Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) (FSHD)

• ClinicalTrials.gov Identifier: NCT04003974
• Recruitment Status: Completed
• First Posted: July 1, 2019
• Last Update Posted: February 10, 2022
• Sponsor: Fulcrum Therapeutics
• Information provided by (Responsible Party): Fulcrum Therapeutics

Tracking Information

• First Submitted Date: June 25, 2019
• First Posted Date: July 1, 2019
• Last Update Posted Date: February 10, 2022
• Actual Study Start Date: August 9, 2019
• Actual Primary Completion Date: January 28, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 22, 2020)

DUX4 activity [ Time Frame: Week 16 or Week 36 if the biopsy could not be obtained at Week 16 due to COVID-19 ]

Change from baseline in DUX4 activity will be measured by quantitative polymerase chain reaction (qPCR) of skeletal muscle using a subset of DUX4-regulated gene transcripts.

Original Primary Outcome Measures (submitted: June 28, 2019)

DUX4 activity [ Time Frame: Week 16 ]

Change from baseline in DUX4 activity will be measured by quantitative polymerase chain reaction (qPCR) of skeletal muscle using a subset of DUX4-regulated gene transcripts.

Current Secondary Outcome Measures (submitted: May 22, 2020)

• Treatment-Emergent Adverse Events [ Time Frame: Date of enrollment and Weeks 4, 12, 16, 24, 36, 48 and 7 days after the last dose of study drug ]
  To evaluate the safety and tolerability of Losmapimod, the incidence of treatment-emergent adverse events will be assessed by clinically significant laboratory test results, ECGs, and vital signs.
• Muscle Fat Fraction [ Time Frame: Week 12, Week 24 if applicable and Week 48 ]
  The change from baseline in muscle fat fraction (MFF) will be measured by musculoskeletal (MSK) magnetic resonance imaging (MRI).
• Lean Muscle Volume [ Time Frame: Week 12, Week 24 if applicable and Week 48 ]
  The change from baseline in skeletal lean muscle lean volume will be measured by musculoskeletal (MSK) magnetic resonance imaging (MRI).
• Muscle Fat Infiltration [ Time Frame: Week 12, Week 24 if applicable and Week 48 ]
  The change from baseline in skeletal muscle tissue replacement by fat will be measured by musculoskeletal (MSK) magnetic resonance imaging (MRI).
• Plasma Concentrations of Losmapimod [ Time Frame: Weeks 4, 12, 16, 24, 36 and 48 ]
  Blood samples will be collected to measure the plasma concentration of losmapimod at specified timepoints.
• Concentration of Losmapimod in Skeletal Muscle [ Time Frame: Week 16 or Week 36 if the biopsy could not be obtained at Week 16 due to COVID-19 ]
  Muscle biopsies will be collected at two specified timepoints to measure the concentration of losmapimod in skeletal muscle.
• Target Engagement [ Time Frame: Week 16 or Week 36 ]
  Change from baseline in phospho-HSP27 and ratio of pHSP27/total HSP27 will be measured in peripheral whole blood and muscle.

Original Secondary Outcome Measures (submitted: June 28, 2019)

• Treatment-Emergent Adverse Events [ Time Frame: Week 25 ]
  Incidence of treatment-emergent adverse events assessed by clinically significant laboratory test results, ECGs, and vital signs.
• Plasma Concentrations of Losmapimod [ Time Frame: Week 24 ]
  Blood samples will be collected to measure the plasma concentration of losmapimod at specified timepoints.
• Concentration of Losmapimod in Skeletal Muscle [ Time Frame: Week 16 ]
  Muscle biopsies will be collected at two specified timepoints to measure the concentration of losmapimod in skeletal muscle.
• Target Engagement [ Time Frame: Week 16 ]
  Change from baseline in phospho-HSP27 and ratio of pHSP27/total HSP27 will be measured in peripheral whole blood and muscle.

