Phase 2 Study of EDG-5506 in Becker Muscular Dystrophy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Edgewise Therapeutics Inc.

Participant type

Patients

Age range

18-64 years

Gender

Male

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16], Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

29 Dec 2022 → ongoing

Decision date (initial)

2024-02-16

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Edgewise Therapeutics

External identifiers

EU CT number

2022-500090-13-00

WHO UTN

U1111-1275-5502

ClinicalTrials.gov

NCT05291091

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Safety

Cohorts 1 and 2:
• To assess the safety and tolerability of sevasemten in adult participants with BMD.
• To assess the effects of sevasemten on serum creatine kinase (CK) in adult participants with BMD.

Cohorts 4 and 5:
• To assess the safety and tolerability of sevasemten in adolescent participants with BMD.

Cohort 6:
• To assess efficacy of treatment with sevasemten in adult participants with BMD.
• To assess the safety and tolerability of sevasemten

Secondary objectives 14

1. 1. Cohorts 1 and 2: To assess effects of sevasemten on North Star Ambulatory Assessment (NSAA) total score in adult participants with Becker Muscular Dystrophy (BMD)
2. 2. Cohorts 1 and 2: To assess effects of sevasemten on loss of function as assessed by the NSAA in adult participants with BMD
3. 3. Cohorts 1 and 2: To assess effects of sevasemten on functional measures in adult participants with Becker Muscular Dystrophy (BMD)
4. 4. Cohorts 1 and 2: To assess the effect of sevasemten on biomarkers of muscle fiber damage, specifically serum myoglobin and TNNI2, in adult participants with BMD
5. 5. Cohorts 1 and 2: To assess the Pharmacokinetics (PK) of sevasemten in adult participants with Becker Muscular Dystrophy (BMD)
6. 6. Cohorts 1 and 2: To assess the change in individual safety parameters in adult participants with Becker Muscular Dystrophy (BMD)
7. 7. Cohorts 4 and 5: To assess the Pharmacokinetics (PK) of sevasemten in adolescent participants with Becker Muscular Dystrophy (BMD)
8. 8. Cohorts 4 and 5: To assess the change in individual safety parameters in adolescent participants with Becker Muscular Dystrophy (BMD)
9. 9. Cohort 6: To assess effects of sevasemten on functional measures in adult participants with Becker Muscular Dystrophy (BMD)
10. 10. Cohort 6: To assess the effects of sevasemten on upper leg muscle fat fraction in adult participants with Becker Muscular Dystrophy (BMD)
11. 11. Cohort 6: To assess the Pharmacokinetics (PK) of sevasemten in adult participants with Becker Muscular Dystrophy (BMD)
12. 12. Cohort 6: To assess the change in individual safety parameters in adult participants with Becker Muscular Dystrophy (BMD)
13. 13. Cohort 6: To investigate the effect of sevasemten on biomarkers of muscle fiber damage, specifically serum CK, TNNI2, and serum myoglobin, in adult participants with Becker Muscular Dystrophy (BMD)
14. 14. Cohort 6: To assess effects of sevasemten on loss of function as assessed by the NSAA in adult participants with Becker Muscular Dystrophy (BMD)

Conditions and MedDRA coding

Becker Muscular Dystrophy (BMD)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

EMA paediatric investigation plan (PIP)

EMEA-003394-PIP01-23

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 1. Adults (aged 18 to 50 years, inclusive, at the time of Screening visit) with a documented dystrophin mutation and phenotype consistent with Becker Muscular Dystrophy (BMD), and history of being ambulatory beyond 16 years of age without steroids; history of being ambulatory beyond 18 years of age with steroids, OR adolescents (12 to 17 years, inclusive) with genetic confirmation of dystrophin mutation and a phenotype consistent with Becker Muscular Dystrophy (BMD) as determined by the Investigator AND EITHER: a. An in-frame mutation in the dystrophin gene (DMD) OR b. If an out-of-frame mutation in the dystrophin gene (DMD), as seen in approximately 10% of BMD individuals, the ability to Stand from Supine <10 seconds, as individuals with DMD are uniformly unable to Stand from Supine in <10 seconds after 10 years of age.
2. 6. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
3. 2. Male sex at birth.
4. 3. Able to complete the 100-meter timed test in <200 seconds with or without use of mobility aid devices
5. 4. Able to perform the North Star Ambulatory Assessment (NSAA) and achieve a score of 5 to 32, inclusive for adults (aged 18-50 years, inclusive at the time of Screening visit) OR a score of ≥5 for adolescents (aged 12-17 years, inclusive) at the Screening visit
6. 5. Willing to comply with contraception requirements described in Section 5.3.1 of the protocol.

