A Phase I, Single Ascending Dose Study of Cimaglermin Alfa (Neuregulin 1β3) in Patients With Systolic Dysfunction and Heart Failure

Abstract

A first-in-human, phase 1, double blind, placebo-controlled, single ascending dose study examined the safety, tolerability, and exploratory efficacy of intravenous infusion of a recombinant growth factor, cimaglermin alfa, in patients with heart failure and left ventricular systolic dysfunction (LVSD). In these patients on optimal guideline-directed medical therapy, cimaglermin treatment was generally tolerated except for transient nausea and headache and a dose-limiting toxicity was noted at the highest planned dose. There was a dose-dependent improvement in left ventricular ejection fraction lasting 90 days following infusion. Thus, cimaglermin is a potential therapy to enhance cardiac function in LVSD and warrants further investigation.

Keywords: AE, adverse event; AUC, area under the curve; DLT, dose-limiting toxicity; GGF, glial growth factor; HF, heart failure; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction; NRG, neuregulin; NYHA, New York Heart Association functional class; TEAE, treatment-emergent adverse event; cardiac repair; growth factor; neuregulin; systolic dysfunction.

Graphical abstract

Figure 1

Treatment Algorithm DLT is defined as 1 of the following events deemed to be at least possibly related to study drug: 1) grade III toxicity or above (would encompass life-threatening events); 2) liver function abnormalities as defined in protocol; or 3) other events clinically judged to necessitate dose reductions. If a DLT occurs in the dose reduction step, the decision on whether to stop the study or to continue (reducing the dose by 1 additional dose level) will be made by sponsor and the principal investigator in consultation with the DSMB. DLT = dose-limiting toxicity; DSMB = Data Safety Monitoring Board; GGF = glial growth factor; PBO = placebo.

Figure 2

Overview of Study Schema (A) The ascending doses of Cimaglermin were randomly assigned, and at the completion of each cohort (n = 6) a safety analysis was done by a DSMB before proceeding to the next dose level. (B) The initial 30-day screening period included assessment of LVEF, age-appropriate cancer screening, cardiology assessment for eligibility, and laboratory testing. (C) Eligible patients were dosed on day 0 with a single infusion of cimaglermin or placebo. Patients were observed in hospital on telemetry for at least 48 h, and multiple safety labs as well as electrocardiographic monitoring were performed. Patients returned on days 8, 14, 28, and 90 for laboratory, physical exam, echocardiography, and other safety assessments. AE = adverse event; DSMB = Data Safety Monitoring Board; LVEF = left ventricular ejection fraction; PK = pharmacokinetics.

Figure 3

Mean Absolute Change in LVEF After Dosing The mean absolute change in LVEF from baseline for the patients in the placebo, pooled low-dose, and high-dose groups are displayed over 90 days. The dashed line represents the high-dose group with cohort 7 (highest dose 1.5 mg/kg, with DLT) data included. Since this dose will no longer be developed clinically, the solid blue line represents the data without this cohort. There was a significant increase in LVEF at 30 days between the high groups compared with placebo (p < 0.01). At 90 days, only the highest dose group showed a significant increase compared with the placebo group (p < 0.01). Abbreviations as in Figures 1 and 2.

Figure 4

Mean AUC for Absolute Change in LVEF Over 90 Days (A) The mean AUC for change in LVEF over 90 days in all patients is displayed for the placebo (grey), low-dose (green), and high-dose (blue) groups (with the lighter portion in the high-dose group including cohort 7). The high-dose group had a significantly greater increase in LVEF when compared with the low-dose or placebo groups. This was significant whether the highest dose (1.5 mg/kg) cohort was included (lighter blue bar) or not (darker blue bar) (p < 0.01). (B) The mean AUC for change in LVEF over 90 days in all patients is displayed for each individual dose cohorts and plotted on a logarithmic scale. The individual dose cohorts that were grouped into the placebo, low and high dose are color coded as in A. R² = 0.6735. The Jonckheere-Terpstra test showed a significant relationship between dose and change in LVEF AUC 0-90 (p = 0.0012). AUC = area under the curve; LVEF = left ventricular ejection fraction.