Current Other Pre-specified Outcome Measures (submitted: May 22, 2020)

• Reachable Work Space (RWS) [ Time Frame: Weeks 4, 12, 24 and 36 ]
  Subjects are seated in front of a 3D camera and asked to perform a standardized upper extremity movement protocol under the supervision of a study clinical evaluator with and without weights.
• Timed Up and Go (TUG). [ Time Frame: Weeks 4, 12, 24 and 36 ]
  Subjects are timed as they start from a seated or laying position, rise to a standing position, walk a total of 6 meters and then return to either a seated or laying position.
• Muscle Strength [ Time Frame: Weeks 4, 12, 24, 36 and 48 ]
  Muscle strength will be assessed by Hand-Held Quantitative Dynamometry.
• Motor Function Measure (MFM) Domain 1. [ Time Frame: Weeks 12, 24, 36 and 48 ]
  The MFM domain 1 is a validated evaluator administered functional measure for neuromuscular disorders, with 13 items related to standing and transfers.
• FSHD Health Index (FSHD-HI). [ Time Frame: Weeks 4, 12, 24, 36 and 48 ]
  The HI is a 15 domain questionnaire designed and based on patient interviews to measure total FSHD health-related quality-of-life, including both motor impairment and the social and emotional impact of FSHD. 116 questions are combined into a total score, the score is transformed onto a percentage scale, with 100 representing maximal disability, and lower scores representing decreasing disability.
• Patients' Global Impression of Change (PGIC). [ Time Frame: Weeks 4, 12, 16, 24, 36 and 48 ]
  The PGIC is a single question that assesses on a scale of 1-7 if there has been an improvement, decline or no change in clinical status.
• Muscle Disease Transcripts [ Time Frame: Week 16 or Week 36 ]
  To evaluate the change from baseline in inflammatory, immune, apoptotic, and muscle disease transcripts in muscle biopsies by quantitative PCR analysis.
• Circulating Proteins [ Time Frame: Weeks 4, 12, 16, 24, 36 and 48 ]
  To evaluate the change from baseline in circulating proteins in plasma and serum by ELISA analysis.

Original Other Pre-specified Outcome Measures (submitted: June 28, 2019)

• Muscle Lean Tissue Volume [ Time Frame: Week 24 ]
  Change from baseline in skeletal muscle lean tissue volume as measured by whole body magnetic resonance imaging (MRI).
• Muscle Tissue Replacement by Fat [ Time Frame: Week 24 ]
  Change from baseline in skeletal muscle tissue replacement by fat as measured by whole body magnetic resonance imaging (MRI).
• Muscle Disease Transcripts [ Time Frame: Week 24 ]
  Change from baseline in muscle disease transcripts related to immune function in muscle biopsy and in plasma and serum.
• Reachable Work Space (RWS) [ Time Frame: Week 25 ]
  Subjects are seated in front of a 3D camera and asked to perform a standardized upper extremity movement protocol under the supervision of a study clinical evaluator with and without weights.
• Timed Up and Go (TUG). [ Time Frame: Week 25 ]
  Subjects are timed as they start from a seated or laying position, rise to a standing position, walk a total of 6 meters and then return to either a seated or laying position.
• Muscle Strength [ Time Frame: Week 25 ]
  Muscle strength will be assessed by Hand-Held Quantitative Dynamometry.
• Motor Function Measure (MFM) Domain 1. [ Time Frame: Week 25 ]
  The MFM domain 1 is a validated evaluator administered functional measure for neuromuscular disorders, with 13 items related to standing and transfers.
• FSHD Health Index (FSHD-HI). [ Time Frame: Week 25 ]
  The HI is a 15 domain questionnaire designed and based on patient interviews to measure total FSHD health-related quality-of-life, including both motor impairment and the social and emotional impact of FSHD. 116 questions are combined into a total score, the score is transformed onto a percentage scale, with 100 representing maximal disability, and lower scores representing decreasing disability.
• Patients' Global Impression of Change (PGIC). [ Time Frame: Week 25 ]
  The PGIC is a single question that assesses on a scale of 1-7 if there has been an improvement, decline or no change in clinical status.

