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

Proposing Complement C3 RNAi for Treating COVID19

Whereas my last blog considered lung-targeted RNAi for addressing COVID19, this entry will look at what a liver-directed RNAi approach could do for the disease.  It is in the liver that RNAi Therapeutics have proven to be extremely potent.  Moreover, it is amenable to subcutaneous administration and therefore appropriate for the current pandemic.

It has quickly become apparent that in a subgroup of patients COVID19 is associated with liver complications.  Managing these with gene silencing of resident liver proteins may be possible in theory and could be contemplated.  More interesting, however, would be intervening upstream of the liver in the respiratory tract.  

It is reported that it is an overactive (innate) immune system rather than cellular damage (cytopathic) by the virus itself that can cause the virus to be fatal.

And when it comes to an immune approach with RNAi at the moment, the complement pathway, many components of which are predominantly expressed by the liver and secreted into circulation comes to mind.

Interestingly, a relatively recent paper (Gralinski et al, 2018) in a mouse model of SARS-CoV-2-related SARS has shown that genetic complement C3 knockout lessened lung damage and overall health as measured by body weight.  This was associated with a reduced influx of neutrophils which are the carpet-bombers of the immune system.

The next question to be asked is that since RNAi gene silencing is not instantaneous but takes time to manifest, whether such intervention would be timely enough in a given patient.  For this, my assessment is that it should be possible based on the pharmacodynamics of a C3 RNAi in development by Silence Therapeutics (SLN500) and Mallinckrodt IF the disease can be diagnosed in time.

Accordingly, it took about 4 days for robust C3 silencing in mice which compares to the about 7-10 days it takes for SARS-CoV-2 to move from the upper respiratory tract (as manifested e.g. by throat pain) to the lower lungs where the critical battleground is.

These are extraordinary times and I believe this approach should be considered.  Besides Silence Therapeutics and Mallinckrodt, Alnylam, and Dicerna (in partnership with Alexion) are also working on RNAi for the complement system.  A monoclonal antibody approach may also be envisioned and could have advantage of a faster onset of action, but may lag in development timelines.

RNAi Therapeutics and mRNA Vaccines for COVID19

This is a time where the biotech industry has to mobilize resources to mitigate the impact of pandemic SARS-CoV-2. 

Nucleic acid-based therapeutics are prime candidates in this battle because of the speed with which drug candidates can be designed and their specificity.  This blog provides an overview of efforts in this area with an emphasis on my two favorite (and IMO most promising) nucleic acid approaches: RNAi Therapeutics and mRNA vaccines.

RNAi Therapeutics

RNAi Therapeutics (and by extension the competing antisense, ASO approach), knocking down genes for therapy, can be used in two ways to address the current pandemic.

First, the RNAi triggers could target the virus itself in an existing infection.  The hope would be that by doing so the damage, mainly lung inflammation leading to respiratory distress, can be mitigated sufficiently for the patient’s immune system to gain time and strength to successfully overcome the infection.  The question then would be how early would be early enough.

The second approach would be to target a host factor critical for viral replication.  The cellular entry receptor ACE2 is the most promising candidate target gene here.  This strategy seems particularly promising for prophylactically protecting those at high-risk of an infection, e.g. medical personnel, as protection may last for a month or so based on the very long durations of efficacy seen in human studies targeting genes in the liver and early studies in the lungs of sheep.

Application in a prophylactic setting would probably have the added delivery advantage in that the lung would be less congested and thus more accessible.  Also, delivery may not have to reach so deep into the lung as it would need to during later stages.   

Delivery

Theory is one thing, but getting the RNAi triggers to where they are needed in the body is and has always been the main challenge for RNAi Therapeutics.  Unlike targeting genes in the liver which is now well-established, RNAi in the lung is a re-emerging area of RNAi development.

Given that COVID19 is a respiratory illness where the virus intrudes the body via the respiratory epithelium, a local, inhaled delivery approach should be adequate and also happens to be the most promising route for RNAi Therapeutics in addressing pulmonary disease.

