Editor’s note: Welcome to Editors' (re)View, our editors’ takes on things going on in the pharma world that deserve some extra consideration.
Amylyx — when need outshines efficacy
This week, Amylyx officially announced that it is pulling its ALS treatment, Relyvrio, from the market — a move that had been anticipated since the drugmaker unveiled disappointing results from a confirmatory study last month.
To the company’s credit, it made good on its promise given during an unorthodox second meeting of an FDA advisory committee back in September 2022.
During that meeting, Dr. Billy Dunn, director of the Office of Neuroscience at the FDA had specifically called on Amylyx’s co-CEOs to go on record saying the company would voluntarily withdraw the drug from the market if the PHOENIX study were to fail. And they did just that. “To be clear, if PHOENIX is not successful, we will do what is right for patients, which includes voluntarily removing the product from the market,” said CEO Justin Klee.
But the outcome, for lack of more eloquent phrasing, sucks on many levels: Amylyx had to lay off 70% of staff and may never recover. Insurers have been paying for a drug (listed at $158,000 a year) that doesn't work. And above all, ~30,000 ALS patients in the U.S. are still left with inadequate treatment options.
The ALS treatment landscape is bleak:
1. Rilutek – Sanofi
In 1995, Sanofi's Rilutek became the first drug to get FDA approval to treat ALS. Riluzole is a benzothiazole derivative that blocks glutamate release. The drug prolongs life by approximately three months. Covis bought the rights to the drug in 2013.
Riluzole, generics of Rilutek, became available in 2013
Tiglutik, an easy-to-swallow thickened riluzole liquid made by ITF Pharma, was approved in September 2018.
Exservan, an oral film formulation of riluzole, developed by Aquestive Therapeutics and licensed by Mitsubishi Tanabe, was approved in November 2019.
2. Radicava – Mitsubishi Tanabe
In May 2017, the FDA approved Mitsubishi Tanabe's infusion therapy, Radicava (edaravone), making it the first new drug for ALS in 22 years. Radicava is a free-radical scavenger, helping to remove the toxic molecules that can contribute to oxidative stress. By lowering oxidative stress, the drug is said to reduce nerve damage and slow ALS progression. An oral formulation was approved in 2022.
3. Qalsody – Biogen
In April 2023, the FDA granted accelerated approval to Biogen's Qalsody for the treatment of an ultra rare form of ALS — patients who have a mutation in the superoxide dismutase 1 (SOD1) gene. Qalsody, which was developed in collaboration with Ionis Pharmaceuticals, is an antisense oligonucleotide that works by blocking the production of the SOD1 protein, which clumps together with copies of itself and damages the nervous system. It is the first approved treatment to target a genetic cause of ALS.
Continued approval hinges on verification of clinical benefit in Biogen's ongoing phase 3 ATLAS study in people with presymptomatic SOD1-ALS.
The ALS treatment space is ripe with unmet need and patient advocacy. This combination (see Alzheimer's for reference) tends to lead to some leniency when it comes to efficacy. There’s a bigger discussion at play here, and I suspect we haven’t heard the end of it: When it comes to drug approvals, should efficacy, safety and need all carry equivalent weight? —Karen Langhauser
Verve trial paused again
Boston-based Verve Therapeutics has paused enrollment for its Heart-1 clinical trial of VERVE-101, a gene editing treatment targeting cardiovascular disease, following safety concerns. A participant experienced increased ALT (a liver enzyme) levels and decreased platelet count, albeit without symptoms.
VERVE-101 aims to combat heterozygous familial hypercholesterolemia (HeFH), a genetic disorder leading to high cholesterol levels, using a one-time, liver-targeted gene editing method to permanently lower cholesterol.
The development of VERVE-101 has faced numerous challenges, notably when the FDA halted its IND application in November 2022. The FDA cited potential risks of accidental germline edits, discrepancies in effectiveness between human and animal studies, and possible unintended effects on non-target cells.
Base editing, the technology behind VERVE-101, differs from traditional gene editing methods like CRISPR-Cas9 by offering a more precise method of genetic modification without the need for double-stranded DNA breaks. It utilizes a modified CRISPR system that includes a deactivated Cas9 protein, fused with a base deaminase enzyme, to chemically convert one DNA base into another directly at the target site. This approach minimizes unintended genetic alterations and reduces the risk of off-target effects associated with the repair process following DNA breaks. While CRISPR-Cas9 is known for its versatility, including gene knockout and insertion, base editing specializes in precise, single-nucleotide modifications, making it particularly useful for correcting point mutations that cause genetic diseases.
Potential applications for base editing span treating genetic disorders, improving agricultural crops, and correcting animal genetic diseases. However, the technology's precision doesn't eliminate risks of off-target effects or ethical concerns over non-therapeutic use and germline modifications.
By spearheading the application of base editing, Verve is not only navigating uncharted territory but also leading the way for regulatory agencies in understanding how to oversee this advanced technology, gaining firsthand lessons into the requirements for successfully — and safely — advancing these therapies. — Andrea Corona
