A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled study in patients with dilated cardiomyopathy (DCM) due to a mutation of the gene encoding the lamin A/C protein (LMNA). The study will further evaluate a dose level of study drug (ARRY-371797) that has shown preliminary efficacy and safety in this patient population. After the primary analysis has been performed, eligible patients may receive open-label treatment with ARRY-371797.

Official Title
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A Phase 3, Multinational, Randomized, Placebo-controlled Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation (REALM-DCM)

Conditions
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Dilated Cardiomyopathy, Lamin A/C Gene Mutation

Intervention / Treatment
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* Drug: ARRY-371797 (PF-07265803)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Selected Key Inclusion Criteria: Patients with symptomatic lamin A/C protein (LMNA)-related cardiomyopathy Class II/III/ or Class IV defined as: Gene positive for a pathogenic, likely pathogenic, or VUS mutation in the LMNA gene as determined by an accredited clinical laboratory. Evidence of cardiac impairment in LVEF <= 50% Patient will have an implantable cardioverter defibrillator/cardiac resynchronization therapy defibrillator (ICD/CRT-D). ICD implanted at least 4 weeks prior to initiation of study treatment or CRT-D initiated at least 6 months prior to initiation of study treatment and defibrillation function activated at least 4 weeks prior to initiation of study treatment. Class II/III patients must have objective functional impairment evidenced by a reduction in 6-minute walk test (6MWT); a. Screening: 6MWT distance >100 m but ≤450 m, AND b. Day -1 visit: 6MWT distance >100 m but ≤485 m, AND c. Baseline visit (Day 1): 6MWT distance >100 m but ≤485 Class II/III patients must be stable for at least 3 months Stable medical and/or device therapy consistent with regional American Heart Association (AHA) / American College of Cardiology (ACC) or European Society of Cardiology (ESC) guidelines at the investigator discretion, without change in heart failure drug(s) dose in the past 1 month. Patients must meet acceptable hematology, hepatic and renal laboratory values within 35 days prior to Day 1 as specified in the protocol. Selected Key Exclusion Criteria: Presence of other form(s) of cardiomyopathy contributing to HF (eg, inflammatory or infiltrative cardiomyopathy), clinically significant cardiac anatomic abnormality (eg,LV aneurysm), clinically significant coronary artery disease (eg, coronary revascularization, exercise induced angina) or uncorrected, hemodynamically significant (ie, moderate-severe) primary structural valvular disease not due to HF, per investigator judgment. Currently receiving intermittent or continuous IV inotrope infusion, or presence of a ventricular assist device, or history of prior heart transplantation. Participants listed for cardiac transplantation may be enrolled provided transplantation is not likely to occur in the next 6 months. Myocardial infarction, cardiac surgical procedures (other than for pacemaker/ICD/CRT-D implantation or replacement), acute coronary syndrome, serious systemic infection with evidence of septicemia, or any major surgical procedure requiring general anesthesia within 3 months prior to screening. Currently receiving or deemed at high risk of requiring chronic renal replacement therapy (eg, hemodialysis or peritoneal dialysis) within 6 months. Initiation of CRT within 6 months prior to screening. Treatment with any investigational agent(s) for HF within 35 days prior to Day 1. Malignancy that is active or has been diagnosed within 3 years prior to screening, except surgically curatively resected in situ malignancies or surgically cured early breast cancer, prostate cancer, skin cancer (basal cell carcinoma, squamous cell carcinoma), thyroid cancer, or cervical cancer, or, with prior review by the medical monitor, other early stage surgically curatively resected malignancies with less than a 20% expected 2 year recurrence rate. Non-cardiac condition that limits lifespan to < 1 year. Serum positive for hepatitis B surface antigen, viremic hepatitis C, or human immunodeficiency virus (HIV) at screening.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study will be conducted in 2 parts: a randomized, double-blind treatment period for at least 24 weeks, followed by an ARRY-371797 (PF-07265803) open-label treatment period.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Double-blind Treatment<br>ARRY-371797 (PF-07265803) tablet orally OR matching placebo tablet orally | Drug: ARRY-371797 (PF-07265803)<br>* 400 mg twice daily (BID)<br>Other: Placebo<br>* BID<br>|
| Experimental: Part 2 Open-label Treatment<br>ARRY-371797 (PF-07265803) tablet orally | Drug: ARRY-371797 (PF-07265803)<br>* 400 mg twice daily (BID)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in 6-minute walk test (6MWT) | The 6 MWT measures the distance walked over a total of six minutes on a hard, and flat surface. | at Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in 6-minute walk test (6MWT) | The 6 MWT measures the distance walked over a total of six minutes on a hard, and flat surface. | at Weeks 4 and 12 | 
| Change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Physical Limitation (PL) domain | The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The PL is a single domain consisting of 7 items scored using a range of 0 - 100, in which higher scores reflect better physical functioning status. | at Weeks 12 and 24 | 
| Change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) as measured by Total Symptom Score (TSS) domain | The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The TSS is a combined score based upon the symptom burden, symptom frequency and symptom severity domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status. | at Weeks 12 and 24 | 
| Change from baseline in Patient Global Impression score of Severity(PGI-S) of heart failure symptoms and physical activity limitations | Measured by the scale of: none, mild, moderate, severe or very severe (listed from better to worse) | at Weeks 12 and 24 | 
| Change from baseline in Patient Global Impression score of Change (PGI-C) in heart failure symptoms and physical activity limitations | Measured by the scale of: very much better, moderately better, a little better, no change, a little worse, moderately worse, very much worse (listed from better to worse). | at Weeks 12 and 24 | 
| Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) |  | at Weeks 4, 12 and 24 | 
| Evaluate the impact of ARRY-371797 (PF-07265803) on composite endpoint of all-cause mortality, or worsening heart failure (WHF). | Defined as the time from randomization to the first occurrence of any event of death due to any cause, or worsening heart failure (HF-related hospitalization or HF-related urgent care visit). | From randomization up to 80 months. | 
| Evaluate the impact of ARRY-371797 (PF-07265803) on overall survival (OS). | Defined as the time from randomization until death due to any cause. | From randomization up to 80 months. | 
| Evaluate the safety of ARRY-371797 (PF-07265803). | Incidence and severity of adverse events. Changes in clinical safety laboratory tests, vital signs, and 12 lead ECGs, and incidence and severity of ventricular or atrial arrhythmias detected. | From randomization up to 80 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cardiomyopathy, Lamin Type A, heart failure, ARRY-797, C4411002