From ZZ to SZ to MZ to potentially MM! The New State of Play for RNA Editing in Alpha-1 Antitrypsin Disease

The last few days and weeks delivered critical datapoints in the race to develop RNA Editing oligonucleotides for the treatment of AATD.  The prize in the form of serving an inadequately addressed rare disease with low single digit hundred thousand ZZ patients in the US, Europe, and Japan is enormous, thus spurring the development of increasingly better RNA Editing candidates.  Capitalism at its best. 

Getting close to the RNA Editing endgame

The picture that emerges shows Wave Life Sciences leading the pack with a clinical profile that could match the less severe SZ genotype (in terms of serum AAT abundance).  This should provide protection against progression of lung (but not liver) disease.  It has an about 2 years headstart in clinical development over competitor AiRNA which has a more realistic shot at replicating the more protective MZ genotype based on comparative mouse studies; and another year over Korro Bio’s AATD encore KRRO-111.  If what they claim is true, they may be getting close to the endgame with near complete Z-correction (MM-like), in the process surpassing what genome editing can do as well.

WVE-006

Wave Life Sciences’  WVE-006 has been discussed a lot on this blog.  I feel like I am slowly getting a handle on the true efficacy of this compound in the clinic- which has been made difficult by the company not broadly providing total serum AAT values.  Instead, it relied on revealing isolated serum M-AAT, the percent reduction of Z-AAT, and somewhat meaningless mean max numbers for total AAT.  Somewhat meaningless, because AAT fluctuates and just capturing the maximum values ever observed clearly introduces a significant bias to the upside.  

Considering that their reported ‘mean max’ barely matches what they say their assay measures for the mean (not even mean max) in ZZ natural history (13.1uM), it cannot be concluded that WVE-006 will achieve protection from progression of lung disease as expected from a MZ-like genotype and will likewise not be potent against AAT liver disease.  Accordingly, the case study they report on where a subject experiences an acute response shows total (Z) AAT serum levels to be similar, if not higher pre-treatment.  So if we wanted to analogize, something more akin to introducing a SZ-type genotype into a ZZ carrier should be the expectation.

AIR-001

Privately-held, pure-play RNA Editing company AiRNA announced having dosed their first clinical trial subject with AIR-001 last month.  AIR-001 is also a GalNAc-conjugated oligonucleotide and its preclinical mouse results have just been presented at the annual ASGCT conference in Boston.

In the same NSG-piz mouse model that Wave Life Sciences is using, and for the same 10mg/kg biweekly subcutaneous dosing regime, AIR-001 appears to achieve somewhat increased levels of RNA editing which in turn translated to somewhat increased serum M-AAT fractions (both up from ~50% to 60%).  Based on the prolonged stability of AIR-001 in monkey over mouse livers, AiRNA predicts a dosing frequency every 2 or 3 months which would be an improvement from Wave’s potential monthly dosing.

AIR-001 is just preclinical and WVE-006 has cleared a number of clinical safety and efficacy hurdles.  Getting closer to having a true MZ-genotype impact could be a best case scenario for AIR-001.

KRRO-111

To rain on everybody’s parade, Korro Bio then PR’d stunning headline results for its new AATD RNA Editing candidate.  KRRO-111 is its GalNAc oligonucleotide version after its LNP-based KRRO-110 seemed to do nothing in the clinic and the company may have to climb a mountain of investor skepticism before they all come onboard.

Still, by reporting near complete Z-AAT elimination and almost full M-AAT reconstitution with repeat-dosing of 3mg/kg in mice, and at one third the dose of the competition at that, one truly has to wonder whether we are closing in on the endgame for RNA Editing in AATD: from ZZ to MM.  The numbers also sound to be better than a single-shot of genome editing ever will be.  Beam Therapeutics conservatively itself bills BEAM-302 as MZ, though I myself believe that based on the >9:1 serum M:Z ratio, they are approaching something more like MM.

