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 AAVrh74 gene therapy trials for limb girdle muscular dystrophy (LGMD).  AAVrh74 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 AAVrh74 gene therapy, but 3 out of ~140 non-ambulatory (à hepatic steatosis risk) patients treated with AAVrh74 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.  

Biotech Should Give Vinay Prasad Benefit of Doubt

The uncertainty stemming from the unpredictability and lack of evidence-based policies of the Trump administration has frozen many investment decisions.  Nevertheless, the new healthcare appointments such as Martin Makary as the FDA commissioner are turning out to not be all that bad for innovative biotech companies- unless, of course, you are in the vaccines space.  The appointment this week of Vinay Prasad as the new Director of CBER regulating, amongst others, gene and cell therapies, has caused renewed panic by expecting him to demand placebo-controlled outcomes trials that enrol thousands of patients in (ultra-)orphan diseases.  That indeed would be the end of the industry.

Here, I will lay out why I believe that many in the biotech industry are probably making false assumptions about Dr Prasad based on caricatured takes on comments he has made on social media and that he may, after all, turn out to be good for evidence-based drug approval processes, but at the same time allowing for speedy access to innovative therapies for underserved patient communities.

 

The Skeptic

Dr Prasad has made a name for himself on Twitter for spotting poorly run clinical trials or trials showing results of questionable medical value that have still led to FDA approvals.  As a hematologist-oncologist, his focus has been on oncology and the issue of having drugs on the market for which drug makers have failed to show benefit in terms of overall survival and quality of life following surrogate-based (typically PFS) accelerated approval.   

I agree that there is substantial money wasted in oncology on prescribing expensive drug regimens without providing actual patient benefit.  Neglecting to conduct confirmatory outcome trials to get at the question of patient benefit has been a routine game played by many in the pharmaceutical industry, including some in the orphan disease space.  

Unsurprisingly, Sarepta has caught his attention here with the approvals of both exon skipper eteplirsen and the more recent gene therapy Elevidys for Duchenne Muscular Dystrophy.  Like him, I have also been very vocal about the shenanigans around eteplirsen, including dubious molecular biology presentations on exon skipping efficiencies and their trial conduct.  It has also struck me, and actually many in the science-minded biotech community and FDA staffers, as wrong how FDA politics in the end overruled FDA staffers in approving eteplirsen.

Aducanumab by Biogen for Alzheimer’s was a similar situation drawing his ire, and although I could never understand how a risk/benefit analysis could favor aducanumab, I am able to see some value in Elevidys.

On the other hand, it would be nice if he would also talk more about what type of pharmaceutical innovations, if any, Prasad is open to.  As a medical hematologist-oncologist, however, I have no doubt that he understands the need for better medicines and that there more than enough people out there advocating for drugs.  Ever been to a big annual medical gathering?  I have been to a few of those and we all know how central pharmaceutical companies are in shaping the agendas. 

Let us be clear: these are big sales shows and unfortunately these are the meetings that Prasad will have attended.  In his new role, I hope he will also attend more patient-centered and sciencey meetings to get a more balanced view of the community and motivation behind drug innovation.

 

Covid19

Vinay Prasad rose to broader prominence during Covid19.  He criticized (mainly on Twitter and Youtube) social distancing measures, masking 2-year olds, indiscriminate vaccine recommendations and the US government showering Pfizer with billions in taxpayer money in the form of vaccine contracts and doing the sales and marketing job for its Covid19 treatment pill PAXLOVID of dubious benefit.

As a father of a daughter who had close to zero risk from Covid19, but had to basically self-teach herself basic language and mathematics skills at home, and then in fourth grade with a mask in school (oh the hot summer), and as somebody who has closely followed the science and politics around covid19 vaccine development, I wholeheartedly agree with his criticism.  Remember when (non-mRNA) Novavax was disadvantaged and delayed at every turn?  Or when it was clear that the risk/benefit would not justify not only giving, but mandating (!) young men to get covid19 boosters, yet many colleges and universities followed ACIP recommendations to do it anyway?

If having been critical of covid19 policies is a problem for the biotech community, then maybe they are indeed ‘woke’ beyond repair.  It is too easy to paint people black or white depending on one’s political views. It is more fruitful to engage in a nuanced, open-minded discussion.  It should be said that Vinay Prasad is beyond the point of emphasizing the value of vaccines, and amply uses them in his practice while considering anti-vaxxers to be weirdos.   

 

Rare disease and ‘gene therapy’

Most of the concern of the gene and cell therapy investor community related to the appointment of Dr Prasad stems him emphasizing the importance of drugs meet clinically meaningful endpoints in randomized controlled trials, not some biomarker endpoint in an uncontrolled trial.  

Clearly, this can be show-stopping criteria in the development of orphan disease drugs and drugs aimed at slow, progressing chronic diseases like Alzheimer’s and a number of metabolic and cardiovascular disorders underlying the ‘chronic health epidemic’.

