POS1156 PHASE 1 TRIALS OF NOVEL ORAL ENZYME THERAPY (ALLN-346) FOR HYPERURICEMIA & GOUT: SAFETY, PHARMACODYNAMICS, AND LACK OF SYSTEMIC ABSORPTION OF SINGLE AND MULTIPLE ASCENDING DOSES IN HEALTHY VOLUNTEERS

Abstract

BackgroundCurrently available therapies for gout in patients with advanced chronic kidney disease (CKD) are either dose-limited or contraindicated due to safety and tolerability concerns. In gout patients with advanced CKD, the intestinal tract becomes the major route of urate elimination, in contrast to healthy people with normal kidney function whose kidneys are the primary route of uric acid excretion.1. Considering some of the limitations of present urate lowering therapies (ULTs) in gout & CKD and the extra-renal pathway of urate secretion, a new oral therapy with ALLN-346 (engineered urate oxidase) is under development as a non-absorbed, urate specific enzyme, designed to enhance degradation and secretion of urate in the intestinal tract. 2ObjectivesTo assess safety and tolerability and evidence for the lack of systemic absorption at various dose levels of ALLN-346 in normal healthy volunteers (NHV) up to 7 days.MethodsTwo randomized, double-blind Phase 1 studies of ALLN-346 or placebo were conducted in adult NHV in a domicile setting; a single-ascending dose (SAD) study of 3 doses on a single day of dosing, and a multiple ascending dose (MAD) study of 2 doses during 7 days (NCT04236219 and NCT04829435, respectively). In the SAD study, subjects received 3 ascending doses of ALLN-346 (3 capsules,6 capsules, and 6 capsules administered twice, or placebo) and were randomized 3:1 (ALLN-346:placebo, n=24). In the MAD study, subjects received 3 (Cohort A) or 5 (Cohort B) of ALLN-346 capsules or placebo (2:1 randomization, n=18) administered orally 3 times daily for 7 days. To assess possible ALLN-346 absorption, a specific ELISA and uricase potency assay were used on PK serum samples collected from all subjects in both studies pre-dose and at intervals post dose.ResultsIn both studies, all randomized subjects completed treatment with 100% compliance. ALLN-346 was well-tolerated, with no serious adverse events (AE) and with no clinically significant safety signals across all cumulative doses. Clinical and laboratory parameters revealed no clinically significant safety signals among all cumulative dosing cohorts across hematology, serum biochemistry, vital signs, or ECGs. The majority of reported AEs were mild with no pattern of differences between ALLN-346 and placebo. No evidence of systemic absorption of ALLN-346 was seen, as confirmed by both ELISA and by uricase potency assay of all PK serum samples from all subjects from SAD (n=240) and MAD (n=324).ConclusionALLN-346, a new oral enzyme therapy in development for the treatment of hyperuricemia and gout in advanced CKD was well tolerated. Consistent with its mechanism of action, no evidence of systemic absorption was demonstrated. Furtherstudies in hyperuricemia patients with gout and CKD are underway.