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A New ALS Drug Has Been Approved
Will Neurologists Recommend It?

Article In Brief

Neurologists told Neurology Today that they would most likely offer a newly approved drug for amyotrophic lateral sclerosis to their patients, but they would be honest in suggesting that the drug may have limited benefit and its high cost could result in delays with insurance companies covering the treatment.

AMX0035, the newly approved therapy for amyotrophic lateral sclerosis (ALS) may be overpriced for its efficacy, according to the Institute for Clinical and Economic Review, but most patients and their families will want it, ALS experts told Neurology Today.

“Will they feel somewhat comforted in that they're taking something? Yes, they will,” said Jeffrey D. Rothstein, MD, PhD, director of the Robert Packard Center for ALS Research at Johns Hopkins University School of Medicine.

From there, his message will focus on hope. “If you're an honest physician, you will tell them that ‘It will not make you better, but it could slow down your disease, and you may live longer because you are taking it. One day, we hope we will have drugs that stop your disease completely,’” he said.

On Sept. 29, the US Food & Drug Administration (FDA) approved AMX0035, an oral combination of sodium phenylbutyrate and taurursodiol, providing a third treatment option to neurologists and their patients with ALS.

Until now, riluzole has been the only FDA-approved therapy proven to slow disease progression and to prolong survival by an average of two to three months.

An oral formulation of edavarone (Radicava), previously available only by intravenous infusion, was approved this past May. Its effectiveness is unknown:;three trials in Japan failed to show that edaravone slowed the decline of motor function in patients with ALS, but the drug won FDA approval after a post-hoc analysis of one trial revealed that it slowed disease progression by 33 percent after 24 weeks for a subset of patients. An analysis of real-world data from 12 ALS clinics published earlier this year did not show that it is effective.

AMX0035, marketed in the United States as Relyvrio, was approved on the basis of a phase 2 clinical trial that showed the drug slowed loss of function by 25 percent and extended overall survival by a few months. An FDA advisory panel voted in March that it did not believe the trial data showed that AMX0035 was effective for treating ALS before reversing its decision in September.

Drugs of ‘Modest Benefit’

ALS experts are used to prescribing treatments that offer modest benefit or have unclear efficacy data. Robert Gardner Jr., MD, a neurologist at Neurologic Associates in Cape Girardeau, MO, said he will offer AMX0035 to any patient who wants to try it because the side effects—diarrhea, abdominal pain, nausea, and upper respiratory tract infection—are relatively minor.

“While the evidence for effectiveness for AMX0035 is not great, there are few treatments for this condition,” Dr. Gardner said in an email. “As a result, many of my ALS patients have traveled internationally and tried other experimental treatments with less efficacy data.”

In Minneapolis, Sam Maiser, MD, medical director of the ALS Center of Excellence at Hennepin Healthcare, said he will discuss and potentially prescribe AMX0035 with any interested patient, but he will only recommend it to patients who want to maintain their function and quality of life as long as possible and are earlier in their disease.

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“This isnt the cure that we need. As exciting and as hopeful as it is, the results of the study do not show disease reversal or anything like that. People have choices about how they spend their time and resources, and this is another choice.”—DR. LAURA FOSTER

“For a few patients that I've seen since the (FDA approval) announcement who have had advanced disease, I have recommended against it because I don't think it will make them feel better, improve their function, or improve their quality of life,” he said.

Anything the FDA approves to treat ALS is a step in the right direction, said Ghazala Hayat, MD, director of the ALS Center of Excellence at St. Louis University School of Medicine and a professor of neurology at the university. She intends to prescribe all three of the FDA-approved treatments simultaneously. Because edaravone is now approved as an oral formulation and AMX0035 is taken orally, the burden of treatment will be minimal.

“The mechanism of action is different, so if they are combined, they hopefully will help our patients more by improving their survival and also decreasing their progression,” she said. “I have always said that, for most neurodegenerative disorders, we will be giving a cocktail of medications.”

Ezgi Tiryaki, MD, FAAN, medical director of the ALS Center of Excellence at the Minneapolis VA Healthcare System, said her patients have been waiting for AMX0035's approval.

“There has also been a lot of excitement among our veterans about this drug,” said Dr. Tiryaki, a professor in the department of neurology at the University of Minnesota. “For the last couple of years now, questions about AMX0035 have kept coming up in clinic visits: Where is this going to go? When is this going to come to market?”

