Multiple Dose Study to Evaluate Efficacy, Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of MYK-224 in Participants with Symptomatic Obstructive Hypertrophic Cardiomyopathy (MERCUTIO)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Myokardia Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

15 Feb 2023 → 28 Feb 2025

Decision date (initial)

2024-03-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

MyoKardia, Inc

External identifiers

EU CT number

2023-508831-29-00

EudraCT number

2022-001292-14

WHO UTN

U1111-1276-3555

ClinicalTrials.gov

NCT05556343

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Others, Pharmacokinetic, Safety

To assess the safety and tolerability of MYK-224 in participants with symptomatic oHCM (Part A)

Secondary objectives 3

1. To evaluate the effect of MYK-224 on LVOT gradient in participants with symptomatic oHCM (Part A)
2. To assess the PK/PD relationship of MYK-224 (Part A)
3. To assess the PK of MYK-224 in participants with symptomatic oHCM (Part A)

Conditions and MedDRA coding

Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. PART A: 1) Has adequate acoustic windows, to enable accurate TTEs as determined by the echocardiography core laboratory.
2. 2) Men or women diagnosed with oHCM consistent with current American College of Cardiology Foundation/American Heart Association and European Society of Cardiology guidelines, satisfying both of the following criteria: - Has unexplained left ventricular (LV) hypertrophy with nondilated ventricular chambers in the absence of other cardiac (eg, hypertension, aortic stenosis) or systemic disease and with maximal LV wall thickness ≥ 15 millimeter (mm) (or ≥ 13 mm with positive family history of hypertrophic cardiomyopathy or with a known disease-causing mutation), as determined by core laboratory interpretation. - Has a LVOT peak gradient during screening as assessed by echocardiography of ≥ 50 millimeters of mercury (mm Hg) at rest, or ≥ XML File Identifier: 4aHMkMObTnpietQCrlOf/erzF34= Page 18/33 30 mm Hg at rest and ≥ 50 mm Hg after Valsalva maneuver (confirmed by echocardiography core laboratory interpretation).
3. 3) Has resting LVEF ≥ 60% at the Screening visit as determined by echocardiography core laboratory.
4. 4) Has a valid measurement of LVOT post-exercise peak gradient at screening as determined by echocardiography core laboratory. - NYHA functional class II or III symptoms at screening
5. 5) NYHA functional class II or III symptoms at screening
6. PART B: Participants that have successfully completed Part A of the study may enroll in Part B, an optional, 2-year open-label extension study. Eligibility for Part B will be assessed following completion of informed consent. Participants that have completed Part A EOS assessments within the Part B 28-day screening window may use those assessments for eligibility determination. Where possible, participants should enroll in Part B of the study on the same background therapy on which they completed Part A.

