Breaking news! The first DMD gene therapy, SRP-9001, has been approved for marketing and is priced at $3.2 million
On June 22nd, the US Food and Drug Administration (FDA) approved the world's first one-time gene therapy SRP-9001 (Elevidys) to treat Duchenne muscular dystrophy (DMD), which is applicable to patients aged 4-5 who can walk independently.
In early May, the FDA launched three target action dates and three advisory committee meetings, including a highly anticipated DMD gene therapy project, SRP-9001. At the subsequent advisory committee meeting, FDA advisors voted 8:6 in favor of approving SRP-9001 for accelerated approval. After several delays following the advisory committee's narrow vote, the gene therapy SRP-9001 was ultimately granted accelerated approval by the FDA.
SRP-9001 is an AAV-based gene therapy developed jointly by Sarepta and Roche for the treatment of Duchenne muscular dystrophy in children aged 4-5 who can walk independently. It is priced at $3.2 million, the second-most expensive gene therapy in the world after Hemagenix, which is priced at $3.5 million. In addition, the drug is contraindicated in DMD children with deletions on exon 8 and/or exon 9. This is the world's first approved AAV gene therapy for Duchenne muscular dystrophy.
One-time gene replacement therapy
According to statistics, globally, one in every 3,500-5,000 male infants is affected by DMD. China is one of the countries with the highest incidence of Duchenne muscular dystrophy, with around 400 to 500 new cases each year, and a total of 70,000 to 80,000 patients.
DMD is a fatal, rare X-linked degenerative neuromuscular disease that primarily affects males. It is caused by mutations or deletions in the dystrophin gene, which leads to the inability to produce dystrophin, a protein necessary for maintaining the stability of muscle and other tissue cell membranes. This results in progressive muscle wasting and degeneration, and ultimately, respiratory or cardiac failure, with a life expectancy of no more than 40 years.
Prior to the approval of Elevidys, there were four "exon skipping" therapies for treating DMD globally, three of which came from Sarepta. These therapies can help patients produce partially functional dystrophin, reducing muscle weakness and degeneration. However, their clinical efficacy has not been ideal, and they can only target about 10% of patients with specific mutations. They also require regular injections and cost nearly $1 million a year.
In contrast, as a gene replacement therapy, Elevidys aims to achieve one-time administration and can fundamentally replace defective genes regardless of where the mutations occur in the dystrophin gene. In 2019, Roche and Sarepta signed a $2.85 billion licensing agreement, granting Roche commercial rights outside of the United States, while Sarepta is responsible for clinical development.
According to the information disclosed by the FDA, this approval was mainly based on two clinical trial data. The first trial involved only four participants, and after three years of treatment with a single dose, the four children showed improvement in their motor function and walking ability. The second randomized controlled trial included 41 children, and after a two-year follow-up, an increase in dystrophin expression was found in the treated group of children aged 4-5.
A key reason why Elevidys was granted FDA approval was its good safety profile. During the clinical trials, no treatment-related serious adverse reactions were observed, and most of the adverse reaction symptoms were mild and were relieved after treatment. This was also an important reason why Elevidys was able to gain a competitive edge. At the end of 2020, Pfizer's similar therapy PF-06939926 was granted fast-track status by the FDA, but subsequent research revealed three serious side effects and the unexpected death of a child, leading to a hold on the trial.
Elevidys also received FDA's fast-track designation, which allows drugs to be approved based on early clinical results. In April 2023, doctors and parents of patients urged for the therapy to be approved as soon as possible at a public meeting and shared videos of children being able to run, ride bicycles, and engage in sports activities, which they attributed to the therapy.
"Elevidys approval represents a milestone in the history of DMD treatment," said Doug Ingram, CEO of Sarepta, in a statement. If the clinical efficacy of Elevidys can be further validated in subsequent trials, the company will quickly take action to submit supplemental materials and expand the scope of Elevidys use.
The price of $3.2 million and uncertain efficacy are both concerning factors regarding the use of Elevidys.
Despite its approval, Elevidys is still a controversial product, which reflects the FDA's recent balancing act between "drug efficacy" and "patient urgent needs" in its regulatory review process.
Similar controversial approvals include the FDA's approval of AMX0035, a new drug for the treatment of amyotrophic lateral sclerosis (ALS), in September of last year. AMX0035 only showed a slight benefit in clinical data and was even considered unlikely to be observed in the real world. However, due to the lack of available treatments for ALS, the FDA ultimately approved this product.
Earlier, in June 2021, the FDA approved the first new drug for Alzheimer's disease in 18 years, Aduhelm, amidst much skepticism and questioning. Clinical trials for Aduhelm only observed effects on biological markers, and evidence for actual disease improvement in the real world was lacking. Despite its approval, it was excluded from the national health insurance program and the commercialization pathway was deemed a failure.
The approval of Elevidys was also based on surrogate endpoints, observing whether the corresponding biological markers have improved, instead of directly verifying whether the patients have truly gained clinical benefits. In the advisory committee meeting in May of this year, FDA advisors supported the approval of Elevidys by a narrow margin of 8:6. Those opposing the approval believed that the clinical trials failed to show significant improvement in the treated children's motor function.
Although the fast-track designation gives the FDA the power to withdraw the drug from the market if it fails to fulfill its early promises, the complex administrative process makes it extremely rare for the FDA to exercise this authority. Industry experts point out that this process could result in the FDA facing pressure from patient groups, leading to a "flexible standard" that could seriously compromise the scientific authority and efficacy of drugs that are approved.
However, from the pricing perspective, Sarepta has already made preparations for the ultimate validity of Elevidys. The one-time treatment cost for Elevidys is $3.2 million, slightly lower than the $3.5 million gene therapy for hemophilia from last year. Analysts point out that the sky-high price is not solely based on the drug's R&D costs. Like other gene therapies, the price of Elevidys is built on the assumption that its benefits will last for years, reducing the burden of disease expenses for society.
In addition to providing social support, disease management, and using other drugs for patients, Sarepta stated that a price range of $5 million to $13 million for Elevidys would still have social cost-effectiveness, and that the current price of $3.2 million is a "conservative consideration."
Like most drugs in the US, the cost of Elevidys is expected to be primarily covered by insurance companies, including private and government insurance. Sarepta speculates that because the number of patients eligible for the drug is extremely small, insurance companies will not set up too many barriers in terms of payment.
The company is currently conducting a clinical trial for 126 patients to determine if Elevidys can ultimately expand the patient age group while avoiding the risk of being withdrawn from the market or experiencing the same fate as Aduhelm's failed commercialization. The relevant data is expected to be released in December of this year.
Families of affected children are also waiting for the results. Currently, insurance coverage is only available for children between the ages of 4 and 5, and some families have to engage in a difficult race against the disease before their child's 6th birthday. According to foreign media reports, senior analysts predict that Elevidys will only be used for 59 patients in Sarepta's fiscal year 2023, with sales of approximately $117 million. However, if it is ultimately proven to be usable for a wider range of patients, the drug's annual sales could exceed $4 billion.
Source: Frontiers of Cell Gene Therapy
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