Q2 Regulatory Watch: Four FDA Decisions That Could Reshape the Biopharma Landscape

The FDA may approve a gene therapy for Duchenne muscular dystrophy, two RSV vaccines, and a highly anticipated ALS drug.

For years, respiratory syncytial virus (RSV) has plagued the industry. Now, the FDA is poised to consecutively approve Pfizer’s and GSK’s marketing applications for the world’s first and second RSV vaccines. Following its record-breaking approval of three gene therapies for genetic diseases in 2022, the FDA’s decision on Sarepta Therapeutics’ gene therapy for Duchenne muscular dystrophy may signal a more open regulatory stance toward this field. Meanwhile, the FDA’s approval of Biogen’s ALS drug tofersen could set an important precedent. Finally, after the FDA approved Rebiotix’s fecal microbiota therapy, Rebyota, last November, the field of microbiome therapeutics development may be approaching another significant milestone, with the fate of the second drug to be decided in April.

The FDA’s four decisions could have broad and significant implications not only for the companies themselves, but also for innovative enterprises and investors across related global sectors, as well as for the biotechnology and pharmaceutical industries.

The FDA approved three gene therapies for genetic diseases last year, a move that industry observers interpret as a sign of the agency’s warming stance toward these complex therapeutics. A fourth approval may arrive this quarter, when the FDA is expected to decide whether to approve Sarepta’s gene therapy for Duchenne muscular dystrophy.

The FDA has approved multiple drugs for the treatment of Duchenne muscular dystrophy (DMD), including three from Sarepta Therapeutics. These three agents all work by skipping exon 53 of the dystrophin gene to promote the production of functional dystrophin protein. However, their clinical benefits are considered limited, and they are applicable only to a subset of patients with DMD.

If approved, SRP-9001 will become the first gene therapy for the treatment of Duchenne muscular dystrophy.. Whether it can be approved largely depends on the efficacy of the therapeutic drug SRP-9001 itself. The company pointed out that, based on controlled trials, patients receiving SRP-9001 treatment may fare significantly better than those who did not receive treatment.

By replacing the defective genes underlying the disease with functional ones, SRP-9001 holds promise for more significantly altering the disease course. However, this remains unproven, and the stance of regulatory authorities is still unclear. More importantly, SRP-9001 failed to meet the primary endpoint of the only placebo-controlled trial conducted to date. Further clinical trials are ongoing, with results expected later this year.

Last month, the FDA expressed its intention to further investigate this issue without convening an advisory committee. However, in a sudden reversal, the agency decided to assemble an expert panel to review Sarepta’s application. The decision deadline was May 29, with the meeting held prior to that date. In 2016, the advisory committee meeting for Sarepta’s first Duchenne muscular dystrophy drug (now approved as Exondys 51) was marked by controversy and drama, yet the drug ultimately gained approval. This upcoming meeting may also prove contentious. Nevertheless, regardless of any twists in the review process, the final outcome remains the critical factor.

In fact, the FDA has historically maintained a highly cautious and conservative stance toward gene therapies due to technical limitations and ethical concerns. Recently, however, the agency has publicly expressed its support for this field. On April 5, Peter Marks, Director of the FDA’s Center for Biologics Evaluation and Research (CBER), stated at a webinar hosted by an FDA-affiliated advocacy group that it would be “a failure” if the FDA were to approve only two or three gene therapy drugs per year over the next few years.

Dr. Marks stated that, in his view, the number of approved gene therapies should experience explosive growth at a near-exponential rate. To achieve this goal, Dr. Marks and the Center for Biologics Evaluation and Research (CBER) proposed four major initiatives: improving gene therapy manufacturing through innovative research; clarifying how to use the accelerated approval pathway for gene therapies; coordinating gene therapy approval decisions with other regulatory agencies worldwide; and applying the same strategies that drove the development of COVID-19 vaccines and therapeutics to accelerate the development of treatments for rare diseases.

Next month could have a major impact on ALS drug development, as the FDA is expected to make a precedent-setting decision on an experimental therapy that has drawn intense scrutiny.

