Has prompt diagnosis of amyotrophic lateral sclerosis become urgent?

Amyotrophic lateral sclerosis (ALS) falls easily into the Food and Drug Administration definition of “rare disease.” With an estimated prevalence in the United States of fewer than 20,000 cases,¹ ALS sits comfortably below the cutoff of 200,000 cases that serves to define a disease as “rare.”

After a recent steep climb, there are something on the order of 50 therapies, across more than 10 drug classes, in clinical trials for the treatment of ALS.² This bounty represents exciting progress toward the development of targeted therapies for a characteristically fatal disease.

That headway is coupled with a sobering limitation, however: Relatively few ALS patients are being enrolled.
 

The knotty problem with therapeutic trials for ALS

“Trials are generally designed for patients with adequate functional reserve and predicted survival, to ensure that a signal of benefit can be seen,” said Nicholas John Maragakis, MD, director of the ALS Clinical Trials Unit at Johns Hopkins University, Baltimore. “Many of my patients are too severely affected at presentation.”

Dr. Maragakis hasn’t calculated the precise percentage of patients he is enrolling in one of the many available trials available at the Johns Hopkins center. He estimates that it is less than 20%, however.

That percentage is comparable to what is reported by Stephen Scelsa, MD, and Daniel J. Macgowan, MD, who share much of the ALS caseload in a dedicated, comprehensive ALS center at Mount Sinai Beth Israel, New York. Both are on the faculty at the Icahn School of Medicine at Mount Sinai.

“The considerable delay in the diagnosis of ALS remains a challenge,” Dr. Scelsa acknowledges. Like Dr. Maragakis, he reports that, by the time patients develop symptoms that make referral to a comprehensive ALS center like Mount Sinai Beth Israel appropriate, many no longer meet eligibility criteria for most experimental treatments.

Some therapeutic targets in clinical trials, such as neuroinflammation, offer potential benefit even in advancing disease, but it is prevention that is usually the goal of experimental ALS therapies. This approach is associated with far more promise than attempting to reverse existing neurologic damage, which might not be possible, according to both Dr. Scelsa and Dr. Macgowan.

“The clinical trials are typically looking for patients with less than 2 years since the onset of symptoms and at least 60% of predicted respiratory function,” Dr. Macgowan said.

Because of these or other similarly restrictive criteria, coupled with common delays before patients arrive at a center where trials are available, “the window for clinical research closes very quickly,” Dr. Macgowan added, and “the band of patients who are eligible is relatively narrow.”

At Hennepin Healthcare in Minneapolis, which, like Johns Hopkins and Mount Sinai, offers an advanced multidisciplinary approach to ALS care in a dedicated clinic, the problem of late referrals is no different. Samuel Maiser, MD, chair of neurology, does attempt to counter this delay by moving quickly.

“I almost always offer a therapeutic trial to a patient with early-stage ALS,” he said. He does so earlier, rather than later, and explains: “I do not want to delay that conversation, because any delay might reduce the chance for getting into a trial.”

 

The generalist can make a difference in therapeutic success

The proliferation of clinical trials has made early diagnosis of ALS urgent. However, the experts interviewed for this article agreed: Accelerating the time to diagnosis is more dependent on the general neurologist or primary care physician than on the ALS specialist. ALS is a diagnosis of exclusion, but there is now very little delay in reaching a probable diagnosis at a dedicated center.

Yet neurodegenerative complaints in early-stage ALS are often nonspecific and mild; confidence in making a potential diagnosis of ALS is limited among primary care clinicians and general neurologists, who almost always see these patients first. Usually, the problem is not failure to include ALS in the differential diagnosis but hesitation in being candid when there is still doubt.

General neurologists, in particular, Dr. Maragakis said, “are often highly suspicious of a diagnosis of ALS very early on but are concerned about using this term until the clinical signs are more compelling.”

This is understandable. There is reluctance to deliver bad news when confidence in the diagnosis is limited. But the experts agreed: Delayed diagnosis is not in the patient’s interest now that there is at least the potential for entering a trial supported by a scientific rationale for benefit.

“Waiting for 100% certainty – this could actually harm our patients,” Dr. Maiser said. The tendency to avoid delivering bad news, he said, “is human nature, and it is not easy to tell people that ALS is the potential cause, but it’s important for early treatment.”

Some evidence suggests that the incidence of ALS is increasing³ but this is not necessarily evident at the clinical level. “It is not my impression that the incidence of ALS is increasing,” Dr. Macgowan said, “so much as I think we are getting better at making the diagnosis.”
 

