Preclinical Data Behind the Ionis Trial Published

Published on Thu, 07/06/2017

In January 2017, Ionis Pharmaceuticals reported results of their phase 1/2 clinical trial of DMPKRx in subjects with DM1. While the field gained considerable insights into the compound, clinical endpoints and future clinical trial design, DMPKRx did not achieve sufficient exposure in skeletal muscle to have the desired effect on RNA splicing. An examination of the totality of data behind DMPKRx can yield further insights as Ionis develops the next generation of antisense oligonucleotide drug candidate for clinical trials in myotonic dystrophy (DM).

Preclinical Evidence Supported Development of Ionis’ Constrained Ethyl-modified Oligonucleotide for DM1

A strong collaborative team in academia and Ionis Pharmaceuticals has recently published their preclinical animal efficacy studies of ISIS 486178, a compound of a similar class to the DMPK antisense oligonucleotide used in the DM1 clinical trial, ISIS-DMPKRx.

The therapeutic candidate molecule, ISIS 486178, was selected after extensive optimization of both oligonucleotide sequence and backbone chemistry, with over 3,000 compounds screened for suppression of DMPK. The study evaluated a battery of molecular and functional endpoints in: (a) myotonic dystrophy type 1 (DM1) and control cell lines and (b) DMSXL mice dosed subcutaneously with the selected compound, ISIS 486178.

The candidate therapeutic produced a 70% reduction in expanded CUG repeat RNA and nuclear MBNL-RNA foci in mouse skeletal muscle and 30% reduction in cardiac muscle. DMSXL muscle histology, forelimb muscle grip strength and body weight were also improved, with no overt safety signals (endpoints: survival, liver enzymes, CPK, creatinine and genome-wide profiling) noted in either mice or cultured myotubes. Changes were not noted in brain DMPK RNA levels, a finding expected with systemic dosing of oligonucleotides. Prior studies of DM1 are supportive of muscle maturational defects as a component of the pathologic mechanism—treatment with ISIS 486178 largely restored the myofiber maturational profile in the soleus of DMSXL mice. DM1-related splicopathy is mild and variable in DMSXL, so drug effect on mis-splicing was not evaluated.

Preclinical Proof of Concept Achieved for Targeting Expanded DMPK RNA

Taken together, treatment of DMSXL mice with ISIS 486178 produced substantial and reproducible reduction in mutant DMPK transcripts, as well as phenotypic improvements. The constrained ethyl backbone chemistry used in ISIS 486178 exhibited differential exposure to two important DM1 targets, skeletal muscle (70% reduction in DMPK transcripts) versus heart (30%). Using their earlier generation oligonucleotide chemistry (2'-O-methoxyethyl modified or MOE), Ionis successfully partnered with Biogen to achieve sufficient CNS exposure after intrathecal delivery, ultimately leading to regulatory approval of Spinraza for all types of spinal muscular atrophy in late 2016. It appears that improving delivery of a DMPK-targeted antisense oligonucleotide is a viable path forward for DM1.

Next Steps

Data published by this investigative team provide a strong scientific rationale for targeting mutant DMPK with oligonucleotides operating by an RNase H mechanism. MDF has a BAC transgenic model under development at Jackson Laboratories that may be a better model for assessing efficacy in restoring splicing in the context of the DMPK locus, as well as assessing multi-system phenotypes. Finally, Ionis has publically announced an ongoing preclinical development program to obtain an antisense oligonucleotide with better exposure and intends to return to clinical trials in DM1.


Targeting DMPK with Antisense Oligonucleotide Improves Muscle Strength in Myotonic Dystrophy Type 1 Mice.
Jauvin D, Chrétien J, Pandey SK, Martineau L, Revillod L, Bassez G, Lachon A, McLeod AR, Gourdon G, Wheeler TM, Thornton CA, Bennett CF, Puymirat J.
Mol Ther Nucleic Acids. 2017 Jun 16;7:465-474. doi: 10.1016/j.omtn.2017.05.007. Epub 2017 May 17.