CRISPR Stocks in Wake of Verve Therapeutics Acquisition by Eli Lilly

 

Last night, news broke that pharma giant Eli Lilly was in talks to acquire Verve Therapeutics.  After a 3-year lull in major CRISPR dealmaking following the Covid bubble, this brings the space the Big Pharma validation that genome editing is not a crazy fantasy, but a core modality of future drug innovation. To my surprise, even hardcore biotech investors had been waiting for such validation before considering the space investable. 

Needless to say, the news will trigger pin action in other CRISPR stocks.  In this blog post, also based on a similar experience I had in the RNAi space about 10 years ago, I will lay out how I see it play out,  

Verve acquisition is a steal

As you will remember, Verve is developing an exciting one-time PCSK9 base editing treatment, VERVE-102, that could transform LDL-cholesterol-driven atherosclerotic cardiovascular disease (ASCVD).  According to the rumors in the Financial Times the proposed acquisition price is ~$1.3B.  This would be a bargain considering the potential of VERVE-102. 

Even with the current small available safety dataset, it is hard for me not to see VERVE-102 as a highly compelling option for the 1-2 million heterozygous familial hypercholesterolemia (heFH) population in the US and Europe alone.  Slap on that a $100,000 treatment price, this alone has Glp1-type market dimensions.

Under normal market conditions, such a steal would not be possible.  But these have been anything but normal biotech investment times. I believe that more than the nice short-term financial reward of an acquisition, Verve management is doing here what is best for VERVE-102 reaching its maximal potential.  Ultimately, it takes the financial resources, experience, and credibility of a pharma giant to develop and commercialize such a revolutionary treatment to such a big market.  

Who is next?

But luckily for investors, Verve Therapeutics has not been the only severely undervalued CRISPR company.  When Alnylam started to gain tremendous traction in 2012-3 after demonstrating that you can make RNAi gene silencing work in humans, still working as a consultant to companies and investors back then, I noticed how funds started to dig into who could be the next Alnylam to invest in.

So on the back of very strong recent clinical data in the space (VERVE-102, NTLA-2001/2, BEAM-302) and now the Big Pharma validation, I expect the same dynamic to unfold here.

Intellia Therapeutics

The first obvious company to benefit from fund inflow should be Intellia Therapeutics.  Verve Therapeutics will be acquired mostly for a therapeutic candidate that has shown promise in the clinic. Intellia therefore with not just one, but three clinically validated market opportunities (ATTR-CM, ATTR-PN, HAE) and a reasonably large market cap of around $900M and good trading liquidity for funds to take needle-moving positions in, will come first on the radar.

What is more, almost the entire market cap can be accounted for by its cash position and the stock has come down from a high of around $200 4 years ago to $9.  The main reservation by the investor community has been that patients will prefer a daily pill over a futuristic-sounding lifetime treatment, if not cure.  I guess they were wrong.  Not only is Eli Lilly’s proposed acquisition a vote of confidence in CRISPR modality, but the KOLs in the ATTR and HAE field are already fully on board.

Beam Therapeutics

Beam with a market cap about 2x of Intellia’s will also come into investor focus.  While I do have a small position in that company, it is by far not as big as the one I have in Intellia.

This is because I consider uncertainties around its two lead candidates, for sickle cell disease (SCD) and alpha-1-antitrypsin disease (AATD), to be higher than for Intellia’s opportunities.  Their sickle cell disease base editing should be superior to that of already approved Casgevy by Crispr Therapeutics and Vertex Pharmaceuticals. 

But will that be enough for the ex vivo autologous hematopoietic stem cell approach to gain quicker commercial traction than Casgevy?  With regard to BEAM-302 for AATD, I am still waiting for more clarity on the liver safety of their (non-GalNAc) LNP.  It was the new safety standard set by VERVE-102 (GalNAc-targeted and ‘Novartis ionizable lipid’) that makes VERVE-102 a viable therapeutic in the first place.

