Vinay Prasad's Days as Head of CBER May Be Numbered

Many industry insiders expected Sarepta CEO Doug Ingram to be out by now.  Instead, a new dynamic is gathering steam: Vinay Prasad, the recently hired head of CBER at the FDA, is coming under increased pressure as he is being identified as sabotaging Republican pro-choice philosophy. 

Last night’s latest panicky press release by ‘the FDA’ (= Prasad) that it is investigating the death of a Brazilian boy with Duchenne’s muscular dystrophy (DMD) who had received the AAV Elevidys gene therapy from Sarepta, speaks volumes.  According to a recount by FirstWordPharma, the death of this boy occurred on June 7 and was logged onto the agency’s FAERS adverse event reporting system on June 18.  The death was deemed unrelated to Elevidys by the reporting physician and caused by flu, possibly exacerbated by immunosuppression.  It remains to be seen whether the immunosuppression was part of the boy’s normal treatment for the disease (corticosteroids are standard of care) or whether aggressive immunosuppression was practiced to control acute liver injury related to Elevidys.

In any case, given that shipments of Elevidys had been halted in the US, press releasing such an 'investigation' into a death deemed unrelated to the gene therapy smacks of desperation…the desperation of Vinay Prasad clinging onto his post.

 

Trump loyalty enforcers zeroing in on Vinay Prasad

When Vinay Prasad was appointed to head CBER 3 months ago, it caused a sell-off in biotech stocks relying on accelerated approval pathways aimed to ultimately provide patient choice in a timely manner.  Gene therapy companies in particular rely on these pathways (e.g. biomarker-based, natural history comparisons) with their ongoing programs and Prasad has been public with his disdain for the Elevidys approval under Peter Marks.

In subsequent weeks and months, the investor and sector panic subsided as Vinay tagged along FDA Chief Makary advocating regulatory flexibility (approval at the slightest sign of efficacy or plausible biological mechanism).  After recent rejections of Capricor’s DMD cell and Replimmune’s oncolytic viral therapies and now the controversy around Elevidys and Sarepta, this view is changing quickly again.

Unsurprisingly, Trump’s loyalty enforcer Laura Loomer has picked up the scent and identified Prasad as a Bernie Sanders-style progressive, a wolf in sheep’s clothing undermining Republican healthcare philosophy.  

To wit, like so many of Trump’s current and past allies, Prasad has made fun of the President in the past.  More importantly, he has been a strict advocatefor healthcare rationing, limiting tests and drugs to circumstances of the highest medical certainty with Father State, not the patient or physician, being the one to decide.  His tone deafness for patient views, also on risk taking, is further illustrated by his statement that the instance you are dead, nobody will ever think of you again.

Yesterday, former Republican Senator Rick and Newsmax contributor Rick Santorum tweeted the following, citing an article that specifically attacked Prasad for his handling of Elevidys (the intro to that piece is quite the read).

 

How we got here

When Sarepta announced its company reorganization last Wednesday, shifting its focus away from gene to synthetic RNAi therapies, it did not mention the death of a non-ambulatory man treated in one of its AAVrh47 gene therapy trials for limb girdle muscular dystrophy (LGMD).  AAVrh47 is also the serotype of Elevidys. 

This death occurred and was reported to the FDA in early July.  To be clear, it was an unforced error by Sarepta to not publicly disclose that death for transparency reasons as it claimed that it retiring most LGMD gene therapy programs had nothing to do with safety.  It is, however, becoming increasingly evident that pre-existing poor liver health such as cholestatic disease (à XLMTM-related AAV gene therapy deaths) is the major risk factor for dying from AAV-related liver failure.  The fact that none of the ~800 ambulatory and therefore younger DMD subjects have died due to high-dose AAVrh47 gene therapy, but 3 out of ~140 non-ambulatory (à hepatic steatosis risk) patients treated with AAVrh47 fits neatly, making it the hypothesis that needs to be disproven first.

Sarepta has made itself many enemies and having just laid off 500 employees added to this pool.  According to BioCentury's Steve Usdin, the reporter who broke this story, there were numerous messages sent to journalists on Wednesday night and Thursday following the re-organization call enquiring why the LGMD patient death went unmentioned.  This resulted in numerous sensationalist media reports and put the publicity-minded FDA in a tough spot.  So after this AI-powered agency had sat on the Brazil and LGMD deaths for almost a month without (understandably) seeing a reason to pull Elevidys for ambulatory DMD patients from the market, it felt it had to act and be seen as a tough regulator.

Two press releases (here and here) and constant Signal chat leaks from an ‘unnamed senior FDA official’ attacking Sarepta followed, one less coherent than the other reaching yesterday’s low point.    

 

What is next

To me it is clear that this is coming down to a showdown between Sarepta, and in particular its CEO Doug Ingram and Board of Directors, and Vinay Prasad.  The company is taking the high road saying that it is working to resolve the shipment halt ‘within the ordinary and well-established FDA channels and procedures’.  You bet, however, that Sarepta is also working through unofficial political channels and Vinay Prasad has not taken into account how Sarepta got to where it is today in the first place and, being tone deaf to patient concern, certainly not the strength of DMD patient advocacy which clearly wants Elevidys to remain a choice for them.  With Replimmune and Capricor showing that Elevidys is part of a broader pattern, his fate has been sealed in my opinion.  If not, expect a Jesse Gelsinger-type scenario for gene therapy.

 

Scientific Post-Scriptum

There are less widely discussed strategies that the systemic AAV gene therapy field in general may want to explore more to increase safety besides refining immunosuppression regimens which, as we all know, carry their own risks.

One is to use RNAi, highly potent for directing gene knockdown in hepatocytes, to downregulate the processing and presentation of AAV antigens attracting the sometimes fatal T-cell response.  Sarepta with their partnership with Arrowhead Pharmaceuticals, is ideally placed to do so.  Another option could be to inhibit hepatic uptake of AAV by co-administering heparin, which should inhibit hepatic AAV uptake via HSPG and may shift the balance towards non-hepatic uptake.   

Related to that and highlighting the failure of Sarepta to have run a proper dose escalation study, with Elevidys doses being sky-high at 1.33 × 10¹⁴ vector genomes per kilogram and muscle delivery being subject to a step function (similar to LNP delivery to hepatocytes), using significantly lower doses will likely not impact microdystrophin expression much, but further decrease liver failure risk.  This and excluding patients with pre-existing liver issues, especially hepatic steatosis in DMD, may be the most rapid way to get Elevidys back onto the US market in a scenario where everybody can save face.  DMD patients and their families do not deserve to be held hostage as Prasad is clinging onto his job.