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

Background: LY3372689, a centrally penetrant 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. Objective: To report the safety and pharmacokinetics (PK) of LY3372689 after single and multiple oral doses in healthy volunteers (HV). Methods: The 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 from 0.15 mg 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; non‐Japanese and Japanese HV were enrolled in the MAD study. Safety was assessed by adverse events (AE), safety laboratories, electrocardiograms, vital signs, physical examinations, and neurological examinations. Plasma pharmacokinetics (PK) was assessed up to 48 hours and 24 hours post‐dose in the SAD and MAD studies, respectively. Results: In 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 deaths or other serious AE were reported. In the SAD, 40 treatment‐emergent AE (TEAE) were reported, which were mostly mild in severity. The most common TEAE were headache, nausea, pain in extremity, pain of skin, vessel puncture site pain, and limb discomfort. There were no subject withdrawals from the study due to AEs, and a maximum tolerated dose was not achieved. In the MAD, 42 TEAE were reported, all of which were mild in severity. The most reported TEAE were headache, abdominal pain, diarrhea, back pain, nausea, constipation, dizziness, medical device site irritation, and feeling cold. One participant discontinued due to an AE of mild influenza, which was judged unrelated to LY3372689. In the SAD and MAD studies, there were no clinically significant changes in safety laboratories, including markers of inflammation, muscle injury, hormones and hepatoxicity. Furthermore, there were no clinically significant changes in ECGs, including QTc and PR prolongation, vital signs and neurological examinations. The safety profile in the MAD was similar in Japanese and non‐Japanese HV. Following single and multiple doses, the tmax and t1/2 were approximately 1 hour and 6 hours, respectively. LY3372689 exposure based on AUC and Cmax increased in a generally dose‐proportional manner in the SAD and MAD studies. At the highest dose of 7 mg QD in the MAD, the ratio of LY3372689 AUC on day 14 to day 1 was approximately 1.1 indicating exposure accumulation was minimal after repeated LY3372689 administration. At 3 mg QD, food intake had a minimal effect on AUC, decreased Cmax by 43% and increased tmax by 5 hours, compared to a fasted state. Renal clearance was not a major contributor of LY3372689 elimination after single or multiple dosing of LY3372689. The PK parameters in Japanese and non‐Japanese HV in the MAD study were similar. Conclusions: LY3372689 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.