Results of two Phase 1, Randomized, Double-blind, Placebo-controlled, Studies (Ascending Single-dose and Multiple-dose Studies) to Determine the Safety, Tolerability, and Pharmacokinetics of Orally Administered LX9211 in Healthy Participants

Abstract

Purpose: For neuropathic pain, current therapies do not provide relief for most patients; less than half achieve a 50% pain reduction. Current analgesics have adverse effects. We present 2 Phase I studies of LX9211, a new small-molecule AP2-associated kinase 1 inhibitor with preclinical effectiveness in pain relief.

Methods: Both randomized, placebo-controlled studies' primary objectives evaluated the tolerability and pharmacokinetic properties of oral LX9211. In the single-ascending dose (SAD) study, single, oral, liquid doses of 5, 10, 15, 20, 30, 40, 80, 120, 160, 200, and 300 mg of LX9211 or placebo were administered in the fasted state and 40 mg in a fed group. In the multiple-ascending dose (MAD) study, a loading dose was administered on day 1 and maintenance doses were administered daily on days 2 to 14. The treatment groups were designated as: 25/2.5, 50/5.0, 100/10, 150/15, and 200/20 mg. The secondary objectives included ECG evaluation.

Findings: The SAD study enrolled 96 participants 19 to 61 years of age (86.5% male) in 12 cohorts (2:6 placebo:LX9211), and the MAD study enrolled 50 participants 20 to 63 years of age (78% male) in 5 cohorts (2:8 placebo:LX9211). Both studies had a good LX9211 safety profile. No deaths or serious adverse events occurred. All treatment-emergent adverse events (TEAEs) were mild, except for moderate nausea and vomiting reported in 1 participant in the SAD 300-mg cohort. All TEAEs were considered recovered or resolved, except for blurred vision (n = 1 in the SAD 300-mg group), which was ongoing at the last visit. One participant in the MAD study (50/5 mg group) discontinued participation in the study early because of TEAEs (angioedema, dermatitis allergic, and urticaria). Headache, dizziness, constipation, and nausea were the most common TEAEs. In the SAD study, 4 participants in the 200-mg cohort developed headache approximately 24 hours after dosing, lasting 24 to 48 hours. Only 1 required treatment (acetaminophen). No notable ECG changes from baseline were found in either study. After both single- and multiple-dose administration, plasma exposure of LX9211 was approximately dose proportional. Steady-state LX9211 plasma concentrations were rapidly attained and maintained by a dosing regimen of a loading dose, followed by daily maintenance doses (1/10 the loading dose). No accumulation was as seen after multiple dosing.

Implications: These studies found that LX9211 was safe and well tolerated in healthy participants. These findings suggest it is appropriate to take LX9211 forward into Phase II studies of patients with diabetic peripheral neuropathic pain and postherpetic neuralgia. LX9211 has received fast track designation by the US Food and Drug Administration.

Keywords: AP2-associated kinase 1 inhibitor; analgesic; multiple-dose; pain; pharmacokinetics; single dose.