Where we stand: Pathophysiology, diagnosis, treatment

Pathophysiology. ALS is characterized by muscle denervation.⁴ In the great majority of cases, the disease represents a proteinopathy involving loss of the TDP-43 protein from nuclei. However, pathological heterogeneity means that other pathophysiological mechanisms – mediated by oxidative stress, mitochondrial dysfunction, and neurotoxicity related to excessive stimulation of postsynaptic glutamate receptors – can participate.^2,5,6

Approximately 10% of patients have a known gene associated with ALS.⁷ The rest have what is considered sporadic ALS, although some experts estimate that heritability will eventually be confirmed in 50% or more of cases that have been given the “sporadic” label.^8,9 More than 30 genes have been linked to ALS in genomewide association studies. Among patients whose disease carries a known familial link, four genes – SOD1, TARDBP, FUS, and C9orf72 – account for approximately 70% of cases.²

Diagnosis. Genetic testing in patients with suspected or confirmed ALS is the standard of care at most, if not all, comprehensive ALS treatment centers, according to the four experts interviewed by Neurology Reviews 2023 Rare Neurological Disease Special Report for this article. Such testing was routine for years because of its potential for helping researchers to understand subtypes of disease; today, testing has assumed even greater practical value with recent approval of the first ALS gene therapy: Tofersen (Qalsody, Biogen), licensed in 2023, is an antisense oligonucleotide therapy that targets SOD1 mRNA to reduce production of the SOD1 protein, a mediator of disease progression.

“Genetic testing has been useful for telling us something about the disease and its prognosis,” Dr. Maragakis said, “but an approved gene therapy means it can have a direct effect on treatment.”

ALS therapeutics. Other gene therapies are in development. Gene signatures are likely to provide even more opportunities for clinical trials in the future.

Following three loading doses of tofersen at 14-day intervals, the maintenance regimen, administered intrathecally by lumbar puncture, is every 28 days. In the phase 3 trial, tofersen reduced levels of SOD1 protein and neurofilament light chain, a biomarker of axonal injury.¹⁰ Tofersen is appropriate only in patients with SOD1-associated ALS; the drug’s favorable clinical impact, including a positive effect, if any, on survival has not been demonstrated. Extension studies are underway.

Tofersen joins three other FDA-approved ALS therapies:

• Riluzole, an oral drug available since 1995 that slows disease progression by blocking glutamate.

• Edaravone, an antioxidant approved in 2017, administered orally or intravenously.

• An orally administered combination of sodium phenylbutyrate and taurursodiol marketed as Relyvrio and formerly known as AMX0035, that was introduced in 2022.

“We offer riluzole, which is safe in combination with other therapies, to most patients,” said Dr. Scelsa, who noted that treatment trials often test experimental drugs on top of riluzole. He moves to edaravone or Relyvrio, which are far more expensive, selectively. Tofersen, which is also expensive, is reserved for patients with SOD1-associated disease; however, not all eligible patients opt for this therapy after reviewing its benefits and risks.

“There is not yet a guarantee that tofersen will improve outcomes, and it requires intrathecal injections for life,”

Dr. Maiser said. “Some patients, particularly my older patients, have said, ‘No thank you,’ based on the available data.”

Dr. Macgowan pointed out that lumbar puncture repeated indefinitely can be “challenging.” He, too, discusses all available treatment options with every patient, including riluzole, which he agreed is associated with a meaningful benefit, particularly when started early.

Because of the safety of riluzole, Dr. Maragakis takes early treatment a step further. For neurologists who have a high level of suspicion of ALS in a given patient, “my advice would be to treat aggressively from the get-go. Even if not 100% certain of the diagnosis, I would start them on riluzole while waiting for confirmation.” Like the other experts interviewed here, he acknowledged that referral to a busy comprehensive ALS center often takes time, making it reasonable to initiate treatment when suspicion is high.

On the front lines, “the neurologist can tell the patient that ALS is just one of several potential explanations for symptoms but there is concern,” said Dr. Maragakis, proposing a strategy to introduce the possibility of ALS and start treatment that might slow disease while waiting for confirmation of the diagnosis. “My biggest concern is that no one is making that call,” he said, trying to address at least one reason for the current delay in making referrals.
 

 

Comprehensive care at specialty centers

Whenever possible, ALS is a disease best managed at a center that offers comprehensive management, including multidisciplinary care. On this point, the four experts agreed.

“Tertiary-care centers for ALS serve a critical purpose,”

Dr. Maiser said. For a disease that affects nearly every aspect of life, the skills of a multidisciplinary support staff offer an “opportunity to stay in front of the disease” for as long as possible. Teamwork often leads to “outside-of-the-box thinking” for helping patients and families cope with the range of disabilities that undermine the patient’s quality of life.

Details of ALS management matter. At Mount Sinai and Hennepin Healthcare, and at Johns Hopkins, where demand recently led to the opening of a second ALS clinic, the ALS center is set up to address the full spectrum of needs. Staff members have multiple skills so that they can work together to make patients comfortable and prepare them for what is inevitably progression – even if the rate of that progression varies.

All these centers incorporate a rational, thorough discussion of end-of-life options in a palliative care approach that targets optimized quality of life. One goal is to prepare patients to consider and be prepared to make decisions when it is time for tracheostomy, percutaneous endoscopic gastrostomy, and other life support options that are not always well tolerated. The goal? Avoiding unnecessary anguish during end-stage disease when impaired respiratory function – the primary cause of ALS-related death – no longer sustains unassisted survival.

“I am concerned for the many ALS patients without access to this type of comprehensive care,” Dr. Macgowan said.

