IONIS-DNM2-2.5Rx

Dynacure has ended its Unite-CNM Phase I/II trial on DYN101, an investigational therapy for the treatment of myotubular and centronuclear myopathies (CNM). In a letter addressed to patients, the company said it is "unable to continue dosing at the low study dose or increase to a dose level at which we would expect to see clinical efficacy." Dynacure noted that while the first cohort of trial participants, who received a single dose of DYN101, tolerated the drug well, those from the second cohort, who received a higher quantity at the lowest level possible to determine efficacy, experienced elevated liver enzyme levels. The researchers tried to adjust the dose based on the patients' actual to ideal body weight, but all six patients still showed elevated liver enzymes. Five out of the six also reported having low platelet counts. After reviewing the study with an independent data monitoring committee, it was decided that dosing should be paused. The patients who had already taken the investigational drug continued with their follow-up visits and did not demonstrate any exposure to further risk. "This is not the news we ever wanted to share, as we know how great your needs are for safe and effective treatments. As a company and as individuals, we are overwhelmed with disappointment," Chris Freitag, M.D., the chief medical officer of Dynacure, said in the letter. "Like all clinical research efforts into CNM, the learnings from Unite-CNM are hard-earned by these study participants and investigators. They will add to the world's growing understanding of CNM. As we continue to review the findings of Unite-CNM, we will stay connected with study investigators, researchers, and patient advocacy organizations around the world. We will fulfill our obligation of making study results public," Freitag added. Dynacure had a promising journey prior to this unfortunate news. In June 2021, the U.S. Food and Drug Administration accepted its Investigational New Drug application for DYN101 due to positive initial results from its UNITE-CNM study. In January, the FDA granted it a Fast Track Designation. "Dynacure is continuing to investigate new approaches to address CNM, but it is too early to comment on any efforts. We remain very grateful for the heroic efforts of the patient who participated in this study, and their families and caregivers who supported these difficult endeavors," the letter concluded. CNMs are rare, life-threatening disorders that affect skeletal muscles from birth and affect around 4,000 to 5,000 patients in Australia, the European Union, Japan and the U.S. People diagnosed with CNM start experiencing muscle weakness from birth to early adulthood, and many patients die within the first 18 months of life. Those who survive longer usually require intense and uninterrupted medical assistance. Current interventions are merely supportive and not curative.

STRASBOURG, France and PHILADELPHIA, Sept. 16, 2021 /PRNewswire/ -- 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, will present three posters at the 26th Annual Congress of the World Muscle Society (WMS). The WMS meeting is being held in a virtual format on September 20-24, 2021. "We are grateful to the WMS for providing an important platform for neuromuscular disease research as we work to advance the understanding of disease progression, prevalence, and potential therapeutic approaches," said Dynacure's Chief Scientific Officer Belinda Cowling, Ph.D. "These are patient communities in desperate need of treatment options, and we are working with urgency to increase our fundamental knowledge of these diseases and to support ongoing innovation." Dynacure's poster presentations at WMS are as follows: 'Statistical modelling of disease progression in a preclinical model of myotubular myopathy' will be presented during the 'Congenital myopathies – Centronuclear myopathies' poster session on Thursday, September 23 between 16:30 – 18:30 BST / 11:30 – 13:30 EDT. 'ASO-mediated Dnm2 knockdown ameliorates the centronuclear myopathy phenotype of Dnm2RW/+ mice in a dose-dependent manner after disease onset' will be presented during the 'Congenital myopathies - Centronuclear myopathies' poster session on Thursday, September 23 between 16:30 – 18:30 BST / 11:30 – 13:30 EDT. 'An integrated modelling methodology for estimating global incidence and prevalence of hereditary spastic paraplegia subtypes SPG4, SPG11, SPG7 and SPG15' will be presented during the 'Other NMDs' poster session on Thursday, September 23 between 16:30 – 18:30 BST / 11:30 – 13:30 EDT. Dynacure is developing DYN101, an investigational antisense product candidate designed to reduce the expression of dynamin 2 (DNM2), for the treatment of Myotubular and Centronuclear Myopathies (CNM). DYN101 is currently being evaluated in a Phase 1/2 clinical trial, UNITE-CNM (DYN101-C101), at multiple clinical sites in Europe. The FDA has recently accepted Dynacure's Investigational New Drug (IND) application, and sites in the U.S. are currently being explored. DYN101 has been granted orphan drug designation by the FDA and European Medicines Agency (EMA) and rare pediatric disease designation by the FDA. There is currently no FDA- or EMA-approved therapeutic treatment for CNM. 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 to 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 (DNM2) for the treatment of 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 of CNM patients, 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 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 rare 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. For more information, please visit . 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)