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

Happy Gene Therapy Talk Presaged Market Correction

In January, many biotech stocks went parabolic shattering all-time-highs.  Now they have started crashing back down to earth.

The run-up was partly driven by real fundamentals.  These include corporate tax reform in the US, a new FDA commissioner (Scott Gottlieb) who makes all the right decisions (speeding access to innovative medicines, fostering generic competition, amenable to rational discussion etc), and a voracious appetite for innovative pipelines in the pharmaceutical industry which has manifested itself in a number of chunky, multibillion dollar acquisitions. 

At the same time, ever-increasing valuations in a deceptively low-volatility stock market environment has emboldened analysts, investors, and managements alike to proclaim that the golden era of curative medicines is upon us.  Gene therapy and genome editing in particular got hyped beyond reason as if all of a sudden critical bottlenecks in tech development had been solved.  CRISPR companies Editas Medicines and CRISPR Therapeutics, without a single drug candidate in the clinic, were bid up to $2B valuations although access to genome editing tools have become a commodity and cannot be considered gate-keeping tech any more.

Not much changed technology-wise

I understand that gene therapies have made tremendous inroads into the pharmaceutical marketplace with the first 3 gene therapy approvals in the US over the last year, one for an eye disease by Spark Therapeutics and two CAR-T cell cancer therapies going after the same target.

While I acknowledge these successes, what is really surprising here is that it took that long to get there given that the related delivery and genetic technologies (AAV, gene insertion, immune cell transfer) have been in existence for a decade or two already.  In that light, the recent Happy Talk around gene therapy seemed overdone.

The CEO of one genome editing company, Sangamo Therapeutics, is a great example of this divergence between scientific progress and clinical reality.  

Having come on board only a year ago, the good Dr. Macrae looks as if he is having a steep learning curve ahead of himself.  The reason I got the impression is that he likes to grandiosely talk about how the company's AAV capsid shuffling will enable them to cure all these CNS disorders while making great progress with LNPs to address the rest of humanity's afflictions.

Well, LNPs have gotten 10x more potent every year for the last 15 years so we must have reached homeopathic doses by now; and looking at the literature, AAV shuffling hasn't changed all that much since I completed my post-doc in an AAV lab in Stanford.  Or maybe Jim Wilson has grown exceedingly gun-shy when he resigns from his well-paying function at AAV company Solid Biosciences over concerns of toxicity from high systemic AAV doses and possibly also his finding that delivery to a certain tissue in the mouse does not predict same delivery in humans.

Certainly, there are also tailwinds supporting gene therapy that had not been around a decade ago.  As alluded to above, society and regulators have finally warmed up to a very sensible approach to medicines in the genomic era.  Moreover, there are established paths now to effectively develop such therapies and the challenge of producing large quantities of viral vectors is gradually being addressed.

Still, amid the hype and stock market giddiness, valuations in many of these companies have run ahead of themselves and were ripe for a pull-back.

Next time you hear so much Happy Talk around a biotech subsector leader as has been the case for gene therapy, watch out for a correction.   

What about RNAi stocks?

RNAi stocks have also benefited from the overall bullishness in the biotech sector with ARWR and DRNA having run up by 300% or so in a matter of months.  While I still hold shares in these companies, I have written calls (largely in-the-money) on essentially all of them meaning that I am fairly insulated should they fall another 10% or so.   

Since I still like ARWR and DRNA ahead of their first clinical GalNAc knockdown data, and in the case of Dicerna the potential removal of the overhang from the Alnylam litigation, I am eyeing (and have been) selling out-of-the money puts on these for 10+% premiums or so.

If the market turns back up, you pocket the premium. 10% or so in a matter of 2 months is not bad in my mind.  If, however, the stocks decline and the puts are in-the-money at expiration, you get handed a stock that you like anyway.  Say Arrowhead for a price of $4.5 instead of $5.45 yesterday.  

But before you place any such options bets, consult with your investment advisor first to familiarize you with the risks of writing options!

On the simple, naked long side, I like Ionis Pharmaceuticals which, as a biotech stock that has essentially missed out on the post-Trump rally and with the upcoming Huntington’s data catalyst, has the potential to become a new biotech bellwether following subsector rotations that usually occur following corrections (remember the 2015 correction following which oligonucleotide stocks turned from sector leaders to laggards?).  Alnylam, meanwhile, looks tired here with a lot of the upside priced in, at least regarding the TTR story.