Like the other experts here, he emphasized that the demands of ALS care can be “overwhelming” outside a comprehensive care setting – for the patient, their family, and individual providers.
 

Looking ahead

There are many reasons to be optimistic about improving the survival and care of patients with ALS. Besides therapies in clinical trials, Dr. Scelsa explained, there is the potential role for monitoring neurofilament light changes, a biomarker of neurodegeneration, in patients who are at risk of ALS.

Dr. Maragakis offered an analogy to the gene therapy onasemnogene abeparvovec, which can prevent the associated neurodegeneration of spinal muscular atrophy if initiated before symptoms appear. He said that, in ALS, neurofilament light changes or other biomarkers might offer an opportunity to halt the progression of disease before it starts – if one or more therapies in development prove workable.

In the meantime, neurologists who do not specialize in ALS should be thinking about how they can participate in speedier diagnostic pathways.

“There are a number of therapies that look promising,” Dr. Maiser told Rare Neurological Disease Special Report. He singled out strategies to degrade TDP-43 or prevent it from forming. If these treatments are found effective, it’s expected that they would be of value in sporadic ALS, the most common form. Again, though, “the challenge is getting patients on this therapy at the earliest stages of disease.”

Dr. Maragakis discloses equity ownership/stock options with Braintrust Bio and Akava; he is a patent holder with Johns Hopkins [ALS] and has received grant/research/clinical trial support from Apellis Pharma, Biogen Idec, Cytokinetics, Helixmith, Calico, Sanofi, Department of Defense ALSRP, Maryland Stem Cell Research Fund, Massachusetts General Hospital, Medicinova, and NINDS. He serves as consultant or advisory board member for Amylyx; Cytokinetics, Roche, Healey Center, Nura Bio, Northeast ALS Consortium, Akava, Inflammx, and Secretome. Dr. Scelsa did not report any conflicts of interest. Dr. Macgowan and Dr. Maiser have no relevant conflicts of interest to disclose.
 

 

References

1. Mehta P et al. Prevalence of amyotrophic lateral sclerosis in the United States using established and novel methodologies, 2017. Amyotroph Lateral Scler Frontotemporal Degener. 2023;24(1-2):108-16. doi: 10.1080/21678421.2022.2059380.

2. Mead RJ et al. Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22(3):185-212. doi: 10.1038/s41573-022-00612-2.

3. Longinetti E and Fang F. Epidemiology of amyotrophic lateral sclerosis: An update of recent literature. Curr Opin Neurol. 2019;32(5):771-6. doi: 10.1097/WCO.0000000000000730.

4. van den Bos MAJ et al. Pathophysiology and diagnosis of ALS: Insights from advances in neurophysiological techniques. Int J Mol Sci. 2019;20(11):2818. doi: 10.3390/ijms20112818.

5. Neumann M et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-3. doi: 10.1126/science.1134108.

6. Ling S-C et al. Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416-38. doi: 10.1016/j.neuron.2013.07.033.

7. Ranganathan R et al. Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia. Front Neurosci. 2020;14:684. doi: 10.3389/fnins.2020.00684.

8. Ryan M et al. Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2019;76(11):1367-74. doi: 10.1001/jamaneurol.2019.2044.

9. van Rheenen W et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021;53(12):1636-48. doi: 10.1038/s41588-021-00973-1.

10. Miller TM et al; VALOR and OLE Working Group. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-110. doi: 10.1056/NEJMoa2204705.

Amyotrophic lateral sclerosis (ALS) falls easily into the Food and Drug Administration definition of “rare disease.” With an estimated prevalence in the United States of fewer than 20,000 cases,¹ ALS sits comfortably below the cutoff of 200,000 cases that serves to define a disease as “rare.”

After a recent steep climb, there are something on the order of 50 therapies, across more than 10 drug classes, in clinical trials for the treatment of ALS.² This bounty represents exciting progress toward the development of targeted therapies for a characteristically fatal disease.

That headway is coupled with a sobering limitation, however: Relatively few ALS patients are being enrolled.
 

The knotty problem with therapeutic trials for ALS

“Trials are generally designed for patients with adequate functional reserve and predicted survival, to ensure that a signal of benefit can be seen,” said Nicholas John Maragakis, MD, director of the ALS Clinical Trials Unit at Johns Hopkins University, Baltimore. “Many of my patients are too severely affected at presentation.”

Dr. Maragakis hasn’t calculated the precise percentage of patients he is enrolling in one of the many available trials available at the Johns Hopkins center. He estimates that it is less than 20%, however.

That percentage is comparable to what is reported by Stephen Scelsa, MD, and Daniel J. Macgowan, MD, who share much of the ALS caseload in a dedicated, comprehensive ALS center at Mount Sinai Beth Israel, New York. Both are on the faculty at the Icahn School of Medicine at Mount Sinai.

“The considerable delay in the diagnosis of ALS remains a challenge,” Dr. Scelsa acknowledges. Like Dr. Maragakis, he reports that, by the time patients develop symptoms that make referral to a comprehensive ALS center like Mount Sinai Beth Israel appropriate, many no longer meet eligibility criteria for most experimental treatments.

