the results in terms of the primary endpoints for that next phase 3 clinical trial,” he said.
Ongoing research
In September 2021, Clene announced a second expanded access program for people with ALS.
The study included a 36-week double-blind treatment period followed by long-term, open-label follow-up. Twenty-three patients received 30 mg CNM-Au8, and 22 received placebo. In the first 36 weeks, the treatment group was more likely to have no disease progression, defined as death, tracheostomy, noninvasive ventilation, or a gastronomy tube (P = .0125). The researchers compared the probability of experiencing a less than 6-point decline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. At 12 weeks, it was about 85% in both groups. At 24 weeks, it was about 60% to 50% in favor of the CNM-Au8 group, and at 36 weeks it was about 50% to 20% (P = .0350).
At 36 weeks, quality of life as measured by the ALS Specific Quality of Life–Short Form was better in the treatment group at 36 weeks (mean change, 0.9; P = .0177).
Survival was better in the treatment group at 96 weeks than the mortality derived from a European Network for the Cure of ALS prediction model (hazard ratio [HR], 0.2974; P = .0068). This benefit also was experienced by patients who received drug throughout the study (HR, 0.36; 95% confidence interval [CI], 0.12-1.1) and those who started out on placebo and converted to active drug during the open-label period (HR, 0.24; 95% CI, 0.064-0.88).
The study was funded by Clene and FightMND. Dr. Kiernan and Dr. Johnson have no relevant financial disclosures.
SEATTLE – , which was the change in the summated motor unit index (MUNIX) from baseline to week 36.
The drug, CNM-Au8, is being developed by Clene, and would represent a novel mechanism of action. “This is a brand-new approach. We used it complementary with riluzole and it was well tolerated, so I see this as an add-on therapy. I think if we can show some more positivity and longer-term results, it’s going to be a game changer for ALS,” Matthew Kiernan, MBBS, PhD, said in an interview. Dr. Kiernan presented the results at the 2022 annual meeting of the American Academy of Neurology.
Riluzole (Rilutek), which received Food and Drug Administration approval in 1995, inhibits glutamate release to counter excitotoxicity, which is believed to play a role in ALS, Huntington’s disease, ischemia, and other acute and chronic neurodegenerative diseases. The other FDA-approved agent for ALS is the neuroprotective agent and free-radical scavenger edaravone (Radicava), approved in 2017.
CNM-Au8 is made up of catalytically active gold nanocrystals that cross the blood-brain barrier, but lacks the toxicity associated with other synthetic gold compounds, according to the company. The formulation is also being investigated for the treatment of Parkinson’s disease and multiple sclerosis. Basic research has shown that it stabilizes mitochondria and reduces accumulation of the TDP-43 protein, which is linked to spread of ALS through the brain, Dr. Kiernan said during his presentation.
The treatment is well tolerated. “Normally in an ALS trial, we see about a 25% dropout rate. There were no dropouts on the active compound in the clinical trial. There are less deaths, so improved survival,” said Dr. Kiernan, the Bushell chair of neurology at the University of Sydney and codirector of the Brain and Mind Center in Sydney.
Good safety signal
The fact that the trial missed its primary endpoint isn’t too concerning, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “ALS clinical trials are incredibly difficult to conduct, especially a phase 2 learning-phase clinical trial. At this phase, I’m much more buoyed by the fact that they have a good safety signal, and that they’re willing to move forward to that phase 3 clinical trial,” Dr. Johnson said in an interview. He is vice chair of research at Virginia Commonwealth University, Richmond.
A phase 3 clinical trial is in development in the United States and Europe. The drug also is included as part of the HEALEY ALS Platform Trial, which is testing multiple ALS therapies simultaneously. “The results from that should be available by the second half of this year and it will also inform us as to what the approach should be,” said Dr. Kiernan.
Dr. Johnson also was enthusiastic. “I’m excited to see the results in terms of the primary endpoints for that next phase 3 clinical trial,” he said.