Prime Medicine

Having just cured p47phox variant chronic granulomatousdisease (CGD) which could entail a valuable priority review voucher, Prime Medicine is now focusing on the relatively large severe genetic liver disease opportunities of Wilson’s Disease and AATD.

While not as clinically advanced as Beam Therapeutics, Prime Medicine has the benefit of learning from the LNP safety of the Intellia, Beam, and Verve programs.  I therefore expect them to bring forward a lower-risk GalNAc-enabled LNP similar to Verve’s when it enters the clinic next year.

From a platform point of view, prime editing is the future of CRISPR medicine due to its versatility and exquisite on-target specificity.  Prime Medicine with a dominant IP position in prime editing, a market cap of $200M, much of which in cash, is therefore a prime candidate for a Big Biotech/Pharma looking to make use of that technology for its in-house targets.

Metagenomi

Going nowhere in its clinical pipeline, but generating new, especially smaller CRISPR editors that could have delivery and immunologic advantages, is Metagenomi.  Its lead candidate is a CRISPR-enabled gene drop-in approach for hemophilia A (MGX-001) which it hopes to bring into the clinic in 2026.

While I consider Metagenomi’s gene drop-in data to be industry-leading, there are questions around its safety profile since it will involve not only LNP, but also AAV for systemic delivery.  So while MGX-001 could be the first ‘gene therapy’ for hemophilia with sustained transgene expression, Metagenomi’s valuation will unlikely get recognition for it until actual clinical data.

The main reason why Metagenomi is interesting here is that it is not only trading 70% below cash ($55M market cap, $200M cash), but that it has an important partnership with Ionis Pharmaceuticals which could view CRISPR as an increasingly important mechanism to shore up its commercial ambitions in ASO-led franchises such as ATTR, HAE, and cardiovascular disease.

If I were Ionis Pharmaceuticals, I would just buy Metagenomi for $200M, retire preclinical MGX-001 for little cost and thus get rid of my future milestone and royalty obligations.  Of course, Ionis may prefer Prime Medicine for its more versatile technology.

Buying a platform-only company in this biotech tape is certainly not for the faint of heart and large funds will shy away from Metagenomic at least initially due to its small size and illiquidity.  I can see it, however, emerge as an attractive second-wave opportunity should interest in CRISPR stocks be sustained enough.  As a backstop, you still have Ionis Pharmaceuticals having to make a decision on investing further into Metagenomi later this year.

You may ask yourself why I have not mentioned the biggest CRISPR company by market cap, $3.6B CRISPR Therapeutics.  This is because of initially overoptimistic expectation for Casgevy sales and with their recent RNAi deal spreading themselves out too thinly and losing their cutting edge so early in the game.  I would also like to see them disclose the liver safety before attributing value to their first generation Cas9 nuclease-based cardiovascular CRISPR franchise.

 

Disclosure: Verve Therapeutics became my largest portfolio position after they disclosed VERVE-102 data two months ago.  While smaller than my positions in Huntington’s disease gene therapy company uniQure and RNA editing company ProQR, Prime Medicine and Intellia Therapeutics are not far behind and very meaningful positions with close to 10% portfolio weightings.

This is not financial advice.  It is intended for those interested in contemplating the stock market repercussions of the rumored Verve Therapeutics acquisition.  Buying a stock is the simple part, successfully trading it for profit much more difficult. 

NTLA-2002 More and More Looks Like a Cure for HAE

When Intellia Therapeutics set out to develop a CRISPR-based prekallikrein knockout for hereditary angioedema (HAE), it was as a compelling alternative to the newer prophylactic treatments. Cas9 nucleause-based NTLA-2002 (aka lonvo-z) was aimed at having similar efficacy and safety/tolerability, but with the added significant benefits of liberating patients from repeated injections, from having to worry about continued drug reimbursement, all while saving the healthcare system money and resources.

