Controversial Case of Sarepta’s eteplirsen, for DMD gained a Support Letter to FDA by Site Investigators and Advisers working on the drug
Reporter: Aviva Lev-Ari, PhD, RN
UPDATED on 7/21/2025
What does Elevidys’ future look like now?
Some backstory first: The FDA first approved Elevidys in June 2023, granting it accelerated clearance for Duchenne patients who were 4 or 5 years old and could still walk. One year later, the agency expanded the treatment’s OK to include ambulatory and non-ambulatory Duchenne patients who were 4 years of age or older.
Both decisions were controversial, as Sarepta’s trial data for Elevidys didn’t prove the therapy could significantly improve motor function. But the Duchenne community mostly embraced Elevidys, propelling it to the fastest market launch of any gene therapy approved in the U.S.
Safety concerns prompted by the recent deaths could now change that. But without Sarepta’s cooperation, the FDA’s options for stopping Elevidys sales altogether are limited. And those it does have at its disposal are likely to take time.
In refusing the FDA’s request to halt sales, Sarepta maintained there has been no new information indicating greater safety risk in younger, ambulatory patients. Both of the Elevidys patients who died were teenagers whose disease had eroded their ability to walk.
The distinction is clinically important as Elevidys is dosed by weight, so younger, lighter patients receive less of the drug. And as they’re earlier in their disease course, the treatment window to forestall further damage may be greater.
The distinction also has regulatory implications. In June 2024, when the FDA expanded Elevidys’ approval it did so by converting its accelerated approval to full for ambulatory patients. In non-ambulatory patients, Elevidys’ clearance remains “accelerated,” which indicates Sarepta is required to produce further evidence of its benefit in this group.
For the time being, the FDA has informed Sarepta that Elevidys’ indication should be limited to ambulatory patients only. The agency said in a statement that it is “committed to further investigating the safety of the product in ambulatory patients and will take additional steps to protect patients as needed.” — Ned Pagliarulo
Why did the FDA wait to step in?
The FDA claimed Friday it took “swift action” by suspending multiple Sarepta trials and requesting the company halt all Elevidys shipments. It took those steps following “new safety concerns” that the agency said showed patients may be exposed to “unreasonable and significant risk of illness or injury.”
“We believe in access to drugs for unmet medical needs but are not afraid to take immediate action when a serious safety signal emerges,” FDA Commissioner Martin Makary said in the statement.
SOURCE
UPDATED on 6/22/2023
After delays, Sarepta’s DMD gene therapy Elevidys finally makes it past the FDA finish line
By Zoey BeckerJun 22, 2023 02:25pm
UPDATED on 12/12/2019
In stunning twist, FDA approves Sarepta’s Duchenne drug it rejected
Vyondys 53, a type of nucleic acid therapy, is now conditionally cleared for the roughly 8% of patients with Duchenne who are “amenable” to exon 53 skipping, the mechanism by which the drug works. Sarepta said it would price Vyondys 53 “at parity” with Exondys 51, which controversially won FDA approval in 2016. Exondys 51 costs about $300,000 per year per child.
Exondys 51 was the first medicine specifically approved to treat Duchenne. Its approval sparked internal debate at the FDA, with agency officials at the Division of Neurology Products, the director of the Office of New Drugs and the acting chief scientist arguing in favor of rejection. They were overruled by Janet Woodcock, head of the FDA’s Center for Drug Evaluation and Research.
The FDA’s rejection of Vyondys 53 had stirred speculation the agency had done so for political reasons tied to the controversy over Exondys 51.
Company CEO Doug Ingram steadfastly refused to say much about the decision other than that it related to infection and kidney toxicity risks, and asked the patient community to not pressure the agency to change its mind.
Approval is conditional on Sarepta running a confirmatory study to prove Vyondys 53 delivers a clinical benefit. The data Sarepta used to support its application showed that treatment increased levels of dystrophin, a critical muscle protein missing in patients with DMD, from 0.1% of normal to 1.02% on average after 48 weeks.