Descriptive Information

• Brief Title: Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD)
• Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 48-Week, Parallel-Group Study of the Efficacy and Safety of Losmapimod in Treating Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD)
• Brief Summary: This is a study to evaluate the safety and efficacy of Losmapimod in treating patients with Facioscapulohumeral Muscular Dystrophy (FSHD) over 48 weeks.

Detailed Description

This study is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter study designed to evaluate the efficacy and safety of losmapimod in treating patients with Facioscapulohumeral Muscular Dystrophy (FSHD) over 48 weeks. Patients will participate in this study for approximately 53 weeks. This will include a 4-week screening period, a 48-week, placebo-controlled treatment period and a 7 day safety follow-up period. Patients must have a confirmed diagnosis of FSHD1 and genetic confirmation must be obtained prior to the screening MRI and baseline muscle biopsy. Patients will be randomized to receive 15 mg of losmapimod or placebo twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily for 48 weeks. All patients will be asked to attend the study clinic for each scheduled visit.

The primary endpoint of the study is to evaluate the efficacy of losmapimod in inhibiting or reducing expression of DUX4, as measured by a subset of DUX4-regulated gene transcripts in skeletal muscle biopsies of FSHD patients. Secondary endpoints include evaluation of the safety and tolerability of losmapimod, the plasma concentrations of losmapimod, levels of losmapimod in skeletal muscle and losmapimod target engagement in blood and skeletal muscle in FSHD patients.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

This study is a randomized, double-blind, placebo-controlled, 48-week parallel-group study.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

This study will be performed in a double-blind fashion. The investigator, study staff, subjects, sponsor and monitor will remain blinded to the treatment until study closure.

Primary Purpose: Treatment

• Condition: Facioscapulohumeral Muscular Dystrophy (FSHD)

Intervention

• Drug: Losmapimod
  This study includes a 48 week treatment period. Patients will receive Losmapimod 15 mg twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily. The study drug should be taken with food and the date and time of each dose taken recorded in the subject diary.
• Drug: Placebo oral tablet
  This study includes a 48 week treatment period. Patients will receive Placebo twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily. The placebo tablets are identical to the Losmapimod tablets. Placebo should be taken with food and the date and time of each dose taken recorded in the subject diary.
  Other Name: Placebo

Study Arms

• Experimental: Treatment
  FSHD1 patients with genetic confirmation will receive Losmapimod 15 mg twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily for 48 weeks.
  Intervention: Drug: Losmapimod
• Placebo Comparator: Placebo
  FSHD1 patients with genetic confirmation will receive a Placebo twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily for 48 weeks.
  Intervention: Drug: Placebo oral tablet

