ALS Association Pressures FDA to Approve Amylyx Drug as Agency Cuts Phase III Trial Requirement

The ALS Association is pushing for rapid FDA approval of Amylyx Pharmaceuticals Inc.’s candidate drug AMX0035 (sodium phenylbutyrate/taurursodiol) for the treatment of amyotrophic lateral sclerosis, or ALS. The advocacy group is well known for its Ice Bucket Challenge fundraising that garnered international attention several years ago. This time, the group is backing a drug that they believe will greatly benefit ALS patients.

After asking for a placebo-controlled Phase III study for the drug in April that upset the ALS Association, the FDA dialed back on the request this week, agreeing to accept only Phase II trial data for evaluation of Amylyx’s drug application.

The move could trigger the same type of controversy that Biogen’s Aduhelm (aducanumab) has become embroiled in after it received an FDA nod for the treatment of Alzheimer’s disease without demonstration of clear clinical benefit. It could also set a precedent for future drug approvals, particularly those for diseases with limited treatment options and an unmet need. The ALS Association has in fact cited the rapid and flexible regulatory approval of Aduhelm as something that should be extended to Amylyx’s ALS drug as well.

The ALS Association has been passionately lobbying the drug for the past year, which may have also contributed to the FDA’s change of heart on clinical data requirements. The group is asking for its speedy approval, and recently submitted a petition of 50,000 signatures in support of its request. In addition, it held a meeting in May, called the “We Can’t Wait” action meeting, with more than ten people with ALS who had the chance to speak directly to FDA leaders, including Patrizia Cavazzoni, the director of the Center for Drug Evaluation and Research (CDER).

ALS is a rare neurological disease that mainly affects neurons involved in voluntary muscle movement; these movements include things like walking, talking and chewing. It is a part of a group of disorders known as motor neuron diseases, which are caused by progressive degeneration of motor neurons.

According to the Centers of Disease Control and Prevention (CDC), approximately 5,000 people are diagnosed with the disease each year in the US. The life expectancy of people with ALS can range between two to five years and several decades; renowned physicist Stephen Hawking lived with the disease for 55 years until he died at age 76.

Related: FDA Trims Broad Label for Biogen’s Alzheimer’s Drug Amidst Harsh Criticism

AMX0035 is Massachusetts-based Amylyx’s first-in-class investigational drug that is an oral formulation of two active compounds, sodium phenylbutyrate (PB) and taurursodiol (TURSO). The complex is designed to target the toxic unfolded proteins in the endoplasmic reticulum, as well as mitochondrial dysfunction, which is being increasingly recognized as a pathogenic mechanism underlying the disease.

Accelerated FDA Approval Modeled on Aduhelm

In a follow-up letter sent to the FDA after the May meeting, the ALS Association brought up the Aduhelm case, asking that the FDA use the same “regulatory flexibility” for AMX0035 that it did for Aduhelm for Alzheimer’s.

The group said it was “good news for people living with Alzheimer’s and their loved ones. But we are left to wonder why the FDA is not using similar flexibility for a promising ALS treatment with strong safety data that provides clinically meaningful benefits. People with ALS and their loved ones cannot wait.”

At the time, the group pointed to the fact that the Phase II trial of AMX0035 met its primary and secondary endpoints and the drug was shown to be generally safe, and questioned why the FDA was requiring another clinical trial of the drug.

It also cited the fact that, “Amylyx is working with Health Canada to potentially bring the drug to market for Canadians living with ALS by the end of the year, it could be several years before Americans with ALS are able to access AMX0035, if at all.” The European Medicines Agency (EMA) is also pushing ahead on the ALS drug candidate. This has brought criticism that US regulators are moving too slow on a drug that has clinical promise and is being backed by other international regulators.

Additionally, the ALS Association pointed to the FDA’s own 2019 ALS clinical trial guidance and its associated regulatory flexibility.

ALS Association’s chief mission officer, Neil Thakur, feels the pressure was worthwhile as the FDA changed its tune about AMX0035 after the association lobbied for the agency to be consistent in adhering to its 2019 guidelines.

“Our job as advocates for the ALS community is to end the disease. If there’s a drug that’s going to help do that, then we’re going to push forward — and if there’s a drug on the market that’s not going to do that, we need to find a way to take that drug off the market. It goes both ways,” Thakur said.

Unmet Medical Need

Amylyx announced this week its intention to submit a new drug application (NDA) to the FDA for AMX0035 in the coming months “following recent discussions with the FDA, including a pre-NDA meeting held on July 15, 2021,” the company said in a statement.

While emphasizing the drug’s high safety profile and potential for success, Thakur is remaining realistic at the same time. The drug is not a magic cure or treatment; however, the ALS Association’s motivation to back AMX0035 and other similar drugs, is for “incremental gains and [to] increase their life span until we figure out some really solid ultimate cures,” he said.

Recently, Alexion Pharmaceuticals, a unit of AstraZeneca, discontinued trials for its ALS drug candidate Ultomiris due to lack of efficacy. Ionis Pharmaceuticals and Biogen, meanwhile, are in the final stages of clinical testing for their drug tofersen, which is designed for patients with certain ALS-causing genetic abnormalities. The late-stage study includes 180 adults with inherited ALS and if it yields positive data, the companies plan to seek FDA approval shortly thereafter.

Currently there are only two FDA-approved treatments for ALS: Rilutek (riluzole) and Radicava (edavarone).

The landscape of drug approvals for rare diseases and diseases with significant unmet need appears to be evolving, and getting trickier, as regulators are faced with the dilemma of ensuring that drugs deliver clear clinical benefit whilst trying to avoid depriving or delaying potentially life-changing treatments for patients.