Over the next three months, the Food and Drug Administration could approve the first vaccines for an elusive virus, the first gene therapy for a deadly neuromuscular disorder and a new treatment for a genetic form of ALS.
Each decision is important in its own right, but each could also have broader implications for the biotech and pharmaceutical sector.
Respiratory syncytial virus, or RSV, has bedeviled researchers for years and the fact that vaccines are now in reach represents a scientific step forward that could buoy other efforts. Sarepta Therapeutics’ gene therapy for Duchenne is the culmination of a long biotech journey and the FDA’s verdict on it will be suggestive of broader agency views on similar therapies. An approval for Biogen’s drug tofersen, meanwhile, could set a precedent that other developers of ALS medicines seek to follow.
Here are five decisions to watch in the second quarter:
Sarepta’s gene therapy for Duchenne muscular dystrophy
The FDA has approved three gene therapies for inherited diseases in the last year, a sign industry watchers have taken to indicate the regulator is warming to the complex medicines. The fourth could come this quarter, when the agency is expected to decide whether to clear Sarepta’s gene-based medicine for Duchenne muscular dystrophy.
Sarepta’s case largely rests on the ability of the treatment, SRP-9001, to help Duchenne patients produce a miniature form of dystrophin, the muscle-boosting protein they lack. The company has also pointed to signs, based on comparisons to historical controls, that patients who received SRP-9001 might be faring better than they would without treatment.
The FDA has already approved multiple Duchenne drugs, including three of Sarepta’s, based on the idea that boosting dystrophin will lead to better function and health. But that still remains unproven, and it’s unclear whether the regulator feels the same way about the “microdystrophin” Sarepta’s gene therapy produces. What’s more, SRP-9001 missed the main goal of the only placebo-controlled trial it has been tested in to date. A definitive and potentially confirmatory trial is underway, with results expected later this year.
The FDA signaled its desire to dig into the issue further last month, when, in a reversal, it chose to convene a panel of experts to review Sarepta’s application. That meeting is expected to come before a May 29 decision deadline and, as was the case with an advisory committee meeting for Sarepta’s first approved Duchenne medicine, is likely to be contentious. — Ben Fidler
Biogen’s tofersen for ALS
The next month could be hugely consequential for ALS drug research, as the FDA is expected to make a precedent-setting decision on an experimental and closely watched therapy.
Known as tofersen, the therapy was designed to treat people with a rare, genetic form of the neurodegenerative disease. Results from a key clinical trial indicated tofersen has the intended effect on the mutated gene in question. However, it ultimately failed to outperform a placebo in slowing the functional decline associated with ALS, or amyotrophic lateral sclerosis.
After meeting with FDA staff, tofersen's developer, Biogen, opted to ask for a so-called accelerated approval based on the drug's apparent effect on a protein of increasing interest to ALS drugmakers. Research has found that when nerve cells are damaged, levels of this "neurofilament light chain" protein are elevated in the blood and fluid surrounding the brain and spine. In Biogen's study, patients taking its drug rather than a placebo experienced substantial declines in neurofilament light chain.
To date, the few ALS treatments that have received approval did so because of their benefits on function or survival. If the FDA greenlights tofersen, it would be the first time "biomarker" data led to an ALS medicine being cleared for market. The agency's decision, which should come no later than April 25, is therefore expected to influence how ALS drugmakers design their clinical trials and engage with regulators moving forward.
On its end, Biogen has argued the key trial of tofersen wasn't long enough to show the drug's full potential. The company is currently running additional studies to gather more evidence of tofersen’s functional benefit.
FDA staff, meanwhile, have signaled they're now more open to accelerated approvals of medicines for brain and nervous system disorders that are debilitating, fatal or have few treatment options. In 2021, the agency granted one of these approvals to another Biogen drug, Aduhelm, based on its ability to decrease levels of a protein tied to Alzheimer's disease. — Jacob Bell
Seres’ SER-109 for recurrent C. diff infections
Last year, the FDA approved the first microbiome-based medicine, a milestone for drugs that work by rebalancing the vast populations of microscopic organisms that reside within us. The second could come this quarter, when the regulator will issue a verdict on SER-109, a pill from biotech Seres Therapeutics.
