Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial.

Autor:	Thornton CA; Neurology, University of Rochester, Rochester, NY, USA., Moxley RT 3rd; Neurology, University of Rochester, Rochester, NY, USA., Eichinger K; Neurology, University of Rochester, Rochester, NY, USA., Heatwole C; Center for Health and Technology, University of Rochester, Rochester, NY, USA., Mignon L; Translational Medicine, Ionis Pharmaceuticals, Carlsbad, CA, USA., Arnold WD; Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA., Ashizawa T; Neuroscience Research Program, Houston Methodist Research Institute, Houston, TX, USA., Day JW; Neuromuscular Medicine, Stanford University, Palo Alto, CA, USA., Dent G; Neurodegeneration Development Unit, Biogen, Cambridge, MA, USA., Tanner MK; Neurology, University of Rochester, Rochester, NY, USA., Duong T; Neuromuscular Medicine, Stanford University, Palo Alto, CA, USA., Greene EP; Neuromuscular Clinic, Houston Methodist Research Institute, Houston, TX, USA., Herbelin L; Neurology, University of Kansas Medical Center, Kansas City, KS, USA., Johnson NE; Neurology, University of Utah, Salt Lake City, UT, USA., King W; Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA., Kissel JT; Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA., Leung DG; Center for Genetic Muscle Disorders, Kennedy Krieger Institute, Baltimore, MD, USA., Lott DJ; Physical Therapy, University of Florida, Gainesville, FL, USA., Norris DA; Pharmacokinetics and Clinical Pharmacology, Ionis Pharmaceuticals, Carlsbad, CA, USA., Pucillo EM; Neurology, University of Utah, Salt Lake City, UT, USA., Schell W; Neuromuscular Clinic, Houston Methodist Research Institute, Houston, TX, USA., Statland JM; Neurology, University of Kansas Medical Center, Kansas City, KS, USA., Stinson N; Center for Genetic Muscle Disorders, Kennedy Krieger Institute, Baltimore, MD, USA., Subramony SH; Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA., Xia S; Biometrics, Ionis Pharmaceuticals, Carlsbad, CA, USA., Bishop KM; Clinical Development, Ionis Pharmaceuticals, Carlsbad, CA, USA., Bennett CF; Ionis Pharmaceuticals, Carlsbad, CA, USA. Electronic address: fbennett@ionisph.com.
Jazyk:	angličtina
Zdroj:	The Lancet. Neurology [Lancet Neurol] 2023 Mar; Vol. 22 (3), pp. 218-228.
DOI:	10.1016/S1474-4422(23)00001-7
Abstrakt:	Background: Myotonic dystrophy type 1 results from an RNA gain-of-function mutation, in which DM1 protein kinase (DMPK) transcripts carrying expanded trinucleotide repeats exert deleterious effects. Antisense oligonucleotides (ASOs) provide a promising approach to treatment of myotonic dystrophy type 1 because they reduce toxic RNA levels. We aimed to investigate the safety of baliforsen (ISIS 598769), an ASO targeting DMPK mRNA. Methods: In this dose-escalation phase 1/2a trial, adults aged 20-55 years with myotonic dystrophy type 1 were enrolled at seven tertiary referral centres in the USA and randomly assigned via an interactive web or phone response system to subcutaneous injections of baliforsen 100 mg, 200 mg, or 300 mg, or placebo (6:2 randomisation at each dose level), or to baliforsen 400 mg or 600 mg, or placebo (10:2 randomisation at each dose level), on days 1, 3, 5, 8, 15, 22, 29, and 36. Sponsor personnel directly involved with the trial, participants, and all study personnel were masked to treatment assignments. The primary outcome measure was safety in all participants who received at least one dose of study drug up to day 134. This trial is registered with ClinicalTrials.gov (NCT02312011), and is complete. Findings: Between Dec 12, 2014, and Feb 22, 2016, 49 participants were enrolled and randomly assigned to baliforsen 100 mg (n=7, one patient not dosed), 200 mg (n=6), 300 mg (n=6), 400 mg (n=10), 600 mg (n=10), or placebo (n=10). The safety population comprised 48 participants who received at least one dose of study drug. Treatment-emergent adverse events were reported for 36 (95%) of 38 participants assigned to baliforsen and nine (90%) of ten participants assigned to placebo. Aside from injection-site reactions, common treatment-emergent adverse events were headache (baliforsen: ten [26%] of 38 participants; placebo: four [40%] of ten participants), contusion (baliforsen: seven [18%] of 38; placebo: one [10%] of ten), and nausea (baliforsen: six [16%] of 38; placebo: two [20%] of ten). Most adverse events (baliforsen: 425 [86%] of 494; placebo: 62 [85%] of 73) were mild in severity. One participant (baliforsen 600 mg) developed transient thrombocytopenia considered potentially treatment related. Baliforsen concentrations in skeletal muscle increased