ATTR Cardiomyopathy

Transthyretin amyloid (ATTR)-cardiomyopathy is an age-associated disease of the heart characterized by intramyocardial deposition of misfolded and aggregated transthyretin. The accumulation of amyloid results in increased ventricular wall thickness and severely impacts heart function and survival. The disease manifests predominantly in men ≥ 60 years of age and can be diagnosed using echocardiography, scintigraphy and biopsies. The prevalence of the disease is currently unknown despite the fact that diagnosis tools are widely accessible. It is estimated that today only 1% or less of the patients are being diagnosed.

Using Neurimmune’s Reverse Translational Medicine technology, we performed high-throughput immune repertoire analyses of healthy elderly subjects for ATTR-reactive B-cell memory. We selected cliramitug (formerly ALXN2220, NI006), a recombinant human monoclonal IgG1 antibody that exclusively targets with high affinity the disease-associated amyloid conformation but not physiological forms of transthyretin. Cliramitug targets both wild-type ATTR as well as ATTR mutants that are linked to hereditary forms of ATTR cardiomyopathy and ATTR polyneuropathy. Cliramitug induces the clearance of pathological ATTR in preclinical models.

Primary results of the Phase 1 study have been presented in Prague at Heart Failure 2023, a scientific congress of the European Society of Cardiology (ESC), and published in The New England Journal of Medicine (Pablo Garcia-Pavia et al., 2023). Results indicated that the safety profile of NI006 is favorable up to the highest dose tested. No apparent dose-limiting toxic effects or drug-related serious adverse reactions were observed. The pharmacokinetic profile was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac amyloid deposition (detected by either scintigraphy or cardiac magnetic resonance imaging) was substantially reduced over a period of 12 months. Reductions were also seen in levels of biomarkers measuring cardiac stress and cardiomyocyte death, N-terminal pro-B-type natriuretic peptide and troponin T.

In 2022, Neurimmune entered into an exclusive global collaboration and license agreement with Alexion, AstraZeneca Rare Disease for cliramitug. Neurimmune is responsible for the Phase 1 study (NI006-101) and the Phase 2 follow-on study (NI006-102, EXCEL), on behalf of Alexion. Alexion is responsible for further clinical development, manufacturing, and commercialization of cliramitug, including the ongoing DEPLETRR-CM Phase III trial to evaluate the safety and efficacy of cliratmitug in adults with ATTR-CM.