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Opening the Lid on Sarepta’s Drug Approvals

Let’s talk Sarepta. And FDA approval, because you can’t bring up that company without immediately starting a regulatory affairs argument. I was not happy when their initial exon-skipping therapy (Exondys, eteplirsen) for Duchenne muscular dystrophy was approved in 2016, because I thought that the efficacy data were simply not strong enough for such approval. Last summer, another exon-skipping application from the company (golodirsen) was rejected by the FDA with a Complete Response Letter (CRL). The agency does not make those letters public at the time, despite many people wanting this to happen, so we’re dependent on whatever the receiving company wants to say about them. At the time, Sarepta’s management said that the rejection was due to concerns about kidney tox and possible risk of infection.

But last month, the FDA suddenly approved golodirsen (known as Vyondys 53). This took everyone by surprise, and there has been no explanation for the change of opinion on the agency’s part. As the Wikipedia article linked above correctly states, “No clinical benefit of using golodirsen has been established”, and honestly, I didn’t think we approved too many drugs without establishing that. But here we are.

The story gets even more complicated as of today, because the FDA has actually posted the CRL for all to see. It’s quite the document. It points out that the surrogate marker the company was using (truncated dystrophin) changed by a very small amount, which would lead one to think that the clinical benefit would be minimal. That’s even if you accept that the marker is a valid one, which is an arguable thesis all by itself. There was, as noted, no correlation between the physical decline of the subjects in the study and the levels of the truncated protein.

The golodirsen package is unavoidably tangled up with the previous eteplirsen story. The CRL details a number of serious infection events (sepsis, death) associated with eteplirsen since its approval. Duchenne patients are at risk for this sort of thing, since they’re taking high doses of corticosteroids. The letter notes furthermore that the golodirsen package manages not to mention any of these despite being a very similar oligonucleotide which will be administered in the same manner:

Some may characterize these infections as device-related rather than drug-related and downplay their importance. This is a weak argument: these individuals would have had no reason for implantation of a central intravenous infusion port other than to receive eteplirsen; many of these infections would not have occurred if the patients had not been receiving eteplirsen.

If these devices are necessary to deliver the drug, then these infections must be construed to be drug-related. Although the aforementioned information was obtained from the eteplirsen postmarketing experience, such information is directly applicable to the potential marketing of golodirsen, which too would be administered through implanted infusion ports in many patients.

As for the renal toxicity, it’s a concern with antisense oligos in general, and it appears that golodirsen just barely make it through preclinical tox studies because of this very issue. It’s excreted unchanged, so any decline in renal function is going to increase exposure in the kidney and make things worse. Which will increase exposure even more, which will. . .you get the idea. The potential for rapid (and likely fatal) kidney tox is always going to be present. And there is no accepted way to monitor renal function in Duchenne patients – the reduced muscle mass makes creatine levels an inappropriate marker.

Now we come to that whole “eteplirsen postmarketing experience” part. The letter points out that no severe infections were seen during eteplirsen’s clinical trials, but it has been a real problem since drug approval. Golodirsen should be in the same situation for that risk, and its kidney tox risk is clearly greater when you compare the two sets of data. So what did that mean for its proposed approval?

When eteplirsen was granted accelerated approval in 2016, you were required to perform a postmarketing study to verify eteplirsen’s clinical benefit. Patients were to be randomized to the approved dosage of eteplirsen (30 mg/kg weekly) or to a dose 7-fold higher, e.g., 30 mg/kg daily. We thought that the considerable increase in dose was acceptable because we were not aware of any significant toxicity related to eteplirsen. The same cannot be said of golodirsen, where nonclinical data have demonstrated considerable risk of renal toxicity.

In summary, therefore, at the time of eteplirsen’s approval, there were no adverse events of note in the clinical data, and no nonclinical concerns. Although we recognized that the clinical database was limited, the drug had no known toxicities, which enabled us to require a confirmatory trial to study a dose that was 7-fold higher than the to-be-marketed dose. The risk of serious and life-threatening infections, including sepsis, was not known in 2016 when eteplirsen gained accelerated approval. In essence, the small potential benefit of eteplirsen was weighed against essentially zero risk.

