On September 29, 2022 the U.S. FDA granted an accelerated approval to Amylyx’s Relyvrio (sodium phenylbutyrate and taurursodiol) for the treatment of amyotrophic lateral sclerosis (ALS) in adults. Relyvrio becomes the third approved treatment for the disease and the first to show both a slowing of disease progression and extended survival. The drug, which is taken orally, consists of a fixed-dose combination of sodium phenylbutyrate and taurursodiol. Its mechanism of action remains incompletely understood, and its effect is thought to be the result of the two components working together to prevent nerve cell death by blocking stress signals within mitochondria and the endoplasmic reticulum. While taurursodiol improves mitochondria energy production, phenylbutyrate helps proteins fold correctly, thereby preventing the formation of protein clumps that cause nerve cell death.
ALS is the most common degenerative disease affecting the motor neuron system. The disease causes the progressive degeneration and atrophy of voluntary skeletal muscles, such as those involved in motion, speech, eating and breathing, ultimately resulting in paralysis and death. It is estimated that about 450,000 people are living with ALS around the globe. About 5,000 Americans are diagnosed with ALS each year, and 20,000 currently live with the disease. While a few individuals with ALS (most notably the late astrophysicist Stephen Hawking) have been known to live for 10 years or more, the median survival from time of diagnosis is 24-48 months. Diagnosing the disease at an early stage is difficult as initial symptoms—such as weakness in an arm or leg—may result from many other, often less serious, treatable conditions.
ALS is a complex disease whose pathogenesis has not yet been elucidated. Molecular, genetic, epigenetic and environmental factors are thought to play causative roles. Researchers have identified at least 15 genes (and potentially as many as 700, according to Stanford School of Medicine researchers) associated with the disease. But none of the potential causes leads unequivocally to the disease, and only 5-10% of all cases are familial, with the remaining 90-95% arising from unknown factors. This offers few known targetable and druggable options. Due to this complexity and the lack of understanding of ALS, there have been few good animal models available to fuel drug discovery. As a result, few treatments were successfully developed in the last three decades. Riluzole, first approved by the FDA in 1995 and now available generically, inhibits glutamate release and modestly prolongs survival by about three months. Radicava (edaravone) from Mitsubishi Tanabe Pharma, approved in 2017, protects neurons from damage by unstable oxygen radicals, slowing disease progression and reducing decline in physical function by about 33%.
Adding to and improving on this therapeutic arsenal has been challenging. In addition to the preclinical research limitations and early-stage research failures, the few programs that advanced to clinical trials have also faced strong headwinds in 2022. Several compounds once thought to be promising recently failed in advanced stages of development, including BioHaven’s verdiperstat, a myeloperoxidase enzyme inhibitor, which in September 2022 failed to meet both primary (disease progression) and secondary (respiratory function, muscle strength and survival) endpoints in a pivotal Phase 2/3 trial.
Biogen’s tofersen, an antisense drug targeting SOD1, also failed to hit its primary endpoint in a Phase 3 trial in 2022, doing no better than placebo in slowing the disease in 60 patients with rapidly progressing ALS. SOD1 encodes the essential antioxidant enzyme Cu, Zn superoxide dismutase; mutations in the SOD1 gene are found in 20% of familial and 5% of sporadic forms of ALS. Biogen is continuing to make tofersen’s case with the FDA, by pointing to other endpoints and treatment outcomes, such as changes in SOD1 production and changes in plasma neurofilament light chain (a potential marker of neuronal degeneration), as well as positive trends in measures of respiratory function, muscle strength, and patient-reported outcomes pertaining to disease severity, quality of life and fatigue. However, safety has also been an issue for tofersen, with about 5% of the treated patients experiencing neurologic adverse events, including two cases of spinal cord inflammation.
Enter Amylyx’s Relyvrio. The drug’s approval in September 2022 was based on the results of a six-month Phase 2 trial in 137 patients with fast-progressing ALS who received either the drug or placebo and who were then rolled into an open-label, long-term extension trial that remains ongoing. Data from the study and the extension trial suggested that treatment with Relyvrio showed a 25% slower decline in physical abilities like walking, speaking, and swallowing than participants given a placebo. From these results, the investigators concluded that Relyvrio could extend patient survival by 6.5 months or more.
The road to Relyvrio’s approval was not smooth. A first FDA Advisory Committee meeting in March 2022 ruled against Relyvrio’s approval. However, the FDA showed flexibility, allowed Amylyx to submit additional data, and held a second Advisory Committee in September. With emotional testimony from many patients and advocates, and an agreement from Amylyx to voluntarily withdraw Relyvrio from the market if Phase 3 trial results do not confirm the drug’s benefit, Advisory Committee members voted 7 to 2 in favor of Relyvrio’s approval.
In preparation for Relyvrio’s launch, Amylyx set a list price of $158,000 per year for the drug in the United States, below the $171,000 list price for the oral formulation of Radicava approved this year. The company has also committed to providing financial assistance to allow insured patients to access the drug without co-payments, and to offer Relyvrio at no cost to the uninsured or under-insured patients who meet financial eligibility criteria. However, Amylyx’s pricing for its drug has been criticized by ICER, which believes a price somewhere between $9,100 – $30,660 per year would meet ICER’s cost-effectiveness criteria.