Initial Golodirsen CRL Raises Alarms Over Eteplirsen Confirmatory Study

Regulatory NewsRegulatory News | 22 January 2020 |  By 

As part of the US Food and Drug Administration’s (FDA) approval package for Sarepta Therapeutics’ Duchenne muscular dystrophy (DMD) injection Vyondys 53 (golodirsen) last month, the agency on Wednesday raised questions about a confirmatory trial for another approval in the golodirsen complete response letter (CRL) from last August.

The letter, which typically remains confidential unless a company later wins approval, raises concerns about both golodirsen and Sarepta’s previous accelerated approval for the DMD treatment Exondys 51 (eteplirsen) in 2016, which was also considered controversial after an advisory committee of outside experts voted against it.

At the time of the CRL in August 2019, Sarepta claimed that FDA had two concerns with golodirsen: “the risk of infections related to intravenous infusion ports and renal toxicity seen in pre-clinical models of golodirsen and observed following administration of other antisense oligonucleotides.” But the company also maintained that renal toxicity with golodirsen was observed in pre-clinical models at doses that were ten-fold higher than the dose used in the clinical studies and that such toxicity was not observed in the study on which the application for golodirsen was based.

In contrast, the CRL, written by Ellis Unger, Director of FDA’s Office of Drug Evaluation I, who previously opposed the accelerated approval of eteplirsen, makes clear that “golodirsen’s risk of renal toxicity poses a significant concern” and that “there is no practicable and proven paradigm for renal monitoring for this drug in this patient population.”

As far as the risk of infections from the ports used with golodirsen, the CRL notes that in the company’s study, drugs were administered via a central venous access port in only about half of the patients (~30 of 60).

And although only about nine patients had device-related adverse events, none of which were serious, Unger explained: “Having recently become aware of postmarketing reports of serious and life-threatening infections with eteplirsen, we now recognize that administration of both drugs via implanted intravenous ports poses considerable risk of serious and life-threatening infections.”

With 469 patients exposed to commercial eteplirsen, Unger explains, FDA has “incontrovertible evidence of a significant likelihood of serious infections, including sepsis, septic shock, and possibly death.”

And in the CRL, Unger sharply criticizes Sarepta, which won accelerated approval for eteplirsen more than three years ago, but has yet to initiate the required confirmatory trial to prove that the treatment is effective.

“Given that you have established a standard paradigm and design for these types of studies, given that you have relationships with a number of DMD referral centers, and given that some 469 patients have received commercial eteplirsen, it is necessary to ask why you have not initiated your required confirmatory study with due diligence. We possess no more knowledge than we did three years ago in terms of the likelihood that small amounts of truncated dystrophin will lead to clinical benefit. Such information, if available now, could have informed our decision-making for golodirsen,” Unger adds.

And in bolded letters he writes in the CRL: “Please understand that your failure to initiate eteplirsen’s confirmatory study with due diligence is very concerning to FDA and is of concern to the public.” The study was initially supposed to be completed by November 2020. Sarepta now says that trial is expected to read out in October 2024.

But four months after the CRL for golodirsen was sent, FDA reversed its decision and approved golodirsen, noting in the approval package that Sarepta has proposed an acceptable renal monitoring plan for DMD patients, and that although the risk of line/port infections cannot be entirely avoided, Sarepta’s proposed educational plan may help to minimize the risk of infections.

“Overall, the risk minimization efforts appear adequate and support an acceptable risk/benefit profile of golodirsen for the treatment of DMD patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping,” FDA says.

According to the approval package, Sarepta filed a formal dispute resolution request with FDA last September, and in November, Peter Stein, director of FDA’s Office of New Drugs, granted the appeal and concluded that clinically meaningful benefits “are reasonably likely to be seen with golodirsen, consistent with evidence on the effects of low levels of dystrophin (vs. complete absence).”

But Stein also asked Sarepta to provide a written commitment, prior to approval of golodirsen, "that if the results of the confirmatory study do not support a clinical benefit (i.e., no relevant analyses finds sufficient evidence of such a benefit), that they will voluntarily withdraw golodirsen from the market.” That trial is expected to be completed in May 2023.

And since both eteplirsen and golodirsen are rare pediatric disease treatments, Sarepta won priority review vouchers (PRVs) for both. The company previously sold its first PRV for eteplirsen to Gilead for $125 million.

Golodirsen CRL

Golodirsen approval 


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