Efficacy and Safety Evaluation of Losmapimod in Patients with Facioscapulohumeral Muscular Dystrophy: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2024-512732-30-00
Protocol: FIS-002-2019
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 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 ensuring patient safety and guiding therapeutic decisions in managing FSHD1.

Secondary objectives include evaluating the plasma concentrations of losmapimod in FSHD1 subjects. This will provide insights into the pharmacokinetics of losmapimod, which is important for understanding its absorption, distribution, metabolism, and excretion in this patient population.

Participants

The clinical trial involves a total of **69 participants** diagnosed with **Facioscapulohumeral Muscular Dystrophy 1 (FSHD1)**. The study population includes both male and female subjects, aged between 18 and 65 years. Participants were selected based on their ability to understand and provide informed consent, and a confirmed diagnosis of FSHD1 with 1 to 9 repeats, verified through genetic testing. The trial population is characterized by a clinical severity score of 2 to 4 on the RICCI scale, and subjects who use a wheelchair or walker are excluded. Participants must have an MRI-eligible muscle for biopsy and be willing to comply with study procedures, including contraceptive guidelines. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study includes a vulnerable population, as indicated by the inclusion of both genders and the age range specified.

Plans and Procedures

The clinical trial is a **Phase 2**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of **Losmapimod** in subjects with **Facioscapulohumeral Muscular Dystrophy 1 (FSHD1)**. The trial is structured as a parallel-group study with an open-label extension (OLE) and is set to last for 48 weeks. The primary objective is to assess the safety and tolerability of long-term dosing of Losmapimod, with secondary endpoints focusing on plasma concentrations of the drug at every 12-week interval. Participants will be randomly assigned to receive either Losmapimod or a placebo, with stratification based on the number of FSHD repeats to ensure balanced treatment allocation.

The trial will commence with an inclusion (screening) visit, where potential participants will undergo genetic confirmation of FSHD1, clinical severity assessment, and MRI eligibility for muscle biopsy. This screening phase will last up to four weeks, during which eligibility criteria such as age, clinical severity score, and willingness to comply with study procedures will be verified. Following successful screening, participants will enter the treatment phase, which includes regular follow-up visits every 12 weeks to monitor safety, tolerability, and drug plasma levels. These visits will involve assessments such as adverse event monitoring, clinical laboratory tests, ECGs, vital signs, and physical examinations.

The expected duration of participant involvement is approximately 48 weeks, with the possibility of early termination if significant adverse events occur or if the participant is unable to comply with study requirements. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the long-term effects of Losmapimod. Participants are required to adhere to contraceptive guidelines throughout the study and for 90 days after the last dose. The trial is anticipated to end by October 31, 2025, with recruitment having started on December 19, 2019.

Treatment

The clinical trial involves the administration of **Losmapimod**, an experimental medication, to evaluate its efficacy and safety in treating subjects with **Facioscapulohumeral Muscular Dystrophy (FSHD)**. **Losmapimod** is provided in the form of a **film-coated tablet** and is administered orally. The maximum daily dose is 30 mg, with a total maximum dose of 65,520 mg over the course of the study. The treatment period extends up to 312 days. The active substance in **Losmapimod** is of chemical origin, and the medication is not formulated specifically for pediatric use. The sponsor product code for **Losmapimod** is FTX-1821, and it is designated as an orphan drug under the number EU/3/20/2263.

In this study, a placebo is used as a comparator treatment to assess the efficacy of **Losmapimod**. The placebo is administered in a manner identical to the experimental medication, ensuring that the study remains double-blind. Participants are randomly assigned to either the **Losmapimod** group or the placebo group, maintaining the integrity of the trial's parallel-group design. Compliance with the dosing schedule is monitored throughout the study to ensure accurate assessment of the medication's effects.

Efficacy

The efficacy of Losmapimod in treating **Facioscapulohumeral Muscular Dystrophy (FSHD)** will be assessed through a Phase 2, randomized, double-blind, placebo-controlled, 48-week, parallel-group study. The primary endpoint focuses on the safety and tolerability of long-term treatment with Losmapimod, evaluated through adverse events (AEs), clinical laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations. The secondary endpoint involves measuring the plasma concentrations of Losmapimod after long-term dosing, with assessments conducted at every 12-week interval. These efficacy parameters will be collected and analyzed using standardized methods to ensure the reliability and validity of the results. The study will include an open-label extension (OLE) to further evaluate the long-term effects of the treatment.