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“If youre an honest physician, you will tell them that ‘It will not make you better, but it could slow down your disease, and you may live longer because you are taking it. One day, we hope we will have drugs that stop your disease completely.’”—DR. JEFFREY D. ROTHSTEIN

At the University of Colorado School of Medicine, Laura Foster, MD, assistant professor of neurology, intends to prescribe AMX0035 to her patients, but her enthusiasm is tempered.

“This isn't the cure that we need,” she said. “As exciting and as hopeful as it is, the results of the study do not show disease reversal or anything like that. People have choices about how they spend their time and resources, and this is another choice.”

Dr. Rothstein said he will prescribe AMX0035 until the results of the phase 3 trial, currently underway, are revealed in 2024.

“Hopefully it will replicate, and since the drug is safe, I don't really have a problem giving it to my patients at all,” he said. “On the other hand, if the drug does not show efficacy equal to what was seen already in phase 2, then I'll stop giving it, and probably most other physicians will stop.”

Will Insurance Cover It?

A year's supply of riluzole, sold as Rilutek, costs less than $10,000 a year. Edaravone, marketed as Radicava, carries a list price of $171,000 a year. The list price for AMX0035 will be $158,000 a year for the first year, according to Amylyx Pharmaceuticals.

Amylyx has said no patients with ALS will have to pay for the drug themselves. The company will provide the drug at no cost to US residents who are uninsured or underinsured and meet eligibility criteria. For patients who have commercial insurance, Amylyx said it will provide financial assistance so they have no co-pay.

Despite that, neurologists are not convinced that patient access to AMX0035 will be easy.

“The insurance is a big hurdle because these are all expensive medications,” Dr. Hayat said.

Because her patients receive health benefits through the VA, Dr. Tiryaki is one of the few ALS specialists who does not have to deal with AMX0035's big price tag. ALS is a military service-connected disease with veterans almost twice as likely to be diagnosed with ALS than people in the general population. All their therapies are covered in full.

Most patients are covered by commercial insurance or Medicare. Dr. Maiser, a site director for the AMX0035 trial, expects neurologists will spend a lot of time wrangling with insurers in the months ahead.

“I think some insurers will cover it, and some will deny it,” he said. “A lot of commercial insurers may follow whatever Medicare decides to do.”

Patients with ALS, regardless of age, are eligible for Medicare as soon as they start receiving Social Security Disability Income benefits, but some patients prefer to keep their commercial insurance. Amylyx's offer to pay patients' copays for AMX0035 if they have private insurance may complicate their decision—whether to stick with private insurance or move to Medicare—because drugmakers are prohibited from paying patient copays for drugs covered by Medicare.

The Centers for Medicare & Medicaid Services (CMS) has not revealed when it will publish its coverage policy for AMX0035.

“I don't think we will fully know what is going to happen for the next three to six months,” Dr. Maiser said. “In the meantime, I suspect there will be denials and lots of appeals and all other processes to try to get it.”

Dr. Hayat pointed out that Medicare covers edaravone, which received FDA approval based on studies conducted in Japan, which was somewhat controversial.

“Our Medicare patients get approved very quickly for edaravone, so I'm hoping we'll have the same with the AMX0035,” she said.

But Dr. Rothstein remembers what happened when edaravone first became available with a list price of more than $150,000.

“Insurance companies went nuts, blocking us from prescriptions,” he said. “It was really challenging because we had to go through all kinds of hoops and hurdles, and quite frankly, they may do it again.”

The Danger of Insurance Hassles

One of the many frustrations associated with ALS is the long ordeal patients go through before getting a diagnosis and treatment.

Bulbar-onset ALS generally is diagnosed much more rapidly than limb-onset, but both presentations leave patients wondering what is wrong for months and even years. As they wait, the disease progresses.

In a Neurology article earlier this year, Hiroshi Mitsumoto, MD, FAAN, the Wesley J. Howe Professor of Neurology at Columbia University at the Neurological Institute of New York and NewYork-Presbyterian Hospital/Columbia University Medical Center, and colleagues urged primary care physicians, non-neurology providers, and neurologists to recognize the urgency of diagnosis and make the necessary practice changes to do so.

“Potential benefits of hastening the diagnosis of ALS include earlier initiation of therapy to slow the fundamental neurodegenerative process,” they wrote.

The emergence of AMX0035 makes early diagnosis all the more urgent, Dr. Mitsumoto said in an interview. He pointed to the long-term survival analysis of participants in the CENTAUR trial of AMX-0035. Adults with ALS were randomized to AMX0035 or placebo. Those who completed the six-month randomized phase were eligible to receive the drug in the open-label extension. Patients who took AMX0035 from the beginning of the study had, on average, a 6.5-months-longer median survival than those who took the placebo during the randomized phase.