Here’s the problem: that postmarketing study has never taken place. In fact, it hasn’t even been started. (Edit: looks like they’ve finally gotten it off the ground since the CRL was issued). The CRL says that because of this failure, we know nothing more now than we did three years ago about whether eteplirsen does any good at all. What we do know, though, is that it’s much riskier than the agency thought, and we also know that golodirsen is even riskier (and with, as mentioned, extremely thin evidence of any benefit). The letter ends with a long, detailed list of what the FDA expected Sarepta to do to remedy the deficiencies in the drug’s approval package.

And then a few months later, they said “Ah, never mind” and just approved it anyway. No explanation (edit: unless you count this response, which I do not find convincing). So those are the drugs that Sarepta has on the market: an initial therapy that was not shown to work in the clinic and has shown significant risks since it was brought to market. And a follow-up which likewise has not been shown to work in the clinic and can already be expected to have ever greater risks once marketed. What the hell is going on? The idea is that the FDA evaluates things on the basis of safety and efficacy, but it can apparently throw both of those out the window when it feels like it? This is infuriating, and it damages things in all directions: not only the health of suffering Duchenne patients, but also the integrity of the whole regulatory process and the reputation of the FDA. You don’t just get those things back easily, you know. That’s what we’re going to be learning for years to come in our current situation, and I’m not just talking about drug approvals. Fairness, competence, impartiality, integrity, and the reputation for having them: they don’t just reappear when you decide later on that you’d rather have them back.

Edit: I meant to add more about the response letter from Peter Stein of the FDA linked above. It requests that Sarepta continue with a confirmatory study for golodirsen, which should read out in 2023, and that the company commit to withdrawing the drug from the market should the results of that study not support its use. In the abstract, I support that idea. But why didn’t the agency hold the company to that sort of agreement with eteplirsen? Why approve yet another therapy in this class, with similarly weak data? Will the FDA commit to re-evaluating its recent tendency to overrule its own scientists if these drugs injure more Duchenne patients in the next three years without doing them any good?

28 comments on “Opening the Lid on Sarepta’s Drug Approvals”

  1. Hap says:

    “Fairness, competence, impartiality, integrity, and the reputation for having them: they don’t just reappear when you decide later on that you’d rather have them back.” I’d like to hope that this will be true, but there seem to be a lot of people and institutions who think these qualities are obstacles (to getting what they want, presumably) rather than beneficial traits (other than appearing to have them, which is beneficial in any case), and so there’s no reason to even bother about having them. Since the institutions or people can’t have these traits, they presume (or assert) that no one or nothing else can aspire honestly to having them, and that any such aspiration is false and dishonest.

    “What the hell is going on” seems near-universally applicable, as well.

  2. Andre Brandli says:

    Derek, I was confused myself after reading a similar report on Endpoints News earlier today. Why was Vyondys 53 approved in light of this damming CRL? The Vyondys 53 approval was initially denied, probably in response to the CRL. This was however reversed in December 2019. I am puzzled about what is going on here. The FDA has to be more transparent about the reasons leading to the unexpected approval of Vyondys 53. If the Vyondys 53 approval is the new FDA standard then Biogen’s aducanumab will be approved without much discussion. At least, it is able to clear plaques from the brains of AD patients.

    1. Andre Brandli says:

      “(Ellis) Unger’s concerns, though, were waved away by Peter Stein, who runs the Office of New Drugs. Stein’s opinion — delivered after Sarepta execs appealed the rejection — was that the risks associated with golodirsen could be monitored and managed. And he was satisfied by the level of efficacy in the data, saying that clinically meaningful benefits were “are reasonably likely to be seen….” Stein also called on the company to provide a letter promising to voluntarily yank the drug from the market if the confirmatory study failed to prove a benefit.”
      Taken from an update to the original Endpoints News article:

  3. Just sayin says:

    What is going on is anyone’s guess. I would guess it is political, as with many other departments these days: the desire for good political optics when voters are told that more drugs are getting approved, damn the science… oh science is a political word too, so damn the idea of whether the drug works or even has adverse effects.

    1. enl says:

      “works” and “adverse” are also politicized.

  4. Magrinho says:

    It’s been a weird and troubling story.

    Also related is the rapidly increasing degree to which the “pharma model” is predicated on extremely high, only in America, drug prices.

    This does not bode well for a good ending. Either prices will continue into the stratosphere for cancer and “rare” diseases OR any drug pricing reform will cause utter chaos to a good part of the industry.

  5. Captain Obvious says:

    Maybe Sarepta booked a big retreat at a Trump property.

