Long-term safety, tolerability, and efficacy of losmapimod treatment in subjects with FSHD

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fulcrum Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

6 Dec 2019 → 8 Nov 2024

Decision date (initial)

2024-04-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Fulcrum Therapeutics

External identifiers

EU CT number

2024-512732-30-00

EudraCT number

2019-001181-15

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others

To evaluate the safety and tolerability of long-term dosing of losmapimod in FSHD1 subjects

Secondary objectives 1

1. To evaluate the plasma concentrations of losmapimod in FSHD1 subjects

Conditions and MedDRA coding

Facioscapulohumeral Muscular Dystrophy 1 (FSHD1)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. "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. "

Exclusion criteria 2

1. "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. "
2. "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."

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint of the OLE is the safety and tolerability of long-term treatment of losmapimod based on AEs, clinical laboratory tests, ECGs, vital signs, and physical examination.

Secondary endpoints 1

1. The secondary endpoint of the OLE is the plasma concentrations of losmapimod after long-term dosing (at every-12-week time points).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fulcrum Therapeutics Inc.

Sponsor organisation

Fulcrum Therapeutics Inc.

Address

26 Landsdowne Street

City

Cambridge

Postcode

02139-4216

Country

United States

Scientific contact point

Organisation

Fulcrum Therapeutics Inc.

Contact name

Marie-Helene Jouvin

Public contact point

Organisation

Fulcrum Therapeutics Inc.

Contact name

Marie-Helene Jouvin

Third parties 8

Locations

2 EU/EEA countries · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications