An Explanation for the Disconnect between Z-AAT Editing Efficiency and Alpha-1 Antitrypsin Output

The commonly stated goal of alpha-1 antitrypsin editing approaches in addressing AATD is to achieve 50% editing of the mutant Z-allele.  This is based on human genetics showing that MZ heterozygotes have a much reduced risk of developing liver and lung disease.  

It therefore baffled me that Beam Therapeutics reported a year ago serum AAT levels of only ~12.4uM at day 28 despite having achieved 75-85% ZàM conversion with a 60mg dose of BEAM-302.  This compares to ~15-19uM concentrations seen in MZ heterozygotes, that is people who have just 50% of their AAT alleles in the M state.  

Back of the napkin math would have predicted ~22-30uM AAT levels with 75% M alleles if there was a corresponding relationship between the fraction of M alleles and AAT output.

Beam Therapeutics now reports improved serum AAT levels

This week, Beam Therapeutics reported that one additional year into the clinical trial, mean serum AAT levels in the 60mg cohort have increased to 16.1uM.  This includes an additional 3 patients over the 2025 data cut who had higher baseline AAT levels compared to the initial cohort of n=3.  Curiously, the company did not show how serum AAT changed over time, and now I think they did so on purpose because they did not want to steal the thunder from a future conference presentation.

Z-AAT relief effect following genetic correction takes time

ZZ homozygotes carry a high risk of developing liver fibrosis and ultimately liver failure in their lifetime because of the accumulation of Z-AAT aggregates in hepatocytes and resultant cell stress.  Consequently, less AAT gets out into circulation.  Arrowhead Pharmaceuticals and Takeda are addressing the liver disease aspect of AATD by Z-AAT RNAi knockdown with fazirsiran and are now running an unexpectedly long 4 year study after initial findings indicated slower than expected clearance of AAT aggregates and subsequent amelioration of fibrosis.

It therefore is plausible that the reason why serum AAT level undershoot following BEAM-302 treatment compared to genetic expectations is due to some lag in normalizing AAT output in subjects where Z-AAT had caused stress to the liver for decades of life already.  The increase from the mean 12.4uM reported last year to now 16.1uM could be a reflection of hepatocytes clearing the aggregates to relief endoplasmic reticulum stress and grease the AAT export machinery.  

Alternatively, you would have to explain why the inferred mean for the last 3 subjects comes out at 19.8uM versus the 12.4uM for the first 3 subjects.  Of course, you could try and explain some of it with the differences in baseline AAT output (which actually could also reflect Z-AAT-related liver stress), or time-dependent AAT increases as a result of a competitive growth advantage of corrected hepatocytes, or differences in the way serum AAT was measured last year and this year (turbidimetry vs LC-MS), but none of them explain both the serum concentration undershoot versus genotype expectation and the apparent increase over time.

Be prepared to be pleasantly surprised as more data from the BEAM-302 program emerges.  Also be wary of out-of-context data from investigator-initiated trials of obscure genome editing compounds like the YOLT-202 copycat.  

Approving AMT-130 Now Will Incentivize Better Huntington's Drugs and Speed Access

To be clear: the FDA has just violated the trust of investors willing to risk significant capital throughout the ups and downs of the markets by reneging on an agreement it had with the sponsor of what it would take to bring the first Huntington's disease-modifying drug to a well educated community begging for treatment options. 

As the drug development and rare disease world is trying to digest the unprecedented turn of events around AMT-130, it has re-opened the wider debate around the term and value of 'flexibility' in the rare, orphan disease drug approval process.  So setting aside for a moment the fact that the FDA is mandated to make drug approval decisions independent of cost to the healthcare system, let us focus on what this debate is really all about: 

cost savings as perceived by supporters of socialized medicine versus speed of access to medicines and better drugs by incentivizing competition.

Cost savings

The argument for reducing healthcare expenditures by making sure that only drugs with crystal-clear, well-defined health benefits get approved for commercialization seems simple and obvious. Why spend a few hundred million or single-digit billions on drugs just deemed “plausible” based on biology and biomarkers and have not run the “gold-standard” double-blind placebo-controlled clinical trial gauntlet and then turn out to be worthless in the end? 

This is what Vinay Prasad, a smug academic Bernie Sanders supporter and proponent of socialized medicine has been all about.  Good riddance (again!).  It all sounds nice in theory, but even the beacon of communist drug development and public healthcare, Cuba, shows that such a mindset does not facilitate healthcare innovation and access to medicines, particularly to those suffering from rare and orphan diseases.