In the early days of RNAi Therapeutics development, the world was facing the SARS outbreak. Seemingly attesting to the promise of speed and specificity against emerging pathogens, Sirnaomics (based in both the US and China) soon published a high-profile paper on the efficacy of RNAi in a monkey model of SARS coronavirus.  

In hindsight and with the benefit of 15 more years of RNAi Therapeutics development up-and-downs, however, these results were probably based on innate immunostimulatory artefacts given the use of unmodified Tuschl-type RNAi triggers and a nasal instillation route of administration making employing sugar water as a carrier.

Today, however, RNAi Therapeutics is much more advanced and an approach that utilizes aerosolized highly modified and thus stabilized RNAi triggers seems most appropriate. 

Arrowhead Pharmaceuticals has emerged as the front-runner in lung RNAi and is close to filing for clinical study approval for addressing cystic fibrosis.  Their approach combines the two most promising elements of today’s RNAi Therapeutics.  In addition to RNAi trigger stabilization, Arrowhead is adding targeting ligands to their agents, in this case small moieties targeting integrin on lung epithelial cells.

While Arrowhead has not announced their entry into the COVID19 race, Sirnaomics and Alnylam Pharmaceuticals (along with partnered Vir Biotechnology) have.  While it is unclear what particular approach Sirnaomics is using 15 years after their SARS work, Alnylam will be using highly modified RNAi triggers.  Whether targeting ligands will be utilized or not is unknown to me (update: the press release refers to 'conjugates of siRNA' so a targeting ligand is likely). 

Of note, Alnylam had suffered an anti-viral innate immunostimulatory fiasco with their first commercial RNAi development program around the same time that Sirnamoics was working on SARS.  That program was for the respiratory syncytial virus (RSV) and Alnylam should be able to capitalize on the the lung RNAi development experience back then.

Other RNAi-related companies with experience in inhaled lung delivery are miRNA Therapeutics company Miragen (miRNAs are structurally quite similar to RNAi triggers), Genevant/Arbutus (descendants of Tekmira which became famous for their Ebola efforts), and Arcturus Therapeutics.

mRNA vaccines

Arcturus Therapeutics and Genevant are now focused on developing messenger RNA (mRNA) therapeutics and vaccines, including for lung disease cystic fibrosis.  The most known name in this area is Moderna Therapeutics which has a high-profile, government-sponsored vaccine effort against SARS-CoV-2.  Ultimately, it is vaccines that will allow the world to fully recover from the COVID19 scare while therapeutics should be used in a much more focused manner.

The delivery challenge for vaccines is also lessened by the fact that it is a gain-of-function approach and that the immune system itself is expert at spotting foreign, in this case viral antigen expression.  The challenge here is that this is has to be achieved in the right immunological context so that a fruitful immune response is formed.  

The fact that Moderna were the first to ship mRNA for imminent trials shows how easy it is for mRNA to go from viral sequence to product candidate and drug material production.  While I used to poke fun at Moderna for building factories and installing robots without having much science behind it to fill the production halls, for emerging biothreats like SARS-CoV-2 this has proven to be prescient.

CureVac, an mRNA competitor of Moderna, has also announced their entree into COVID19.  While they may lag behind Moderna in terms of robotics and manufacturing capacity, they should be more expert in vaccine development (‘a little innate immune stimulation by the mRNA agent itself may go a long way’).

The most intriguing and differentiated entrant in the mRNA vaccine area to me, however, is Arcturus Therapeutics (disclosure: no stock position, but considering taking one) to me.  This is because they are using a self-replicating RNA ('STARR') that they claim to require ~40-fold less RNA to be intramuscularly injected. Formulation into an LNP 'LUNAR' particle may further lower the required dose.  Given that vaccinating the world will in the end also be a manufacturing challenge, being able to start with 40-times or thereabouts less material is a serious practical advantage.

COVID19 shall pass and therapeutics and vaccines will play an important role here.  Even more important, however, is that everybody does their part in minimizing and slowing the spread of the virus ('flatten the curve', #SocialDistancing), particularly to protect those most at risk without having to resort to draconian measures.