Happy trading and be mindful.

Mr. Anonymous Thwarted in Zamore US Patent Re-exam

Silence Therapeutics reported that a number of valuable RNAi trigger patents related to the Zamore Design Rules that were issued last year in the US were upheld following a re-examination request by an anonymous 3^rd party. Even stronger claims related to the same Zamore patent series have been issued in Europe, and unsurprisingly Alnylam, but also Novartis and Alcon are opposing them with the outcome to be decided (EP 1633890 B1). However, given the importance of both the US and Europe in the commercialization of innovative drugs, having a patent position in one jurisdiction alone can be considered a valuable strategic asset already.

The Zamore Design Rule patents are owned by the University of Massachusetts and exclusively licensed to Silence Therapeutics for medical uses. As described in more detail in other blog entries before (here and here), they cover methods of promoting the incorporation of the desired guide strand into the RISC gene silencing complex as well as of enhancing RISC turnover resulting in more effective and selective RNAi knockdown.

Especially the patent covering guide strand selectivity methods (‘thermodynamic end-stability rule’; US 7,750,144) is widely recognized in the art for greatly increasing the likelihood of finding efficacious RNAi triggers and is incorporated in essentially all bioinformatic sequence pre-selection algorithms. It has to be said though that the claims do not cover the entire spectrum of approaches of achieving differential end-stability. They do, however, cover chemical and structural approaches that have been reported by a few companies such as Marina Biotech and Sirna/Merck before. Moreover, because the coverage involves modified nucleotides, there will be the concern that even if such modifications were applied for other purposes (e.g. stability or immune abrogation), they may fall under the patents. Consequently, a company with a promising late-stage candidate may want to take a license instead of taking a chance in an infringement lawsuit.

This makes it the second time within a week (see PKN3 opposition by Alnylam) that important patents by Silence Therapeutics were upheld essentially unchanged following challenges. Alnylam’s management once laughed off the value of the Zamore patents in a conference call following their issuance last year. They obviously considered them serious enough to oppose them in Europe and Alnylam is certainly the most likely identity behind Mr. Anonymous (have your say by participating in the survey on the right). Less likely, but not entirely out of the question would be a Big Pharma company like Novartis which is considering taking a license to the Zamore patents, but first wanted to kick the tires before it did so (patents that have been unsuccessfully challenged are considered stronger).

With all these patent successes, and at least one more likely to come, Silence Therapeutics need to monetize their assets in the form of non-dilutive funding.

Hemophilia Gene Therapy Success Bodes well for ddRNAi Therapeutics

Following years of public scorn and derision, including by Alnylam which in 2006 waved off ddRNAi Therapeutics and gene therapy as ‘dangerous’, gene therapy is back with a vengeance. This week, a consortium of researchers reported in the New England Journal of Medicine that an self-complementary AAV8-delivered Factor IX transgene was able to significantly correct hemophilia B in a small clinical trial.

4 out of the 6 patients treated were able to largely discontinue the standard frequent (often 2-3 times a week) and expensive use of prophylactic recombinant FactorIX protein therapy which accounts for estimated healthcare costs north of $20M a lifetime. This means that even in the limited duration of the trial (6-16 months of follow-up), the low cost of the gene therapy ($30k cost of goods for a treatment that is expected to last many years if not a lifetime) meant that this therapy is already saving money (and improving quality of life). If the results can be confirmed in a larger trial and the side-effects, including transient liver enzyme elevations can be controlled with similar efficiency as in this small one, approval may not be that far away.

The hemophilia results also bode well for ddRNAi Therapeutics. First of all, the study has validated the safety and efficacy of delivering the highly promising AAV vector family by peripheral vein infusion to the liver. This represents progress over a previous hemophilia gene therapy study which employed considerably more invasive direct hepatic infusion. In particular, it is likely that, should the ddRNAi collaboration by Tacere/Pfizer for HepC continue, it would involve not only the same vector family (AAV) and target organ (liver), but also the same serotype (AAV8) and self-complementary genome strategy as employed in this hemophilia trial.

Benitec and City of Hope Start RNA-targeted HIV Phase I Clinical Trial

After some delay, Benitec and their collaborators from the City of Hope finally announced that they obtained regulatory approval to start phase I clinical trials for an RNA-based HIV gene therapy antiviral. The delay was caused by Benitec’s uncertain corporate future and difficulties generating sufficient amounts of clinical-grade lentiviral vectors, but scientifically the risk-(potential) benefit profile of these studies are promising.