 

Better drugs by incentivizing competition

Yes, the failure to confirm benefit in stringent outcome trials following accelerated approvals can be frustrating, but I will make the case that this is a price worth paying. Even in instances where this has happened—Sarepta’s exon 51 skipper eteplirsen is a good example—the ability to generate financial returns earlier has spurred tremendous investments across dozens of biotechs funded by private, risk-taking capital to come up with improved versions of eteplirsen. The result: companies like Avidity and Dyne Therapeutics have invested hundreds of millions in new exon skippers backed by solid evidence of clinical efficacy.

I used to be a big critic of eteplirsen early on, suspecting shady science and Sarepta clearly dragging its feet on the confirmatory studies.  Yet in hindsight even I can now see the overall benefits that the accelerated approval of eteplirsen has brought to the DMD rare disease community, so that the argument of spending precious healthcare dollars while generating confirmatory evidence and spurring competition becomes quite compelling to me.

So as long as companies play by the rules and get busy on their confirmatory studies, the system is working very well.

Why approving AMT-130 for Huntington’s Disease does not entail much risk and cost

In this more libertarian view of drug approval, drugs that have been demonstrated in clinical trials to be “safe and well tolerated” should get approved when there is some evidence of efficacy. Importantly, safety can be demonstrated in studies that are not placebo-controlled.

The safety of AMT-130 has not been at the center of the recent controversy, so let’s accept that for a uniformly terminal disease like Huntington’s, AMT-130 meets that bar.

Given that the market for disease-modifying medicines for HD is significant, similar to Cystic Fibrosis which allowed Vertex Pharmaceuticals to build a franchise worth $100B around, accelerated approval for AMT-130 would energize uniQure’s competition to come up with drugs that have demonstrably better therapeutic profiles.

If everybody would just rely on the same type of natural history comparisons as AMT-130, competition would bring down prices rapidly as seen for HCV drugs which are a wildly successful story in effective and affordable healthcare following an initial public outrage around the '$1000 pills'.. Those that can demonstrate superior profiles will be rewarded with pricing power further incentivizing private risk capital to improve on AMT-130. Alnylam’s ALN-HTT02, an intrathecally repeat-administered synthetic RNAi trigger, could very well be that first molecule to achieve that. It also targets the critical exon 1a transcript and appears to have superior knockdown efficacy. There is also no reason why ALN-HTT02 cannot be given to an HD patient who had already received AMT-130.

After that, it will likely be systemically administered RNAi molecules targeting exon 1a transcript and with triplet repeat expansion inhibitors. The regulatory flexibility is a critical factor determining how much investment flows into HD drug development and how soon patients for whom every day is an opportunity missed can access promising drugs.

Finally, let’s be real: not every HD patient will get AMT-130 which I expect would to cost around $3M as a one-time treatment with a high cost of goods based on viral vector production.  In addition to surgical capacity constraints, a label that will likely expand not too much beyond the early symptomatic manifest study participants will throw up access barriers that insurance companies and government payors will seize on.  Still, the revenues would allow uniQure to stay at the forefront of HD drug development and help flesh out the actual value of AMT-130.

Plea to Sarepta and Arrowhead: Just Focus on Aberrant Exon 1 Transcript in Huntington’s Disease

Last week, uniQure achieved a breakthrough in developing disease-modifying therapies for Huntington’s Disease by showing that AMT-130 slowed disease progression by 75%.  AMT-130 is a DNA-directed RNAi construct targeting a sequence in the triplett-expanded exon 1 of the 67 exons-containing huntingtin gene.  Since other approaches aimed at lowering full-length huntingtin, but leaving exon 1 mRNA untouched, have fallen short (e.g. tominersen by Ionis and Roche) this is very strong support that targeting the aberrant exon 1 transcript is essential for success.

The aberrant exon 1 transcript, and likely the protein produced from that, is loaded with polyglutamine-encoding CAG tripletts, has been shown in animal studies to be exceptionally toxic and is also produced in patients (see previous blog entry 'Huntington's Disease Therapeutics Finally Breaking Through!'), the amount of which is correlated with triplett expansion size based on comments by uniQure CMO Walid Abi-Saab at a conference earlier this year.  Add to this the observation that a phase 3 trial with tominersen had to be stopped due to the oligo performing worse than control, maybe it is time for a heretical new idea:

accept that the old notion of Huntington’s Disease being an autosomal dominant disease caused by toxic full-length triplett-expanded huntingtin has been wrong, and full-length huntingtin indeed is an important protein to have. Instead, leave full-length huntingtin alone and exclusively target the aberrant exon 1 ‘fragment’.   Hey, have you ever considered the possibility that the polyQ htt protein aggregates are not cleavage products from full-length Htt?  Why always so complicated?  Why consider both exon 1 and full-length Htt contributing meaningfully to disease?  Shouldn't the properties of a short protein largely made up of polyglutamine be radically different from that of a much larger one containing the same polyglutamine stretch?