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“The mechanism of action is different, so if they [edaravone and AMX0035] are combined, they hopefully will help our patients more by improving their survival and also decreasing their progression. I have always said that, for most neurodegenerative disorders, we will be giving a cocktail of medications.”—DR. GHAZALA HAYAT

“If you start the medication earlier, the benefit is far greater,” Dr. Mitsumoto said. That means it is more cost-effective—greater efficacy for the money—than later, and insurance delays fritter away the benefit.

“Insurers do not want to give such an expensive medication for such dismal benefit, so time passes—sometimes months and months—and the benefit of medication will be reduced,” he said. “To get a better benefit, medication should be started as soon as possible.”

In Minneapolis, Dr. Maiser said he will prescribe AMX0035 to any patient who wants it, but he will only recommend it to patients who want to maintain their quality of life.

“For a few patients that I've seen since the [FDA approval] announcement who have had advanced disease, I have recommended against it because I can't imagine it making them feel better or improving their quality of life,” he said.

Is AMX0035 Worth $158,000 a Year?

AMX0035 is priced slightly less than edaravone, so a case could be made that it is priced fairly considering other ALS treatments. That doesn't mean the cost is justified, Dr. Rothstein said.

“Is it worth that much? Of course not,” said Dr. Rothstein, a site director for the AMX0035 phase 2 trial. “It's not like a company that spent 20 years discovering a brand-new drug, synthesizing it, and optimizing it. These are two existing drugs that are being compounded together. There's no challenge in that—it's been done for ages in medicine.”

If Medicare does not cover AMX0035—or the copay would be difficult for patients' families—Dr. Hayat will discourage them from paying out of pocket. She will tell them about the study results but make clear that the therapy will not cure their illness.

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“If the patient has to pay out of pocket and they dont have any money, I dont want them to feel [like] ‘I have to die because I dont have any money’—thats a terrible feeling. So I tell them this medication is so modest that it doesnt do very much. So if you have to pay out of your pocket, dont do it.”—DR. HIROSHI MITSUMOTO

“I always tell patients, ‘Do not use your life savings for this,’” she said.

Dr. Mitsumoto shares that philosophy.

“If the patient has to pay out of pocket and they don't have any money, I don't want them to feel [like] ‘I have to die because I don't have any money’—that's a terrible feeling,” he said. “So I tell them this medication is so modest that it doesn't do very much. So if you have to pay out of your pocket, don't do it.”

Link Up for More Information

• Cudkowicz ME, Shefner JM. Regulatory approval in ALS; When is a single study enough https://onlinelibrary.wiley.com/doi/10.1002/ana.26371. Ann Neurol 2022;91(6):737–739.
• Makam AN, Suh K, Nikitin D, et al. AMX0035 and oral edaravone for ALS; Evidence report https://icer.org/wp-content/uploads/2022/02/ICER_ALS_Evidence-Report_080422.pdf. Institute for Clinical and Economic Review, August 4, 2022.
• Mitsumoto H, Kasarskis EJ, Simmons Z. Hastening the Diagnosis of Amyotrophic Lateral Sclerosis https://n.neurology.org/content/99/2/60. Neurology 2022;99(2):60–68.
• Paganoni S, Macklin E, Hendrix S, et al. Trial of sodium phe?nylbutyrate–taurursodiol for amyotrophic lateral sclerosis https://www.nejm.org/doi/full/10.1056/nejmoa1916945. NEJM 2020; 383:919–930.
• Paganoni S, Hendrix S, Dickson SP, Knowlton N, et al. Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis https://onlinelibrary.wiley.com/doi/10.1002/mus.27091. Muscle Nerve 2021;63:31–39.
• Paganoni S, Berry J, Schoenfeld D. Approvals of ALS drugs need to focus on actual data and events, Viewpoint https://journals.lww.com/neurotodayonline/Fulltext/2022/06160/Approvals_of_ALS_Drugs_Need_to_Focus_on_Actual.9.aspx. Neurol Today 2022:22(12):31.
• Witzel S, Maier A, Steinbach R, Grosskreutz J, et al. Safety and effectiveness of long-term intravenous administration of edaravone for treatment of patients with amyotrophic lateral sclerosis https://jamanetwork.com/journals/jamaneurology/fullarticle/2787473. JAMA Neurol 2022;79(2):121–130.