Seres has been one of the leading developers of microbiome medicines. Founded by Flagship Pioneering more than a decade ago, the biotech was the first of its peers to go public. Since its 2015 initial public offering, it has had a difficult journey trying to bring a microbiome drug to market, however.
SER-109, for recurring infections of a bacterium called Clostridioides difficile, or C. diff., failed a Phase 2 trial in 2016. A potential ulcerative colitis treatment fell short in testing a few years later. Those setbacks left Seres with a depressed share price, as well as looming commercial competition. Ferring Pharmaceuticals won approval of a rival C. diff treatment, known as Rebyota, in late 2022.
Seres adjusted its testing plans for SER-109 after the 2016 data and reported success in a Phase 3 trial in 2020. It believes it’ll have an edge over its rival as, unlike Rebyota, which is given via enema, SER-109 is taken orally.
The FDA’s decision has important financial implications for Seres, which has a “slimming cash balance,” Jefferies analyst Chris Howerton wrote in March. The company had $181 million in the bank at the end of 2022, but stands to receive a $125 million milestone payment from partner Nestle Health Science upon U.S. approval.
The regulator is expected to decide whether to approve Seres’ application by April 26. — Christopher Newman
Pfizer’s and GSK’s vaccines for RSV
Pfizer and GSK are on the cusp of potentially gaining FDA clearance for their respective respiratory syncytial virus vaccines in older adults. Approvals, if they come by the agency’s decision deadlines in May, would be a first for RSV, a pathogen that’s evaded researchers’ best efforts for decades.
The vaccines are backed by data from late-stage clinical trials that enrolled tens of thousands of participants. Last August, Pfizer reported its shot was 67% effective at preventing infections with at least two symptoms in older adults compared to a placebo. Protection was stronger against more severe disease. GSK's Phase 3 results, released in October, showed its shot was 83% effective in preventing cases of lower respiratory infection.
While panelists agreed the data proved the vaccines’ effectiveness, they had questions around safety, co-administration with other shots and long-term protection.
Two cases of the rare autoimmune syndrome Guillain-Barré were recorded after administration of Pfizer's vaccine, while one was reported in GSK's trial. Investigators in GSK’s trial also observed two instances of acute disseminated encephalomyelitis, a neurological disorder, that occurred when the RSV vaccine was co-administered with a flu vaccine. One of those affected died three weeks later.
Advisers sought more data about the safety of Pfizer's vaccine and its profile when given alongside other shots, the latter of which Pfizer has not reported. GSK said it is conducting additional safety studies to further assess the risks associated with its vaccine.
RSV infections are responsible for at least 60,000 hospitalizations among adults 65 and older as well as at least 6,000 deaths each year in the U.S. Along with Pfizer and GSK, Moderna and Bavarian Nordic are also developing vaccines. J&J, which up until March was among the furthest along in testing, recently said it would end development of its RSV shot.
Regeneron’s high-dose Eylea for macular degeneration
More than a decade after its initial approval, Eylea remains one of the world’s top-selling medicines. The drug, used to treat a common form of age-related vision loss, has dodged competitive threats as would-be rivals have fallen short in clinical testing. In 2022, global sales reached nearly $10 billion for its developer, Regeneron, and partner Bayer.
But competitors may finally be catching up. Biosimilar versions of a similar vision loss drug, Lucentis, are on the market, and Eylea copycats could follow as early as next year. Other treatments requiring fewer injections than Eylea, which is administered once every two months, are gaining ground. Gene therapies are advancing, too.
Regeneron’s defense is a higher-dose form of Eylea that requires fewer injections. Success in Phase 3 trials last year positioned it for an approval that could come by June 27. Regeneron is counting on it to blunt the competition and extend its pricing power.
Eylea is consistently among the top expenses in Medicare Part B, and is likely a target for the Centers for Medicare & Medicaid Services’ new authority to negotiate prices on certain drugs. Regeneron executives have argued that,because the high dose version was submitted under a new application, it would be considered a separate drug and immune from price negotiation for many years.
Guidance issued last month by CMS raised concerns about that plan, as the agency said it will group together different medicine formulations that contain the same active ingredient.
CMS’ new power to negotiate prices is limited to drugs without competition, however. The arrival of an Eylea biosimilar could therefore “prevent high-dose Eylea from being subject to negotiation,” wrote RBC Capital Markets’ Brian Abrahams. — Ben Fidler