Benzinga | Jan 10, 2021 05:10PM EST

Dyne Therapeutics Announced Myotonic Dystrophy Type 1 Program Achieved Robust RNA Knock Down of Toxic Human Nuclear DMPK in Preclinical Study

Dyne Therapeutics, Inc. (NASDAQ:DYN) today announced new preclinical data from its myotonic dystrophy type 1 (DM1) program demonstrating robust RNA knockdown of toxic human nuclear DMPK, the genetic basis of the disease.

Dyne's FORCE™ platform leverages the importance of transferrin1 receptor, TfR1, in muscle biology as the foundation for its novel approach. TfR1, which is highly expressed on the surface of muscle cells, is required for iron transport into muscle cells. Dyne links therapeutic payloads to its TfR1-binding fragment antibody (Fab) to develop targeted therapeutics for muscle diseases. Dyne's DM1 lead candidate consists of a Fab conjugated to an antisense oligonucleotide (ASO) to enable targeted delivery to muscle tissue to reduce accumulation of toxic DMPK RNA in the nucleus, release splicing proteins, allow normal mRNA processing and translation of normal proteins, and potentially stop or reverse the disease.

These new preclinical data build on previous results showing significant reduction in cytoplasmic wild type DMPK RNA in a mouse model that expresses human TfR1(hTfR1). To assess the ability of its lead DM1 candidate to reduce toxic human nuclear DMPK RNA, Dyne developed an innovative hTfR1/DMSXL mouse model that expresses the human TfR1 and carries a human DMPK gene that represents a severe DM1 phenotype with more than 1,000 CTG repeats. In this model, two doses (2 x 10 mg/kg) of Dyne's candidate resulted in significant toxic human nuclear DMPK knockdown at 14 days: 60 percent in the heart; 56 percent in the diaphragm; 54 percent in the tibialis anterior and 39 percent in the gastrocnemius. In the study, Dyne's candidate was well tolerated. Dyne expects to share data from the hTfR1/DMSXL model at a scientific meeting during 2021.

"At Dyne we are focused on developing therapies designed to target the genetic basis of the disease with the goal of delivering disease modification for patients," said Romesh Subramanian, Ph.D., chief scientific officer of Dyne. "Multiple genetic studies in DM1 have suggested that a 30 to 50 percent knockdown of toxic human DMPK has the potential to be disease modifying. We are very pleased with the robust toxic human DMPK reduction observed in the hTfR1/DMSXL model, which, along with our previous preclinical data showing correction of splicing and reversal of myotonia, indicates the potential to have an impact for patients living with a disease with no approved therapies. We intend to utilize this novel model to conduct IND-enabling work as we progress toward the clinic."

"In DM1, it is critical to target the nucleus where the disease-causing toxic DMPK resides and forms foci," said Valeria Sansone, M.D., Ph.D., Clinical and Scientific Director, Clinical Center NeMO, Milan; Associate Professor of Neurology, University of Milan. "The innovative preclinical model used in this study has the potential for translation into human disease. The data demonstrate compelling reduction in levels of DMPK RNA and suggest this approach may be effective in targeting nuclear DMPK and delivering a therapeutic to muscle for diseases such as DM1."

The new preclinical data from the hTfR1/DMSXL model are included in an updated corporate presentation available in the Investors & Media section of the Company's website and add to the robust in vitro and in vivo findings generated previously in Dyne's DM1 program:

Reduction in nuclear foci and correction of splicing in DM1 patient cellsCorrection of splicing and reversal of myotonia in well-validated HSALR modelEnhanced muscle distribution as evidenced by reduced levels of cytoplasmic wild type DMPK RNA in non-human primates (NHPs)Durability of response of up to 12 weeks after a single dose in a wild type mouse modelFavorable tolerability observed in multiple NHP studies"Today's exciting data further validate our FORCE platform which drives our efforts to deliver targeted, modern oligonucleotide therapies with the potential to be life-transforming for patients with serious muscle diseases," said Joshua Brumm, president and chief executive officer of Dyne. "We remain on track to submit INDs for our three programs between the fourth quarter of 2021 and the fourth quarter of 2022, with DM1 and DMD submissions anticipated in the earlier part of that window, followed later by FSHD."