Some therapeutic targets in clinical trials, such as neuroinflammation, offer potential benefit even in advancing disease, but it is prevention that is usually the goal of experimental ALS therapies. This approach is associated with far more promise than attempting to reverse existing neurologic damage, which might not be possible, according to both Dr. Scelsa and Dr. Macgowan.

“The clinical trials are typically looking for patients with less than 2 years since the onset of symptoms and at least 60% of predicted respiratory function,” Dr. Macgowan said.

Because of these or other similarly restrictive criteria, coupled with common delays before patients arrive at a center where trials are available, “the window for clinical research closes very quickly,” Dr. Macgowan added, and “the band of patients who are eligible is relatively narrow.”

At Hennepin Healthcare in Minneapolis, which, like Johns Hopkins and Mount Sinai, offers an advanced multidisciplinary approach to ALS care in a dedicated clinic, the problem of late referrals is no different. Samuel Maiser, MD, chair of neurology, does attempt to counter this delay by moving quickly.

“I almost always offer a therapeutic trial to a patient with early-stage ALS,” he said. He does so earlier, rather than later, and explains: “I do not want to delay that conversation, because any delay might reduce the chance for getting into a trial.”

 

The generalist can make a difference in therapeutic success

The proliferation of clinical trials has made early diagnosis of ALS urgent. However, the experts interviewed for this article agreed: Accelerating the time to diagnosis is more dependent on the general neurologist or primary care physician than on the ALS specialist. ALS is a diagnosis of exclusion, but there is now very little delay in reaching a probable diagnosis at a dedicated center.

Yet neurodegenerative complaints in early-stage ALS are often nonspecific and mild; confidence in making a potential diagnosis of ALS is limited among primary care clinicians and general neurologists, who almost always see these patients first. Usually, the problem is not failure to include ALS in the differential diagnosis but hesitation in being candid when there is still doubt.

General neurologists, in particular, Dr. Maragakis said, “are often highly suspicious of a diagnosis of ALS very early on but are concerned about using this term until the clinical signs are more compelling.”

This is understandable. There is reluctance to deliver bad news when confidence in the diagnosis is limited. But the experts agreed: Delayed diagnosis is not in the patient’s interest now that there is at least the potential for entering a trial supported by a scientific rationale for benefit.

“Waiting for 100% certainty – this could actually harm our patients,” Dr. Maiser said. The tendency to avoid delivering bad news, he said, “is human nature, and it is not easy to tell people that ALS is the potential cause, but it’s important for early treatment.”

Some evidence suggests that the incidence of ALS is increasing³ but this is not necessarily evident at the clinical level. “It is not my impression that the incidence of ALS is increasing,” Dr. Macgowan said, “so much as I think we are getting better at making the diagnosis.”
 

Where we stand: Pathophysiology, diagnosis, treatment

Pathophysiology. ALS is characterized by muscle denervation.⁴ In the great majority of cases, the disease represents a proteinopathy involving loss of the TDP-43 protein from nuclei. However, pathological heterogeneity means that other pathophysiological mechanisms – mediated by oxidative stress, mitochondrial dysfunction, and neurotoxicity related to excessive stimulation of postsynaptic glutamate receptors – can participate.^2,5,6

Approximately 10% of patients have a known gene associated with ALS.⁷ The rest have what is considered sporadic ALS, although some experts estimate that heritability will eventually be confirmed in 50% or more of cases that have been given the “sporadic” label.^8,9 More than 30 genes have been linked to ALS in genomewide association studies. Among patients whose disease carries a known familial link, four genes – SOD1, TARDBP, FUS, and C9orf72 – account for approximately 70% of cases.²

Diagnosis. Genetic testing in patients with suspected or confirmed ALS is the standard of care at most, if not all, comprehensive ALS treatment centers, according to the four experts interviewed by Neurology Reviews 2023 Rare Neurological Disease Special Report for this article. Such testing was routine for years because of its potential for helping researchers to understand subtypes of disease; today, testing has assumed even greater practical value with recent approval of the first ALS gene therapy: Tofersen (Qalsody, Biogen), licensed in 2023, is an antisense oligonucleotide therapy that targets SOD1 mRNA to reduce production of the SOD1 protein, a mediator of disease progression.

“Genetic testing has been useful for telling us something about the disease and its prognosis,” Dr. Maragakis said, “but an approved gene therapy means it can have a direct effect on treatment.”

ALS therapeutics. Other gene therapies are in development. Gene signatures are likely to provide even more opportunities for clinical trials in the future.

Following three loading doses of tofersen at 14-day intervals, the maintenance regimen, administered intrathecally by lumbar puncture, is every 28 days. In the phase 3 trial, tofersen reduced levels of SOD1 protein and neurofilament light chain, a biomarker of axonal injury.¹⁰ Tofersen is appropriate only in patients with SOD1-associated ALS; the drug’s favorable clinical impact, including a positive effect, if any, on survival has not been demonstrated. Extension studies are underway.

