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.    

Clinical Data Support PepGen’s Potentially Disruptive Myotonic Dystrophy Type 1 Approach

Yesterday, PepGen showed first clinical data for PGN-EDODM1 in Myotonic Dystrophy Type 1 (DM1).   Although it is years behind the DMPK knockdown competition by Avidity Biosciences and Dyne Therapeutics, the single-dose data hint that its differentiated mechanism of action may prove superior in this big orphan disease indication.

DMPK1 knockdown versus CUG structural disruption

Myotonic dystrophy is an autosomal dominant condition caused by the CUG triplett expansion in the 3’ UTR non-coding region of the DMPK1 gene.  It is thought that this sequesters the MBNL1 protein and the subsequent inability of MBNL1 to carry out its RNA processing functions (alternative splicing).  As DMPK1 is largely expressed in muscle (including heart) and the CNS, the disease symptoms (most noticeably myotonia, but also muscle weakness, heart arrythmia and cognitive impairment etc) relate to muscle and to some degree the nervous system. 

Avidity’s AOC-1001 (phase 3 enrolment to be complete in mid-2025) and Dyne’s DYNE-101 address this by reducing DMPK1 transcript levels thereby liberating bound MBNL1.  Although Avidity uses RNAi triggers conjugated to an antibody and Dyne RNaseH antisense oligos attached to Fab fragments, these 2 Tfr1-targeted molecules both achieve ~-40% DMPK1 RNA knockdown of the nuclear retained transcript.

PepGen’s PGN-EDODM1, however, approaches the problem by targeting oligonucleotides to the CUG repeat itself thereby disrupting the repeat CUG helical structures that act as MBNL1 sponges.

The reason why I quite like this approach is because it does not affect DMPK1 expression.  Mouse models show that DMPK deficiency causes deficits like myotonia and cardiac conduction problems.  In DM1, due to the nuclear retention of the CUG-expanded RNA, DMPK levels are already reduced by 50% and reducing it by another 40% (as AOC-1001 and DYNE-101 do…on average) raises on-target safety questions not posed by the PepGen approach. 

Early splice data support validity of CUG disruption

PepGen has now evaluated about a handful patients each after 28 days following a single dose of 5mg/kg and 10mg/kg for the CASI22 score.  CASI22 is a measurement of MBNL1-related alternative splicing and should be the first measurable change along the mechanistic therapeutic trajectory.  At this early timepoint, there is a nice dose-dependent response of -12.3 and -29.1 for the 5 and 10mg/kg cohort, respectively.

Such clean dose dependency has not been seen in the Avidity and Dyne programs.  Moreover, -29.1 is clearly superior that of -12 (2mg/kg) and -9 (4mg/kg) seen with not 1, but 2 doses of Avidity’s molecule and roughly on par with Dyne’s -25 after 2 doses of 6.8mg/kg.

Whether this translates to the clear functional improvements in myotonia and other symptoms specific to DM1 as for AOC-1001 and DYNE-101 remains to be seen, but logic would say ‘yes’.

A concern with the PepGen approach is that it uses oligonucleotides attached to a cationic cell-penetrating peptide for delivery.  Not only is that less specific than the Tfr1-targeting of Avidity and Dyne, similar approaches, for example by Sarepta in their next-gen DMD exon skipping program, have run into safety issues.  This certainly needs to be watched as PepGen escalates doses further and repeat doses.