Sarepta and Arrowhead have shared plans to enter the clinic with a systemically administered RNAi conjugate for Huntington’s Disease.  A systemically administered option would be a very valuable one since, especially in light of the one-time administered AMT-130, repeat intrathecal administration is less attractive.   The Tfr1-targeted ARO-HTT being prepared for clinical trial application this year apparently does not affect exon 1 transcript.  The excuse given is that it is difficult to find an effective RNAi trigger in the merely 102 nucleotide exon 1 target space.

The good news: by focusing exlusively on aberrant exon 1 transcript, 7000+ nucleotides of additional target space (from 5’ end of intron 1) opens up.  

What good is it to have a trigger that is great at knocking down a transcript when it is aimed at the wrong target?  It is not too late and can be explained to the market.

PepGen Disrupts Myotonic Dystrophy Type I

Yesterday was a memorable day in the development of drugs for two of the main severe monogenic diseases without treatments to change disease trajectory: Huntington’s Disease and myotonic dystrophy type I.

A lot has been written in the press and social media on the fantastic results by uniQure in Huntington’s Disease (see also my preview on why I had thought exon 1-targeting, including AMT-130, is the most promising current approach), so I focus on yet another biotech data bomb dropped last time: single-dose data from the 15mg/kg cohort in PepGen’s early-stage trial in myotonic dystrophy type I.  In short, similar to AMT-130, the data blew away expectations in terms of the key prognostic biomarker in DM1, the CASI splice index, leaving the more advanced competition by Avidity and Dyne in the dust.

 

To knock down or to disrupt

DM1 is an autosomal dominant disease caused by triplet expansion in the 3’ UTR of DMPK.  When triplets exceed 50 copies, they form an RNA structure that attracts and thereby interferes with muscle blind (MBNL1) protein to carry out its functions in RNA splicing (spliceopathy).  By measuring the degree of splice disruption of a number of MBNL1-target genes, the CASI score is therefore a key prognostic biomarker.

People living with DM1 experience muscle weakness, including cardiac problems, and myotonia, in addition to developing neurological, endocrine, and other systemic symptoms.  Such systemic disease manifestation is normally observed in muscle diseases and it is often unclear whether this relates to gene expression (here DMPK1) in non-muscle cells or whether they are the result of feedback mechanisms.  

Early efforts in developing disease-modifying treatments have focused on knocking down DMPK1 either by RNAi (Avidity Biosciences, AOC-1001) or RNaseH antisense (Dyne Therapeutics, DYNE-101).  The idea here is that by lowering the abundance of DMPK, less MBNL1 will be sequestered.  Indeed, both Avidity and Dyne have shown convincing data that this approach works in addressing muscle disease as measured by the vHOT myotonia assay.

Both companies target the oligonucleotide with antibody/antibody fragments targeted to Tfr1 which is expressed on muscle cells.  Interestingly, Tfr1 is also expressed on the blood-brain-barrier and may thus allow for addressing some of the prominent neurological symptoms as well.

The downside to the knockdown approach is that knocking down DMPK1 too much may be toxic based on the lack of DMPK1 knockouts in human genome databases.  Also, I expect this approach to lose efficacy with the size of the triplett expansion.

By contrast, antisense oligos targeted to the toxic RNA structure should be soaked up synergistically the longer the repeats and thus higher local repeat concentrations.  Binding a few repeats may unravel the structure and free MBNL1 to do its job.  There should also be no theoretical limit as to how many target transcripts can be engaged without causing target-related toxicity.

The two lead candidates for the DMPK1 structure disruptors, PGN-EDODM1 by PepGen and VX-670 from Vertex Pharmaceuticals, comprise of PMO-based oligos conjugated to cationic peptides for broad biodistribution and enhanced cellular uptake and thus may have the additional benefit of addressing DMPK1 toxicity in more cell types than the Tfr1-targeting drugs.