All this is changing as the company is presenting longer-term data strongly suggesting that NTLA-2002 could be a life-time functional cure for many, if not most people living with HAE.

Today, at the EAACI Annual Meeting, Intellia showed that there have been no more HAE attacks since the last update a year ago.  All 10 subjects in this now open-label extension trial have now been attack-free for at least 15 months with a median of almost 2 years.  These 10 patients would have conservatively had around 500 attacks based on their disease history.

500 versus zero, nothing short of a revolution in the management of HAE.  Importantly, with 9 of the 10 subjects having reached 20-30 months after dosing, no drug-related adverse event has been documented after day 28 following NTLA-2002 infusion.

As the data gets better over time, it looks like tonic PKK reduction below a certain threshold may normalize the bradykinin system und put a brake on a neurogenic attack feedback loop.  We know that attacks are frequently triggered by mental and hormonal stress.  In turn, attacks can increase anxiety.  It now looks similar to chronic itch that once the feedback loop is interrupted (HAE attack and scratching) there is a real chance of sustained outcomes.  That this is possible is also illustrated by the fact that people with C1 Inhibitor mutations (the causal mutation in HAE) often do not have any attacks before puberty.

Today’s development illustrates that CRISPR genome editing going after the same targets as competitive modalities can lead to superior outcomes and actually free people from disease instead of keeping them dependent on medicines.  Needless to say, patients are queuing up for the treatment and the pivotal phase 3 trial has been fully enrolled- well ahead of schedule.

MAHA Vows to Disrupt Sick-Care Model in Favor of Cures

There is now overwhelming evidence that the new US healthcare administration is serious in its mission of making its citizens inherently healthier by putting more emphasis on disease prevention and actual cures to move away from the current sick-care system of chronically medicating sick people.  Importantly, CMS Administrator Dr. Oz who wields outsized influence on how healthcare dollars are spent is working on adjusting financial incentives to make developing cures a viable business model.

False alarm

When RFK Jr was appointed HHS Secretary under Donald Trump, alarm bells went off in the healthcare industry driven by a  concern that this could spell the end of evidence-based medicine.  This was largely because of his natural bent towards seeing conspiracies and skepticism of the pharmaceutical industry that became radicalized following some government overreaches during Covid19.  Although proposed 40% NIH budget cuts could turn out to be an instance of unfortunate politicization of health research, concerns scientific evidence will be generally replaced with arbitrary political views as the guiding principle in shaping healthcare turn out to be misplaced.  This is due in large part of RFK having surrounded himself with well-intentioned people of reason who want to better the health of the American people and beyond.

This could also be genome editing’s moment.

FDA cell and gene therapy roundtable

There has never been a more transparent FDA.  Even the politically charged waters of Covid19 vaccine regulation were elegantly navigated through communication and eventually approving vaccines from both Novavax (protein) and Moderna (mRNA) with some limitations as to who can access it and a randomized trial obligation for Moderna’s novel bipartite mRNA design.  Who knows, at the end of this, confidence and use of vaccines may actually increase with this slightly more restrictive stance as opposed to their rapid decline under a much looser regulatory regime before.

The transparency drive is paired with listening to patients, physicians, scientists, and industry to inform their initiatives.  Last week’s cell and gene therapy session organized by Vinay Prasad’s CBER was a major event in that regard and offered the intriguing insight that genome editing is shaping up to be exemplary of what MAHA movement wants to achieve.

CRISPR lovefest

The event was attended by those wielding major power in the US healthcare and drug development system, with HHS Secretary Kennedy, CMS Administrator Dr. Oz, NIH Director Bhattacharya, FDA commissioner Makary and CBER chief Prasad all in attendance.  The speaker line-up featuring widely respected top scientists and patient advocates underlined that this event was not abusive political theater, but directed at making true progress in healthcare.

