Despite Phase 3 Trial Failure, World’s Second-Most-Expensive Drug Elevidys Generates $200 Million in Sales Within Six Months of Launch

Recently, at the JPM 2024 conference, Sarepta Therapeutics (Sarepta), a cell and gene therapy (CGT) research and development company, announced that sales of its Duchenne muscular dystrophy (DMD) gene therapy product, Elevidys, reached $131 million in the fourth quarter of 2023. Since its market launch in August 2023, Elevidys has generated total revenues of $200 million for the full year 2023.

In June 2023, Elevidys received FDA approval for marketing to treat patients aged 4–5 years with Duchenne muscular dystrophy (DMD), making it the only gene therapy currently approved by the FDA for the treatment of DMD. Priced at $3.2 million per dose in the United States (approximately RMB 23 million), it is the second most expensive drug worldwide.

In December 2019, Roche entered into a $2.85 billion R&D collaboration agreement with Sarepta to jointly develop Elevidys. Under the terms of the agreement, Roche secured commercialization rights for Elevidys outside the United States, paid Sarepta a $750 million upfront fee, and subscribed to $400 million worth of Sarepta’s equity. Upon regulatory approval of Elevidys and achievement of certain sales milestones, Sarepta becomes eligible to receive up to $1.7 billion in additional payments.

Elevidys works by addressing the root cause of DMD through the targeted production of functional components of dystrophin in muscle tissue. Elevidys packages a transgene encoding truncated dystrophin (mini-dystrophin) into an AAV viral vector; a single intravenous infusion enables patients’ muscles to produce a recombinant protein with partial dystrophin function, making it effective for patients harboring any type of DMD-causing genetic variant.

The prior FDA approval of Elevidys was based on clinical study data showing that it increases the production of mini-dystrophin in muscle cells, with boys treated with Elevidys tending to exhibit better motor function than those untreated. Therefore, the FDA concluded that, based on the data submitted by Sarepta, the increase in micro-dystrophin expression (a surrogate endpoint) associated with Elevidys could provide clinical benefit to DMD patients aged 4–5 years.

It is worth noting that Elevidys did not receive unanimous support from the FDA for its market approval. In May 2023, the FDA advisory committee voted 8-6 in favor of accelerated approval for Elevidys, and the FDA granted full approval one month later. However, because Sarepta used micro-dystrophin expression levels as a surrogate endpoint, the FDA required the company to complete confirmatory clinical trials to verify clinical benefit.

Subsequently, Sarepta conducted a global, randomized, double-blind, placebo-controlled Phase 3 clinical trial named EMBARK in DMD patients aged 4–7 years. The EMBARK trial enrolled 125 patients, who were randomized 1:1 to receive either Elevidys or placebo. The primary endpoint was the NSAA score, and secondary endpoints included protein expression levels, TTR, 10MWR, and others.

However, this clinical validation ended in failure. EMBARK data showed that at Week 52 after Elevidys treatment, participants’ NSAA scores improved but did not meet the prespecified primary clinical endpoint, reaching only the key secondary endpoint.

Nevertheless, this setback did not dampen Sarepta’s confidence. The company announced that it would submit a supplemental Biologics License Application (BLA) to the FDA based on EMBARK data to expand the approved indication for Elevidys, extending coverage to DMD patients aged 4–7 years. Furthermore, the sales outlook for Elevidys remains unaffected. According to data released by Sarepta, following its official commercial launch in August 2023, Elevidys generated net product revenues of $69.1 million in the third quarter, with total annual revenues reaching $200 million.

At this year’s JPM Conference, Doug Ingram, CEO of Sarepta, stated that Elevidys’ sales figures have far exceeded Wall Street’s forecasts, and its sales potential has yet to be fully realized, with even more promising performance expected in 2024. As part of its future plans, the company will conduct three additional clinical trials for Elevidys, including two Phase 3 trials.