Fortunately, Dr Prasad seems to acknowledge that this causes a quandary for the rare disease space and has shown openess to the idea of speeding up the approval of ‘gene therapies’ that have shown promise.  For example, in 2021 he noted:

“Uncontrolled data from Israel might be acceptable for an accelerated approval in a rare disease setting with dire outcomes, pending confirmatory study. It is not appropriate for a regulatory decision affecting 50 million healthy people.”

In fact, last year, a small biotech company in the rare disease space, Amylyx Pharmaceuticals, did exactly this: pull a drug for ALS from the market the moment the confirmatory study failed to achieve its goals.  As we know, the real problem with accelerated approvals has been in enforcing that the confirmatory studies get finished in a timely manner.  Fortunately this is being addressed by demanding that a confirmatory trial is underway at the time an accelerated approval is granted.  There is good reason to expect that the current framework can work and bad players like Sarepta (eteplirsen confirmatory trial that never reported results) should frankly be penalized for their conduct.

One concern dug up by those concerned about genome editing and CRISPR were posts on X ridiculing ‘the woke media’ (me paraphrasing here) for celebrating the results by Verve Therapeutics with its 1st generation PCSK9 CRISPR medicine VERVE-101.  This despite of concerning safety signals in a small trial, including cardiac events, liver enzyme elevations, and low platelet counts.  He called for halting the development of VERVE-101 and questioned why people would ever take this 'particular gene therapy’ when pills against the same target exist.

With regard to halting the development of VERVE-101, I had to agree with him.

 

The key question: How Open-Minded is Dr Prasad?

The fact that Dr Prasad repeatedly called genome editing drugs ‘gene therapy’ and did not point out that the short-term tox signals seen with VERVE-101 had to do with drug delivery and not the long-term effect of genome (here base) editing, strongly indicate that he is not a genome editing expert.  It is also important to recognize that Prasad's comment was not against gene therapy per se, but directed at this 'particular' one.  

A key question therefore is whether Dr Prasad is open-minded enough to take advantage of having immediate access to the world’s experts on all types of medical specialties and technologies and adjust his views accordingly.  They would not only tell him about the delivery problem with VERVE-101, but also that many CRISPR genome editing candidates are amongst the safest drugs from a genotox point of view in the universe of drug development.  No ‘swelling up’ of side effects over time, but cleansing, healing genetics.

I would love to hear from him in the coming months about what he thinks of the fact that Verve not only paused (voluntarily, not by mandate) the development of VERVE-101, but has since come up with VERVE-102 based on excellent science and impressive clinical results.  This is how drug development is supposed to work and he should be excited by that.

Or what does he make of the observation that while bluebird's 'gene therapy' was associated with cancer based on lentiviral vector integration, CRISPR Therapeutics' Casgevy has so far escaped that?

Also, if he or his buddies (for example his boss at the FDA Makary and his love for life-long hormone replacement therapy for women starting with menopause) believe that people will stick to taking daily pills starting in their 30s and 40s until death, so be it and good luck with that.  

I would take the opposite view that a one-time, early genome editing intervention would lead to much better outcomes if the target is chosen wisely.  So will Prasad, Makary and all those others in the new administration who are pro-choice in medicine use his powers at the FDA to prevent a potentially revolutionary drug and technology from coming to the market, instead of having patients and docs decide about its adoption?  That would be ironic indeed for pro-choice libertarians and deprive the fight against the chronic disease epidemic in the US an invaluable tool in the form of genome editing.

Investors do not like uncertainty and biotech is no different.  We are all holding our breath for when Vinay Prasad will provide a first insight into how he would change CBER processes to align with his view of evidence-based, patient outcome-focused drug approval without depriving patients of new promising treatments they are in dire need of.  My hope is that it will reflect his recognition of the great responsibility laid upon him and show a willingness to listen to and learn from the interaction with all stakeholders, including the top experts he will be exposed day in, day out.

I must say that Dr Prasad strikes me as somebody who is willing to look at the evidence and listen. Biotech companies who embrace good science and aim at truly changing the lives of patients for the better should not be afraid of the leadership change.  In the end, healthcare dollars are limited and should go to those that provide the most value, also in terms of pushing the boundaries of medicine, and not to those trying to game the system by keeping ineffective drugs on the market indefinitely or by preventing generic competition through monopolistic practices.

Update (9 May, 2025)

Subsequent to this entry, the FDA posted an ad hoc conversation with FDA commissioner Makary and CBER Director Prasad.  Clearly, the tumultuous reaction to Prasad's appointments, also in the gene and cell therapy stock market, forced their hand to be more transparent.  Congrats and thank you for coming out like that to the public and not just some select audiences.

In comments consistent with remarks made in a first address to FDA staffers by Prasad the day before, Prasad emphasized that he does not intend to be disruptive and continue CBER policy of being flexible depending on need, severity, and size of a patient population.  Change will largely be 'at the edges' of current operations.  'Nuance' and 'open-mindedness' are also terms that were repeatedly used in these dialogues.   