So while Avidity and Dyne are on track to see their DM1 knockdown drugs approved in late 2026 and 2027, respectively, the RNA structure disruptors led by PepGen and Vertex Pharmaceuticals need watching as they represent a very differentiated approach and the efficacy could thus be in an entirely different ballpark.

 

PepGen’s Disruptive Biomarker Data

And in an entirely different ballpark indeed they are based on data presented last night by PepGen from the 15mg/kg single-dose portion of their early-stage trial.  Though the previously reported single-dose 10mg/kg data were numerically the highest observed in the clinic so far (29.1% vs 16.1% for 2 doses of AOC-1001 and 25% for 2 doses of DYNE-101; discussed in a blog entry here), the newly reported 53.7% splicing improvement based on the 28-gene panel (CASI) is opening up entirely new horizons for what should be possible.

The surprising increase in efficacy (I was looking for 15mg/kg mainly to confirm the highly promising 10mg/kg results) correlated with muscle concentrations of PGN-EDODM1 that were more than dose proportional.  This is a critically valuable insight as the company is continuing with the multiple-ascending dose portion of the study with results expected in early 2026.  But before that, expect more details from the 15mg/kg single-dose portion on October 11 at the World Muscle Society meeting.

Results from VX-670 may also be reported over the coming months.  Although I may be biased here as a PepGen shareholder, I am a bit cautious with regard to the safety and efficacy of VX-670 since the partner from Vertex, Entrada Therapeutics, has been advertising how much better their new delivery peptides are for muscle delivery than the one used for VX-670.  

Disclosure: I owned close to 5% of PepGen as the ~$35M market cap just a month ago was just a crazy disconnect compared to the $6B market cap of Avidity Biosciences when PepGen had the stronger CASI numbers.  After reporting a $100M offering (priced at $3.2 a share), my ownership will be diluted to about 2.5%.  Frankly, the $100M pre-money valuation of the offering is theft in broad daylight and the company should have reported data first and then do the offering after further price discovery.  The pre-money would have been at least $300M in my opinion.   Removing the ‘financing overhang’ along with announcing data is so yesterday, the new biotech playbook allows for offerings in the days after data.  This is a new chapter in publicly traded biotechs where stocks react to data.    

Vinay Prasad's Days as Head of CBER May Be Numbered

Many industry insiders expected Sarepta CEO Doug Ingram to be out by now.  Instead, a new dynamic is gathering steam: Vinay Prasad, the recently hired head of CBER at the FDA, is coming under increased pressure as he is being identified as sabotaging Republican pro-choice philosophy. 

Last night’s latest panicky press release by ‘the FDA’ (= Prasad) that it is investigating the death of a Brazilian boy with Duchenne’s muscular dystrophy (DMD) who had received the AAV Elevidys gene therapy from Sarepta, speaks volumes.  According to a recount by FirstWordPharma, the death of this boy occurred on June 7 and was logged onto the agency’s FAERS adverse event reporting system on June 18.  The death was deemed unrelated to Elevidys by the reporting physician and caused by flu, possibly exacerbated by immunosuppression.  It remains to be seen whether the immunosuppression was part of the boy’s normal treatment for the disease (corticosteroids are standard of care) or whether aggressive immunosuppression was practiced to control acute liver injury related to Elevidys.

In any case, given that shipments of Elevidys had been halted in the US, press releasing such an 'investigation' into a death deemed unrelated to the gene therapy smacks of desperation…the desperation of Vinay Prasad clinging onto his post.

 

Trump loyalty enforcers zeroing in on Vinay Prasad

When Vinay Prasad was appointed to head CBER 3 months ago, it caused a sell-off in biotech stocks relying on accelerated approval pathways aimed to ultimately provide patient choice in a timely manner.  Gene therapy companies in particular rely on these pathways (e.g. biomarker-based, natural history comparisons) with their ongoing programs and Prasad has been public with his disdain for the Elevidys approval under Peter Marks.

In subsequent weeks and months, the investor and sector panic subsided as Vinay tagged along FDA Chief Makary advocating regulatory flexibility (approval at the slightest sign of efficacy or plausible biological mechanism).  After recent rejections of Capricor’s DMD cell and Replimmune’s oncolytic viral therapies and now the controversy around Elevidys and Sarepta, this view is changing quickly again.

Unsurprisingly, Trump’s loyalty enforcer Laura Loomer has picked up the scent and identified Prasad as a Bernie Sanders-style progressive, a wolf in sheep’s clothing undermining Republican healthcare philosophy.  