The CRISPR base editing for the child with a rare urea cycle disorder became the posterchild of how the new FDA wants to facilitate speedy, patient-oriented, common sense drug development- in this case, as the child is now at home, arguably a cure at that.  It is based on having a plausible mechanism, general platform knowledge (LNP-mRNA CRISPR for the liver), and the right to try.  Top genome editing scientists Dr. Liu and Dr. Urnov highlighted that other CRISPR therapeutics, including first curative prime editing in humans, have showcased the transformational nature of this technology. 

Daily pills not a panacea

Like many who try to live a healthy life by eating well and exercising- whatever this may mean to them-, RFK Jr looks at pills as toxic chemical compounds, placed next to oil-based food colorings on the chemical shelf.  I hope that this view will be mollified as he, as the head of HHS, will inevitably learn more about modern drug development and regulation and the people who conduct it. 

We also know that such views can have tragic consequences for example when a person that is at high risk of stroke does not take blood thinners and eats blood-thinning food instead or when a person insists on beating an aggressive cancer by healthy living alone.

In any case, taking daily pills for him is to keep patients sick and a recurring revenue opportunity for pharmaceutical companies.  According to RFK, they did not exist in the 60s and are now pervasive and keep people ‘barely functional’.

To be clear, I like a ‘daily pill’ if there are no good alternatives, but as we know from the cardiovascular and ocular disease space as examples, this can be not only burdensome financially, strain healthcare resources and impact quality of life (e.g. monthly intraocular injections), and still lead to suboptimal outcomes as many patients ultimately fail to adhere to their treatments.

Righting incentives in favor of cures

So why on earth have investors steered clear of genome editing and gene therapy despite of these technologies having resulted in the major recent pharmaceutical breakthroughs (urea cycle base editing, Intellia’s emerging NTLA-2001 long-term ATTR outcomes, prime editing cures for CGD, Beam Therapeutics’ base editing for AATD)?  The insanity has degenerated to the point where on platforms like X it has become the mainstream believe among biotech influencers that taking daily pills was preferable to actually curing people and preventing disease when there is a choice.

And why is it even a discussion if paying $2M for a life-time cure is more expensive than spending $200,000-500,000 annually for decades?

Take for example hereditary angioedema where the current best treatment paradigm involves start taking the highly effective and well tolerated drugs in the 20s until basically the end of life.  While a godsent compared to old ineffective treatments that came with a high side effect burden und moderate efficacy, the fact that this orphan disease of maybe 10000 patients in the US and Europe is attracting a dozen or so drug developers is due to these treatments commanding around $500,000 annually.  So when an equally effective and safe one-time CRISPR treatment in the form of NTLA-2002 by Intellia Therapeutics comes to market, the $2.5M price that I project it will cost should amortize very quickly and pulverize the HAE prophylactic drug market.  Let alone the quality of life benefit of essentially curing a good fraction of patients and letting them forget about their disease, including not having to worry about drug access in an increasingly uncertain world  (longer-term data for NTLA-2002 coming up in a week).

The billions saved annually through this marketplace disruption could be spent on other innovative treatments for other diseases.

Or take VERVE-102 as an example of using genome editing for disease prevention.  I expect this one-time medicine to initially cost around $100,000 in return for essentially eliminating the risk of dying or being sick due to LDL-cholesterol driven cardiovascular disease.  As I grow older (48 years) I am increasingly aware that my LDLc of 150mg/dL means that heart attack or stroke are my most likely causes of death and that over the next 5-10 years I need to get real serious about addressing it, ideally in the form of a one-time PCSK9 gene edit and then get on with life.  This assumes that VERVE-102’s acute liver safety profile is holding up.

The frequently hostile and belittling views of gene therapies and genome editing can be explained by the many perverse incentives of healthcare systems where physicians and hospitals make money from buy-and-bill medicines that are regularly administered in the office, co-pay systems that depend on who, how, and where a drug is administered, and where insurers and PBMs make money from a convoluted maze of discounts, drug bundling and who knows what other tactics.  And following the healthcare situation in Germany, politicians could not care less about cost implications beyond their 4-year terms. 