Currently, the FDA has accepted Sarepta’s Biologics License Application (BLA) and will review the data submitted from the EMBARK study for a label expansion. However, the outcome of the FDA’s review remains undetermined.

Nevertheless, on January 9, Peter Marks, the FDA’s top regulator for gene therapy, stated in an interview that he was not troubled by the failed Phase 3 clinical validation results for Elevidys. He emphasized that the crux of a product lies in its efficacy, and as long as the data are sufficiently robust, gene therapy developers need not be overly concerned about whether clinical trials are deemed successful. Peter Marks was one of the eight individuals who supported the approval of Elevidys. Regarding the application submitted by Sarepta, he indicated that the FDA would conduct an expedited review of the data¹.

In 2023, other gene therapy products approved for market launch alongside Elevidys included Lantidra, the world’s first allogeneic cell therapy product; Vyjuvek, the first topical gene therapy; and Casgevy, the first gene-editing drug. That year, a total of seven CGT therapeutic drugs received FDA approval, marking a harvest year for the field.

Since the approval and market launch of Novartis’s Kymriah and Gilead’s Yescarta, two CAR-T cell therapy drugs, in 2017, other CGT (Cell and Gene Therapy) drugs have been successively introduced to the market. This year is therefore regarded as the “Year One of Commercialization for CGT Therapies.” As the clinical efficacy of CGT therapies has become increasingly evident, and with the application of new technologies such as CRISPR gene editing, the CGT industry has entered a phase of rapid development, attracting both multinational corporations (MNCs) and biotechnology companies (Biotechs) to enter this field.

However, amid the capital winter and the downturn in the pharmaceutical industry, the heavily “involuting” CGT sector has encountered significant development hurdles. A stark manifestation of this trend is that multinational corporations (MNCs) have sharply cut back on their CGT pipelines: In February 2023, GlaxoSmithKline (GSK) announced the termination of its R&D investment in CGT; in the same month, Novartis announced the cessation of its collaboration with Intellia Therapeutics, a pioneer in genome editing development, on an ex vivo CRISPR-edited stem cell therapy for sickle cell disease (SCD). In September 2023, Moderna announced cuts to four mRNA therapy programs.

In addition, the wave of layoffs and contract terminations has also severely impacted CGT companies. According to incomplete statistics from VCBeat, as of early December 2023, a total of 166 Biotech companies in China had carried out at least one round of layoffs, among which 43 were cell and gene therapy companies, accounting for more than 1/4.

Despite these challenges, the CGT industry continues to demonstrate robust vitality. According to data from Precedence Research, the global market size for cell and gene therapies was $18.61 billion in 2022 and is projected to exceed $93.78 billion by 2030, representing a compound annual growth rate (CAGR) of 22.41% from 2022 to 2030. In response to this promising landscape, companies in the CGT sector are striving to survive by cutting costs through layoffs to redirect funds toward R&D, as well as through collaborations and mergers and acquisitions. For instance, in January 2023, gene therapy company Editas Medicine announced a 20% workforce reduction and significant cuts to drug development expenditures to focus on the research and development of EDIT-301, a CRISPR-based therapy for sickle cell disease and beta-thalassemia. In December 2023, AstraZeneca acquired Gracell Biotechnologies for $1.2 billion, thereby obtaining its GC012F CAR-T cell therapy.

Data released by the Alliance for Regenerative Medicine (ARM) at the 2024 BIO International Convention indicates that 17 new cell and gene therapy (CGT) drugs are expected to gain approval in 2024. Previously, the U.S. Food and Drug Administration (FDA) had projected that 10 to 20 CGT therapies would be approved annually by 2025.

In the future, with technological innovation and advancing R&D, the CGT industry, which holds broad clinical prospects, may achieve new breakthroughs.

References:

1.https://www.statnews.com/2024/01/09/fda-peter-marks-full-approval-sarepta-duchenne-gene-therapy/