Tofersen joins three other FDA-approved ALS therapies:

• Riluzole, an oral drug available since 1995 that slows disease progression by blocking glutamate.

• Edaravone, an antioxidant approved in 2017, administered orally or intravenously.

• An orally administered combination of sodium phenylbutyrate and taurursodiol marketed as Relyvrio and formerly known as AMX0035, that was introduced in 2022.

“We offer riluzole, which is safe in combination with other therapies, to most patients,” said Dr. Scelsa, who noted that treatment trials often test experimental drugs on top of riluzole. He moves to edaravone or Relyvrio, which are far more expensive, selectively. Tofersen, which is also expensive, is reserved for patients with SOD1-associated disease; however, not all eligible patients opt for this therapy after reviewing its benefits and risks.

“There is not yet a guarantee that tofersen will improve outcomes, and it requires intrathecal injections for life,”

Dr. Maiser said. “Some patients, particularly my older patients, have said, ‘No thank you,’ based on the available data.”

Dr. Macgowan pointed out that lumbar puncture repeated indefinitely can be “challenging.” He, too, discusses all available treatment options with every patient, including riluzole, which he agreed is associated with a meaningful benefit, particularly when started early.

Because of the safety of riluzole, Dr. Maragakis takes early treatment a step further. For neurologists who have a high level of suspicion of ALS in a given patient, “my advice would be to treat aggressively from the get-go. Even if not 100% certain of the diagnosis, I would start them on riluzole while waiting for confirmation.” Like the other experts interviewed here, he acknowledged that referral to a busy comprehensive ALS center often takes time, making it reasonable to initiate treatment when suspicion is high.

On the front lines, “the neurologist can tell the patient that ALS is just one of several potential explanations for symptoms but there is concern,” said Dr. Maragakis, proposing a strategy to introduce the possibility of ALS and start treatment that might slow disease while waiting for confirmation of the diagnosis. “My biggest concern is that no one is making that call,” he said, trying to address at least one reason for the current delay in making referrals.
 

 

Comprehensive care at specialty centers

Whenever possible, ALS is a disease best managed at a center that offers comprehensive management, including multidisciplinary care. On this point, the four experts agreed.

“Tertiary-care centers for ALS serve a critical purpose,”

Dr. Maiser said. For a disease that affects nearly every aspect of life, the skills of a multidisciplinary support staff offer an “opportunity to stay in front of the disease” for as long as possible. Teamwork often leads to “outside-of-the-box thinking” for helping patients and families cope with the range of disabilities that undermine the patient’s quality of life.

Details of ALS management matter. At Mount Sinai and Hennepin Healthcare, and at Johns Hopkins, where demand recently led to the opening of a second ALS clinic, the ALS center is set up to address the full spectrum of needs. Staff members have multiple skills so that they can work together to make patients comfortable and prepare them for what is inevitably progression – even if the rate of that progression varies.

All these centers incorporate a rational, thorough discussion of end-of-life options in a palliative care approach that targets optimized quality of life. One goal is to prepare patients to consider and be prepared to make decisions when it is time for tracheostomy, percutaneous endoscopic gastrostomy, and other life support options that are not always well tolerated. The goal? Avoiding unnecessary anguish during end-stage disease when impaired respiratory function – the primary cause of ALS-related death – no longer sustains unassisted survival.

“I am concerned for the many ALS patients without access to this type of comprehensive care,” Dr. Macgowan said.

Like the other experts here, he emphasized that the demands of ALS care can be “overwhelming” outside a comprehensive care setting – for the patient, their family, and individual providers.
 

Looking ahead

There are many reasons to be optimistic about improving the survival and care of patients with ALS. Besides therapies in clinical trials, Dr. Scelsa explained, there is the potential role for monitoring neurofilament light changes, a biomarker of neurodegeneration, in patients who are at risk of ALS.

Dr. Maragakis offered an analogy to the gene therapy onasemnogene abeparvovec, which can prevent the associated neurodegeneration of spinal muscular atrophy if initiated before symptoms appear. He said that, in ALS, neurofilament light changes or other biomarkers might offer an opportunity to halt the progression of disease before it starts – if one or more therapies in development prove workable.

In the meantime, neurologists who do not specialize in ALS should be thinking about how they can participate in speedier diagnostic pathways.

“There are a number of therapies that look promising,” Dr. Maiser told Rare Neurological Disease Special Report. He singled out strategies to degrade TDP-43 or prevent it from forming. If these treatments are found effective, it’s expected that they would be of value in sporadic ALS, the most common form. Again, though, “the challenge is getting patients on this therapy at the earliest stages of disease.”

Dr. Maragakis discloses equity ownership/stock options with Braintrust Bio and Akava; he is a patent holder with Johns Hopkins [ALS] and has received grant/research/clinical trial support from Apellis Pharma, Biogen Idec, Cytokinetics, Helixmith, Calico, Sanofi, Department of Defense ALSRP, Maryland Stem Cell Research Fund, Massachusetts General Hospital, Medicinova, and NINDS. He serves as consultant or advisory board member for Amylyx; Cytokinetics, Roche, Healey Center, Nura Bio, Northeast ALS Consortium, Akava, Inflammx, and Secretome. Dr. Scelsa did not report any conflicts of interest. Dr. Macgowan and Dr. Maiser have no relevant conflicts of interest to disclose.
 