Biogen’s antisense oligonucleotide drug, tofersen, is designed for the treatment of ALS. According to results from a Phase III clinical trial, tofersen can slow and reduce disease progression in motor neuron disease caused by SOD1 gene mutations. Although the primary endpoint of significant clinical improvement at 28 weeks was not met, researchers observed significant improvements in motor and pulmonary function when the trial was extended to 52 weeks.

Despite not meeting the primary endpoint, Biogen submitted an application for accelerated approval of the drug to the FDA.

In February, the FDA convened an advisory panel to gather information on tofersen. Biogen stated that the study results were positive, including a substantial reduction in neurofilament light chain (NfL), a “biomarker.” Levels of this neurofilament light chain protein rise in the blood and cerebrospinal fluid surrounding the brain and spinal cord when nerve cells are damaged. In Biogen’s study, patients receiving its investigational drug exhibited a significant decrease in neurofilament light chain levels compared to those receiving placebo.

At this meeting, the nine advisory panel members present at the FDA voted unanimously that tofersen’s effect on this protein was “reasonably likely” to predict clinical benefit, a core requirement for accelerated approval.

To date, the few approved ALS drugs have all been based on their benefits in terms of function or survival.If the FDA approves tofersen, it will be the first time a drug for ALS is approved based on “biomarker” data.The FDA’s final decision, due no later than April 25, is expected to influence how ALS drug developers design their clinical trials and engage with regulatory authorities.

QurAlis is also a biotech company focused on ALS and other neurodegenerative diseases. Kasper Roet, the company’s CEO, stated, “I think it would be fantastic if we could get ALS therapies approved using biomarkers such as ‘neurofilament light chain’—it would truly represent a very positive advancement.” Dr. Angela Genge, Chief Medical Officer at QurAlis, which assists Biogen with patient recruitment for clinical trials, told BioSpace that this development would have significant implications for companies beyond Biogen and Ionis. “In the field of ALS, we have been waiting 30 years to identify a biomarker that predicts treatment efficacy and changes in disease progression,” she said. “I sincerely hope this marks the beginning of an era in which ALS therapy development is driven by biomarkers and precision medicine.”

In November last year, the FDA approved Rebiotix’s fecal microbiota therapy, Rebyota (RBX2660), for market launch. This marks the first microbiome therapy approved by the FDA and represents a significant milestone in the field.

The second approved drug could emerge this quarter, with the outcome hinging on the FDA’s decision regarding SER-109, a drug developed by Seres Therapeutics. If SER-109 gains approval, it will reinvigorate confidence across the entire microbiome therapeutics sector.

Seres has long been one of the leading developers of microbiome therapeutics. Founded by Flagship Pioneering more than a decade ago, this biotechnology company was the first public listing in the sector. However, since its IPO in 2015, the company has faced significant challenges in its efforts to bring a microbiome-based drug to market.

SER-109 is indicated for the treatment of recurrent Clostridioides difficile (C. diff) infection. The failure of its Phase II clinical trial in 2016 dealt a blow to the emerging field of microbiome-based therapeutics as a whole. Several years later, therapeutic approaches for ulcerative colitis also failed to demonstrate efficacy. These setbacks have kept Seres’ stock price persistently depressed.

After the 2016 data, Seres adjusted its trial plan for SER-109 and reported successful Phase III trial results in 2020. It believes it holds an advantage over its competitors,Unlike Rebyota, which is administered rectally, SER-109 is taken orally.

Chris Howerton, an analyst at Jefferies, wrote in March that,The FDA’s decision has significant financial implications for Seres, as the company’s cash balance is dwindling.As of the end of 2022, the company had $181 million in bank deposits; however, upon receiving FDA approval, it will receive a $125 million milestone payment from its partner, Nestlé Health Science.

The FDA is expected to decide whether to approve Seres’ application by April 26.

In addition to Seres, other companies, including Finch Therapeutics and Vedanta Biosciences, are also developing microbiome-based therapeutics for inflammatory bowel disease.

