AG10, A Novel, Potent and Selective Transthyretin Stabilizer, is Well Tolerated at Doses Resulting in Target Therapeutic Blood Levels, and Demonstrates Clinical Proof-of-Concept in Healthy Volunteers

Introduction AG10 is a novel, potent and selective oral transthyretin (TTR) stabilizer under clinical development to treat TTR amyloidosis (ATTR). Both mutant and wild-type ATTR are under-diagnosed diseases with no FDA-approved therapies. As ATTR is caused by the destabilization of TTR tetramers due to inherited mutations or aging, AG10 is designed to treat the disease at its source. Hypothesis AG10 is safe and well tolerated at exposures reaching target therapeutic plasma concentrations, resulting in complete stabilization of TTR following repeat dosing in healthy volunteers (HV), and predicting clinical efficacy in treating both mutant and wild-type ATTR. Methods Single and multiple ascending oral doses of AG10 were administered in a double blind manner to 4 single and 3 multiple dose cohorts consisting of 8 HV per cohort randomized 3:1 (AG10: placebo). Safety and tolerability were assessed by vital signs, ECG, adverse events, and safety labs to monitor kidney and liver function, electrolytes, and hematology. Pharmacokinetics were measured using a validated bioanalytical assay. Pharmacodynamics (PD) were assessed via two established ex vivo assays for TTR stabilization, fluorescent probe exclusion and Western blot. Results Single oral doses of 50, 150, 300 and 800 mg, and multiple oral doses to steady state of 100, 300 and 800 mg q12h were well tolerated with a clean safety profile. AG10 was rapidly absorbed with t max max and AUC were dose-dependent, terminal t 1/2 was ∼25 hr, and there was little food effect (slightly increased T max , blunted C max , and 11% increase in AUC following a high fat meal). The PD profile, as assessed by either assay, demonstrated complete stabilization of TTR at C max following single doses of 300 mg or more, and >95% stabilization on average across the entire dosing interval of 800 mg q12h at steady state with low inter-subject variability (Figure). Conclusions AG10, a novel, potent and selective oral TTR stabilizer, is safe and well-tolerated following oral dosing in healthy volunteers and completely stabilizes TTR (>90%) across the dosing interval, establishing clinical proof of concept. Based on these data, AG10 has the potential to be a safe and effective treatment for patients with ATTR.