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ECLAIR: Phase 2A Safety and PK Study of Cabotegravir LA in HIV-Uninfected Men

ECLAIR: Phase 2A Safety and PK Study of Cabotegravir LA in HIV-Uninfected Men. Martin Markowitz, 1 Ian Frank, 2 Robert M. Grant, 3 Kenneth H. Mayer, 4 David A. Margolis, 5 Krischan J. Hudson, 5 Britt S. Stancil, 6 Susan L. Ford, 6 Alex R. Rinehart, 5 William R. Spreen 5.

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ECLAIR: Phase 2A Safety and PK Study of Cabotegravir LA in HIV-Uninfected Men

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  1. ECLAIR: Phase 2A Safety and PK Study of Cabotegravir LA in HIV-Uninfected Men Martin Markowitz,1 Ian Frank,2 Robert M. Grant,3 Kenneth H. Mayer,4 David A. Margolis,5 Krischan J. Hudson,5 Britt S. Stancil,6Susan L. Ford,6 Alex R. Rinehart,5 William R. Spreen5 1The Aaron Diamond AIDS Research Center, an affiliate of the Rockefeller University, New York, NY; 2Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 3Institute of Virology & Immunology, Gladstone Institutes, San Francisco, CA; Department of Medicine, University of California, San Francisco, CA; 4The Fenway Institute, Fenway Health, Boston, MA; Beth Israel Deaconess Medical Center, Boston, MA; Harvard Medical School, Boston, MA; 5ViiV Healthcare, Research Triangle Park, NC; 6PAREXEL International (formerly employed by GlaxoSmithKline), Research Triangle Park, NC

  2. Disclosures • Dr. Martin Markowitz has received research grants from GSK/ViiV and Gilead Sciences awarded to his institution • Dr. Markowitz has served as a consultant to Merck • Dr. Markowitz is a speaker on behalf of Gilead Sciences Markowitz et al. CROI 2016; Boston, MA. Abstract 106.

  3. Introduction • Daily oral PrEP has proven effective in randomized clinical trials in MSM, discordant couples, and IDUs, but less so in other populations • Efficacy strongly related to adherence • LA injections may overcome barriers to adherence • CAB is a potent INSTI that has been formulated in an LA suspension Markowitz et al. CROI 2016; Boston, MA. Abstract 106. CAB, cabotegravir; IDU, intravenous drug user; INSTI, integrase strand transfer inhibitor; LA, long-acting; MSM, men who have sex with men; PrEP, pre-exposure prophylaxis.

  4. Objectives Primary • To evaluate the safety and tolerability of IM CAB LA injections through Week 41 Secondary • To evaluate the pharmacokinetics of CAB LA injection through Week 41 • To evaluate the safety and tolerability of oral CAB • To assess the acceptability of CAB LA injections Markowitz et al. CROI 2016; Boston, MA. Abstract 106. IM, intramuscular.

  5. Study Population Key Inclusion Criteria • Healthy men 18 to 65 years of age • At low risk of acquiring HIV, defined as having at least one casual sex partner in the past 24 months Key Exclusion Criteria • At high risk for HIV infection • Recent use of ART (eg, for PEP or PrEP) in the past 30 days or 5 half-lives • Current or chronic history of liver disease Markowitz et al. CROI 2016; Boston, MA. Abstract 106. ART, antiretroviral therapy; PEP, post-exposure prophylaxis.

  6. ECLAIR Study Design Phase IIa, randomized, multi-site, 2-arm, double-blinded study in men at low risk of acquiring HIV Follow-up phase Oral phase Injection phase D1 W2 W4 W5 W17 W29 W41 W53 W65 W77 W81 CAB 30 mg PO QD CAB LA 800 mg IM Q12W Follow-up Placebo PO QD Saline placebo IM Q12W Follow-up Note: not all scheduled study visits are shown in this study schematic. 5:1 Randomization IM IM IM PO, orally; Q12W, every 12 weeks; QD, once daily. Markowitz et al. CROI 2016; Boston, MA. Abstract 106.

  7. ECLAIR Study Disposition Screened (N=205) Not randomized (N=78) • 87 of 94 (93%) who received CAB LA injection and 20 of 21 (95%) who received placebo injections completed the injection phase • 4 subjects withdrew from CAB LA injections due to injection intolerability (n=3, subject decision; n=1, investigator discretion) Randomized (N=127) • CAB (N=106) • Decision by subject (n=1, 1%) Placebo (N=21) Entered oral phase (n=21, 100%) • Entered oral phase (n=105, 99%) • Adverse event (n=7, 7%) • Decision by subject (n=3, 3%) • Investigator discretion (n=1, 1%) • Entered injection phase (n=21, 100%) • Reached protocol-defined stopping criteria (n=1, 5%) • Entered injection phase (n=94, 89%) • Subject decision (n=3, 3%) • Investigator discretion (n=3, 3%) • Lost to follow-up (n=1, 1%) Completed injection phase (n=20, 95%) Completed injection phase (n=87, 82%) Markowitz et al. CROI 2016; Boston, MA. Abstract 106.