Importantly, Prasad reiterated his belief in the importance of vaccines and that he was amply using them also in the care post allogeneic transplantation.  This familiarity with blood stem cell transplantation is also positive for CRISPR-based HSC approaches like Casgevy which do away with the need for burdensome post-transplant immune suppression. 

nuance, open minded

CRISPR Therapeutics Provides First ANGPTL3 Data

Good morning, biotech.

Yesterday, regulatory uncertainty hit fever pitch with the appointment of Dr. Vinay Prasad to head the CBER division regulating biologics, including gene therapies and genome editing at the FDA.  Instead of assuming the worst for this line of drug development, I remain a firm believer that those that matter most, very sick people, will continue to push for medicines that can be shown to be safe and effective, and that Dr Prasad keeps to his view that the FDA should not make it harder, and therefore more costly, to develop drugs for severe rare diseases which have shown promise.

With that out of the way, let’s dive into the first data snapshot provided by CRISPR Therapeutics on its first-in-human trial with CTX310 (Cas9 knockout of ANGPTL3) for disorders related to high lipds, especially triglycerides and LDL cholesterol.

 

ANGPTL3 as a genetically and pharmacologically validated target

There is strong genetic evidence that reduced ANGPTL3 activity is associated with cardiovascular benefit.  A (life-long) 50% reduction in ANGPTL3 due to heterozygous loss-of-function variants cuts the odds of developing cardiac artery disease by almost half (Dewey et al,2017).  These subjects have modestly lower triglyceride (-27%) and LDL-cholesterol (-9%) levels.

Pharmacologic inhibition is even more impactful.  The ANGPTL3-targeting monoclonal antibody evinacumab from Regeneron for example lowers TG by about -80% in hypertriglyeridemia patients (Ahmad et al, 2019).  RNAi knockdown with ARO-ANGPTL3 from Arrowhead Pharmaceuticals with an ANGPTL3 knockdown efficiency of ~-70% resulted in approximately -60% TG, -60% remnant cholesterol (known ASCVD risk factor), and a modest -10% LDL-cholesterol reduction in mixed hyperlipidemia patients (Rosenson et al, 2024).

It should be noted, however, that besides an approval in very rare homozygous familial hypercholesterolemia, approval and development in other indications has somewhat stalled with ANGPTL3 inhibitors/knockdown agents.  Indeed, a study with evinacumab in multifactorial severe hypertriglyceridemia subjects failed to show statistically significant triglyceride lowering (Rosenson et al 2023)!  This and the fact that outcomes studies using non-genome editing modalities are lacking, makes ANGPTL3 potentially the most difficult cardiovascular disease target to bring to a large patient populations among the PCSK9, Lpa, and ANGPTL3 trifecta.

 

CTX310 shows steep dose response…and a surprise

CTX310 is an LNP formulation comprising an mRNA encoding Cas9 nuclease and a guide RNA aimed at the angiopoietin-like 3 gene.  Although the company wants to develop CTX310 for homozygous familial hypercholesterolemia which is characterized by LDL-receptor deficiency, the same receptor that standard LNPs rely on for uptake in hepatocyte, I assume that CTX310 does not include ASGPR-targeting via the addition of GalNAc ligands.

CTX310 was tested at 4 doses. It should be added here that the company provided doses on the ‘basis of lean body weight’ probably in the hope that it may in fact be a better predictor of drug delivery to the liver compared to dosing based on pure body weight or fixed doses.

Anyway, the 2 lowest doses (0.1 and 0.3mg/kg) showed no desired pharmacodynamic effect.  In fact, mean LDL-cholesterol strangely increased from baseline by 35% just 30 days after drug administration (n=3).  At 0.6mg/kg (n=3) and 0.8mg/kg (n=1; ~0.48mg/kg not adjusted for lean muscle), however, there was knockdown of serum ANGPTL3 of ‘up to -75%’ with concomitant decreases of TGs and LDLc of -56% and - 29%, respectively, at 0.6mg/kg.  At 0.8mg/kg the company reported a remarkable -65% LDL-cholesterol reduction on day 30 reaching a whopping -80% on day 90 in a patient with severe hypertriglyceridemia (TG>500mg/dL).  Triglycerides were also lowered by over -80% in this subject.

Safety findings, particular in terms of changes in liver enzymes and platelets, were characterized as 'not clinically significant', and clearly need further disclosure.  

Also because of its likely non-ASGPR-targeting nature, severe hypertriglyceridemia should be the most promising indication for CTX310, for example to prevent pancreatitis. The LDL cholesterol effects, however, warrant further investigation and may justify development for ASCVD.  Given that this was seen in just one subject, the 0.1 and 0.3mg/kg LDL-cholesterol increases in LDLc indicating there may be something odd with the assay, and that it is in great contrast to the genetic and pharmacodynamic evidence presented above, further subjects dosed at 0.8mg/kg may not show such dramatic effects.  If the values are real, however, and given the near opposite findings with evinacumab in severe hypertriglyceridemia, a closer look at the genetics of this subject may lead to fresh insights into lipid biology and render ANGPTL3 a more predictable target.