The importance of distinct cardiac MRI regional analyses to assess the effects of cliramitug on amyloid depletion from the Phase 1b study NI006-101

Introduction Cliramitug (formerly NI006 and ALXN2220) is an investigational monoclonal antibody for the treatment of ATTR amyloidosis. Cliramitug is designed to bind ATTR deposits and activate their elimination through phagocytosis. Data from the Phase 1b study NI006-101 indicate that cliramitug is generally safe and well tolerated. Time- and dose-dependent reductions in LV midventricular extracellular volume (ECV) were previously reported. Purpose Investigation of time- and dose dependency of regional changes in ECV, cardiac structure and systolic function in the subgroup of participants followed longitudinally with cardiac MRI during the study. Methods The study evaluated six ascending dose levels of cliramitug (0.3 to 60 mg/kg q4w) in 46 patients with confirmed ATTR-CM. Depending on enrollment cohort and initial allocation to cliramitug or placebo, participants received up to 24 infusions of cliramitug with up-titration of all participants to 30 mg/kg during the open-label extension. Serial cardiac MRIs were performed in a subset of participants according to participating sites and analyzed centrally in this post hoc analysis. Results 15 patients (all male, median age 68 years, 33% ATTRv, 94% on baseline tafamidis, median LVEF 51.4%) were followed longitudinally with a median of 4 post-baseline cardiac MRIs over a median study duration of 28 months. During this time, participants received a median [IQR] cumulative cliramitug dose of 31.2 g [23.2 to 32.1]. Baseline MRI characteristics included elevated LV ECV (median ECV in four-chamber view 58 % [54 to 63]), increased LV wall thickness (12.7 mm [10.7 to 13.3] across basal AHA segments) and increased LV mass (198 g [177 to 227]). Global longitudinal and circumferential strain were impaired at baseline (-12.6% [-11.1 to -15.5] and -15.6% [-13.7 to -20.2], respectively), while radial strain was elevated (+70.4% [49.9 to 81.4]). Exposure-response analyses including all available MRI measurements indicated correlations between cliramitug and reductions in LV ECV in both midventricular short-axis and four-chamber view (A), and reductions in LV mass (B). On a regional level, reductions in ECV and LV wall thickness were observed across all AHA segments, with most pronounced effects on apical and midventricular levels (C). Segmental analysis of longitudinal and circumferential strain did not indicate relevant changes, whereas radial strain improved further upon treatment with cliramitug. Conclusions In this post hoc MRI analysis, treatment initiation with cliramitug up to approximately 30 g cumulative dose was associated with reduced ECV and wall thickness across all regions of the LV. Radial strain emerged as a potential indicator of improved systolic function. These observations provide additional insights into the regional effects of amyloid depleting therapy in ATTR-CM, and support the further development of cliramitug.