SOURCE
https://www.biopharmadive.com/news/fda-surprise-approval-sarepta-vyondys-53-duchenne-drug/569015/
On 1/23/2016 I published
Gene Editing for Exon 51: Why CRISPR Snipping might be better than Exon Skipping for DMD
Reporter: Aviva Lev-Ari, PhD, RN
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Monday, March 21, 2016 | By John Carroll
Sarepta ($SRPT) enjoyed a rare spike in its share price today after several dozen experts in Duchenne muscular dystrophy, including a host of site investigators and advisers working on the drug, circulated a detailed letter explaining why the FDA should support the company’s application for eteplirsen–despite a withering internal assessment from agency insiders. On a point-by-point basis these physicians took exception to the FDA review, noting that despite the extremely small number of patients in the key study–with data on only 12 boys–their experience observing patients in their practices suggest that the drug was clearly effective. As news of the letter spread, Sarepta’s share price surged 20%. “The collective signatories note that the group of 12 eteplirsen treated boys, even accounting for daily deflazacort usage or twice-weekly prednisone, is clearly performing better than our collective clinical experience and the published literature would predict,” the lineup of physicians asserts. “Collectively, a portion of us represent a group of physicians who have observed over 5,000 DMD patients in our practices over an average of more than 15 years. Published external natural history data and our clinical experience strongly support that the 12 boys treated for over 4 years show a milder clinical progression, likely due to a positive treatment effect of eteplirsen.” A quick check of Sarepta’s websites and online records also revealed that many of the as-advertised experts have close ties to Sarepta, often listed as the very investigators who have been helping Sarepta gather the controversial data together and analyze it for regulators. Among those who have worked on drug trials related to eteplirsen and signed the letter are UCLA’s Perry Shieh (a principal investigator for one study), Stanford’s John Day (who lists Confirmatory Study of Eteplirsen in DMD Patients on his resume; and Kathy Mathews at the University of Iowa (a hub site investigator and principal). Harvard Med School’s Louis Kunkel and the University of Washington’s Jeff Chamberlain, who signed on to the company’s advisory board, are also signers on the lobbying letter, along with many trial site leaders, including Anne Connolly, Susan Apkon, Nancy Kuntz and Basil Darras, all listed on Sarepta’s website. Dr. M. Carrie Miceli and Dr. Stanley Nelson, co-director of the Center for Muscular Dystrophy at UCLA, took the lead on the letter, which was dated February 24 and addressed to Dr. Billy Dunn, director of the division of neurology products at the FDA. The wife/husband team launched a public campaign advocating for new drugs to be approved for Duchenne, which afflicts their teenage son. Miceli, Nelson and Chamberlain also sit on the advisory board of CureDuchenne, an advocacy group which has offered its full-throated support of eteplirsen’s approval, along with Sarepta CEO Ed Kaye. In their view, which you can see here, the best approach would be to go ahead and approve eteplirsen and then go ahead and let upcoming data provide confirmatory results. “The FDA Briefing Document also implies that the ongoing non-placebo controlled confirmatory eteplirsen trial (NCT02255552) and additional eteplirsen safety studies (NCT02420379 and NCT02286947) initiated in response to FDA guidance may not be considered sufficiently robust to allow for approval,” the letter reads. “Given the relative paucity of patients with amenable mutations, the flexibility afforded by FDASIA, and the fact that many of the boys between the ages of 4 and 21 years with relevant mutations are already receiving eteplirsen in the context of these trials, it would be difficult to conduct a large placebo controlled study in the near future. Thus, it would be dubiously ethical to veer from the currently recommended study path at this point. In keeping with the criteria imposed by FDASIA for accelerated approval for rare disease with unmet need, we conclude that the aggregate data, described in the briefing documents, are providing substantial evidence of efficacy and use in the greater population of boys amenable to exon 51 skipping is appropriate. We suggest that the most scientifically robust way forward and the most ethical choice for the Duchenne community is in the context of an accelerated approval followed by a confirmatory trial.” Just how persuasive this group can be, with such close ties to Sarepta, won’t be clear until April 25, when the FDA’s advisory committee will finally meet for a review. The FDA’s internal assessment virtually dismissed Sarepta’s case. But the biotech has enjoyed intense support from parents and patients–as well as the professional community, which has played a big role in testing the drug. Related Articles: Sarepta has a new date with an FDA AdComm for Duchenne drug eteplirsen Sarepta shrinks as execs wait for FDA’s decision on Duchenne drug Sarepta faces another FDA delay with its much-scrutinized DMD drug Sarepta shares crash on a harsh FDA review of Duchenne’s drug |
SOURCE
From: FierceBiotech <editors@FierceBiotech.com>
Reply-To: <editors@FierceBiotech.com>
Date: Tuesday, March 22, 2016 at 1:31 PM
To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>
Subject: | 03.22.16 | Eli Lilly raises big questions in quest to salvage Alzheimer’s drug; Sarepta investigators join lobbying effort for eteplirsen
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