To wit, like so many of Trump’s current and past allies, Prasad has made fun of the President in the past.  More importantly, he has been a strict advocatefor healthcare rationing, limiting tests and drugs to circumstances of the highest medical certainty with Father State, not the patient or physician, being the one to decide.  His tone deafness for patient views, also on risk taking, is further illustrated by his statement that the instance you are dead, nobody will ever think of you again.

Yesterday, former Republican Senator Rick and Newsmax contributor Rick Santorum tweeted the following, citing an article that specifically attacked Prasad for his handling of Elevidys (the intro to that piece is quite the read).

 

How we got here

When Sarepta announced its company reorganization last Wednesday, shifting its focus away from gene to synthetic RNAi therapies, it did not mention the death of a non-ambulatory man treated in one of its AAVrh74 gene therapy trials for limb girdle muscular dystrophy (LGMD).  AAVrh74 is also the serotype of Elevidys. 

This death occurred and was reported to the FDA in early July.  To be clear, it was an unforced error by Sarepta to not publicly disclose that death for transparency reasons as it claimed that it retiring most LGMD gene therapy programs had nothing to do with safety.  It is, however, becoming increasingly evident that pre-existing poor liver health such as cholestatic disease (à XLMTM-related AAV gene therapy deaths) is the major risk factor for dying from AAV-related liver failure.  The fact that none of the ~800 ambulatory and therefore younger DMD subjects have died due to high-dose AAVrh74 gene therapy, but 3 out of ~140 non-ambulatory (à hepatic steatosis risk) patients treated with AAVrh74 fits neatly, making it the hypothesis that needs to be disproven first.

Sarepta has made itself many enemies and having just laid off 500 employees added to this pool.  According to BioCentury's Steve Usdin, the reporter who broke this story, there were numerous messages sent to journalists on Wednesday night and Thursday following the re-organization call enquiring why the LGMD patient death went unmentioned.  This resulted in numerous sensationalist media reports and put the publicity-minded FDA in a tough spot.  So after this AI-powered agency had sat on the Brazil and LGMD deaths for almost a month without (understandably) seeing a reason to pull Elevidys for ambulatory DMD patients from the market, it felt it had to act and be seen as a tough regulator.

Two press releases (here and here) and constant Signal chat leaks from an ‘unnamed senior FDA official’ attacking Sarepta followed, one less coherent than the other reaching yesterday’s low point.    

 

What is next

To me it is clear that this is coming down to a showdown between Sarepta, and in particular its CEO Doug Ingram and Board of Directors, and Vinay Prasad.  The company is taking the high road saying that it is working to resolve the shipment halt ‘within the ordinary and well-established FDA channels and procedures’.  You bet, however, that Sarepta is also working through unofficial political channels and Vinay Prasad has not taken into account how Sarepta got to where it is today in the first place and, being tone deaf to patient concern, certainly not the strength of DMD patient advocacy which clearly wants Elevidys to remain a choice for them.  With Replimmune and Capricor showing that Elevidys is part of a broader pattern, his fate has been sealed in my opinion.  If not, expect a Jesse Gelsinger-type scenario for gene therapy.

 

Scientific Post-Scriptum

There are less widely discussed strategies that the systemic AAV gene therapy field in general may want to explore more to increase safety besides refining immunosuppression regimens which, as we all know, carry their own risks.

One is to use RNAi, highly potent for directing gene knockdown in hepatocytes, to downregulate the processing and presentation of AAV antigens attracting the sometimes fatal T-cell response.  Sarepta with their partnership with Arrowhead Pharmaceuticals, is ideally placed to do so.  Another option could be to inhibit hepatic uptake of AAV by co-administering heparin, which should inhibit hepatic AAV uptake via HSPG and may shift the balance towards non-hepatic uptake.   

Related to that and highlighting the failure of Sarepta to have run a proper dose escalation study, with Elevidys doses being sky-high at 1.33 × 10¹⁴ vector genomes per kilogram and muscle delivery being subject to a step function (similar to LNP delivery to hepatocytes), using significantly lower doses will likely not impact microdystrophin expression much, but further decrease liver failure risk.  This and excluding patients with pre-existing liver issues, especially hepatic steatosis in DMD, may be the most rapid way to get Elevidys back onto the US market in a scenario where everybody can save face.  DMD patients and their families do not deserve to be held hostage as Prasad is clinging onto his job.  

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.