    1. Nothing makes sense anymore says:

      That’s obviously how one does business nowadays. Very disappointing.

      1. Captain Obvious says:


  6. Earl Boebert says:

    I think it’s pretty obvious that in today’s political environment, regulatory capture is complete. Look at the examples outside pharma:

    Boeing 737 MAX (FAA and Dutch regulators)
    El Faro (USCG)
    Conception (USCG)
    Offshore and onshore drilling (Interior)
    Meat inspection (USDA)

    (You may have to google on some of these.)

    For all practical purposes, we are living in a deregulated society, and good luck with that.

  7. Zee Bendelstein says:

    eteplirsen set a dangerous precedent and perhaps now consistency with that decision requires similar levels of permissiveness towards similarly useless/dangerous drugs?
    Will physicians/payors now become de facto regulators?

  8. loupgarous says:

    Who got to CDER? Apparently, someone did, because it has not been FDA’s policy until recent years to say:

    “… I request that the company 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.”

    Used to be, FDA would, given post-marketing indications that showed lack of efficacy for a newly-approved drug, quietly require encourage the new drug’s manufacturer to withdraw the drug in question.

    It’s what happened after Eli Lilly and their PR guys, Belsito & Co stormed FDA with a PR offensive promoting Xigris (drotrecogin alfa). The ADCOM on Xigris was deadlocked 20-20 for/against approval. FDA granted approval for Xigris for severe sepsis on the condition further research be performed in pediatric cases and those patients with APACHE II scores below 25 (the ADDRESS study found increased incidence of serious bleeding and no evidence for benefit to patients).

    A 2006 paper in NEJM dissected the PROWESS study on which FDA’s approval decision was initially based, found several damning errors, including changes to the eligibility and exclusion criteria after the first year data were collected. No other study had reproduced PROWESS’s results. By 2012, the PROWESS-SHOCK study showed no decrease in death rates for patients in septic shock who were given Xigris. At this point, Eli Lilly pulled Xigris off the market after years in which it was used for septic shock at $8,000/patient.

    This is an example of what happens when drug companies are given approval for drugs with questionable efficacy by FDA despite initial qualms. It looks like history could be repeating itself.

  9. Dr. Winters says:

    Golodirsen would have been approved back in August if Unger has not interfered due to personal vendetta. This is the right decision and supported by the Department of Neurology. This is what first generation drug looks like. Many companies like Prosensa (later Biomarin), Wave, PTC failed in their efforts. Sarepta is the only one that made it work.

    1. KP says:

      But, they haven’t. That’s the point.

    2. loupgarous says:

      Dr. Winters: “Golodirsen would have been approved back in August if Unger has not interfered due to personal vendetta.”

      Extraordinary claims require extraordinary proof. Don’t feel bad – the FDA and Sarepta missed that, too, apparently.

  10. Mike says:

    I think digging into the Prescribing Information for Vyondys 53 gives some major insights into how the FDA’s thinking changed.

    In the CRL, the FDA saw the risk of central line infections to be inseparable from the drug itself. “If these devices are necessary to deliver the drug, then these infections must be construed to be drug-related.”

    If you look at the approved PI at the link above, there is zero mention of the risk of central line infections. So for whatever reason, Sarepta came back with an argument that the infection aren’t drug-related.

    Since the core reason for the CRL was the risk-benefit ratio (high risk of infection – data only suggests weak efficacy), if Sarepta convinced the FDA that the risk wasn’t there, then the approval is similar to Exondys – weak efficacy data, but little risk as well.

    1. loupgarous says:

      Ellis Unger and Peter Stein at CDER seem to be on opposing sides of that argument. Ellis Unger to Sarepta:

      Late in the review cycle I learned that reports of significant infections, bacteremia, sepsis, septic shock, and deaths have been submitted through quarterly Periodic Adverse Drug Experience Reports (PADERs) to the eteplirsen New Drug Application (NDA) file….

