Evaluation of Losmapimod's Safety, Tolerability, and Biomarker Impact in Facioscapulohumeral Muscular Dystrophy 1 (FSHD1) Patients

Trial ID: 2024-512736-29-00
Protocol: FIS-001-2019
Sponsor: Fulcrum Therapeutics Inc.

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Diseases & Conditions

Facioscapulohumeral muscular dystrophy

Objectives

The primary objective of this study is to evaluate the **safety** and **tolerability** of long-term dosing of **losmapimod** tablets in subjects with **Facioscapulohumeral Muscular Dystrophy 1 (FSHD1)**. This is clinically relevant as it aims to determine the potential risks and adverse effects associated with prolonged use of losmapimod, which is crucial for assessing its viability as a therapeutic option for FSHD1 patients.

Participants

The clinical trial involves participants diagnosed with **Facioscapulohumeral Muscular Dystrophy 1 (FSHD1)**, focusing on evaluating the safety and tolerability of long-term dosing of losmapimod tablets. The study population includes both male and female subjects aged between 18 and 65 years. Participants are required to have a confirmed genetic diagnosis of FSHD1, with specific criteria regarding the size of the D4Z4 array on chromosome 4. The trial includes individuals who are not wheelchair or walker-dependent, as indicated by a Clinical Severity Score between 2 and 4 on Ricci’s scale. Participants must be able to complete various assessments, including the RWS, Timed Up and Go (TUG), and FSHD patient-reported outcomes. The trial population selection is based on the completion of the main study through the Week 60 visit, and subjects must comply with study procedures, including scheduled visits and muscle biopsies. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed to evaluate the **safety** and tolerability of long-term dosing of **losmapimod** tablets in subjects with **Facioscapulohumeral Muscular Dystrophy 1 (FSHD1)**. This is a Phase 4, open-label, pilot study with an extension phase. The trial employs a non-randomized, controlled design, focusing on the collection of safety data through adverse events (AEs), clinical laboratory test results, electrocardiograms (ECGs), and vital signs. The trial is expected to run from August 23, 2019, to January 1, 2026, with a maximum treatment period of 321 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, genetic confirmation of FSHD1, and clinical severity score. The screening process includes a confirmatory genetic diagnosis, which may extend the screening window if necessary. Following successful screening, participants will enter the main study phase, which includes regular follow-up visits to monitor safety and collect data on clinical outcomes. The study requires participants to complete specific assessments, including skeletal muscle needle biopsies and whole-body MRI scans, as well as patient-reported outcomes.

The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to ensure participant safety and gather comprehensive data on the long-term effects of the treatment. Participants are expected to remain in the study for the full duration unless conditions arise that necessitate early termination, such as non-compliance with study procedures or the occurrence of significant adverse events. The trial's design and procedures are structured to ensure rigorous data collection while prioritizing participant safety and adherence to ethical standards.

Treatment

The clinical trial involves the administration of **Losmapimod**, an experimental medication, to evaluate its safety and tolerability in subjects with **Facioscapulohumeral Muscular Dystrophy 1 (FSHD1)**. **Losmapimod** is provided in the form of a **film-coated tablet** and is intended for **oral use**. The active substance, **Losmapimod**, is of chemical origin and is manufactured by Fulcrum Therapeutics, Inc. The maximum daily dose of **Losmapimod** is 30 mg, with a total maximum dose of 67,410 mg over the course of the study. The treatment period extends up to 321 days. The medication is not formulated specifically for pediatric use and has been designated as an orphan drug under the designation number EU/3/20/2263.

In this study, **Losmapimod** is the primary investigational product, and no additional non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified. The administration of the drug will be monitored to ensure participant compliance with the dosing schedule. The study aims to gather data on the long-term effects of **Losmapimod** in the target population, focusing on both biomarker changes and clinical outcomes.

Efficacy

The efficacy of Losmapimod in the treatment of **Facioscapulohumeral Muscular Dystrophy 1 (FSHD1)** will be assessed through changes in biomarker and clinical outcome assessments. The primary endpoints focus on safety and tolerability, evaluated through adverse events (AEs), clinical laboratory test results, electrocardiograms (ECGs), and vital signs. The study will involve the administration of Losmapimod in a film-coated tablet form, with a maximum daily dose of 30 mg and a total treatment period of up to 321 days. Participants will undergo various assessments, including skeletal muscle needle biopsies and whole-body magnetic resonance imaging (MRI), to monitor changes in muscle condition and function. Additionally, patient-reported outcomes (PROs) such as the Ricci Clinical Severity Score, Timed Up and Go (TUG) test, and FSHD-specific scales (FSHD-RODS and FSHD-HI) will be utilized to evaluate clinical efficacy. These assessments will be conducted at specified intervals throughout the trial to ensure comprehensive data collection and analysis.