In 2017, the Chinese Academy of Sciences launched the Human Microbiome Project, ushering in a new wave of research and development in microbiome technologies. Microecological therapy entered a phase of rapid growth, with domestic companies such as Xbiome and MoonBiome emerging as key players in the field.

Pfizer and GSK are engaged in intense competition over RSV vaccines. On February 28 and March 1 of this year, Pfizer and GSK respectively underwent questioning by the same FDA advisory panel, with the two meetings held just one day apart.

On February 28, Pfizer announced that the FDA advisory committee had supported the approval of its RSV vaccine. The committee voted 7-4 in favor of recognizing the safety and efficacy of the RSV vaccine. The FDA is expected to make a final decision by May 2023.

On March 1, 2023, GSK announced that the FDA advisory committee had voted 12-0 in favor of the efficacy and 10-2 in favor of the safety of its RSV vaccine, supporting its approval for market launch. The FDA will make a final decision on May 3.

If they are approved before the May deadline, they will become the first and second RSV vaccines to receive approval.

Exploration of RSV vaccines began in the 1960s. For six decades, researchers’ efforts failed to conquer RSV; today, sixty years on, RSV vaccine development is finally showing signs of promise.

The RSV vaccines from both companies are backed by late-stage clinical trial data involving tens of thousands of volunteers. Last August, Pfizer reported that its vaccine was 67% effective in preventing symptomatic infections (with at least two symptoms) among older adults compared with placebo, and provided stronger protection against more severe disease. In October, GSK released Phase III clinical results showing that its vaccine was 83% effective in preventing cases of lower respiratory tract infection.

Although the panel members unanimously agreed that the data demonstrated the vaccine’s efficacy, they still had questions regarding its safety, co-administration with other vaccines, and long-term protection.

Two rare cases of Guillain-Barré syndrome, an autoimmune disorder, were reported following administration of the Pfizer vaccine, and one case was observed in GSK’s trials. Investigators in the GSK trial also noted two cases of acute disseminated encephalomyelitis (a neurological condition) that occurred when GSK’s RSV vaccine was co-administered with the influenza vaccine. One of these patients died three weeks later.

FDA advisors seek more data on Pfizer vaccine safety and its use alongside other vaccines. SVB analyst David Risinger wrote, “We believe that despite the committee’s lukewarm support for Pfizer’s vaccine, it is still likely to be approved.” However, the FDA may request additional data and delay the vaccine’s market launch. GSK stated that it is conducting further safety studies to better assess risks associated with its vaccine.

In the United States, at least 60,000 adults aged 65 and older are hospitalized annually due to RSV infection, with at least 6,000 deaths. In addition to Pfizer and GSK, Moderna and Bavarian Nordic are also developing vaccines. Moderna’s RSV mRNA vaccine has also achieved promising results in Phase III clinical trials, with a marketing application expected to be submitted by mid-year.

Furthermore, Johnson & Johnson recently announced unexpectedly that it would halt the development of its RSV vaccine.

If approved, GSK’s vaccine could soon become one of the company’s leading vaccines, with executives recently predicting it may achieve success comparable to its shingles vaccine, Shingrix. Evan Wang, an analyst at Guggenheim Securities, forecasts that annual peak sales of GSK’s RSV vaccine could reach $2.8 billion.

Overseas, the "Big Three" are locked in fierce competition, with a battle for a multi-billion-dollar market poised to erupt; in China, however, the landscape is markedly different.Currently, there are few players in the domestic RSV vaccine market. Chinese-made RSV products in clinical development include those from Aikebaifa, Aidivaxin, and YouRui Pharma. On November 14, 2022, YouRui Pharma announced that its application for Phase III clinical trials of the MVA-BN RSV vaccine had been approved in China. Yesterday, its overseas partner, the Danish biotechnology company Bavarian Nordic, announced the completion of enrollment for the Phase III clinical trial, with efficacy data expected to be released by mid-year. Aidivaxin’s independently developed BARS13 is currently in Phase II clinical trials.

References: FDA decisions to watch in the second quarter, Biopharma Dive