A Phase 3 study to determine the Efficacy and Safety of Losmapimod in Treating Patients with Facioscapulohumeral Muscular Dystrophy (REACH)

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] - Nervous System Diseases [C10], Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

30 Sep 2022 → 20 Nov 2024

Decision date (initial)

2024-08-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Fulcrum Therapeutics

External identifiers

EU CT number

2024-512737-33-00

EudraCT number

2022-000389-16

ClinicalTrials.gov

NCT05397470

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Pharmacokinetic, Efficacy

Part A: To evaluate the efficacy of losmapimod for the treatment of FSHD on disease progression assessed by RWS quantification of total RSA Q1-Q5 with 500 g wrist weight averaged over both arms.
Part B: To assess the long-term safety and tolerability of losmapimod in patients with FSHD

Secondary objectives 1

1. Part A: 1. To evaluate PGIC relative to placebo 2. To evaluate efficacy of losmapimod to slow accumulation of fat in muscle by MFI with WB MSK MRI relative to placebo 3. To evaluate relative change from baseline in shoulder strength by hand-held quantitative dynamometry relative to placebo 4. To evaluate the change in Neuro-QoL UE relative to placebo 5. To assess safety and tolerability of losmapimod in patients with FSHD Part B: No Secondary objectives

Conditions and MedDRA coding

Facioscapulohumeral Muscular Dystrophy (FSHD)

Study design 4 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. Part A: 1. Patient will sign and date an ICF 2. Patients will have a diagnosis of FSHD1 or FSHD2 verified by genetic testing − Randomization will be stratified for FSHD1 to ensure that treatment allocation is balanced across FSHD repeat number categories (ie, 1 to 3 repeats versus 4 to 9 repeats). − Randomization will be stratified for FSHD2 to ensure that an equal number of patients will be allocated to treatment and placebo. 3. Patients will have a Clinical Severity Score of 2 to 4 (Ricci score; range 0 to 5) at screening. Patients who are wheelchair-dependent or dependent on walker or wheelchair for activities are not permitted to enroll in the study. 4. Patients with screening total RSA (Q1-Q4) without weight in the dominant UE assessed by RWS ≥ 0.2 and ≤ 0.7. 5. Willing and able to comply with scheduled visits, treatment plan and other study procedures 6. No contraindications to MRI 7. Patients (male and female) will be between the ages of 18 and 65 years at the time of consent, inclusive − A female patient is eligible to participate if she is of non-child bearing potential, defined as pre-menopausal females with a documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy; if she is postmenopausal, defined as no menses for 12 months without an alternative medical cause; OR − if of child-bearing potential, she is using a highly effective method for avoidance of pregnancy for the duration of dosing and until 90 days after the last dose of study drug − Male patients must agree to use one of the contraception methods. This criterion must be followed from the time of the first dose of study medication and until 90 days after the last dose of study drug Part B: 1. Patient completed 48 weeks of treatment during Part A. 2. Patient will sign and date an ICF. 3. Patient is willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures. 4. Patient agrees to the following methods of contraception: - Female patients of childbearing potential agree to continue using a highly effective method for avoidance of pregnancy for the duration of dosing and until 90 days after the last dose. - Male patients must agree to use one of the contraception methods listed in Section 5.5.1 of the protocol. This criterion must be followed from the time of the first dose of study medication and until 90 days after the last dose of study drug.

Exclusion criteria 2

1. Part A: 1. 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 patient. 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 patients who are on drug(s) or supplements that may affect muscle function or that are included in the list of drugs presented in Appendix 3 of the Protocol: pt 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. 4. History of febrile illness within 5 days before the first study drug dose 5. Known active opportunistic or life-threatening infections including HIV and hepatitis B or C 6. Known active or inactive tuberculosis infection. 7. Current acute liver disease or chronic liver disease as defined by any of the following: current ALT ≥2 × upper limit of normal (ULN) or total bilirubin >1.5 × ULN (unless participant has Gilbert's syndrome characterized by the combination of total bilirubin < 3 × ULN, direct bilirubin within the normal range and normal ALT and AST, or the presence of mutations in the UDP-glucuronosyltransferase 1 gene, indicative of Gilbert's syndrome); or Positive for hepatitis B or surface antigen; or Positive for hepatitis C antibody unless additional testing for hepatitis C viral RNA is negative, ALT is < 2 × ULN and total bilirubin is ≤1.5 × ULN, indicating inactive/resolved hepatitis C infection 8. Known severe renal impairment (defined as a glomerular filtration rate of < 30 mL/min/1.73 m2). 9. Standard 12-lead ECG demonstrating QTcF >450 msec for male patients and QTcF >470 msec for female patients 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 patient's eligibility. 10. History of cardiac dysrhythmias requiring anti-arrhythmia treatment(s); or history or evidence of abnormal ECGs 11. Male patients with a female partner who is planning to become pregnant during the study or within 90 days after the last study drug dose
2. 12. Concomitant use of cytotoxic chemotherapy for cancer or known ongoing or anticipated use of chronic severe immunosuppressive agents. 13. Positive pregnancy test or known to be pregnant or lactating or planning to become pregnant during study drug administration and until 90 days after last dose 14. Any current mental condition (psychiatric disorder, senility or dementia) 15. Patient has any condition possibly affecting drug absorption 16. History of alcohol, analgesic/opioid, and/or illicit drug abuse, as defined by the 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. Use of CBD/THC is permitted 17. Use of another IP within 30 days or 5 half-lives 18. Current or anticipated participation in a natural hx study. 19. Known hypersensitivity or intolerance to losmapimod or any of its excipients 20. Previous participation in a Fulcrum-sponsored FSHD losmapimod study 21. Anticipated inability to comply with any study procedures, study visits according to the visit schedule through 48 weeks. 22. Abnormal laboratory results indicative of any significant medical disease 23. Pt, or close relative of the patient to staff directly involved with the conduct of the study 24. Pt is vulnerable (i.e., deprived of freedom), including inmates of psychiatric wards and prison or state institutions, patients with commitments to an institution, or a patient who is detained or committed to an institution by a law court or by legal authorities. 25. For Italy only: Vaccination with a live attenuated vaccine within 6 weeks prior to randomization until the safety follow-up visit Part B: 1. 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 patient. 2. Male patients with a female partner who is planning to become pregnant during the study or within 90 days after the last study drug dose. 3. Anticipated inability to comply with any study procedures, including participation in study visits.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Part A: Change from baseline in average total RSA Q1-Q5 with 500 g wrist weight at Week 48, where average is applied over both arms Part B: Safety and tolerability of long-term treatment with losmapimod, based on the assessment of AEs, clinical laboratory tests, ECGs, vital signs, and physical examinations

Secondary endpoints 2

1. Part A: 1. PGIC at Week 48 2. Change from baseline in WB longitudinal composite MFI of B muscles at Week 48 3. Relative change from baseline in average shoulder abductor strength by hand-held quantitative dynamometry at Week 48 4. Change from baseline in Neuro-QoL UE at Week 48
2. 5. Safety and tolerability, based on the assessment of AEs, clinical laboratory tests, ECGs, vital signs and physical examinations. Part B: No secondary endpoints

Investigational products

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

Test 1

Placebo 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

Fulcrum Therapeutics

Public contact point

Organisation

Fulcrum Therapeutics Inc.

Contact name

Fulcrum Therapeutics

Third parties 13

Locations

6 EU/EEA countries · 14 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 96 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