Unlike many biotech investors right now which can be grouped into CRISPR haters and lovers, I myself welcome the emerging choice for AATD patients.  Let us not forget that as alveolar damage from too little alpha-1 antitrypsin is not reversible (liver fibrosis may be) and gradual suffocation is an awful way to die (trust me).  The true AATD medical endgame would therefore also involve treating ZZ carriers as early as possible, certainly before symptoms emerge.  A genome editor would have to have an LNP delivery safety profile such that a person in her early 20s could be routinely administered; an RNA Editor convenient and sufficiently tolerated such that a carrier would be willing to repeatedly inject himself despite having no symptoms.

Disclosure: I am currently long Beam Therapeutics and Korro Bio.  No position in Wave Life Sciences as I want to sit out the feedback they will receive from the FDA on the development path for WVE-006.  Not investment advice.

Wave Life Sciences Sets 30% RNA Editing Bar for AATD

Wave Life Sciences (here) and Beam Therapeutics (and here) just presented important updates on their alpha-1 antitrypsin disease (AATD) programs at the American Thoracic Society 2026 meeting in Orlando.  Based on the latest disclosures, it is now possible to derive a reasonably robust estimate of not only the relative potencies of the competing product candidates (RNA editing WVE-006 and DNA base editing BEAM-302), but also the absolute editing efficiency for WVE-006, the industry’s lead RNA editing agent.

30% RNA editing for 200mg biweekly

Taking into account that misfolded mutant Z-AAT is less efficiently exported from hepatocytes than wildtype M-AAT, 1.8-fold difference based on Wave’s estimate, and deriving the mean serum AAT values from the spaghetti plots instead of going with the mean individual max values Wave highlights when it presents absolute numbers, the actual A-to-I editing efficiency in hepatocytes lies between 25-30% at steady-state when WVE-006 is given every other week.

To be sure, this is an excellent value for the first clinical RNA editing candidate and I expect to see much less when ProQR will present its first clinical target engagement data over the next month.  Nevertheless, given that the RNA editing competition, especially Korro, now claim much higher (preclinical) editing values for alpha-1, Wave may have a hard time competing in the long-term with WVE-006 and should develop a more potent next-gen candidate alongside WVE-006.

30% editing puts WVE-006 more into the range of the SZ genotype (instead of the stated MZ goal).  SZ is still significantly less pathogenic than ZZ and now appears to be Wave's newly stated goal.  However, it should be inadequate when addressing the liver manifestation of AATD, especially if treatment were to be started at F2 fibrosis stage or later.

 BEAM-302 appears to check it all

By contrast, one-time DNA base editing competitor BEAM-302 has a ~3x higher editing efficiency than WVE-006, and a pristine safety profile.  There is minor transient and very mild grade 1 liver enzyme elevations at the go-forward 60mg dose, but nothing really of concern, especially at later timepoints.  This not only means that it addresses the lung manifestation of the disease, also demonstrated by showing for the first time a near total suppression of neutrophil elastase activity in the clinic, but with a ~85% Z-AAT knockdown likely also liver disease.  Reversing existing liver disease, as indicated by Fazirsiran (see below), is a slower process, but this is as close to a cure you can get for AATD, if not an outright cure if BEAM-302 were to be given in early adulthood.

It has to be said that an 85% DNA base editing knockdown is not equivalent to a similar knockdown value obtained with an RNAi medicine as BEAM-302 works digitally at the individual hepatocyte level versus a more uniform gene suppression expected for an RNA agent like Arrowhead's/Takeda's Fazirsiran (note: Fazirsiran’s knockdown is closer to 93% for 200mg).   The digital nature of DNA base editing might actually work in favor of DNA editing as the lower doses show how corrected hepatocytes start replacing diseased ones over time.

Beam Therapeutics now needs to finish dosing an additional 50 subjects at 60mg, mainly to beef up the safety database, before it can submit 302 for accelerated approval.  Wave Life Sciences by contrast needs to carefully consider how much it wants to invest in further developing WVE-006  when its inhibinE candidate is their most promising pipeline candidate with multiple possible applications and development paths.  FDA feedback expected over the next month or two for 006 should provide more clarity.

FDA Plays Cynical Political Games to Keep Effective Cancer Drug from Patients

Under the current FDA, patients don't tire of losing. This time, the FDA re-rejected a drug which, when given together with anti-PD1 therapy, achieved a 32.9% overall response rate (ORR) in the IGNYTE trial in patients with unresectable advanced cutaneous melanoma who had progressed on anti-PD1 therapy. This is a far cry from the 6–7% expected ORR in this patient population with anti-PD1 monotherapy rechallenge (Ribas et al. 2018).

The FDA's Real Objections

In fact, it was not the question of whether oncolytic virus RP-1 had anticancer activity at all that the FDA took issue with. Instead, it was the academic questions of how much RP-1 contributed to the efficacy and how much of it was due to generating a systemic antitumor immune response beyond the oncolytic activity at the injected tumors.

Another issue that was raised was that the patient population in the trial was heterogeneous and whether certain subjects would have been better served receiving another existing treatment option. This partly accuses trial investigators of not having the best interest of their patients in mind, and is a question better suited for the melanoma societies to flesh out in the post-marketing setting. The more evidence for early treatment the sponsor, Replimune, provides, the more it would obviously be utilized.

Arguing Science Is a Waste of Time

But arguing the case for approving RP-1 based on science is a big waste of time. The FDA set Replimune up for a CRL from the moment it allowed it to resubmit its BLA. To achieve this, it replaced the primary review staff that until last summer wanted to approve RP-1, before a late-stage intervention from Pazdur and controlled-trial absolutist Prasad. Whereas Pazdur has already left the FDA, Prasad will leave it by the end of this month and has played a big part in reshaping it, degrading its quality of regulatory science — his handwriting is all over this CRL.

"Maintaining Objectivity" Is Evil Cynicism

So the claim that, to "maintain objectivity," the FDA replaced the review staff that had been in favor of RP-1 is just evil cynicism.  For example, in a since deleted Linkedin comment, Dr Peter Bross, former Chief of Oncology Branch 1 who had been involved in the first BLA review stated:

 He has subsequently been purged by CBER Chief Prasad.

Also, accusing the company of injecting all accessible tumors with RP-1 — which supposedly made it difficult to divine the systemic activity to be gained from adding RP-1 to anti-PD1 — is confusing actual patients with guinea pigs. Is the FDA requesting that patients be left undertreated and exposed unnecessarily to disease progression, just for the sake of scientific curiosity? Seriously?

Similarly, running a trial with three cohorts that would be required to figure out "contribution of components" (cohort 1: RP-1 mono; cohort 2: anti-PD1 mono; cohort 3: combo) is clearly unethical, and may be something you would possibly expect from ICER — the self-anointed body for determining the value of drugs to society and which is receiving substantial funding by ex-Enron trader John Arnold.

Mischaracterizing the FDA–Replimune Relationship

The "maintain objectivity" framing is also meant to mischaracterize the FDA–Replimune relationship as having been adversarial from the outset. While the agency would have preferred a different trial design in 2021 — that is, before this Trump FDA came to power — it did go along with the 6–7% ORR null hypothesis, granted RP-1 breakthrough therapy designation upon initial review of the data in November 2024, and until the very last minute wanted to approve RP-1 following the first BLA submission.

The Cherry on Top

The cherry on top of the cynicism came when the CRL explained why Replimune was allowed to submit the BLA in the first place despite the single-arm study design being unacceptable to the FDA. They claim to have only noticed the design issue "on review" of the BLA: 

Hey, you geniuses at the FDA, how about consulting ClinicalTrials.gov next time? And while you newcomers are at it, maybe align with your colleagues and get some coaching about SEC compliance — dropping the CRL online was the second time in a row that an FDA rejection was made public before a trading halt was instituted (see also the uniQure–Makary CNBC interview).

Bottom Line

Desperately ill patients are once again denied access to a clearly efficacious drug because the study design did not please aesthetically. This is all in fact a pretext to save money from being spent on expensive medicines for small patient populations — a key objective of the John Arnold Foundation, which has been a main financial influencer of the current FDA leadership.

To keep face and keep hopes of melanoma patients and treating physicians alive, a promptly scheduled Advisory Committee meeting to hear testimony from the melanoma expert und patient community, perhaps following the announcement of the new CBER Chief, could be a solution.  Absent signs of a potential reversal by the FDA, Replimune will be forced to kill RP-1 once and for all for financial reasons in yet another blow to the US biotech ecosystem.

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.