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.