Objectives: Acoramidis (AG10) is a novel investigational stabilizer of transthyretin (TTR or prealbumin) that achieves ≥ 90% TTR stabilization, in development for the treatment of TTR amyloid cardiomyopathy (ATTR-CM), a progressive, fatal disease in which the deposition of amyloid resultant of dissociation of either variant or wild-type TTR causes progressive heart failure. The Phase 3, 30-month ATTRibute-CM study showed a 25% risk reduction in all-cause mortality (ACM) with acoramidis relative to placebo. The objective was to evaluate exposure-efficacy relationships based on this study and two Phase 2 studies. Too few serious adverse events (SAE) occurred to establish an exposure-response model between acoramidis exposure and incidence of any particular SAE. Cardiovascular (CV)-related SAEs were excluded from the analysis since ATTR-CM patients are inclined to experience CV-related AEs and acoramidis exposure decreased the expected number of hospitalizations due to CV AEs.
Methods: Using individual-subject steady-state exposure measures (plasma AUC, Cmax, and Cmin) estimated with a population pharmacokinetic model based on 8 clinical studies (Phase 1-3), exposure-efficacy relationships were modeled for cumulative CV-related hospitalization (CVH) counts using Poisson regression. Other efficacy measures could not be related directly to exposure but were related to change in serum TTR, an in vivo measure of TTR stabilization that increased with plasma exposure and served as an indirect exposure measure. ACM was modeled with logistic regression, and over time with Cox proportional hazards (CPH), while percent change from baseline (%CfB) in the Six Minute Walk Test (6MWT) at Month 30 was modeled as linear.
Results: Change in serum TTR was predictive of ACM risk (p=0.00539) when adjusting for baseline demographic variables, diuretics, New York Heart Association (NYHA) class, baseline serum TTR, TTR variant vs wild-type and National Amyloidosis Centre (NAC) stage. For every 5 mg/dL increase in serum TTR from baseline to Day 28, the models predicted a 26.1% decrease in instantaneous mortality risk (CPH model) and a 30.9% (logistic model) decrease in the odds of mortality by Month 30, and the linear 6MWT model predicted an increase of 8.9 meters in the CfB 6MWT at Month 30. For every 1000 ng/mL increase in acoramidis steady-state Cmax, the Poisson model for CVH predicted a 2.7% decrease in the expected number of cumulative CVH events.
Conclusions: Acoramidis exposure was found to directly predict cardiovascular hospitalizations, but change in serum TTR, which increases with acoramidis exposure, was needed to predict improved survival and 6MWT performance in ATTR-CM patients. The need for this indirect exposure measure could be due to limited and sparse concentration data at a single dose.