Exclusion criteria 14

1. 1. Medical history or clinically significant physical examination/laboratory result that, in the opinion of the investigator, would render the participant unsuitable for the study.
2. 6. Moderate or severe renal or hepatic impairment (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2). eGFR will be based on Cystatin C formula [eGFR = 133 x min(Scys/0.8, 1) -0.499 x max (Scys/0.8, 1)-1.328 x 0.996Age].
3. 7. Positive test for hepatitis C antibody (unless negative hepatitis C virus polymerase chain reaction), hepatitis B surface antigen, or human immunodeficiency virus antibody.
4. 8. Receipt of oral corticosteroids for the treatment of BMD in the previous 6 months. - Receipt of low dose ≤5 mg equivalent per day oral corticosteroids for indications other than BMD or receipt for a short duration (≤10 days in previous 6 months), along with receipt of chronic inhaled/intranasal steroids, is permitted.
5. 9. Receiving moderate or strong cytochrome P450 CYP3A4 inhibitors or inducers.
6. 10. Receipt of an investigational drug within 30 days or 5 half-lives (whichever is longer) of the screening visit in the present study.
7. 11. Participants who, in the opinion of the Investigator, would not be a suitable candidate for participation in the study.
8. 12. Medical history or other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior, recent (within the past year) history of substance abuse or dependency or laboratory result or abnormality that may increase the risk of study participation or, in the Investigator’s judgment, make the participant inappropriate for the study.
9. 2. History of malignant neoplastic disease (except for adequately treated non-melanomatous skin carcinoma).
10. 3. Echocardiogram ejection fraction <40%.
11. 4. A 12-lead electrocardiogram (ECG) that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.
12. 5. Forced vital capacity (FVC) predicted <60% or using daytime (mechanical or noninvasive) ventilatory support.
13. 13. Participants with a known allergy to sevasemten or its excipients.
14. 14. Participants who are submitted to an institution by virtue of an order of a court or government authority to comply with Section 40a No. 2 of the German Medical Products Act.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. 1. Cohorts 1 and 2: Incidence, frequency, and severity of adverse events (AEs) and serious adverse events (SAEs) during treatment with sevasemten or placebo.
2. 2. Cohorts 1 and 2: Change from Baseline in serum creatine kinase (CK) averaged across months 6, 9 and 12.
3. 3. Cohorts 4 and 5: Incidence, frequency, and severity of adverse events (AEs) and serious adverse events (SAEs) during treatment with sevasemten or placebo
4. 4. Cohort 6: Month 18 change from Baseline in total North Star Ambulatory Assessment (NSAA) score
5. 5. Cohort 6: Incidence, frequency, and severity of adverse events (AEs) and serious adverse events (SAEs) during treatment with sevasemten or placebo

Secondary endpoints 14

1. 1. Cohorts 1 and 2: Month 12 change from Baseline in total North Star Ambulatory Assessment (NSAA) score.
2. 2. Cohorts 1 and 2: Cumulative loss of function on the NSAA over 12 months
3. 3. Cohorts 1 and 2: Month 12 Change from Baseline in: − Total North Star Assessment for Limb Girdle Muscular Dystrophies (NSAD) score − 10-meter walk/run − 100-meter timed test
4. 4. Cohorts 1 and 2: • Change from Baseline in serum myoglobin averaged across Months 6, 9, and 12 • Change from Baseline in TNNI2 averaged across Months 6 and 12
5. 5. Cohorts 1 and 2: Pharmacokinetics (PK) of sevasemten as measured by steady state (Css) plasma concentration of sevasemten.
6. 6. Cohorts 1 and 2: Incidence of treatment-emergent abnormal laboratory test results (clinical chemistry, hematology, coagulation). Change from Baseline in: − Safety laboratory parameters − Vital signs − Electrocardiogram (ECG) parameters − Cardiac function as assessed by an echocardiogram − Pulmonary function as assessed by forced expiratory volume in 1 second (FEV1) , forced vital capacity (FVC)
7. 7. Cohorts 4 and 5: Pharmacokinetics (PK) of sevasemten as measured by steady state (Css) plasma concentration of sevasemten.
8. 8. Cohorts 4 and 5: Incidence of treatment-emergent abnormal laboratory test results (clinical chemistry, hematology, coagulation). Change from Baseline in: − Safety laboratory parameters − Vital signs − Electrocardiogram (ECG) parameters − Cardiac function as assessed by an echocardiogram − Pulmonary function as assessed by forced expiratory volume in 1 second (FEV1) , forced vital capacity (FVC) − Growth (as assessed by height centile on WHO growth charts)
9. 9. Cohort 6: Month 18 change from Baseline in: - 100-meter timed test - 10-meter walk/run - Stride velocity (95th percentile) -Total North Star Assessment for Limb-Girdle Type Muscular Dystrophies (NSAD) score
10. 10. Cohort 6: Month 18 change from Baseline in fat fraction of upper leg muscles (as assessed by MRI)
11. 11. Cohort 6: Pharmacokinetics (PK) of sevasemten as measured by steady state (Css) plasma concentration of sevasemten
12. 12. Cohort 6: Incidence of treatment-emergent abnormal laboratory test results (clinical chemistry, hematology, coagulation). Change from Baseline in: − Safety laboratory parameters − Vital signs − Electrocardiogram (ECG) parameters − Cardiac function as assessed by an echocardiogram − Pulmonary function as assessed by forced expiratory volume in 1 second (FEV1) , forced vital capacity (FVC)
13. 13. Cohort 6: Month 18 change from Baseline in: - Serum Creatine kinase (CK) - Fast skeletal muscle troponin I (TNNI2). - Serum myoglobin
14. 14. Cohort 6: Cumulative loss of function on the North Star Ambulatory Assessment (NSAA) over 18 months

Investigational products

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

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Edgewise Therapeutics Inc.

Sponsor organisation

Edgewise Therapeutics Inc.

Address

1715 38th Street

City

Boulder

Postcode

80301-2603

Country

United States

Scientific contact point

Organisation

Edgewise Therapeutics Inc.

Contact name

Edgewise Clinical Studies

Public contact point

Organisation

Edgewise Therapeutics Inc.

Contact name

Edgewise Clinical Studies

Third parties 1

Locations

7 EU/EEA countries · 17 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

Documents 146 files

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

Application history

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