      When eteplirsen was approved in 2016, the theoretical possibility of infections related to indwelling ports was raised; however, no serious infections had been reported in the development program. Importantly, therefore, the possibility of infections did not figure into eteplirsen’s risk-benefit calculus at the time of its approval. Three years later, with 469 patients exposed to commercial eteplirsen, we have incontrovertible evidence of a significant likelihood of serious infections, including sepsis, septic shock, and possibly death. Thus, the risk of serious and life-threatening infections is no longer theoretical. Moreover, the infection risk is a function of the patient population and the delivery system – not the drug. Accordingly, the risk is fully applicable to golodirsen, and the 2.3% frequency from eteplirsen’s voluntary postmarketing reporting probably represents a conservative estimate of the risk, given the typical under-reporting of spontaneous adverse events.” (quoted from Endpoints News)

      There doesn’t seem to be a consensus at FDA about how much risk eteplirsen and golodirsen pose to patients, compared to a benefit smaller than the 2.3% risk of infection during eteplirsen treatment Sarepta says isn’t drug-related. (The norm in safety studies isn’t to assume that an adverse event is non-drug related, but to let analysis over the entire study dataset point to potential drug-related AEs.)..

      1. loupgarous says:

        For anyone interested in the context of the quotes from Ellis Unger’s CRL to Sarepta, John Carroll’s article in Endpoints News “UPDATED: FDA’s golodirsen CRL: Sarepta’s Duchenne drugs are dangerous to patients, offering only a small benefit. And where’s that confirmatory trial?” discusses the Unger CRL with plenty of commentary and context.

  11. Barry says:

    I’ve advocated for years that many (most?) drug approvals should be provisional, permanent approval to be contingent on the outcome of post-market (“Phase IV”) studies. Of course, the FDA would have to penalize companies that renege on such agreements (beyond “just” revoking approval)

    1. Dr CNS says:

      Not a bad idea, Barry.
      The problem here is one of confidence in the personal integrity of those deciding and credibility of a system. Or lack thereof.

      1. Barry says:

        The big barrier to Phase III studies is that they’re expensive, and there’s no guarantee of pay-back. For “Phase IV studies” however, they’re already on the market, the revenue is flowing in, and the motive is to keep that revenue flowing.
        We invented the FDA in 1906 because we couldn’t trust all drug makers. Sed quis custodiet ipsos custodes* as they say

        *who will guard the guards?

  12. Lambchops says:

    The EMA were pretty blunt on their assessment of eteplirsen. The highlighted similar concerns but came to the decision which I’m sure many of us here seems more reasonable based on the evidence available:

    “The CHMP was concerned that the main study, which involved just 12 patients, did not compare Exondys with placebo beyond 24 weeks, during which there was no meaningful difference between Exondys and placebo in the 6-minute walking distance. The methods for comparing results of the main studies with historical data were not satisfactory for showing that the medicine was effective. The Committee considered further data were needed to show that the very low amounts of shortened dystrophin produced as a result of Exondys treatment bring lasting benefits relevant to the patient.

    Therefore, the CHMP was of the opinion that the balance of benefits and risks of Exondys in the treatment of DMD could not be established and recommended that the marketing authorisation be refused. The CHMP refusal was confirmed after re-examination.”

    More detail in the EPAR for anyone interested:

    1. no expert says:

      As someone who knows precious little about DMD, I looked up the epidemiology of MD after reading this post and found that the exon 51 skipping mutation represented 13% of the MD patients which would represent about 32,500 patients in the US. A clinical trial with 12 patients seems very small to me.

  13. Lorry Turner says:

    Great news for Biogen! Even if their Alzheimer’s drug doesn’t work and causes harm…seems this agency will whisk them through for the royal treatment!

  14. loupgarous says:

    Most of the proven risk with eteplirsen is due to route of administration – central line. That is also the route of administration for golodirsen. If the only reason those kids get a central line is in hopes they’ll be made less sick, and neither eteplirsen nor golodirsen can demonstrate a benefit to the patient as clear as the risk of having it administered, that seems to me to be enough to withhold approval.

  15. Simon Auclair says:

    Government and regulations are evil. According to the GOP and our orange freak show. They slow down profits!

    Thats their entire philosophy as witnessed by Boeing writing its own safety certificate for the 737 max scareliner. We all saw how THAT turned out…

    If you don’t like it, you must be a communist.

  16. KwadGuy says:

    My guess is blackmail.

    Sort of like how Scientology got religious tax-free status after they lawyers looked into blackmail-worthy dirt on IRS officials and then they met with the head of IRS Goldberg behind closed doors.

    Alternatively, it could be hookers and blow, like in music biz. But I’ll go with blackmail.

    And this has nothing to do with Trump or the Trump administration. This is business as usual for bureaucrats.

    Your government at work.

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