Single and multiple ascending dose studies in healthy volunteers to assess the safety and PK of LY3372689, an inhibitor of the O‐GlcNAcase (OGA) enzyme

Abstract

AbstractBackgroundLY3372689, an OGA enzyme inhibitor, is being developed as a potential treatment for tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. We report the safety and pharmacokinetics (PK) of LY3372689 after single and multiple oral doses in healthy volunteers (HV).MethodThe single ascending dose (SAD) and multiple ascending dose (MAD) studies were single center, subject‐ and investigator‐blind, placebo‐controlled and randomized. In the SAD study [NCT03819270], 6 LY3372689 dose levels up to 16 mg and placebo were evaluated. In the MAD study [NCT04106206], LY3372689 (1, 3 and 7 mg) or placebo was given once daily (QD) for 14 days. Safety was assessed by adverse events (AE), safety laboratories, electrocardiograms, vital signs, physical exams, and neurological exams. Plasma pharmacokinetics (PK) was assessed in the SAD and MAD studies.ResultIn the SAD, 23 HV (15 males, 8 females; 22 – 63 years) participated, of which 18 HV completed. In the MAD, 40 HV (5 males, 35 females; 29 – 65 years) participated in the study, of which 39 HV completed. LY3372689 was generally well tolerated up to the highest dose in each study, and no serious AE were reported. In the SAD, 40 treatment‐emergent AEs (TEAEs) were reported, which were mostly mild in severity. The most common TEAEs were headache, nausea, pain in extremity, pain of skin, vessel puncture site pain, and limb discomfort. In the MAD, 42 TEAEs were reported, all of which were mild in severity. The most reported TEAE was headache. In both studies, there were no clinically significant changes in safety laboratories, including markers of inflammation, muscle injury, hormones and hepatoxicity. Following QD dosing of LY3372689, the tmax and t1/2 was about 1 hour and 6 hours, respectively, and LY3372689 exposure accumulation was minimal. Renal clearance was not a major contributor of LY3372689 elimination.ConclusionLY3372689 demonstrated an acceptable safety and PK profile following single and multiple doses of LY3372689 in HV. These results support investigation of LY3372689 in efficacy trials for tauopathies and help support dose selection for those trials.