Evaluation of Safety, Tolerability, and Changes in Biomarker and Clinical Outcome Assessments of Losmapimod for FSHD1 With Extension

An Open-Label Pilot Study of Losmapimod to Evaluate the Safety, Tolerability, and Changes in Biomarker and Clinical Outcome Assessments in Subjects With Facioscapulohumeral Muscular Dystrophy 1 (FSHD1) With Extension

This clinical trial is a study to evaluate the safety, tolerability, and changes in biomarker and clinical outcome assessments of Losmapimod for patients with Facioscapulohumeral Muscular Dystrophy 1 (FSHD1) with an open-label extension.

This study is a single-centre, open-label pilot study that will investigate the safety, tolerability, pharmacokinetics (PK), and target engagement during long-term dosing with losmapimod tablets in adult subjects with FSHD1. Subjects will be evaluated during an 8- week pre-treatment period (Visits 1 through 3) to establish pre-treatment baseline assessments. Subjects will then be treated with losmapimod for approximately 1 year (Visits 4 through 9) and assessed at relatively regular intervals for change from pre-treatment assessments. All subjects will undergo two muscle biopsies; one at baseline, pre-treatment (Visit 4, Week 8 ± 1 week) and the second on-treatment muscle biopsy approximately 4 or 8 weeks later (Visit 5, Week 14 ± 2 weeks). Up to 8 subjects will have an on-treatment biopsy at 4 weeks and up to 8 subjects will have the on-treatment biopsy at 8 weeks.

Only subjects who participated in and competed all study procedures in the OLS Study treatment period (Week 60) will be eligible to participate in the open-label extension study.

The extension of this study will enable continued investigation of the safety and tolerability of long-term dosing with losmapimod tablets in adult subjects with FSHD1. During the extension study, subjects will receive 15 mg of losmapimod by mouth twice daily for a total of 30 mg by mouth daily. All subjects will attend clinic visits approximately every 24 weeks and have a safety phone call 12 weeks between in-person clinic visits until 90 days after commercial drug is available post regulatory approval or until study termination.

The primary endpoint of the main study is to evaluate the safety and tolerability of long-term dosing of losmapimod tablets in subjects with FSHD1. Secondary endpoints include assessment of target engagement of losmapimod in blood and skeletal muscle and repeated dose pharmacokinetics in subjects with FSHD1 over long-term dosing.

The extension will continue investigation of efficacy with assessment of skeletal muscle by ultrasound as well as the safety, tolerability, pharmacokinetics (PK), and exploration of efficacy measures including whole body skeletal muscle MRI and selected clinical outcome assessments during long- term dosing with losmapimod tablets in adult subjects with FSHD1. Secondary endpoints include assessment of efficacy as evaluated by whole body skeletal muscle MRI parameters, safety and tolerability of long-term dosing, target engagement of losmapimod in blood and skeletal muscle and repeated dose pharmacokinetics in subjects with FSHD1 over long-term dosing.

Inclusion Criteria:

• FSHD1 subjects age 18-65 years.
• Subject will sign and date an informed consent form (ICF).
• 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; genetic confirmation can come from previous testing if verified with appropriate documentation.
• Must 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.
• Both male and female subjects must be willing to practice an approved method of birth control.
• 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.
• Commitment to complete the 2 visits for skeletal muscle needle biopsy and all visits for whole-body MRI.
• Able to complete the RWS, TUG, and FSHD PROs (FSHD-RODS and FSHD-HI) at the screening visit.
• Must have 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 open-label extension study.

Exclusion Criteria:

• 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, history of relevant drug or food allergies; history of cardiovascular or central nervous system disease; history or presence of clinically significant pathology; clinically significant history of mental disease; and history of cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical carcinoma in situ (all 3 with no recurrence for the last 5 years).
• Subject has a known or clinically suspected infection with human immunodeficiency virus or hepatitis B or C viruses.
• Subject has current clinically significant liver (alanine aminotransferase > 2X upper limit of normal or total bilirubin >1.5 X upper limit of normal) or kidney (GFR < 30 mL/min/1.73m2) dysfunction.
• Subject screens positive for hepatitis B surface antigen, hepatitis C virus (HCV) antibody, or antibodies against human immunodeficiency viruses 1 and 2 (HIV 1/HIV 2 antibodies).
• Subject has any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy, or other gastrointestinal tract surgery, except appendectomy).
• 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, the ECG will be repeated 2 more times, and the average of the 3 QTcF values will be used to determine the subject's eligibility.
• Subject has a history of cardiac dysrhythmias requiring anti-arrhythmia treatment(s); or history or evidence of abnormal ECGs that, in the opinion of the investigator or Medical Monitor, 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, as determined by the investigator.
• Vaccination with a live attenuated vaccine within 6 weeks of randomisation.
• Subject has a history of alcohol, analgesic/opioid, and/or illicit drug abuse as defined by the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, in the last 6 months before screening, or a positive test for drugs of abuse at screening.
• Subject has participated in a clinical trial in which they have received an investigational product within the following time period prior to enrolment in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever was longer).
• For subjects that are on drug(s) or supplements that may affect muscle function as determined by the treating physician or included in the list of drugs presented in Section 15: subjects must be on a stable dose of that drug(s) or supplement for at least 3 months prior to enrollment in the study and remain on that stable dose for the duration of the study (list of drugs presented in Section 15). 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.
• Subject has a history of sensitivity to any of the study medications or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicated their participation.
• Female subject is pregnant as determined by positive urine Human Chorionic Gonadotropin (HCG) test at Screening or prior to dosing.
• 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 enrollment.
• Subject has abnormal laboratory results indicative of any significant medical disease that, in the opinion of the investigator or the medical monitor, would preclude the subject's participation in the study.
• Subject, or close relative of the subject, is the investigator or a subinvestigator, research assistant, pharmacist, study coordinator, or other staff 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.