CMS Administrator suggests socialization of costs

At the end of the day, CMS Administrator Dr Oz agrees that it is unacceptable to deny $2M for a CRISPR genome editing cure for sickle cell disease when $4 trillion are being spent annually in the US healthcare system.  Insurance companies and PBMs partly hinder access because they can only think out 1-2 years into the future instead of considering the overall healthcare benefits.

Dr. Oz suggested at the roundtable that in this situation a reinsurance scheme could be the solution as it would socialize and thus buffer the unevenly distributed, chunky payments for one-time therapeutics.  This strikes me as one of the best solutions to this problem I have heard of and falls short of introducing a single payor system.  It may be combined with a pay-for-performance model where there are rebates for non-responsive patients or where payment is staggered over a period of time and tied to continued treatment response.  The latter could be useful when there is concern that for example expression levels following AAV gene therapy are not sustained (e.g. in hemophilia).

It is encouraging to see concrete solutions being developed so that gene therapies and genome editing can be viewed as attractive investment opportunities.  Importantly, Dr Prasad noted that not only cures will be rewarded, but, especially for severe, rare diseases of high unmet medical needs, also steps in the right direction.  After all, without investments the new FDA has little to brag about in its mission to turn the current sick-care paradigm into one focused on disease prevention and cures.  Personally, I believe having new, well-intentioned leadership may have been the missing necessary catalyst to finally realize the 21st century cures era.   

 

 

2nd Patient with Chronic Granulomatous Disease Successfully Treated with Prime Editing

Prime editing researchers are so excited about the technology that sponsor Prime Medicine is unable to control the newsflow on their CGD trial.  As happened 3 weeks ago at the ASGCT where news of a first patient successfully treated with PM359 leaked, Prime Medicine co-founder Dr. David Liu just dropped (23:00min mark) that a second subject has been treated…with even greater efficacy.

 

90% gene correction efficacy

As was detailed in a subsequent press release by Prime Medicine, the first patient saw a 66% correction of the GT deletion in the mutated NCF1 gene in hematopoietic stem cells that had been treated with prime editing ex vivo.  Importantly, neutrophil (day 14) and platelet (day 19) engraftment occurred extremely fast following transplantation compared to prior experiences with Cas9 nuclease (e.g. Casgevy, ~30 days) and similar to base editing (Beam Therapeutics sickle cell program).  This indicates that non-double-strand DNA cleavage methods are preferable for ex vivo HSC editing from that perspective alone.

Following a company re-organization where Prime Medicine announced it would not further pursue PM359 in favor of commercially more attractive genetic disease in the liver, the future of that program seemed in limbo.  However, with a second patient now treated, and at remarkable 90% gene correction efficacy according to David Liu, it now looks like Prime Medicine will complete the first patient cohort and seek ways to monetize the priority review voucher potential (PRV) of that program.  PRVs have recently sold for ~$150M a piece and provide a critical incentive for the development of treatments for rare pediatric diseases.

The PRV incentive was highlighted by David Liu, the intention to complete the first cohort confirmed in a fireside chat yesterday at Jefferies by the new CEO Allan Reine.  Considering the rarity of this form of CGD (~1 in 600,000 births), I would not be surprised if the new FDA granted PM359 early approval after this cohort considering that HSC gene editing is now well established.

 

Update on arbitration with Beam Therapeutics

Clinical results with CGD and preclinical data from Prime Medicine’s in vivo liver programs show that, with optimization and know-how, prime editing efficacies can be as high as with the simpler, but somewhat dirtier Cas9 nuclease and base editing.  This makes them the preferred CRISPR editing modality for virtually all indications and has led to a conflict with Beam Therapeutics as they see their lead alpha-1-antitrypsin (AATD) base editing program under threat.

