The Institute for Clinical and Economic Review provided a low efficacy rating to AMX0035, an ALS drug an FDA committee recently recommended for agency approval, deeming it overpriced because of its limited effectiveness.

Emerging treatments for amyotrophic lateral sclerosis (ALS) received a lackluster evaluation from the Institute for Clinical and Economic Review (ICER), a nonprofit organization that assesses the cost-effectiveness of medical therapies.

AMX0035, an oral combination of sodium phenylbutyrate and taurursodiol, and the oral formulation of edaravone (Radicava ORS) both received relatively low ratings for efficacy when the ICER-convened Midwest Comparative Effectiveness Public Advisory Council (CEPAC) met on Aug. 19. ICER issued its final report in mid-September.

AMX0035's rocky path toward US Food & Drug Administration (FDA) approval continued on Sept. 7 with an unusual second meeting of its Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee. The committee recommended approval of the drug by a vote of 7-2. The FDA was expected to issue a final decision by Sept. 29.

The FDA in May approved oral edaravone based on its bioequivalence to the intravenous (IV) formulation originally approved in 2017.

Because of both therapies' limited effectiveness, ICER deemed them overpriced. In ICER's view, edaravone would be cost effective at $1,400 to $3,200 annually rather than its $171,000 asking price. And AMX0035, priced at roughly $169,000 (in equivalent US dollars) in Canada, would be cost effective in the $9,100 to $30,600 per year range.

Both drugs pose a frustrating dilemma for neurologists, patients with ALS, their families, and their advocates. In each case, the evidence for efficacy is controversial, and the cost is high. But advocates want more treatment options for the fatal disease, even if they are not optimal.

“Everyone with ALS should be provided immediate and full coverage and affordable access to new therapies—that's the bottom line,” Jinsy A. Andrews, MD, MSc, FAAN, director of neuromuscular clinical trials and associate professor of neurology in the department of neurology at Columbia University, said in an interview with Neurology Today. “We want to make sure that anything that's been tested rigorously in a clinical trial and has good safety and tolerability is accessible. And we also concurrently gain and gather data to understand the drug as fully as possible in terms of efficacy.”

AMX0035 is designed to safeguard neurons by targeting the endoplasmic reticulum and mitochondria. Sabrina Paganoni, MD, PhD, co-director of the MGH Neurological Clinical Research Institute, organized the CENTAUR multicenter phase 2 clinical trial to test the effectiveness of AMX0035. The trial, involving 137 patients, included a six-month randomized, placebo-controlled phase and an open-label, long-term follow-up phase.

The results were published in the New England Journal of Medicine in 2020: AMX0035 resulted in 25 percent slower functional decline than the placebo as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale—Revised (ALSFRS-R) score over a period of 24 weeks. Patients receiving AMX0035 experienced no serious harms, but about one-third suffered diarrhea and nausea, and 20 percent dropped out because of adverse events. Secondary outcomes were not significantly different between the two groups.

Although the FDA typically wants evidence of effectiveness from two clinical trials, it will consider one “adequate and well-controlled clinical investigation plus confirmatory evidence” under certain circumstances, and Amylyx hoped AMX0035 would fit the bill.

In 2019, the FDA had published guidance, specifically for ALS drug development, noting that survival time for the condition varies greatly and loss of data because of patient deaths can confound functional endpoints. For that reason, the FDA recommended that researchers use an analysis method, such as the joint rank test, that combines survival and function in a single overall measure.

FDA staff noted that the analysis in the CENTAUR study did not appropriately account for deaths that occurred during the study period, potentially rendering the study inadequate to justify AMX0035 approval.

Meanwhile, Dr. Paganoni and her colleagues evaluated the data from the open-label extension study to reveal a survival benefit. Treatment with AMX0035 resulted in an approximately five-months-longer median survival compared with the placebo, the researchers reported in the January 2021 issue of Muscle & Nerve.

Again, the FDA staff expressed concern about whether the survival benefit was correctly interpreted given the large number of dropouts during the open-label extension period.

Despite its reservations, the agency invited Amylyx to submit a new drug application without waiting for results of a phase 3 study, expected in 2024. On March 30, the PCNS committee—a group of independent experts, including neurologists—met to weigh in on the matter. In addition to the staff concerns about the statistical analysis used in CENTAUR, the committee heard about the potential for unblinding because of AMX0035's taste and a randomization implementation error that was identified and addressed early in the study.

The PCNS committee gave AMX0035 a thumbs-down, but the vote was narrow: Six members said evidence was inadequate to prove effectiveness, while four said it sufficed.

The outcry from the neurology community was swift and loud. Just three weeks after the committee meeting, Annals of Neurology published an editorial by Merit Cudkowicz, MD, director of the Sean M. Healey & AMG Center for ALS and chief of neurology at Massachusetts General, and Jeremy M. Shefner, MD, PhD, FAAN, executive chairman of neurology at the University of Arizona in Phoenix and co-founder of the Northeast ALS Clinical Trials Consortium. Before launching into a point-by-point defense of the CENTAUR study's design and execution, they wrote: “We ... argue strongly that virtually all of the criticisms are undeserved.”

Meanwhile, more than 35 neurologists who specialize in ALS wrote to the FDA asking for immediate approval of AMX0035.

“We understand that a single trial with modest p-values may provide uncertainty in the knowledge and firmness of scientific data. But ALS moves too fast to wait for certainty,” the neurologists wrote.