 

References

1. Mehta P et al. Prevalence of amyotrophic lateral sclerosis in the United States using established and novel methodologies, 2017. Amyotroph Lateral Scler Frontotemporal Degener. 2023;24(1-2):108-16. doi: 10.1080/21678421.2022.2059380.

2. Mead RJ et al. Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22(3):185-212. doi: 10.1038/s41573-022-00612-2.

3. Longinetti E and Fang F. Epidemiology of amyotrophic lateral sclerosis: An update of recent literature. Curr Opin Neurol. 2019;32(5):771-6. doi: 10.1097/WCO.0000000000000730.

4. van den Bos MAJ et al. Pathophysiology and diagnosis of ALS: Insights from advances in neurophysiological techniques. Int J Mol Sci. 2019;20(11):2818. doi: 10.3390/ijms20112818.

5. Neumann M et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-3. doi: 10.1126/science.1134108.

6. Ling S-C et al. Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416-38. doi: 10.1016/j.neuron.2013.07.033.

7. Ranganathan R et al. Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia. Front Neurosci. 2020;14:684. doi: 10.3389/fnins.2020.00684.

8. Ryan M et al. Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2019;76(11):1367-74. doi: 10.1001/jamaneurol.2019.2044.

9. van Rheenen W et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021;53(12):1636-48. doi: 10.1038/s41588-021-00973-1.

10. Miller TM et al; VALOR and OLE Working Group. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-110. doi: 10.1056/NEJMoa2204705.

Amyotrophic lateral sclerosis (ALS) falls easily into the Food and Drug Administration definition of “rare disease.” With an estimated prevalence in the United States of fewer than 20,000 cases,¹ ALS sits comfortably below the cutoff of 200,000 cases that serves to define a disease as “rare.”

After a recent steep climb, there are something on the order of 50 therapies, across more than 10 drug classes, in clinical trials for the treatment of ALS.² This bounty represents exciting progress toward the development of targeted therapies for a characteristically fatal disease.

That headway is coupled with a sobering limitation, however: Relatively few ALS patients are being enrolled.
 

The knotty problem with therapeutic trials for ALS

“Trials are generally designed for patients with adequate functional reserve and predicted survival, to ensure that a signal of benefit can be seen,” said Nicholas John Maragakis, MD, director of the ALS Clinical Trials Unit at Johns Hopkins University, Baltimore. “Many of my patients are too severely affected at presentation.”

Dr. Maragakis hasn’t calculated the precise percentage of patients he is enrolling in one of the many available trials available at the Johns Hopkins center. He estimates that it is less than 20%, however.

That percentage is comparable to what is reported by Stephen Scelsa, MD, and Daniel J. Macgowan, MD, who share much of the ALS caseload in a dedicated, comprehensive ALS center at Mount Sinai Beth Israel, New York. Both are on the faculty at the Icahn School of Medicine at Mount Sinai.

“The considerable delay in the diagnosis of ALS remains a challenge,” Dr. Scelsa acknowledges. Like Dr. Maragakis, he reports that, by the time patients develop symptoms that make referral to a comprehensive ALS center like Mount Sinai Beth Israel appropriate, many no longer meet eligibility criteria for most experimental treatments.

Some therapeutic targets in clinical trials, such as neuroinflammation, offer potential benefit even in advancing disease, but it is prevention that is usually the goal of experimental ALS therapies. This approach is associated with far more promise than attempting to reverse existing neurologic damage, which might not be possible, according to both Dr. Scelsa and Dr. Macgowan.

“The clinical trials are typically looking for patients with less than 2 years since the onset of symptoms and at least 60% of predicted respiratory function,” Dr. Macgowan said.

Because of these or other similarly restrictive criteria, coupled with common delays before patients arrive at a center where trials are available, “the window for clinical research closes very quickly,” Dr. Macgowan added, and “the band of patients who are eligible is relatively narrow.”

At Hennepin Healthcare in Minneapolis, which, like Johns Hopkins and Mount Sinai, offers an advanced multidisciplinary approach to ALS care in a dedicated clinic, the problem of late referrals is no different. Samuel Maiser, MD, chair of neurology, does attempt to counter this delay by moving quickly.

“I almost always offer a therapeutic trial to a patient with early-stage ALS,” he said. He does so earlier, rather than later, and explains: “I do not want to delay that conversation, because any delay might reduce the chance for getting into a trial.”

 

The generalist can make a difference in therapeutic success

The proliferation of clinical trials has made early diagnosis of ALS urgent. However, the experts interviewed for this article agreed: Accelerating the time to diagnosis is more dependent on the general neurologist or primary care physician than on the ALS specialist. ALS is a diagnosis of exclusion, but there is now very little delay in reaching a probable diagnosis at a dedicated center.