Previously, I had viewed Beam Therapeutics to have the upper-hand with regard to correcting the Z allele as this, as a single transition application, would seem to fall within its exclusive field of use of prime editing under their agreement with Prime Medicine.  Allan Reine, however, hinted at Jefferies that the edit Prime Medicine is pursuing is aimed at restoring the wildtype amino acid…not necessarily wildtype DNA.  This could mean that Prime Medicine’s strategy is to replace the AAG lysine codon in the 342 Z allele to GAA glutamic acid, instead of GAG as Beam Therapeutics is doing.  This would involve two, not a single transition and thus arguably fall outside the scope of Beam’s exclusive field 😊.

Disclosure: I am long Prime Medicine with about 7% of my portfolio allocated.  Given yesterday’s bullish regulatory (FDA CBER listening session), legal, and clinical developments and the basic premise that prime editing is the preferred CRISPR modalities in the foreseeable future, I am looking to add to my position.  Hard to believe a company controlling such a monumental technology can go bankrupt as the markets seem to price in.

RNAi Therapeutics A Bright Spot In Dark Biotech Winter

Over the last couple of weeks, we have seen business development activities in the RNAi space that made me realize that the modality has firmly established itself as the third drug development pillar next to antibodies and small molecules.  At the same time, surviving RNAi variations DNA-directed RNAi and microRNAs are catching a bid.

Biogen and Abbvie invest

Most Big Pharma companies have a history of making significant investments in the sector.  The early (2004-2009) significant moves by Roche, Novartis, Takeda, and Merck were not well rewarded.  This was partly because they lacked patience and the willingness to protect early platform development from the incongruent demands from their in-house therapeutic area groups.  Novo Nordisk got the timing right when acquiring Dicerna in late 2021.  Similar to Eli Lilly (through license to Dicerna IP and subsequent in-house work), they are now well placed to capitalize on the promise of RNAi for large cardiovascular and metabolic disease applications.

Amgen and Takeda stand to benefit from two opportunistic deals with Arrowhead Pharmaceuticals for candidates that are now in advanced phase 3 clinical development.  The RNAi agents for alpha1-antitrypsin-related liver disease (Takeda) and Lp(a) (Amgen) for cardiovascular disease will read out as early as next year.  Both companies speak highly of these products.  Amgen in particular highlights the Lp(a) program as its most exciting development candidate in corporate presentations and I expect the company to be back for more RNAi.

Two pharma/big biotech companies that stood out for having watched the developments from the sidelines are Biogen and Abbvie. 

Biogen has gone out of their way and tried it seems every oligonucleotide modality but RNAi.  This includes RNaseH antisense and splice modulation with Ionis and Stoke Therapeutics and microRNAs with Regulus.  It had done so after laughing off RNAi as a scientist’s sandbox idea when presented with it early on by Phil Sharp, scientific co-founder of both Biogen and Alnylam, and thus turned down the opportunity of a life-time to take a major stake in it.  

Instead, a certain former Biogen employee, John Maraganore would go on to build Alnylam into a major biotech player with Alnylam's market cap now exceeding Biogen's.  In a personal anecdote to illustrate the lack of appreciation of RNAi at Biogen at the time (2002), when I did an internship at Biogen and attended a job interview presentation there by a scientist on his RNAi work at Cold Spring Harbor, I was pretty much the only attendee not directly involved in the hiring process.   

It took a leadership generation and a realization that Biogen has become a dinosaur in the drug development industry that it recently finallyinvested $46M in a deal for a CNS target with you would not believe it: City Therapeutics, co-founded by John Maraganore. 

2 weeks before it, Abbvie did a broader collaboration and license option agreement with ADARx for $335M upfront.  Abbvie’s predecessor Abbott had dabbled a little bit in RNAi delivery around the early RNAi bubble, but with no serious intention behind it, really.