“It is the first time an ALS clinical trial has showed such promise in both function and survival in a phase 2 trial. While these effects may seem incremental, they are meaningful to us as ALS specialists and to our patients.”

In addition, Dr. Paganoni; James Berry, Winthrop Family Scholar in ALS Sciences and chief of the division of ALS and Motor Neuron Diseases at Massachusetts General; and biostatistician David Schoenfeld, PhD, professor emeritus at Harvard Medical School, wrote to Neurology Today to address concerns raised during and after the PCNS meeting.

“The public and subjective way these concerns were raised has the potential to impact confidence in the integrity of the trial,” the researchers said in a June 16 Viewpoint. “Given the significant unmet need in ALS and the number of ongoing clinical trials, it is imperative that discussions that take place when considering the approval of a new potential treatment are focused on the data and the events as they happened.”

Amylyx celebrated the drug's approval for use in Canada in June. Marketed as ALBRIOZA in that country, AMX0035 was approved with conditions, including provision of data from the ongoing phase 3 trial.

In its draft report, ICER used its rating scale to score AMX0035 as “high certainty” that it does not cause harm and “moderate certainty” that it provides a comparable to substantial benefit compared with standard care.

Richard Bedlack, MD, PhD, FAAN, professor of neurology at Duke University School of Medicine and director of the Duke ALS Clinic, served as an expert reviewer for ICER's assessment of ALS therapies. At the CEPAC meeting, Dr. Bedlack implored the council to prioritize neurologists' views over the criticisms made by the FDA.

“To give you the perspective of somebody that's been working in this field for 22 years, trying to do clinical trials, this is the best study that we've ever had in a hundred years of research,” he said. “Every single point that was made by the FDA review committee has been thoroughly rebutted in an editorial by what I think are the two greatest ALS clinical trialists living, Dr. Cudkowicz and Dr. Shefner. After reading that, I don't know how you could say that there's any question that this study shows benefits.”

But Midwest CEPAC member Timothy J. Wilt, MD, MPH, professor of medicine at the University of Minnesota School of Medicine and a physician at the Minneapolis VA Center for Chronic Disease Outcomes Research, said that even “moderate certainty” that AMX0035 confers a benefit is a stretch.

“The data that is presented is from a single small study that is reported to have methodologic flaws,” he said. “And ... many experts say the only way to figure out whether it works is to have more studies. So, I just really struggle to find moderate certainty of a net benefit.”

Currently, only one FDA-approved therapy—riluzole—both slows disease progression and is believed to prolong survival by an average of two to three months.

AAN practice guidelines issued in 2009—before edavarone was approved—recommended riluzole to slow progression. Those guidelines were reaffirmed in 2020, after its approval, but did not discuss the use of edaravone.

The use of edaravone as an intravenous infusion has been limited because of the logistics—patients with limited mobility must travel to an infusion center—and the risks associated with long-term use of a PICC line or port catheter. Those challenges went away when the FDA in May approved an oral formulation based on bioequivalence. But evidence of the drug's efficacy continues to be confusing.

Three randomized clinical trials performed in Japan failed to show that edaravone slowed the decline of motor function in patients with ALS. However, a post-hoc analysis of one trial revealed that edaravone slowed disease progression by 33 percent after 24 weeks for a subset of patients with disease duration of two years or less, preserved respiratory function, and was associated with minor functional impairment and moderate disease progression.

On that basis, the FDA approved edaravone for treatment of ALS—and did not restrict it to the subset of patients for which efficacy had been demonstrated. The drug is approved for ALS treatment in Japan but not approved by the European Medical Agency for use in the European Union.

An analysis of real-world data from 12 academic ALS referral centers associated with the German Motor Neuron Disease Network, published in February in JAMA Neurology, provided no encouragement for using edaravone. A propensity score-matched cohort study of 324 patients treated between June 2017 and March 2020 found no significant difference in disease progression rates, time to noninvasive ventilation, and survival probability for those treated with edaravone, compared with those receiving only standard therapy.

For patients who met the criteria of the successful trial, ICER summed up the evidence this way: “Moderate certainty” that oral edaravone added to standard of care is comparable or incremental compared to standard of care alone. For all other patients with ALS, the evidence for efficacy was rated insufficient.

Again, CEPAC member Dr. Wilt said more trials are needed to confirm whether edaravone delivers a benefit.

“The world of research often has small studies that show statistical significance—that's why repeatability is so important,” he said. “I think the body of evidence is at best low and possibly insufficient about its effectiveness, even in the subgroup.”

Dr. Bedlack said there is a good explanation for why only one of the three Japanese trials demonstrated a slowing in the patients' rate of decline.

“That's the study that picked the people early in their disease with lots of points (on the ALSFRS-R scale) who were progressing quickly,” he said. “It's not surprising that the other two studies didn't see a benefit because those people were either far advanced with no points on the scale to start with, or they were progressing very slowly, so you wouldn't expect to see a 30 percent change in a six-month study.”

Dr. Andrews focused on the fact that edaravone is effective for some patients. “We actually don't know who responds best and how people respond in general to edaravone,” she said. “As we provide the medication to a broader ALS patient population, we will learn about the general efficacy of that drug. So, given that there is no other alternative for people living with ALS, I think having access to edaravone is very important.”

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Vol. 22, Issue 19 - p. 1-23

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