The US FDA approved this new ALS drug, why is it controversial?

“Rather than thinking you’re protecting me, I want you to approve the drug so I can have a chance at life.”


Writing | Jun Ling

Source | “Medical Community” Public Account

On September 29, local time, amid the controversy, the US FDA approved a new drug for the treatment of ALS-AMX0035.

The decision is believed to have shaken the FDA’s new drug review standards yet again. In March this year, due to insufficient evidence of efficacy, an independent FDA committee voted 6:4 on the preliminary rejection of the marketing application. But since then, tens of thousands of emails from the ALS community have been sent to the FDA office asking for a reassessment of the decision. At a second meeting on Sept. 7, the same committee recommended approval of the drug.

Industry analysis and public opinion may play a key role in the approval of AMX0035. Mark Weston, one of the committee members, expressed disappointment at the lack of evidence of the new drug’s efficacy, but still voted “yes”, he told the “New York Times” because of “the inability to decouple objective views from their own unmet needs” – He is also an ALS patient.

Currently, there are approximately 500,000 ALS patients worldwide, with approximately 6,000 new cases each year. The patient’s body muscles will gradually atrophy, and the ability to speak and move will be lost. The average survival time is 3 to 4 years. Previously, only two drugs have been approved for marketing in the United States, but the effect is extremely limited. One of the drugs, the data shows, may only delay survival by 2-3 months.

Twisted approval decisions

AMX0035 was originally conceived by two undergraduate students in the United States who proposed that the combination of sodium phenylbutyrate and taurine diol could protect the brain from ALS due to progression dead neurons. They later formed a company dedicated to the development of the drug.

Co-inventor of AMX0035

The pivotal Phase 2 clinical data for the marketing application was published in 2020, including 137 patients with ALS, 2/3 using AMX0035 and 1/3 using placebo. The results showed:

At 24 weeks, patients in the treatment group had ALSFRS-R scores that were 2.32 points higher than those in the placebo group—the ALSFRS-R, considered the gold standard for ALS drug development, includes 12 Physical functions such as walking, language, swallowing, breathing, etc. are scored. On average, patients with AMX0035 experienced a 1.24 decrease in monthly scores compared with 1.66 in the placebo group, and AMX0035 appeared to delay disease progression.

Data from another unblinded extension study showed that among 90 patients, those who received AMX0035 early had an increased median time to hospitalization, ventilator use, or death. for about 6.5 months.

However, these data did not initially impress the FDA, including the small number of participants, the flaws in the design of trial details and implementation, etc. In April 2021, the FDA believes that a larger 3 Phase clinical results are released – the drug’s marketing application will not be accepted until mid-2024.

In September 2021, the FDA changed its tune, allowing the drug to be submitted for a marketing application based on the results of a Phase 2 clinical trial, subject to further evaluation. In March 2022, an independent advisory committee of the FDA met and voted unanimously by a vote of 6:4, arguing that the Phase 2 clinical data were insufficient to prove the efficacy of AMX0035.

But just another 6 months — without any new efficacy data coming out — on September 7, the FDA’s attitude changed radically. Until yesterday (29th), AMX0035 was officially approved for listing.

ALS community “joint letter”

Dr. Billy Dunn, director of the FDA’s Office of Neuroscience, put the question to drugmakers at a Sept. 7 hearing if AMX0035 is approved now, but in Phase 3 in two years If the clinical results prove to be ineffective, will the company withdraw from the market voluntarily, saving the FDA’s time in the process of withdrawing the drug?

Relevant person in charge of the pharmaceutical company said, yes. The New York Times analyzed that this commitment persuaded the FDA.

But it wasn’t just corporate commitment that ultimately moved the FDA. As early as 2014, the “Ice Bucket Challenge” initiated by patients with ALS became popular all over the world. The event aims to make more people aware of ALS and raise funds. Of the funds raised at the time, $2.2 million was donated to support the development of AMX0035.