MicroRNA dinosaur Regulus taken out by Novartis

As with CRISPR now, the early RNAi bubble phase saw numerous start-ups not only around the core RNAi platforms, but also derivative technologies.  One of them was microRNA therapeutics, a technology targeting or mimicking the endogenous small RNAs of the RNAi apparatus. When the RNAi industry went through the 2010-12 financial bottleneck most of these companies either died or were well on their way. 

Regulus Therapeutics co-founded in 2007 by Alnylam and Ionis around microRNA-targeting oligonucleotides, had the good fortune of having deep-pocketed, influential backers that eventually enabled them to doggedly progress anti-miR17 antisense oligonucleotide farabursen for autosomal dominant polycystic kidney disease (ADPKD) to a stage where the FDA aligned with them on a speedy pivotal trial development plan earlier this year.

This triggered a bidding war between Novartis and an undisclosed bidder that on April 30 resulted in a ~10x premium over its 52-week low that will be paid by Novartis, including a $800M upfront and contingent value rights.

 

DNA-directed RNAi Therapeutics create tremendous value for uniQure

In the vibrant field of developing disease-modifying medicines for Huntington’s disease, uniQure stands out with its chance to gain FDA approval in less than a year should 3-year data replicate that seen after 2 years.  This is the big regulatory news of the day for genetically-targeted therapeutic development as uniQure aligned on a path towards accelerated approval, including a comparison with an external natural history cohort.  Turns out, new CBER chief Vinay Prasad is actually human and has compassion for those suffering from severe genetic diseases.

What few people are talking about is that AMT-130 is an RNAi Therapeutic.  It is a DNA-directed RNAi version where the RNAi trigger is expressed from a DNA template following AAV delivery.  The key to uniQure’s success is that delivery is done locally by intracranial access to where the gene suppression is thought to be required (Spronck et al 2021; cool video illustration here).  In the case of Huntington’s disease, it is the striatum; in the case of AMT-260 for mesial temporal lobe epilepsy where uniQure presented intriguing seizure reductions in the past week, the hippocampus. 

By precisely following how the target structure is filled up with the AAV solution, potential toxicities in off-target tissues can be avoided.  Obviously a big advantage at a time when the AAV field is struggling with toxicities due to systemic administration of large vector doses.

What is more, DNA-directed RNAi allows for durable, potentially permanent gene silencing without the need for an exogenous protein.  This comes as genome editing, be it via CRISPR or Sangamo’s zinc fingers, are hammering away at solutions for gene knockdown that require exogenous protein expression.  Sometimes the old ways are more elegant after all.  Being out of fashion has the advantage of allowing you to build value with less friction. uniQure is about to capitalize on that in a big way.

 

Pure-play RNAi stocks budding during biotech winter

All this is happening as RNAi bellwether Alnylam ($40B market cap) is hitting new all-time highs and is about to catch up with and likely overtake Regeneron ($53B market cap) to become the 3^rd most valuable biotech behind Amgen and Vertex Pharmaceuticals.  Besides the ATTR amyloidosis opportunity, this prices in the potential of Alnylam's pipeline to address huge markets such as Alzheimer’s and obesity with well tolerated, infrequently administered RNAi.

Silence Therapeutics has also risen slowly, but surely over 200% in the last 2 months.  As Lp(a) RNAi is increasingly seen as a must-have in the cardiovascular disease space, its phase 3-ready candidate SLN360 alone could be well worth a multiple of its current $275M market cap.  Add to this its 25 year experience as a pure-play RNAi developer and inhibinE for obesity being an easy target with their technology, Silence Therapeutics is ripe for an acquisition.

Arrowhead Pharmaceuticals is also up over 80% in the same period as revenues in the form of ApoCIII knockdown for high triglyceride-related disease and co-commercialization and royalty/milestone revenues come into closer focus.  Amgen would be an obvious candidate to make a play for Arrowhead, also because Arrowhead can now manufacture large amounts of RNAi triggers within the US.