Yet neurodegenerative complaints in early-stage ALS are often nonspecific and mild; confidence in making a potential diagnosis of ALS is limited among primary care clinicians and general neurologists, who almost always see these patients first. Usually, the problem is not failure to include ALS in the differential diagnosis but hesitation in being candid when there is still doubt.

General neurologists, in particular, Dr. Maragakis said, “are often highly suspicious of a diagnosis of ALS very early on but are concerned about using this term until the clinical signs are more compelling.”

This is understandable. There is reluctance to deliver bad news when confidence in the diagnosis is limited. But the experts agreed: Delayed diagnosis is not in the patient’s interest now that there is at least the potential for entering a trial supported by a scientific rationale for benefit.

“Waiting for 100% certainty – this could actually harm our patients,” Dr. Maiser said. The tendency to avoid delivering bad news, he said, “is human nature, and it is not easy to tell people that ALS is the potential cause, but it’s important for early treatment.”

Some evidence suggests that the incidence of ALS is increasing³ but this is not necessarily evident at the clinical level. “It is not my impression that the incidence of ALS is increasing,” Dr. Macgowan said, “so much as I think we are getting better at making the diagnosis.”
 

Where we stand: Pathophysiology, diagnosis, treatment

Pathophysiology. ALS is characterized by muscle denervation.⁴ In the great majority of cases, the disease represents a proteinopathy involving loss of the TDP-43 protein from nuclei. However, pathological heterogeneity means that other pathophysiological mechanisms – mediated by oxidative stress, mitochondrial dysfunction, and neurotoxicity related to excessive stimulation of postsynaptic glutamate receptors – can participate.^2,5,6

Approximately 10% of patients have a known gene associated with ALS.⁷ The rest have what is considered sporadic ALS, although some experts estimate that heritability will eventually be confirmed in 50% or more of cases that have been given the “sporadic” label.^8,9 More than 30 genes have been linked to ALS in genomewide association studies. Among patients whose disease carries a known familial link, four genes – SOD1, TARDBP, FUS, and C9orf72 – account for approximately 70% of cases.²

Diagnosis. Genetic testing in patients with suspected or confirmed ALS is the standard of care at most, if not all, comprehensive ALS treatment centers, according to the four experts interviewed by Neurology Reviews 2023 Rare Neurological Disease Special Report for this article. Such testing was routine for years because of its potential for helping researchers to understand subtypes of disease; today, testing has assumed even greater practical value with recent approval of the first ALS gene therapy: Tofersen (Qalsody, Biogen), licensed in 2023, is an antisense oligonucleotide therapy that targets SOD1 mRNA to reduce production of the SOD1 protein, a mediator of disease progression.

“Genetic testing has been useful for telling us something about the disease and its prognosis,” Dr. Maragakis said, “but an approved gene therapy means it can have a direct effect on treatment.”

ALS therapeutics. Other gene therapies are in development. Gene signatures are likely to provide even more opportunities for clinical trials in the future.

Following three loading doses of tofersen at 14-day intervals, the maintenance regimen, administered intrathecally by lumbar puncture, is every 28 days. In the phase 3 trial, tofersen reduced levels of SOD1 protein and neurofilament light chain, a biomarker of axonal injury.¹⁰ Tofersen is appropriate only in patients with SOD1-associated ALS; the drug’s favorable clinical impact, including a positive effect, if any, on survival has not been demonstrated. Extension studies are underway.

Tofersen joins three other FDA-approved ALS therapies:

• Riluzole, an oral drug available since 1995 that slows disease progression by blocking glutamate.

• Edaravone, an antioxidant approved in 2017, administered orally or intravenously.

• An orally administered combination of sodium phenylbutyrate and taurursodiol marketed as Relyvrio and formerly known as AMX0035, that was introduced in 2022.

“We offer riluzole, which is safe in combination with other therapies, to most patients,” said Dr. Scelsa, who noted that treatment trials often test experimental drugs on top of riluzole. He moves to edaravone or Relyvrio, which are far more expensive, selectively. Tofersen, which is also expensive, is reserved for patients with SOD1-associated disease; however, not all eligible patients opt for this therapy after reviewing its benefits and risks.

“There is not yet a guarantee that tofersen will improve outcomes, and it requires intrathecal injections for life,”

Dr. Maiser said. “Some patients, particularly my older patients, have said, ‘No thank you,’ based on the available data.”

Dr. Macgowan pointed out that lumbar puncture repeated indefinitely can be “challenging.” He, too, discusses all available treatment options with every patient, including riluzole, which he agreed is associated with a meaningful benefit, particularly when started early.

Because of the safety of riluzole, Dr. Maragakis takes early treatment a step further. For neurologists who have a high level of suspicion of ALS in a given patient, “my advice would be to treat aggressively from the get-go. Even if not 100% certain of the diagnosis, I would start them on riluzole while waiting for confirmation.” Like the other experts interviewed here, he acknowledged that referral to a busy comprehensive ALS center often takes time, making it reasonable to initiate treatment when suspicion is high.