Publications *

• Barbour AM, Sarov-Blat L, Cai G, Fossler MJ, Sprecher DL, Graggaber J, McGeoch AT, Maison J, Cheriyan J. Safety, tolerability, pharmacokinetics and pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers. Br J Clin Pharmacol. 2013 Jul;76(1):99-106. doi: 10.1111/bcp.12063.
• Cheriyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SM, Maki-Petaja KM, Collier DJ, Morgan J, Fang Z, Willette RN, Lepore JJ, Cockcroft JR, Sprecher DL, Wilkinson IB. Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. Circulation. 2011 Feb 8;123(5):515-23. doi: 10.1161/CIRCULATIONAHA.110.971986. Epub 2011 Jan 24.
• de Greef JC, Lemmers RJ, van Engelen BG, Sacconi S, Venance SL, Frants RR, Tawil R, van der Maarel SM. Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD. Hum Mutat. 2009 Oct;30(10):1449-59. doi: 10.1002/humu.21091.
• Han JJ, Kurillo G, Abresch RT, de Bie E, Nicorici A, Bajcsy R. Reachable workspace in facioscapulohumeral muscular dystrophy (FSHD) by Kinect. Muscle Nerve. 2015 Feb;51(2):168-75. doi: 10.1002/mus.24287. Epub 2014 Nov 19.
• Jagannathan S, Shadle SC, Resnick R, Snider L, Tawil RN, van der Maarel SM, Bradley RK, Tapscott SJ. Model systems of DUX4 expression recapitulate the transcriptional profile of FSHD cells. Hum Mol Genet. 2016 Oct 15;25(20):4419-4431. doi: 10.1093/hmg/ddw271.
• Statland JM, Tawil R. Risk of functional impairment in Facioscapulohumeral muscular dystrophy. Muscle Nerve. 2014 Apr;49(4):520-7. doi: 10.1002/mus.23949. Epub 2014 Feb 10.
• Wang LH, Friedman SD, Shaw D, Snider L, Wong CJ, Budech CB, Poliachik SL, Gove NE, Lewis LM, Campbell AE, Lemmers RJFL, Maarel SM, Tapscott SJ, Tawil RN. MRI-informed muscle biopsies correlate MRI with pathology and DUX4 target gene expression in FSHD. Hum Mol Genet. 2019 Feb 1;28(3):476-486. doi: 10.1093/hmg/ddy364.
• Jagannathan S, de Greef JC, Hayward LJ, Yokomori K, Gabellini D, Mul K, Sacconi S, Arjomand J, Kinoshita J, Harper SQ. Meeting report: the 2021 FSHD International Research Congress. Skelet Muscle. 2022 Jan 17;12(1):1. doi: 10.1186/s13395-022-00287-8.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 6, 2020): 80
• Original Estimated Enrollment (submitted: June 28, 2019): 66
• Actual Study Completion Date: January 28, 2021
• Actual Primary Completion Date: January 28, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• The patient must have consented to participate and must have provided signed, dated and witnessed IRB-approved informed consent form that conforms to federal and institutional guidelines.
• Male or female subjects
• Patients must be between 18 and 65 years of age, inclusive
• Confirmed diagnosis of FSHD1 with 1 to 9 repeats via assessment of the size of the D4Z4 array on chromosome 4. Genetic confirmation must be obtained prior to the screening MRI and baseline muscle biopsy.
• Clinical severity score of 2 to 4 (RICCI Score; Range 0-5), inclusive at screening
• Must have a MRI-eligible muscle for biopsy
• Must be willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines and other study procedures.
• Will practice an approved method of birth control

Exclusion Criteria:

• Has a history of any illness or any clinical condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject. This may include, but is not limited to, a history of relevant drug or food allergies; history of cardiovascular or central nervous system disease; neuromuscular diseases except FSHD (eg, myopathy, neuropathy, neuromuscular junction disorders); or clinically significant history of mental disease.
• For subjects who are on drug(s) or supplements that may affect muscle function, as determined by the treating physician, or that are included in the list of drugs presented in the protocol, subjects must be on a stable dose of that drug(s) or supplement for at least 3 months prior to the first dose of study drug and remain on that stable dose for the duration of the study. Changes to the dose or treatment discontinuation during the study can only be done for strict medical reasons by the treating physician with clear documentation and notification to the sponsor.
• Acute or chronic history of liver disease or known to have current alanine aminotransferase ≥2 × upper limit of normal (ULN) or total bilirubin >1.5 × ULN, or known history of hepatitis B or C.
• Known severe renal impairment (defined as a glomerular filtration rate of <30 mL/min/1.73m2).
• Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or antibodies against human immunodeficiency virus (HIV)-1 and -2.
• Male subjects with a female partner who is planning to become pregnant during the study or within 90 days after the last dose of study drug.
• Use of another investigational product within 30 days or 5 half-lives (whichever is longer), or according to local regulations, or currently participating in a study with an investigational product. Note: concurrent participation in other non-drug studies may be acceptable if confirmed in writing by the sponsor.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, France, Spain, United States
• Removed Location Countries: Germany

Administrative Information

• NCT Number: NCT04003974
• Other Study ID Numbers: FIS-002-2019
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Fulcrum Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Fulcrum Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Michelle Mellion, MD; Fulcrum Therapeutics

• PRS Account: Fulcrum Therapeutics
• Verification Date: February 2022