A Rollover Study of ARRY-371797 in Patients With LMNA-Related Dilated Cardiomyopathy

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events between baseline up to 30 days after last dose of study drug (i.e., maximum up to 282 weeks) that were absent before treatment or that worsened relative to pre-treatment state. AEs included both serious and non-serious adverse events.

In this outcome measure, number of participants with baseline laboratory hematology values as per National Cancer Institute Common Terminology Criteria (NCI-CTC) grade (Grade 0= within normal limits, Grade 1=Mild, Grade 2=Moderate, Grade 3= Severe, Grade 4= Life-threatening) and corresponding changes/shift to the worst CTC grades post baseline were presented. Shift data have been reported for hematology parameters: hemoglobin (g/L), platelets (10^9/L), leukocytes (10^9/L), neutrophils (10^9/L), lymphocytes (10^9/L) and eosinophils (10^9/L). Baseline was defined as last non-missing value before the initial administration of study treatment in parent study and worst post-baseline value defined as worst value between first dose of study drug up to the maximum of 282 weeks. Only those categories in which at least 1 participant had data were reported.

In this outcome measure, number of participants with baseline laboratory chemistry values as per NCI-CTC grade (Grade 0= within normal limits, Grade 1=Mild, Grade 2=Moderate, Grade 3= Severe, Grade 4= Life-threatening) and corresponding changes/shift to the worst CTC grades post baseline were presented. Shift data have been reported for laboratory parameters: alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, international unit per liter (IU/L), albumin, bilirubin, urea nitrogen, calcium, creatinine, glucose, magnesium, protein and phosphate grams per deciliter (g/dL), potassium and sodium, millimol per liter (mmol/L). Baseline was defined as last non-missing value before the initial administration of study treatment in parent study and worst post-baseline value defined as worst value between first dose of study drug up to the maximum of 282 weeks. Only those categories in which at least 1 participant had data were reported.

Physical examination included the assessment of skin, head, ears, eyes, nose, throat, cardiovascular system, abdomen and lungs. Abnormality in physical examination were based on investigator's discretion.

Following vital signs parameters were analyzed using prespecified range of results for signs of clinical significance: systolic blood pressure in millimeters of mercury (mmHg): <90 mmHg and ≥160 mmHg, diastolic blood pressure: <60 mmHg and ≥100 mmHg, heart rate in beats per minute (bpm): <40bpm and >120 bpm, temperature in degree Celsius (C): <36.1 and > 37.2 degree C.

Following ECG parameters were analyzed using prespecified range of results for signs of clinical significance: heart rate: <40bpm and >120 bpm; QT/QTcF (QT interval corrected using Fridericia's formula) criteria: QT interval >500 ms; QTcF interval >450 ms; or change from baseline in QTcF >30 ms.

6MWT was the distance that a participant could quickly walk on a flat, hard surface in a period of 6 minutes. Participants were asked to walk a set course of 30 meters for 6 minutes (timed), and the distance walked (in meters) was recorded. Change from baseline in 6MWT distance at specified time points were reported. Baseline was defined as last non-missing value before the initial administration of study treatment in parent study.

LVESVI and LVEDVI were echocardiographic assessment of left ventricular remodeling. Baseline was defined as last non-missing value before the initial administration of study treatment in parent study.

LVM is the weight of the left ventricle in grams estimated by echocardiography. For this outcome measure, Baseline is the pre-dose baseline of parent study.

LVEF was the fraction of the end-diastolic volume (EDV) that was ejected out of left ventricle with each contraction, estimated by echocardiography. EDV was the volume of blood within a ventricle immediately before a contraction. Baseline was defined as last non-missing value before the initial administration of study treatment in parent study.

LVM divided by the end diastolic volume, estimated by echocardiography. Baseline was defined as last non-missing value before the initial administration of study treatment in parent study.

The internal diameter of the right ventricle at the end of diastole, measured by echocardiography. Baseline was defined as last non-missing value before the initial administration of study treatment in parent study.

Right ventricular fractional area change is a measure of global right ventricular systolic function estimated by echocardiography. For this outcome measure, Baseline is the pre-dose baseline of parent study.

The SF-36 health survey is a participant-reported survey to measure participant's health. It is a 36-item questionnaire used to measure 8 various aspects of health (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health). The score range for each of the 8 aspects was from 0 (maximum disability) to 100 (no disability), higher scores indicating good health condition. For this analysis, baseline was defined as last non-missing value before the initial administration of study treatment in parent study.

KCCQ was a 23-item heart failure specific questionnaire quantified into following 10 summary scores: physical limitation score, symptom frequency score, symptom severity score, symptom stability score, total symptoms score, quality of life score, social interference score, self-efficacy score, overall summary score and clinical summary score. These scores ranged from 0 to 100, where higher scores indicated better functioning, fewer symptoms, and better disease specific quality of life. For this analysis, baseline was defined as last non-missing value before the initial administration of study treatment in parent study.

Plasma concentrations of ARRY-371797 and its metabolites (AR00420643, AR00428028 and AR00486705) was summarized on Day 1, Weeks 12 and 24 at both pre and post dose.