On the front lines, “the neurologist can tell the patient that ALS is just one of several potential explanations for symptoms but there is concern,” said Dr. Maragakis, proposing a strategy to introduce the possibility of ALS and start treatment that might slow disease while waiting for confirmation of the diagnosis. “My biggest concern is that no one is making that call,” he said, trying to address at least one reason for the current delay in making referrals.
 

 

Comprehensive care at specialty centers

Whenever possible, ALS is a disease best managed at a center that offers comprehensive management, including multidisciplinary care. On this point, the four experts agreed.

“Tertiary-care centers for ALS serve a critical purpose,”

Dr. Maiser said. For a disease that affects nearly every aspect of life, the skills of a multidisciplinary support staff offer an “opportunity to stay in front of the disease” for as long as possible. Teamwork often leads to “outside-of-the-box thinking” for helping patients and families cope with the range of disabilities that undermine the patient’s quality of life.

Details of ALS management matter. At Mount Sinai and Hennepin Healthcare, and at Johns Hopkins, where demand recently led to the opening of a second ALS clinic, the ALS center is set up to address the full spectrum of needs. Staff members have multiple skills so that they can work together to make patients comfortable and prepare them for what is inevitably progression – even if the rate of that progression varies.

All these centers incorporate a rational, thorough discussion of end-of-life options in a palliative care approach that targets optimized quality of life. One goal is to prepare patients to consider and be prepared to make decisions when it is time for tracheostomy, percutaneous endoscopic gastrostomy, and other life support options that are not always well tolerated. The goal? Avoiding unnecessary anguish during end-stage disease when impaired respiratory function – the primary cause of ALS-related death – no longer sustains unassisted survival.

“I am concerned for the many ALS patients without access to this type of comprehensive care,” Dr. Macgowan said.

Like the other experts here, he emphasized that the demands of ALS care can be “overwhelming” outside a comprehensive care setting – for the patient, their family, and individual providers.
 

Looking ahead

There are many reasons to be optimistic about improving the survival and care of patients with ALS. Besides therapies in clinical trials, Dr. Scelsa explained, there is the potential role for monitoring neurofilament light changes, a biomarker of neurodegeneration, in patients who are at risk of ALS.

Dr. Maragakis offered an analogy to the gene therapy onasemnogene abeparvovec, which can prevent the associated neurodegeneration of spinal muscular atrophy if initiated before symptoms appear. He said that, in ALS, neurofilament light changes or other biomarkers might offer an opportunity to halt the progression of disease before it starts – if one or more therapies in development prove workable.

In the meantime, neurologists who do not specialize in ALS should be thinking about how they can participate in speedier diagnostic pathways.

“There are a number of therapies that look promising,” Dr. Maiser told Rare Neurological Disease Special Report. He singled out strategies to degrade TDP-43 or prevent it from forming. If these treatments are found effective, it’s expected that they would be of value in sporadic ALS, the most common form. Again, though, “the challenge is getting patients on this therapy at the earliest stages of disease.”

Dr. Maragakis discloses equity ownership/stock options with Braintrust Bio and Akava; he is a patent holder with Johns Hopkins [ALS] and has received grant/research/clinical trial support from Apellis Pharma, Biogen Idec, Cytokinetics, Helixmith, Calico, Sanofi, Department of Defense ALSRP, Maryland Stem Cell Research Fund, Massachusetts General Hospital, Medicinova, and NINDS. He serves as consultant or advisory board member for Amylyx; Cytokinetics, Roche, Healey Center, Nura Bio, Northeast ALS Consortium, Akava, Inflammx, and Secretome. Dr. Scelsa did not report any conflicts of interest. Dr. Macgowan and Dr. Maiser have no relevant conflicts of interest to disclose.
 

 

References

1. Mehta P et al. Prevalence of amyotrophic lateral sclerosis in the United States using established and novel methodologies, 2017. Amyotroph Lateral Scler Frontotemporal Degener. 2023;24(1-2):108-16. doi: 10.1080/21678421.2022.2059380.

2. Mead RJ et al. Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22(3):185-212. doi: 10.1038/s41573-022-00612-2.

3. Longinetti E and Fang F. Epidemiology of amyotrophic lateral sclerosis: An update of recent literature. Curr Opin Neurol. 2019;32(5):771-6. doi: 10.1097/WCO.0000000000000730.

4. van den Bos MAJ et al. Pathophysiology and diagnosis of ALS: Insights from advances in neurophysiological techniques. Int J Mol Sci. 2019;20(11):2818. doi: 10.3390/ijms20112818.

5. Neumann M et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-3. doi: 10.1126/science.1134108.

6. Ling S-C et al. Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416-38. doi: 10.1016/j.neuron.2013.07.033.

7. Ranganathan R et al. Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia. Front Neurosci. 2020;14:684. doi: 10.3389/fnins.2020.00684.

8. Ryan M et al. Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2019;76(11):1367-74. doi: 10.1001/jamaneurol.2019.2044.

9. van Rheenen W et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021;53(12):1636-48. doi: 10.1038/s41588-021-00973-1.

10. Miller TM et al; VALOR and OLE Working Group. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-110. doi: 10.1056/NEJMoa2204705.