  8. Baseline Characteristics of the Randomized Population Markowitz et al. CROI 2016; Boston, MA. Abstract 106. BMI, body mass index; PBO, placebo.

  9. Adverse Events—Oral Phase Markowitz et al. CROI 2016; Boston, MA. Abstract 106. aGrade 2 (n=1), Grade 4 (n=2). bGrade 2 (n=2), Grade 3 (n=1). cGrade 2.

  10. Adverse Events—Injection Phase (Primary Safety Evaluation) • No laboratory adverse events, including liver laboratory abnormalities, led to discontinuation throughout the injection phase Markowitz et al. CROI 2016; Boston, MA. Abstract 106. aPBO: deep vein thrombosis (drug-related); CAB: appendicitis.

  11. ISR Symptoms—Injection Phase • No subjects discontinued due to AEs during the injection phase; 4 subjects who withdrew consent cited injection tolerability as a reason Markowitz et al. CROI 2016; Boston, MA. Abstract 106. aPercentages are out of total number of injections. With the exception of Grade 3 pain, all ISRs listed were Grade 1-2. bSubject was misdosed with CAB on third injection.

  12. Predicted and Observed Mean (SD) CAB Concentration Markowitz et al. CROI 2016; Boston, MA. Abstract 106. CT, concentration at the end of the dosing interval; PA-IC90, protein binding–adjusted 90% inhibitory concentration; SD, standard deviation.

  13. Numbers of Subjects in CAB Concentration Ranges by Injection Visit (ECLAIR) Markowitz et al. CROI 2016; Boston, MA. Abstract 106. Percentages shown as percentage of reportable troughs at each injection visit within window.

  14. HIV Seroconversions Case 1: 24-year-old man, PBO arm, HIV seroconversion at Week 23; referred to ID provider Case 2: 22-year-old man, CAB LA injection arm, HIV seroconversion at Week 53 (24 weeks after final injection) • Subject reported unprotected sex with a casual partner between the visits at Weeks 41 and 53 • Concomitant transaminitis at Week 53 (Grade 3 ALT/Grade 2 AST) • No pheno/genotype resistance mutations to INIs (DTG, RAL, EVG, or CAB), NNRTIs, or NRTIs for samples collected at Weeks 53 and 65 • Subject was referred to ID provider, and initiated on darunavir+ritonavir, emtricitabine/tenofovir Markowitz et al. CROI 2016; Boston, MA. Abstract 106. ALT, alanine aminotransferase; AST, aspartate aminotransferase; DTG, dolutegravir; EVG, elvitegravir; ID, infectious disease; INI, integrase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NQ, not quantifiable; PK, pharmacokinetic; RAL, raltegravir.

  15. Study Medication Satisfaction Questionnaire (Week 18 LA Compared With Oral) How satisfied would you be to continue with your present form of study medication? How satisfied are you with your current study medication? Also see Poster#471: Tolerability and acceptability of cabotegravir LA injection: results from ECLAIR study; Presenter: Miranda Murray; Session date: Wednesday, February 24, 2016, 2:45 PM to 4:00 PM CAB (n=91) CAB (n=91) PBO (n=21) PBO (n=21) Markowitz et al. CROI 2016; Boston, MA. Abstract 106.

  16. ECLAIR Conclusions • Both CAB oral and LA were well tolerated, permitting continued development of CAB for PrEP • The absorption rate following CAB LA injection was faster than predicted by early PK population models, leading to higher peak and lower trough exposures • 15% to 31% of trough concentrations were <PA-IC90, whereas 30% to 37% were ≥4 × PA-IC90 across injection visits, below initial predictions • Given observed trough levels, an 8-week dosing interval is currently under evaluation • Participant satisfaction with IM CAB LA injections was high, including a preference for injections Q12W compared with oral CAB once-daily tablets Markowitz et al. CROI 2016; Boston, MA. Abstract 106.

  17. Acknowledgments • We thank everyone who has contributed to the success of this study, including • All study participants and their families • The ECLAIR clinical investigators and their staff • The GSK and ViiV Healthcare study team • PPD • Quest, Covance, and Monogram Biosciences • This study was funded by ViiV Healthcare Markowitz et al. CROI 2016; Boston, MA. Abstract 106.

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