Ongoing research
In September 2021, Clene announced a second expanded access program for people with ALS.
The study included a 36-week double-blind treatment period followed by long-term, open-label follow-up. Twenty-three patients received 30 mg CNM-Au8, and 22 received placebo. In the first 36 weeks, the treatment group was more likely to have no disease progression, defined as death, tracheostomy, noninvasive ventilation, or a gastronomy tube (P = .0125). The researchers compared the probability of experiencing a less than 6-point decline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. At 12 weeks, it was about 85% in both groups. At 24 weeks, it was about 60% to 50% in favor of the CNM-Au8 group, and at 36 weeks it was about 50% to 20% (P = .0350).
At 36 weeks, quality of life as measured by the ALS Specific Quality of Life–Short Form was better in the treatment group at 36 weeks (mean change, 0.9; P = .0177).
Survival was better in the treatment group at 96 weeks than the mortality derived from a European Network for the Cure of ALS prediction model (hazard ratio [HR], 0.2974; P = .0068). This benefit also was experienced by patients who received drug throughout the study (HR, 0.36; 95% confidence interval [CI], 0.12-1.1) and those who started out on placebo and converted to active drug during the open-label period (HR, 0.24; 95% CI, 0.064-0.88).
The study was funded by Clene and FightMND. Dr. Kiernan and Dr. Johnson have no relevant financial disclosures.
AT AAN 2022
FDA advisory panel rejects new ALS drug
Six of 10 members of the FDA Peripheral and Central Nervous System Drugs Advisory Committee decided there is not enough evidence to support approval of the drug from Amylyx Pharmaceuticals. The evidence from a single phase 2 trial is insufficient, the panel said.
The fate of the drug, known as AMX0035, and the panel’s vote, has been closely watched as new treatments for this devastating disease are greatly needed. Committee members said they were moved by passionate testimony from patients, caregivers, and others. But, they believe the evidence does not meet the required standard for FDA approval.
“We were asked to look for substantial evidence of persuasiveness and robustness, and I think this one trial doesn’t quite meet that bar and was problematic,” said Kenneth Fischbeck, MD, investigator with the National Institute of Neurological Disorders and Stroke. “It would be a disservice to patients and their families to move ahead and approve a treatment that is of uncertain benefit,” said Dr. Fischbeck.
The committee’s vote is not binding. While the FDA often follows its advisors’ decisions, the agency last year approved a controversial new drug for Alzheimer’s disease after a similar advisory committee voted against it.
Phase 3 study in the works
This new ALS drug was shown to slow the decline caused by ALS, sometimes known as Lou Gehrig’s disease, Jamie Timmons, MD, head of scientific communications at Amylyx Pharmaceuticals, said. The study found the drug slowed decline by 25%, compared with patients taking a placebo. That change is considered clinically meaningful.
This is the first time a treatment has shown a benefit on both function and survival in ALS, the two key measures in a relentlessly progressive, fatal disease, said Joshua Cohen, co-CEO and co-founder of Amylyx.
During the meeting, patients with ALS said they were willing to accept greater risk for the possibility of having even a little more time with their loved ones and argued that the drug contains two compounds that are already available. They pleaded for the FDA to exercise its regulatory flexibility in approving this experimental drug.
However, the FDA panel raised a number of issues with the trial. These concerns included the study’s small sample size and no survival benefit at 24 weeks.
Many panel members said they hope an ongoing phase III trial will be more definitive because it’s so much larger. The results of that trial are expected by early 2024.
A version of this article first appeared on WebMD.com.
Six of 10 members of the FDA Peripheral and Central Nervous System Drugs Advisory Committee decided there is not enough evidence to support approval of the drug from Amylyx Pharmaceuticals. The evidence from a single phase 2 trial is insufficient, the panel said.
