NNC6019–0001, a humanized monoclonal antibody, in patients with transthyretin amyloid cardiomyopathy (ATTR-CM): rationale and study design of a phase 2, randomized, placebo-controlled trial
Authors: Fontana M , Buchholtz K , Engelmann M D M , Grogan M , Hovingh G K , Kristen A V , Poulsen P , Shah S J , Maurer M S 
Published: October 2022

Abstract

Introduction
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a chronic condition associated with progressive heart failure, resulting from extracellular deposition of misfolded transthyretin (TTR) protein as amyloid fibrils in the myocardium. Currently, there are few disease-modifying treatments. NNC6019–0001 is a humanized monoclonal antibody designed to deplete amyloid via antibody-mediated phagocytosis by targeting a unique epitope that is exposed only on misfolded monomeric and aggregated forms of TTR. In a phase 1, open-label, 3-month dose escalation trial, NNC6019–0001 was well tolerated at all doses tested (up to and including 30 mg/kg).1 The maximum tolerated dose was not reached. Exploratory cardiac endpoints were stable or indicated a possible benefit.

Purpose
To evaluate the effect of NNC6019–0001 30 mg/kg and 100 mg/kg on cardiac functional endpoints and predictive biomarkers in patients with ATTR-CM, and to assess pharmacokinetics, safety and tolerability, to establish the optimal dose for a phase 3 trial.

Methods
This is a randomized, double-blind, placebo-controlled trial recruiting 99 patients with hereditary or wild-type ATTR-CM (Figure). Inclusion criteria are New York Heart Association (NYHA) class II or III heart failure, left ventricle wall thickening (LVWT) ≥12 mm, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels ≥650 pg/mL in sinus rhythm and &gt;1000 pg/mL in atrial fibrillation, and a 6-minute walk test (6MWT) distance of 150–450 m. Patients will be randomly assigned to receive intravenous NNC6019–0001 30 mg/kg or 100 mg/kg or placebo, each in addition to standard of care, every 4 weeks for 52 weeks, followed by a 12-week follow-up. In a sentinel dosing phase, three patients per arm will receive the study drug or placebo, in combination with 24-hour inpatient cardiac monitoring and 7 days of continuous cardiac (tele-) monitoring. The primary endpoints are change from baseline to week 52 in 6MWT and in NT-proBNP levels. Secondary endpoints include cardiac measures: extracellular volume on cardiac magnetic resonance imaging, global longitudinal strain, troponin T levels, hospitalization due to cardiovascular events, and urgent visits due to heart failure. Quality of life will be assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ). All-cause mortality, pharmacokinetics and treatment-emergent adverse events will also be assessed.

Results
The trial will start mid-2022 with global recruitment.

Conclusion
Disease-modifying treatments are needed for patients with ATTR-CM, where treatment is often limited to managing symptoms and best supportive care; the first disease-modifying therapies recently became available. This phase 2 trial will be used to determine the appropriate dose for the phase 3 trial of NNC6019–0001, a novel antibody therapy designed to deplete amyloid in patients with ATTR-CM.

Funding Acknowledgement
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This trial was funded by Novo Nordisk A/S. Medical writing support was provided by Johanna Scheinost PhD, PharmaGenesis Oxford Central, Oxford, UK, with funding from Novo Nordisk A/S.