Bayesian statistical approach based on natural history study could address clinical trial design challenges in centronuclear myopathy

FOR IMMEDIATE RELEASE: STRASBOURG/PHILADELPHIA, January 15, 2021 –

Dynacure, a clinical-stage company focused on developing and commercializing novel therapies to transform the lives of patients with rare diseases who have limited or no treatment options, announced the publication of a paper entitled, Hierarchical Bayesian modelling of disease progression to inform clinical trial design in centronuclear myopathy (CNM). The paper was published this month in Orphanet Journal of Rare Diseases, a scientific, peer-reviewed publication and can be accessed here.

CNM is a group of rare and severe neuromuscular diseases that result from genetic mutations that impair the function of protein within muscle cells. People with CNM begin experiencing muscle weakness at any time from birth to early adulthood and many patients die within the first 18 months of life. Patients who survive longer require intense medical management and nearly uninterrupted support, including permanent ventilation, brace with head support and feeding tubes. There is currently no FDA- or EMA-approved therapeutic treatment for CNM.

“There are profound and urgent needs that exist within the CNM patient community, but as with most rare diseases, the clinical variability and genetic heterogeneity of CNM result in major challenges in clinical trial design,” said Laurent Servais, M.D, Professor of Pediatric Neuromuscular Diseases, MDUK Oxford Neuromuscular Center, Department of Pediatrics at the University of Oxford.  “We must continue to look for innovative ways to thoughtfully conduct clinical trials in small and severely affected disease populations with urgent medical needs and I believe we have successfully developed an innovative method to approach the challenges in clinical trial design.”

The Hierarchical Bayesian model used prospective, multicenter natural history and 4-year follow-up data from 59 patients carrying mutations in the MTM1 or DNM2 genes, which are the primary mutations that cause CNM. Each patient’s own natural history study data was used to predict progression in the absence of treatment, simulate the evolution of symptoms for individual patients over time, and compare these simulated trajectories with post-treatment outcomes.

The Bayesian model was designed by Pharmalex, a global leader in innovative clinical trial design and statistics. “Bayesian statistics offer the opportunity to compare the outcomes of patients at a given time after treatment to the simulated endpoint scores at the same given time without a treatment,” said Brad Carlin, Senior Advisor, Statistics and Data Science at Pharmalex. “This approach allowed us to predict an individual patient trajectory with a certain probability and to estimate the probability that an observed deviation from that predicted trajectory would have happened without intervention.”

“We believe that the Bayesian model as applied to CNM with the use of natural history is encouraging and worthy of further exploration among the treatment community,” said Leen Thielemans, Chief Development Officer at Dynacure. “We are tremendously grateful to the patient community for participating in the natural history study, which was led by the Institute of Myology in Paris, for their valuable contribution to our continued understanding of CNM.”

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About Myotubular and Centronuclear Myopathies

Myotubular and Centronuclear Myopathies (CNM) are serious, rare, life-threatening disorders that affect skeletal muscles from birth. CNM derives its name based on the central location of the muscle fiber nucleus, which is an abnormal finding observed in muscle biopsies. People with CNM begin experiencing muscle weakness at any time from birth to early adulthood and many patients die within the first 18 months of life. Patients who survive longer require intense medical management and nearly uninterrupted support, including permanent ventilation, brace with head support and feeding tubes.  The disease is driven by mutations in multiple genes including MTM1, DNM2 and BIN1 and Dynacure scientists have discovered a link between an increase in DNM2 protein and the direct cause of the disease 4. The three classical forms of CNM are X-linked myotubular myopathy (XLCNM), autosomal dominant CNM (ADCNM), and autosomal recessive CNM (ARCNM), which are all associated with poor prognosis. Myotubular and Centronuclear Myopathies affect an estimated 4,000 and 5,000 patients in the European Union, United States, Japan and Australia1.

About DYN101

DYN101, an investigational antisense oligonucleotide product candidate using Ionis Pharmaceuticals’ proprietary antisense technology, is designed to reduce the expression of dynamin 2 protein (DNM2) for the treatment of Myotubular and Centronuclear Myopathies (CNM). Preclinical studies have shown that DYN101 has the potential to be disease modifying in CNM, with preclinical activity observed in animal models of XLCNM and ADCNM 2,3 . Prevention and reversion of the disease was observed with a dose-dependent improvement in whole body strength and mice survival. The development plan for DYN101 was designed to be broad and it is the only known program investigating a treatment for the majority CNM populations, comprised of those who have XLCNM or ADCNM. DYN101 is currently under clinical investigation in several European countries. DYN101 has been granted Orphan Drug designations by the U.S. FDA and EMA and rare pediatric disease designation by the FDA.

About Dynacure

Dynacure is a clinical-stage company focused on developing and commercializing novel therapies to transform the lives of patients with rare diseases who have limited or no treatment options. The Dynacure team leverages its proven track record in rare disease drug development to build a pipeline of novel drug candidates. Dynacure is developing DYN101, an investigational antisense product candidate designed to reduce the expression of dynamin 2 protein for the treatment of Myotubular and Centronuclear Myopathies, in strategic collaboration with Ionis Pharmaceuticals. Dynacure is also building a complementary research portfolio targeting other orphan disorders, including its DYN201 program for the treatment of Hereditary Spastic Paraplegias (caused by mutations in the SPG11 gene).

Dynacure is headquartered in Strasbourg, France with a corporate office in Philadelphia, PA, USA. Dynacure’s investors include Andera Partners, Bpifrance Large Venture, Bpifrance through its FABS and Fonds Biothérapies Innovantes et Maladies Rares funds, Idinvest, Ionis Pharmaceuticals, Kurma Partners, Perceptive Advisors, Pontifax and funds managed by Tekla Capital Management LLC.

For more information, please visit www.dynacure.com.

Juniper Point – U.S. Investor & Media Relations
Amy Conrad
amy@juniper-point.com
+1 858 366 3243

Dynacure – Corporate Communications
Lori McKenna Gorski
Lori.gorski@dynacure.com
+1 508 410 0104

1. Neuromuscul Disord. 2018 Sep;28(9):766-777. doi: 10.1016/j.nmd.2018.06.012. Epub 2018 Jul
2. Nat Commun. 2017 Jun 7;8:15661. doi: 10.1038/ncomms15661.
3. Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):11066-11071. doi: 10.1073/pnas.1808170115. Epub 2018 Oct
4. (Cowling et al 2014 JCI)