The fate of the drug, known as AMX0035, and the panel’s vote, has been closely watched as new treatments for this devastating disease are greatly needed. Committee members said they were moved by passionate testimony from patients, caregivers, and others. But, they believe the evidence does not meet the required standard for FDA approval.
“We were asked to look for substantial evidence of persuasiveness and robustness, and I think this one trial doesn’t quite meet that bar and was problematic,” said Kenneth Fischbeck, MD, investigator with the National Institute of Neurological Disorders and Stroke. “It would be a disservice to patients and their families to move ahead and approve a treatment that is of uncertain benefit,” said Dr. Fischbeck.
The committee’s vote is not binding. While the FDA often follows its advisors’ decisions, the agency last year approved a controversial new drug for Alzheimer’s disease after a similar advisory committee voted against it.
Phase 3 study in the works
This new ALS drug was shown to slow the decline caused by ALS, sometimes known as Lou Gehrig’s disease, Jamie Timmons, MD, head of scientific communications at Amylyx Pharmaceuticals, said. The study found the drug slowed decline by 25%, compared with patients taking a placebo. That change is considered clinically meaningful.
This is the first time a treatment has shown a benefit on both function and survival in ALS, the two key measures in a relentlessly progressive, fatal disease, said Joshua Cohen, co-CEO and co-founder of Amylyx.
During the meeting, patients with ALS said they were willing to accept greater risk for the possibility of having even a little more time with their loved ones and argued that the drug contains two compounds that are already available. They pleaded for the FDA to exercise its regulatory flexibility in approving this experimental drug.
However, the FDA panel raised a number of issues with the trial. These concerns included the study’s small sample size and no survival benefit at 24 weeks.
Many panel members said they hope an ongoing phase III trial will be more definitive because it’s so much larger. The results of that trial are expected by early 2024.
A version of this article first appeared on WebMD.com.
Six of 10 members of the FDA Peripheral and Central Nervous System Drugs Advisory Committee decided there is not enough evidence to support approval of the drug from Amylyx Pharmaceuticals. The evidence from a single phase 2 trial is insufficient, the panel said.
The fate of the drug, known as AMX0035, and the panel’s vote, has been closely watched as new treatments for this devastating disease are greatly needed. Committee members said they were moved by passionate testimony from patients, caregivers, and others. But, they believe the evidence does not meet the required standard for FDA approval.
“We were asked to look for substantial evidence of persuasiveness and robustness, and I think this one trial doesn’t quite meet that bar and was problematic,” said Kenneth Fischbeck, MD, investigator with the National Institute of Neurological Disorders and Stroke. “It would be a disservice to patients and their families to move ahead and approve a treatment that is of uncertain benefit,” said Dr. Fischbeck.
The committee’s vote is not binding. While the FDA often follows its advisors’ decisions, the agency last year approved a controversial new drug for Alzheimer’s disease after a similar advisory committee voted against it.
Phase 3 study in the works
This new ALS drug was shown to slow the decline caused by ALS, sometimes known as Lou Gehrig’s disease, Jamie Timmons, MD, head of scientific communications at Amylyx Pharmaceuticals, said. The study found the drug slowed decline by 25%, compared with patients taking a placebo. That change is considered clinically meaningful.
This is the first time a treatment has shown a benefit on both function and survival in ALS, the two key measures in a relentlessly progressive, fatal disease, said Joshua Cohen, co-CEO and co-founder of Amylyx.
During the meeting, patients with ALS said they were willing to accept greater risk for the possibility of having even a little more time with their loved ones and argued that the drug contains two compounds that are already available. They pleaded for the FDA to exercise its regulatory flexibility in approving this experimental drug.
However, the FDA panel raised a number of issues with the trial. These concerns included the study’s small sample size and no survival benefit at 24 weeks.
Many panel members said they hope an ongoing phase III trial will be more definitive because it’s so much larger. The results of that trial are expected by early 2024.
A version of this article first appeared on WebMD.com.