There are a lot of lessons to be learned from the history of RNAi Therapeutics.  One is that financial bottlenecks can richly reward those that persevere, also because it creates scarcity value and reduces competition.  In general, the current biotech winter which forces companies to focus on their most promising and competitive product candidates will translate into greater profitabilities down the line.  In a twist of irony, as the CRISPR field is going through its own bottleneck, CRISPR Therapeutics now spending money on a non-core RNAi asset, thus keeping spend unnecessarily high and losing focus, is not what the doctor would order based on RNAi history. 

I believe that as long as Trump’s trade war does not result on a run on the US dollar pushing interest rates up, anticipation of Fed Chief Powell’s replacement in May 2026 will allow these assets to come to fruition in a much less capital-constrained environment for biotechs.

Grade 4 Liver Enzyme Elevation in Intellia’s Phase 3 ATTR Amyloidosis Trial

 Last night, Intellia filed a material event report (8-k) with the SEC.  In there, they revealed a case of very high, grade 4 liver enzyme elevations in a single subject treated with NTLA-2001 (nex-z) in the ongoing MAGNITUDE phase 3 ATTR-CM trial.  This case appears to be resolving without any hospitalization or medical intervention.

For context, Intellia has now dosed around 400 subjects with its particular LNP-mRNA formulation across the ATTR and HAE trials.  This is the first such case to be reported.  Earlier cases of liver enzyme elevations were rare.  There were 2 milder, but significant AST elevations in the first month following dosing among the 36 subjects in the phase I/II portion of ATTR-CM development of nex-z (Fontana etal, 2024).  These cases similarly resolved within days.

Liver safety is a key consideration in the development of systemically administered LNP-delivered nucleic acids.  Following delivery, the liver soaks up these LNPs containing non-natural lipids that could insert themselves into normal lipid biology.  It is therefore important that they degrade and get removed from the body- the sooner the better.

There has for example been a case of so called Hy’s Law with Alnylam’s LNP-formulated Patisiran (RNAi) in its phase 3 trial in ATTR-CM (APOLLO-B), meaning that bilirubin was concurrently elevated (excerpt from the APOLLO-B Briefing Docs):

  

Clearly, more context, including the temporal association with nex-z administration, any changes in bilirubin, and the general health and behavior of the subject involved, need to be eventually provided by Intellia for better judgement of the event (it is a blinded study).  It needs to be remembered, too, that nex-z (or most other CRISPR-LNPs) is administered only once which allows for close monitoring in clinical practice.  The fact that the trial is allowed to continue is a positive sign.

Update (5 June, 2025): Since the initial 8-k came out, the company had meetings with analysts during which it emerged that the liver enzyme elevations occured and waned in week 4-5 following administration.  This is inconsistent with acute LNP toxicity as I speculated.  For example, VERVE-101 triggered such an acute response with ALT peaking in the first week.  

This leaves a rare adaptive immune response to the CRISPR editing enzyme (Cas9) or a delayed response to the editing mechanism (double-strand breaks) as the two main other plausible mechanisms.  Pre-existing immunity to various Cas9 enzymes is quite common, so that might be a line of investigation and lead to future adaptations of use.  If hepatocytes that highly express Cas9 for a prolonged period of time got preferentially attacked by cytotoxic T-cells, there should be a decrease in editing levels following the immune attack.

There was also the disclosure that the subject had taken 3g paracetamol for 8 days prior to receiving therapy, a medicine known for occasional severe hepatotoxicity (yes, even common, over-the-counter medicines can cause grade 4 and higher liver enzyme elevations).  Keeping your liver happy around systemic LNP-RNA administration, for example by abstaining from alcohol should be good practice in any case.

1 1/2 weeks following the hepatotoxicity disclosure, no clinical halt has been placed on NTLA-2001 by any of the global regulatory bodies involved in the phase 3 trial, giving extra comfort around its overall safety profile.