Inclusion and Exclusion Criteria

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Inclusion Criteria

"1. Capable of understanding the written informed consent, and providing signed, dated, and witnessed written informed consent. 2. Male or female subjects between the ages of 18 and 65 years, inclusive. 3. Confirmed diagnosis of FSHD1 with 1 to 9 repeats via assessment of the size of the D4Z4 array on chromosome 4. Randomization will be stratified to ensure that treatment allocation is balanced across FSHD repeat number categories (ie, 1 to 3 repeats versus 4 to 9 repeats). Genetic confirmation must be obtained before the subject is randomized and before the baseline muscle biopsy is performed; genetic confirmation can come from previous testing if verified with appropriate documentation from an accredited laboratory. 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 assessments, including 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. 4. Clinical severity score of 2 to 4 (RICCI score; range 0-5), inclusive, at screening. Subjects who use a wheelchair or walker for any activity are not permitted to enroll in the study. 5. Has an MRI-eligible muscle for biopsy, as determined by a central reader. 6. Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures. 7. Willing to practice an approved method of birth control: − A female subject is eligible to participate if she is of non-child-bearing potential, defined as premenopausal females with permanent sterilization (includes hysterectomy, bilateral oophorectomy, or bilateral salpingectomy in a female subject of any age); or postmenopausal, defined as 12 months of spontaneous amenorrhea; or, if of child-bearing potential, if she is using a highly effective method for avoidance of pregnancy and will continue to use these methods for the duration of the study and until 90 days after the last dose of study drug. The decision to include or exclude women of child-bearing potential may be made at the discretion of the investigator and in accordance with local practice in relation to adequate contraception. − Male subjects must agree to use one of the contraception methods listed in the protocol. This criterion must be followed for the duration of the study and until 90 days after the last dose of study drug. "

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Exclusion Criteria

"1. 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. 2. Previously diagnosed cancer that has not been in complete remission for at least 5 years. Localized carcinomas of the skin and carcinoma in situ of the cervix that have been resected or ablated for cure are not exclusionary. 3. 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 Appendix 13.2: 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. 4. History of febrile illness within 5 days before randomization. Subjects who were healthy during screening but develop febrile illness in the 5 days before randomization need to have the baseline visit postponed until the febrile illness is fully resolved. Once the febrile illness is fully resolved, the subject’s baseline visit can be scheduled. The duration of the screening visit in such cases can be extended for up to 35 days. 5. Known active tuberculosis, active opportunistic, or life-threatening infections. 6. 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. 7. Known severe renal impairment (defined as a glomerular filtration rate of <30 mL/min/1.73m2). 8. Positive screen for hepatitis B surface antigen (HbsAg), hepatitis C virus (HCV) antibody, or antibodies against human immunodeficiency virus (HIV)-1 and -2. 9. Standard 12-lead ECG demonstrating QTcF >450 msec for male subjects or 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. 10. 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. 11. Blood donation (of approximately 1 pint [500 mL] or more) or any significant loss of blood within 90 days before the first dose of study drug, as determined by the investigator. 12. Vaccination with a live attenuated vaccine within 6 weeks of randomization and throughout the study. 13. Use of any anticoagulants for at least 1 month and antiplatelet agents for at least 1 week before the baseline biopsy, as they increase the risk of hematomas following skeletal muscle biopsy. 14. 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. 15. Positive pregnancy test or is known to be pregnant or lactating. All female subjects of child-bearing potential must have a negative serum β-human chorionic gonadotropin (βhCG) pregnancy test at screening and a negative urine pregnancy test prior to randomization. "
"16. Alcohol, analgesic/opioid, and/or illicit drug abuse, as defined by the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (American Psychiatric Association, 2013), in the last 6 months before screening or a positive test for drugs of abuse at screening. 17. Any current mental condition (psychiatric disorder, senility, or dementia) that, in the opinion of the investigator, may affect study compliance or prevent understanding of the aims, investigational procedures, or possible consequences of the study. 18. 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 prospective study with an investigational product, whether it concerns an experimental drug or a medical device. Note: concurrent participation in natural history studies (non-drug, non-device studies) may be acceptable if confirmed in writing by the sponsor. 19. Anticipated inability to comply with any study procedures, including participation in study visits according to the visit schedule. 20. Abnormal laboratory results indicative of any significant medical disease that, in the opinion of the investigator, would preclude the subject’s participation in the study. 21. 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. 22. Contraindication to needle biopsy. 23. Contraindication to MRI as per clinic standard practice."