This is the 8th RNAi clinical program and the second involving DNA-directed shRNAs. The gene therapy agent is a lentiviral vector expressing 3 different RNA molecules, each designed to interfere with a different aspect of HIV replication, each through a distinct mechanism of action. The plan is to immunise CD34+ hematopoietic progenitor cells and thereby all their progenies, including T-cells, with such vectors ex vivo and then re-administer the cells to the patients.

The RNAi portion is a U6-driven hairpin RNA targeting the tat/rev mRNA by RNAi. A nucleolar-localised TAR decoy RNA, also under the direction of a U6 promoter, is designed to mimic the HIV TAR element, thereby diverting TAR-binding factors by mimicry. Finally, a ribozyme against the CCR5 mRNA, a co-receptor for HIV infection, complements the 3-pronged approach. This approach is inspired by the current HAART HIV treatment paradigm where a cocktail of antiretroviral drugs has proven to be highly effective in suppressing HIV replication with only slow development of drug resistance.

In fact, the RNA-based vector which has been shown in tissue-culture experiments to be considerably active in inhibiting HIV replication may be synergistic with present therapies due to their unique mechanism of action, although non RNA-based anti-CCR5 treatments are currently developed by other companies as well. While Benitec used to pursue a triple RNAi approach for the treatment of HCV (a program now owned by Tacere), the present strategy may be advantageous since it is known that co-transcribed shRNAs or co-transfected siRNAs may compete with each other for cellular RNAi factors.

Ultimately, I expect that long-term expression of ideally all 3 RNAs will be important to confer a survival advantage onto the lentivirally transduced CD34+-derived cells. However, even if expression should be silenced eventually, the treatment is likely to give AIDS patients some reprieve. The study population will be 5 AIDS-related leukaemia patients from which CD34+ will be enriched from blood by apheresis, genetically modified, and then returned to the donor patient.

Given that this is a gene therapy with a vector that hasn’t been used in the clinic before, it is expected that this therapy will be used in AIDS/Lymphoma patients who are no more responsive to conventional treatments. Nevertheless, expect to hear results from this promising phase I trial within a year.

What’s the Problem with DNA-directed RNAi?

I apologise for having been somewhat quiet recently on the blog. It is not that I lost my belief in RNAi Therapeutics, quite the opposite actually. RNAi has already been shown in hundreds of research labs to be a gift of biology (or God, as one famous biologist, whom I shall leave here anonymous, once noted), and it is now up to many of us individuals and organisations to carefully uncover its therapeutic potential.

One area where progress has been slow is DNA-directed RNAi (ddRNAi). Except for Nucleonics’ Hepatitis B Virus RNAi program, all other clinical studies currently make use of synthetic small interfering RNAs (siRNAs) for therapeutic gene knockdown. While I agree that siRNAs have many advantages over ddRNAi for many applications applications, ddRNAi may be in principle superior to siRNAs e.g. where durable gene knockdown is desirable or where viral delivery methods may get to more efficiently than formulated siRNAs. One can agree that it is an interesting concept to immunise the immune system against HIV by giving the patient stem cells that generate T-cells expressing shRNAs directed against HIV (actually such a trial is imminent at the City of Hope). Why has progress been so slow? ddRNAi-based companies have had great difficulties in attracting funding. Benitec, arguably one of the early contenders to be the darling of ddRNAi, eventually ran out of money, had to cut down most of their development programs and went back to Australia to wait for something good to happen. Instead of focusing on research and investor relations, money was spent on lawyers in early patent battles about rights to ddRNAi. It is interesting that while patent issues are being talked about in the siRNA space, full-blown legal battles about the core siRNA patents have been the exception. It is expected that these will be sorted out at later stages through cross-licensing and royalty agreements, closer to the approval of the first siRNA-based drugs. Makes sense. Another problem is that ddRNAi carries the stigma of being a traditional gene therapy with all the historical ballast of immunogenicity and cancer through insertional mutagenesis.

So how could ddRNAi stage a comeback? One way might be to consolidate the IP in one company and remodel it as a champion of ddRNAi, similar to what Alnylam is for siRNA Therapeutics. This would make investors feel confident that their company has the freedom to operate and attract funding and clinical support through collaborations. This also requires credible management that has access to key decision makers in big biopharmaceutical companies. Failure to do so would not only put the technology at risk of ever being fully developed, but also rob patients of important treatment options.