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ÉCLAIR: Phase 2A Safety and PK Study of Cabotegravir LA in HIV-Uninfected Men
Martin Markowitz1; Ian Frank2; Robert Grant3; Kenneth H. Mayer4; David A. Margolis5; Krischan J. Hudson5; Britt S. Stancil5; Susan L. Ford5; Alex R. Rinehart5; William Spreen5
1Aaron Diamond AIDS Rsr Cntr, New York, NY, USA;2Perelman Sch of Med, Univ of Pennsylvania, Philadelphia, PA, USA;3Univ of California San Francisco, San Francisco, CA, USA;4The Fenway Inst, Fenway Hlth, Boston, MA, USA;5ViiV Hlthcare, Research Triangle Park, NC, USA
Cabotegravir (CAB, GSK1265744) is an INSTI in development as a long-acting (LA) injectable for treatment and prevention of HIV-1. ÉCLAIR evaluated CAB LA injections for HIV PrEP. Dose selection was based on Phase 1 studies of CAB LA and target trough concentrations of 4X PA-IC90 (0.664mg/mL), supported by animal studies of SHIV transmission.
Phase 2a, randomized, multicenter, double-blinded study in healthy males, excluding subjects at high risk of acquiring HIV-1 at screening. Subjects were randomized (5:1) to QD oral CAB 30mg or placebo (PBO) tablets for 4 weeks. Following a safety assessment, eligible subjects received gluteal IM injections of 800mg CAB LA or saline PBO Q12 weeks X3. Safety, tolerability, and PK results through three injection cycles (Week 41 primary endpoint) are presented.
Of 127 subjects randomized (83% MSM 31% African-American and 15% Hispanic), 126 were treated (CAB: 105; PBO 21). Eighteen individuals withdrew from CAB during the study: Five during oral dosing, six after oral dosing but prior to injections, and seven during the injection phase. In total, Grade 2-4 adverse events (AEs) occurred in 13/21 (62%) PBO and 84/105 (80%) of CAB subjects. Of Grade 2-4 AEs, injection site pain (55/94, 59%) occurred most frequently for subjects receiving CAB LA. During the Oral Phase, 7/105 (7%) CAB subjects had AEs that led to withdrawal (WD) including 3 events each of neutropenia and blood CPK increased, and one event of fatigue. During the Injection Phase, injection intolerability led to WD in 4/94 (4%) CAB LA subjects (none attributed to individual AEs), and 1/21 (5%) of PBO subjects had an AE (HIV-1 seroconversion) that led to WD. Through Week 41, 14/105 (13%) of CAB and 1/21 (5%) of PBO subjects had Grade 2-4 drug-related lab abnormalities. Geometric mean CAB Ct values ranged from 0.302-0.387mg/mL; AUC(0-t) ranged from 3415-4021mg·h/mL, with minimal accumulation upon repeat administration. Following repeat injections, 67/91 (74%) of subjects favored continuing CAB LA compared to Oral CAB.
CAB LA was well tolerated through Week 41 with a majority of subjects reporting satisfaction with CAB LA IM injections. A higher peak to trough fluctuation driven by faster absorption from the depot site resulted in mean Ct below the minimum target of 4x PA-IC90. An alternative dosing strategy of 600mg Q8 weeks is being investigated with the aim of achieving targeted exposure prior to conduct of Phase 3 efficacy trials.