Exclusion criteria 25

1. PART A: 1) Presence of any medical condition that precludes exercise stress testing.
2. 2) History of syncope or sustained ventricular tachyarrhythmia within 6 months prior to screening.
3. 3) Known infiltrative or storage disorder causing cardiac hypertrophy that mimics HCM, such as Fabry disease, amyloidosis, or Noonan syndrome with left ventricular hypertrophy.
4. 4) Has been successfully treated with invasive septal reduction (surgical myectomy or percutaneous alcohol septal ablation [ASA]) within 6 months prior to Screening or plans to have either of these treatments during the study (Note: Individuals with an unsuccessful myectomy or percutaneous ASA procedure performed > 6 months prior to Screening may be enrolled if study eligibility criteria for LVOT gradient criteria are met).
5. 5) Implantable cardioverter-defibrillator (ICD) placement or pulse generator change within 2 months prior to screening or planned new ICD placement during the study (pulse generator changes, if needed during the study are allowed)
6. 6) Has a history of resuscitated sudden cardiac arrest (any time) or known history of appropriate implantable cardioverter-defibrillator (ICD discharge for life-threatening ventricular arrhythmia within 6 months prior to screening
7. 7) Has paroxysmal, atrial fibrillation with atrial fibrillation present per the Investigator's evaluation of the subject's ECG at the time of Screening
8. 8) Has persistent or permanent atrial fibrillation not on anticoagulation for at least 4 weeks prior to Screening and/or not adequately rate controlled within 6 months prior to Screening
9. 9) Has QT interval with Fridericia correction (QTcF) > 500 msec when QRS interval < 120 msec or QTcF > 520 msec when QRS ≥ 120 msec if participant has left bundle branch block or any other 12-lead ECG abnormality considered by the investigator to pose a risk to participant safety (eg, second-degree atrioventricular block type II)
10. 10) Has known moderate or severe (per investigator's judgment) aortic valve stenosis at screening
11. 11) History of LV systolic dysfunction (LVEF < 45%) at any time during their clinical course
12. 12) Clinically significant pulmonary disease associated with exertional dyspnea
13. 13) Has known significant unrevascularized obstructive coronary artery disease (>70% stenosis in one or more main epicardial coronary XML File Identifier: 4aHMkMObTnpietQCrlOf/erzF34= Page 19/33 arteries) or history of myocardial infarction Note: participants with prior coronary artery bypass grafting (CABG) or percutaneous coronary interventions (PCIs) are allowed if the procedure was performed at least 12 weeks prior to Screening.
14. 14) Prior treatment with mavacamten or aficamten. An exception may be made in cases where myosin inhibitor use was not within 4 months of the Screening visit, and with the agreement of both the Investigator and the Sponsor Medical Monitor. Prior treatment with cardiotoxic agents such as anthracyclines (eg, doxorubicin) or similar
15. Part B: Medical conditions 1) Presence of any medical condition that precludes exercise stress testing
16. 2) Interval history of syncope or sustained ventricular tachyarrhythmia between the Part A EOS visit and the Part B Screening visit for participants that have a separate Screening visit for Part B
17. 3) Active infection
18. 4) Has been treated with invasive septal reduction (surgical myectomy or percutaneous alcohol septal ablation [ASA]) following enrollment in Part A
19. 5) Has an interval history of resuscitated sudden cardiac arrest or of appropriate implantable cardioverter-defibrillator (ICD) discharge for life-threatening ventricular arrhythmia between Part A EOS visit and Screening for Part B
20. 6) Has paroxysmal, intermittent atrial fibrillation with atrial fibrillation present per the Investigator's evaluation of the subject's ECG at the time of Screening for Part B
21. 7) Has persistent or permanent atrial fibrillation not on anticoagulation for at least 4 weeks prior to Screening for Part B and/or not adequately rate controlled (Note: Participants with persistent or permanent atrial fibrillation who are anticoagulated and adequately rate-controlled are allowed. Please see restricted therapies in Appendix 5).
22. 8) Heart transplant or listed for heart transplant following enrollment in Part A
23. 9) Currently implanted LV assist device
24. 10) Clinically significant pulmonary disease associated with exertional dyspnea
25. 11) Has known significant unrevascularized obstructive coronary artery disease (> 70% stenosis in one or more epicardial coronary arteries) or history of myocardial infarction since enrollment in Part A

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 10

1. Incidence, severity, and causality of AEs and SAEs
2. Incidence of symptomatic resting LVEF < 50% by TTE
3. Incidence of resting LVEF ≤ 30% by TTE
4. Incidence of MACE, including cardiovascular death, nonfatal stroke, nonfatal myocardial infarction
5. Incidence of hospitalizations (due to cardiovascular and noncardiovascular events)
6. Incidence of HF events (including hospitalizations and urgent emergency room/outpatient visits for HF)
7. Incidence of atrial fibrillation/flutter (new from screening and recurrent)
8. Incidence of appropriate implantable cardioverter defibrillator therapy and resuscitated cardiac arrest
9. Incidence of ventricular tachyarrhythmias (includes ventricular XML File Identifier: 4aHMkMObTnpietQCrlOf/erzF34= Page 20/33 tachycardia, ventricular fibrillation, and Torsades de Pointes)
10. Results of vital signs, physical exams, 12-lead ECG assessments (including HR), and clinical laboratory tests

Secondary endpoints 3

1. Effect on LVOT gradient
2. PK/PD relationship
3. PK concentrations

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Myokardia Inc.

Sponsor organisation

Myokardia Inc.

Address

1000 Sierra Point Parkway

City

Brisbane

Postcode

94005-1804

Country

United States

Scientific contact point

Organisation

Myokardia Inc.

Contact name

GSM-CT

Public contact point

Organisation

Myokardia Inc.

Contact name

GSM-CT

Third parties 4

Locations

3 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 7 files

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

Application history

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