with dose. Interpretation: Baliforsen was generally well tolerated. However, skeletal muscle drug concentrations were below levels predicted to achieve substantial target reduction. These results support the further investigation of ASOs as a therapeutic approach for myotonic dystrophy type 1, but suggest improved drug delivery to muscle is needed. Funding: Ionis Pharmaceuticals, Biogen. Competing Interests: Declaration of interests CFB, LM, DAN, and SX are employees of Ionis Pharmaceuticals, which funded the trial, and own stock options in Ionis Pharmaceuticals. CAT received support from Ionis Pharmaceuticals for consultation and sponsored research and carried out collaborative research with CFB under National Institutes of Health (NIH) grant U01NS072323; provides consulting to Biogen, Vertex, Entrada, and Avidity Biosciences; received honoraria from Sanofi; served on scientific advisory boards for Dyne and Pepgen; and serves on the Myotonic Dystrophy Foundation Board. KE received consulting fees from Ionis Pharmaceuticals, Avidity, and Dyne Therapeutics; and received honoraria from the Myotonic Dystrophy Foundation and the Muscular Dystrophy Association. CH receives royalties for the use of multiple disease specific instruments; provided consultation to Biogen, Ionis Pharmaceuticals, aTyr Pharma, AMO Pharma, Acceleron Pharma, Cytokinetics, Expansion Therapeutics, Harmony Biosciences, Regeneron Pharmaceuticals, Astellas Pharmaceuticals, AveXis, Recursion Pharmaceuticals, IRIS Medicine, Takeda Pharmaceutical Company, Scholar Rock, Avidity Biosciences, Novartis Pharmaceuticals Corporation, SwanBio Therapeutics, and the Marigold Foundation; and receives grant support from the Department of Defense, Duchenne UK, Parent Project Muscular Dystrophy, Recursion Pharmaceuticals, Swan Bio Therapeutics, Neurocrine Biosciences, the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, the Friedreich's Ataxia Research Alliance, Cure Spinal Muscular Atrophy, and the Amyotrophic Lateral Sclerosis Association. WDA received a consulting fee and grant funding from Avidity Biosciences and a consulting fee from Dyne Therapeutics. TA received a grant or contract from the Myotonic Dystrophy Foundation and was on the Myotonic Dystrophy Foundation scientific advisory board. JWD received consulting fees from Affinia Therapeutics and Shift Therapeutics; honoraria from Biogen and Roche Pharmaceuticals; participated in advisory boards for AMO Pharmaceuticals, Avidity Biosciences, Biogen, Cytokinetics, Epirium Bio, Ionis Pharmaceuticals, Kate Therapeutics, Novartis Gene Therapies, Roche/Genentech Pharmaceuticals, Sarepta Therapeutics, Scholar Rock, Shift Therapeutics, and Vertex Pharmaceuticals; has leadership roles for Muscular Dystrophy Association, Myotonic Dystrophy Foundation, and Cure Congenital Muscular Dystrophy. GD is an employee of Biogen and owns stock options in Biogen. TD received consulting fees from Dyne, Roche/Genentech Pharmaceuticals, Biogen, Trinds, and ATOM; speaking honoraria for Genentech, Biogen, Roche, and Sarepta; has served on Advisory boards for Novartis, Pfizer, Actigraph, Scholar Rock, Sarepta, Sanofi Genzyme, and Cytokinetics; has unpaid leadership roles for myotonic dystrophy exercise recommendations and physical therapy guidance and the CureSMA Medical Advisory Council. NEJ received royalties or licenses from University of Rochester; received consulting fees from AMO Pharma Fulcrum Therapeutics, Avidity Biosciences, Dyne, Vertex, Arthex, and Entrada; participated in a Data Safety Monitoring Board for Biogen; and owns stock or stock options in ML Bio Solutions. DJL received funding from the DuchenneXchange Advisory Council, Cure Duchenne. JMS received consulting fees from Dyne Therapeutics, Roche, Avidity, ML Bio, Fulcrum Therapeutics, MT Pharma, Sarepta, and Amylyx; payment or honorarium from MDA; and stock or stock options from Dyne Therapeutics. SHS received consulting fees from Reata Pharmaceuticals, Avidity Biosciences, and Dyne therapeutics. KMB was an employee of Ionis Pharmaceuticals at the time the trial was conducted; is a current employee of and owns stock options in Acadia Pharmaceuticals; is an advisor to non-profit organisations Myotonic Dystrophy Foundation and SMA Foundation; and is a Board Member of DTx Pharma. CFB is a Board member of Flamingo Therapeutics and Hereditary Disease Foundation. RM is the chair of three clinical trials in Duchenne muscular dystrophy funded by TRiNDS. All other authors declare no competing interests. (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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