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
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