Ice Bucket Challenge

Starting in April 2021, the ALS community began to “press” the FDA on a large scale, including soliciting signatures, sending emails, and organizing events.

“Instead of thinking that you are protecting me, I want you to approve the drug so thatI have a chance to live. ” 41-year-old patient Brian Wallach testified that ALS had severely damaged his language skills.

According to the FDA’s previous plan, to confirm the efficacy of AMX0035, at least the Phase 3 clinical results in 2024, but for ALS patients with a median survival of only 39 months, The two-year wait time is unbearable.

In fact, every year thousands of people with ALS die while waiting for new treatments, and they are still alive and suffering irreversible loss of bodily function. Their attitude towards the launch of new drugs is simple and intuitive: even if there are obvious side effects, they are willing to try treatments that can only be exchanged for weak effects.

One ​​of the clinical trial participants, Gregory Canter, said that since starting the drug three years ago, “the rate of my functional decline has slowed considerably.” In addition, some clinicians who have experienced ALS treatment also supported the approval of AMX0035, and their “sympathetic” speeches also appeared in their testimony to the FDA.

In a summary memo about the drug, the FDA wrote:

The evidence of efficacy of AMX0035 is uncertain, but this level of uncertainty is acceptable given the severity of ALS and the large unmet need. At the same time, the benefits outweighed the risks, as there were no major safety concerns in the trial.

Controversy continues

“The company could give patients the treatment for free while waiting for better evidence. But I don’t think it’s up to the mark yet to allow them to sell this drug.” NIH Dr. Kenneth Fischbeck told The New York Times that he voted against it at the meeting.

Dr. Kenneth Fischbeck is not the only expert who disagrees. Many people are concerned about the FDA’s “flexibility standard”. If the FDA gives the “green light” for AMX0035, similar situations will be encountered in the future. , where is the limit? How much should the standard be lowered?

In fact, as the authority for new drug review, the impact of FDA decisions is often multi-faceted.

At present, the pathogenesis of ALS is still unclear. Does the approval of AMX0035 mean that its treatment route has been “officially recognized”? If a lot of manpower, material resources, and time related to ALS-related scientific research and commercial development are invested in this technical route, AMX0035 turns out to be a failure. Will it delay the development of ALS treatment?

On the other hand, the FDA has “turned over the cart once” on lowering the standards for marketing review.

On June 7, 2021, the FDA approved Aduhelm, the first new Alzheimer’s drug in 18 years, amid skepticism. Alzheimer’s disease and ALS share too many similarities, with the condition worsening over time without any effective treatment.

However, Aduhelm’s clinical trials have only observed effects at the level of biomarkers, with little evidence of real-world disease improvement, and due to relatively large side effects, despite being approved for marketing , but was excluded from the national medical insurance plan, and the road to commercialization failed.

Currently, the post-market price of AMX0035 has not been disclosed, but a June report from the Institute for Clinical and Economic Review casts doubt on the drug’s cost-effectiveness. A compromise is that the payer (medical insurance/commercial insurance, etc.) pays almost cost until there is sufficient evidence of efficacy, allowing the drug price to rise to the market price.

“The goal is that every patient who is eligible for this drug gets treatment as quickly and effectively as possible because we know people with ALS and their families don’t have time to wait.” At the FDA After announcing the approval, the company said in a statement.

It is foreseeable that the controversy will continue until the final results of Phase 3 are released. But for the ALS group, at least for now, they see unprecedented hope.

American ALS Association President Calaneet Balas said in a statement that the FDA’s decision is a victory for the entire ALS community, who have come together to advocate for the early approval of AMX0035.


[1]FDA approves first ALS drug in 5 years after pleas from patients, fda-approval/

[2]F.D.A.Approves A.L.S.Treatment Despite Questions About Effectiveness, https:< /p>

Source: Medicine

Proofreading: Zang Hengjia

Editor in charge: Tian Dongliang

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