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

  • Lancet Neurol. 2023 Mar;22(3):218-228. doi: 10.1016/S1474-4422(23)00001-7.
Charles A Thornton  1 ,  Richard Thomas Moxley 3rd  1 ,  Katy Eichinger  1 ,  Chad Heatwole  2 ,  Laurence Mignon  3 ,  W David Arnold  4 ,  Tetsuo Ashizawa  5 ,  John W Day  6 ,  Gersham Dent  7 ,  Matthew K Tanner  1 ,  Tina Duong  6 ,  Ericka P Greene  8 ,  Laura Herbelin  9 ,  Nicholas E Johnson  10 ,  Wendy King  4 ,  John T Kissel  4 ,  Doris G Leung  11 ,  Donovan J Lott  12 ,  Daniel A Norris  13 ,  Evan M Pucillo  10 ,  Wendy Schell  8 ,  Jeffrey M Statland  9 ,  Nikia Stinson  11 ,  Sub H Subramony  14 ,  Shuting Xia  15 ,  Kathie M Bishop  16 ,  C Frank Bennett  17
Affiliations
  • 1. Neurology, University of Rochester, Rochester, NY, USA.
  • 2. Center for Health and Technology, University of Rochester, Rochester, NY, USA.
  • 3. Translational Medicine, Ionis Pharmaceuticals, Carlsbad, CA, USA.
  • 4. Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
  • 5. Neuroscience Research Program, Houston Methodist Research Institute, Houston, TX, USA.
  • 6. Neuromuscular Medicine, Stanford University, Palo Alto, CA, USA.
  • 7. Neurodegeneration Development Unit, Biogen, Cambridge, MA, USA.
  • 8. Neuromuscular Clinic, Houston Methodist Research Institute, Houston, TX, USA.
  • 9. Neurology, University of Kansas Medical Center, Kansas City, KS, USA.
  • 10. Neurology, University of Utah, Salt Lake City, UT, USA.
  • 11. Center for Genetic Muscle Disorders, Kennedy Krieger Institute, Baltimore, MD, USA.
  • 12. Physical Therapy, University of Florida, Gainesville, FL, USA.
  • 13. Pharmacokinetics and Clinical Pharmacology, Ionis Pharmaceuticals, Carlsbad, CA, USA.
  • 14. Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA.
  • 15. Biometrics, Ionis Pharmaceuticals, Carlsbad, CA, USA.
  • 16. Clinical Development, Ionis Pharmaceuticals, Carlsbad, CA, USA.
  • 17. Ionis Pharmaceuticals, Carlsbad, CA, USA. Electronic address: [email protected].
PMID: 36804094 DOI: 10.1016/S1474-4422(23)00001-7
Abstract

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.

Products