A Phase 2b/3, Adaptive, Randomized, Double-blind, Placebo-controlled, Multicenter Study to Assess the Efficacy and Safety of Danicamtiv in Participants with Symptomatic Genetic and Familial Dilated Cardiomyopathy (KINSHIP-DCM).

This study evaluates danicamtiv in participants with symptomatic genetic and familial dilated cardiomyopathy. The primary objective is divided into two parts. Part 1 aims to assess the effect of danicamtiv on cardiac function using transthoracic echocardiogram in Cohort 1. This assessment is clinically relevant as it directly measures changes in myocardial performance, a key parameter in evaluating therapeutic interventions for dilated cardiomyopathy. Part 2 aims to evaluate the impact of danicamtiv on exercise capacity using cardiopulmonary exercise testing in Cohort 1. This objective is important as exercise capacity serves as a functional endpoint that reflects the clinical status and quality of life in patients with heart failure secondary to dilated cardiomyopathy. No secondary objectives are specified for this trial.

This clinical trial enrolled a total of **154 participants** diagnosed with symptomatic **genetic and familial dilated cardiomyopathy**. The study population consisted of **adult participants aged 18 years and older**, including both **male and female subjects**. Participants were required to have a confirmed diagnosis of **dilated cardiomyopathy** due to probable disease-causing variants of **myosin heavy chain 7 (MYH7)**, **titin (TTN)**, or other identified genetic variants, or with familial dilated cardiomyopathy. The trial included individuals classified as **New York Heart Association (NYHA) Class II-IV** with stable symptoms for at least one month prior to screening. Participants were required to have at least mild **left ventricular enlargement** confirmed by echocardiography and adequate acoustic windows for accurate assessment. The study population was selected to include individuals with chronic dilated cardiomyopathy not attributed to acute or reversible conditions, substance abuse, **amyloidosis**, **sarcoidosis**, or other secondary forms of cardiomyopathy. Participants needed to demonstrate **sinus rhythm**, stable atrial or ventricular pacing, or adequately rate-controlled **paroxysmal atrial fibrillation**. Additionally, participants were required to perform upright **cardiopulmonary exercise testing** with a **peak oxygen consumption** of 80% or less of predicted for a healthy individual. The trial population included vulnerable populations as defined by regulatory standards.

This is a Phase 2b/3, adaptive, **randomized**, **double-blind**, **placebo-controlled**, multicenter study designed to assess the efficacy and safety of **Danicamtiv** in participants with symptomatic genetic and familial **dilated cardiomyopathy**. The study investigates the effect of Danicamtiv, a new chemical entity administered orally as a tablet, compared to placebo tablets containing the same excipients except the active substance. The trial employs an adaptive design to optimize the evaluation of treatment effects across different patient populations.

The study is conducted in two parts with distinct primary objectives. Part 1 aims to assess the effect of Danicamtiv on cardiac function using **transthoracic echocardiogram** (TTE) in Cohort 1, with the primary endpoint being the change from baseline to Week 26 in **left atrial function index** (LAFI). Part 2 evaluates the impact of Danicamtiv on exercise capacity using **cardiopulmonary exercise testing** (CPET) in Cohort 1, with the primary endpoint being the change from baseline to Week 26 in **peak oxygen consumption** (pVO2). The maximum treatment period with the investigational medicinal product is 26 weeks.

Eligible participants must be adults aged 18 years or older with a diagnosis of dilated cardiomyopathy due to probable disease-causing variants of **myosin heavy chain 7** (MYH7), **titin** (TTN), or other identified genetic DCM variants, or with familial DCM. Participants must have **New York Heart Association** (NYHA) Class II-IV symptoms at screening with stable symptoms for at least one month. Additional inclusion criteria require at least mild **left ventricular enlargement** by American Society of Echocardiography criteria (LVEDD ≥3.1 cm/m² for males, ≥3.2 cm/m² for females) confirmed by the Echocardiography Core Laboratory, and adequate acoustic windows to enable accurate TTEs. Participants must have chronic DCM not attributed to acute or reversible conditions, substance abuse, **amyloidosis**, **sarcoidosis**, or other secondary forms of cardiomyopathy. Cardiac rhythm must be **sinus rhythm**, stable atrial or ventricular pacing, or **paroxysmal atrial fibrillation** that is adequately rate-controlled to allow TTE assessments. Participants must be able to perform an upright CPET with a pVO2 of 80% or less of predicted for a healthy individual and respiratory exchange ratio (RER) of ≥1.05 on the screening CPET, as confirmed by the CPET Core Laboratory. All sexually active participants must use highly effective birth control methods from the screening visit through three months after the last dose of investigational medicinal product.

The study recruitment is estimated to begin in February 2026, with an estimated completion date in September 2027. Participant involvement extends through the treatment period of up to 26 weeks, plus follow-up assessments and a three-month period for contraceptive use after the last dose. The study includes a screening visit to assess eligibility, baseline assessments on Day 1, follow-up visits during the treatment period to monitor efficacy and safety parameters including echocardiographic assessments and cardiopulmonary exercise testing, and an end-of-study visit. Conditions that may lead to early termination from the study would be determined according to protocol-specified criteria, though specific termination conditions are not detailed in the available information.

**Danicamtiv** (also known as BMS-986434 or MYK-491) is administered as the experimental medicinal product in this clinical trial. The **active substance** is danicamtiv, a new chemical entity of chemical origin. The pharmaceutical form is an oral **tablet** administered via **oral use**. The maximum treatment period is 26 weeks. Danicamtiv is manufactured by KARDIGAN, INC.

**Placebo tablets** are used as the comparator treatment in this randomized, double-blind, placebo-controlled study. The placebo tablets contain the same excipients as danicamtiv tablets except the active substance. This formulation ensures blinding integrity by maintaining identical appearance and composition to the experimental product, with the exception of the pharmacologically active component.

Efficacy will be assessed in this clinical trial through two primary endpoints evaluated in Cohort 1. The first primary endpoint is the change from baseline (Day 1) to Week 26 in **left atrial function index** (LAFI), which will be measured using transthoracic echocardiogram (TTE). The second primary endpoint is the change from baseline (Day 1) to Week 26 in **peak oxygen consumption** (pVO2), which will be evaluated using **cardiopulmonary exercise testing** (CPET). These assessments are designed to evaluate the effect of danicamtiv on cardiac function and exercise capacity in participants with symptomatic genetic and familial **dilated cardiomyopathy**. The treatment period for efficacy evaluation is 26 weeks. Echocardiographic assessments will be confirmed by an Echocardiography Core Laboratory, and CPET results will be confirmed by a CPET Core Laboratory to ensure standardized and accurate measurements.