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Safety and efficacy...
Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial
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- Tawil, Rabi (författare)
- Univ Rochester, NY USA
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- Wagner, Kathryn R. (författare)
- Johns Hopkins Sch Med, MD USA
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- Hamel, Johanna I (författare)
- Univ Rochester, NY USA
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- Leung, Doris G. (författare)
- Johns Hopkins Sch Med, MD USA
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- Statland, Jeffrey M. (författare)
- Univ Kansas, KS USA
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- Wang, Leo H. (författare)
- Univ Washington, WA USA
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- Genge, Angela (författare)
- Montreal Neurol Hosp & Inst, Canada
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- Sacconi, Sabrina (författare)
- Nice Univ Hosp, France; Univ Cote Azur, France
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- Lochmueller, Hanns (författare)
- Ottawa Hosp, Canada; Univ Ottawa, Canada
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- Reyes-Leiva, David (författare)
- Hosp Univ Santa Creu & St Pau, Spain
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- Diaz-Manera, Jordi (författare)
- Hosp Univ Santa Creu & St Pau, Spain; Newcastle Univ, England
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- Alonso-Perez, Jorge (författare)
- Hosp Univ Nuestra Senora Candelaria, Spain; Hosp Santa Creu & Sant Pau, Spain
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- Muelas, Nuria (författare)
- Hosp Univ & Politecn La Fe, Spain; Neuromuscular Reference Ctr, Spain; Inst Invest Sanitaria La Fe, Spain; Ctr Invest Biomed Red Enfermedades Raras, Spain; Univ Valencia, Spain
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- Vilchez, Juan J. (författare)
- Inst Invest Sanitaria La Fe, Spain
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- Pestronk, Alan (författare)
- Washington Univ St Louis, MO USA
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- Gibson, Summer (författare)
- Univ Utah, UT USA
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- Goyal, Namita A. (författare)
- Univ Calif Irvine, CA USA
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- Hayward, Lawrence J. (författare)
- Univ Massachusetts, MA USA
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- Johnson, Nicholas (författare)
- Virginia Commonwealth Univ, VA USA
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- LoRusso, Samantha (författare)
- Ohio State Univ, OH USA
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- Freimer, Miriam (författare)
- Univ Massachusetts, MA USA
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- Shieh, Perry B. (författare)
- Univ Calif Los Angeles, CA USA
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- Subramony, S. H. (författare)
- Univ Florida, FL USA
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- van Engelen, Baziel (författare)
- Radboud Univ Nijmegen, Netherlands
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- Kools, Joost (författare)
- Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
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- Dahlqvist Leinhard, Olof (författare)
- Linköpings universitet,Avdelningen för diagnostik och specialistmedicin,Medicinska fakulteten,Centrum för medicinsk bildvetenskap och visualisering, CMIV,AMRA Med, Linkoping, Sweden
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- Widholm, Per (författare)
- Linköpings universitet,Avdelningen för diagnostik och specialistmedicin,Medicinska fakulteten,Region Östergötland, Röntgenkliniken i Linköping,AMRA Med, Linkoping, Sweden
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- Morabito, Christopher (författare)
- Fulcrum Therapeut, MA 02139 USA
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- Moxham, Christopher M. (författare)
- Fulcrum Therapeut, MA 02139 USA
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- Cadavid, Diego (författare)
- Fulcrum Therapeut, MA 02139 USA
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- Mellion, Michelle L. (författare)
- Fulcrum Therapeut, MA 02139 USA
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- Odueyungbo, Adefowope (författare)
- Fulcrum Therapeut, MA 02139 USA
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- Tracewell, William G. (författare)
- Fulcrum Therapeut, MA 02139 USA
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- Accorsi, Anthony (författare)
- Fulcrum Therapeut, MA 02139 USA
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- Ronco, Lucienne (författare)
- Fulcrum Therapeut, MA 02139 USA
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- Gould, Robert J. (författare)
- Fulcrum Therapeut, MA 02139 USA
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- Shoskes, Jennifer (författare)
- Fulcrum Therapeut, MA 02139 USA
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- Rojas, Luis Alejandro (författare)
- Fulcrum Therapeut, MA 02139 USA
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- Jiang, John G. (författare)
- Fulcrum Therapeut, MA 02139 USA
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(creator_code:org_t)
- ELSEVIER SCIENCE INC, 2024
- 2024
- Engelska.
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Ingår i: Lancet Neurology. - : ELSEVIER SCIENCE INC. - 1474-4422 .- 1474-4465. ; 23:5, s. 477-486
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Background Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38 alpha MAPK, a regulator of DUX4 expression, and p38 beta MAPK) for the treatment of facioscapulohumeral muscular dystrophy. Methods We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. Findings Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45<middle dot>7 (SD 12<middle dot>5) years. Least squares mean changes from baseline in DUX4driven gene expression did not differ significantly between the losmapimod (0<middle dot>83 [SE 0<middle dot>61]) and placebo (0<middle dot>40 [0<middle dot>65]) groups (difference 0<middle dot>43 [SE 0<middle dot>56; 95% CI -1<middle dot>04 to 1<middle dot>89]; p=0<middle dot>56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drugrelated) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. Interpretation Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
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Tawil, Rabi
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Wagner, Kathryn ...
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Hamel, Johanna I
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Leung, Doris G.
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Statland, Jeffre ...
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Wang, Leo H.
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visa fler...
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Genge, Angela
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Sacconi, Sabrina
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Lochmueller, Han ...
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Reyes-Leiva, Dav ...
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Diaz-Manera, Jor ...
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Alonso-Perez, Jo ...
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Muelas, Nuria
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Vilchez, Juan J.
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Pestronk, Alan
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Gibson, Summer
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Goyal, Namita A.
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Hayward, Lawrenc ...
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Johnson, Nichola ...
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LoRusso, Samanth ...
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Freimer, Miriam
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Shieh, Perry B.
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Subramony, S. H.
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van Engelen, Baz ...
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Kools, Joost
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Dahlqvist Leinha ...
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Widholm, Per
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Morabito, Christ ...
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Moxham, Christop ...
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Cadavid, Diego
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Mellion, Michell ...
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Odueyungbo, Adef ...
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Tracewell, Willi ...
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Accorsi, Anthony
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Ronco, Lucienne
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Gould, Robert J.
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Shoskes, Jennife ...
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Rojas, Luis Alej ...
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Jiang, John G.
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- MEDICIN OCH HÄLSOVETENSKAP
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