Inclusion and Exclusion Criteria

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Inclusion Criteria

FSHD1 subjects age 18-65 years.
Subject will sign and date an informed consent form (ICF).
Subjects will have a confirmed diagnosis of FSHD1 with 1 to 9 repeats via assessment of the size of the D4Z4 array on chromosome 4 using the calculator provided by the sponsor. Genetic confirmation must be obtained prior to the screening MRI and baseline muscle biopsy; genetic confirmation can come from previous testing if verified with appropriate documentation. Due to stable transmission of repeat sizes within families, subjects with a clinical diagnosis of FSHD who have a first degree relative with a genetically confirmed diagnosis of FSHD1 may be entered into the study for screening and MRI. During screening, a confirmatory genetic diagnosis is conducted. If genetic testing during screening is necessary, the 4-week screening window will not start until the results are obtained and verified by the principal investigator.
Subject will be willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, scheduled needle muscle biopsies, and other study procedures.
Male or female subjects: a. A female subject is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhoea or if of childbearing potential is using a highly effective method for avoidance of pregnancy (refer to Section 5.5) for the duration of the clinical trial and until 90 days following the last dose. The decision to include or exclude women of childbearing potential may be made at the discretion of the investigator and in accordance with local practice in relation to adequate contraception. b. Male subjects must agree to use one of the contraception methods listed in Section 5.5. This criterion must be followed from the time of the first dose of study medication until 90 days after the last study drug dose.
Subject has a Clinical Severity Score between 2 and 4 on Ricci’s scale (scale range is from 0 to 5). Subjects that use a wheelchair or walker for any activity are not permitted to enroll in the study.
Subject commitment to complete the 2 visits for skeletal muscle needle biopsy and all visits for whole-body MRI.
Subject is able to complete the RWS, Timed Up and Go (TUG), and FSHD patientreported outcomes (PROs) (FSHD-RODS and FSHD-HI) at the screening visit.
Subject has an MRI-eligible muscle for biopsy as determined by the central reader.
Subject must complete the main study through the Week 60 visit in order to participate in the extension.

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Exclusion Criteria

Subject has a history of any illness or any clinical condition that might confound the results of the study or pose an additional risk in administering study drug to the subject.
Subject has a known or clinically suspected infection with human immunodeficiency virus or hepatitis B or C viruses.
Subject has current clinically significant liver or kidney dysfunction.
Subject screens positive for hepatitis B surface antigen, HCV antibody, or antibodies against HIV 1/HIV 2 antibodies.
Subject has any condition possibly affecting drug absorption,
Subject has a standard 12-lead ECG demonstrating QT interval by Fredericia (QTcF) >450 msec for male subjects and QTcF >470 msec for female subjects at Screening. If QTcF exceeds 450 msec for males or 470 msec for females.
Subject has a history of cardiac dysrhythmias requiring anti-arrhythmia treatment(s); or history or evidence of abnormal ECGs that would preclude the subject’s participation in the study.
Male subject has a female partner who is planning to become pregnant during the study or within 90 days after the last study drug dose.
Subject has donated blood (of approximately 1 pint [500 mL] or more) or has had any significant loss of blood within 90 days before the first study drug dose
Vaccination with a live attenuated vaccine within 6 weeks of randomisation.
Subject has a history of alcohol, analgesic/opioid, and/or illicit drug abuse.
Subject has participated in a clinical trial in which they have received an investigational product 30 days prior to enrolment in the current study.
For subjects that are on drug(s) or supplements that may affect muscle function must be on a stable dose of that drug(s) or supplement for at least 3 months prior to enrolment in the study and remain on that stable dose.
Subject has a history of sensitivity to any of the study medications or components thereof, or a history of drug or other allergy that contraindicated their participation.
Female subject is pregnant.
Female subject is lactating.
Subject is unwilling or unable to follow the procedures outlined in the protocol.
Subject has any contraindication for MRI (including severe claustrophobia and any shrapnel or metal implants in the body that are not MRI compatible).
Subject was mentally or legally incapacitated up to 2 years prior to enrolment.
Subject has abnormal laboratory results indicative of any significant medical disease That would preclude the subject’s participation in the study.
Subject, or close relative of the subject, is not a staff member directly involved with the conduct of the study at that site.
Subject has taken any anticoagulants for at least 1 month and anti-platelet agents for at least 1 week before each muscle biopsy.