Cabotegravir plus rilpivirine, once daily, maintains virologic suppression following induction with cabotegravir plus NRTIs in antiretroviral-naive adults with HIV-1 infection: Final results from the LAI116482 (LATTE) study
David A Margolis, Cynthia C Brinson, Graham HR Smith, Jerome de Vente, Debbie P Hagins, Joseph J Eron, Sandy K Griffith, Marty H St. Clair, Marita C Stevens, Peter E Williams, Susan L Ford, Britt S Stancil, Melinda M Bomar, Krischan J Hudson, Kimberly Y Smith, William R Spreen, extended LAI116482 Study Team
Lancet Infectious Diseases 2015. In press CABOTEGRAVIR GSK1265744 (744)
• HIV-1 integrase inhibitor, dolutegravir analogue.
• Oral drug (t1⁄2 = 40 hours) • Long-acting SC or IM injection
(apparent t1⁄2 ≈ 40 days) • Good virologic response at 5 and 30 mg/day as oral 10-day monotherapy.
Spreen et al. HIV Clin Trials.2013;14:192-203.
Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA LATTE Objectives
• Investigate the safety, tolerability and efficacy of oral 744 across 3 doses for HIV treatment. • Select an oral dose of 744 for further evaluation. • Demonstrate safety and efficacy with a novel 2-drug regimen formaintenance therapy, 744 + rilpivirine. • Facilitate the conduct of a second phase IIb study, evaluating the long-acting injectable regimen, 744 LA + TMC278 (rilpivirine) LA.
Margolis et al. CROI 2014; Boston, MA. Abstract 91LB. 21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA LATTE Study Design
• Phase IIb, randomized, multicenter, partially blind, dose-ranging study. • 744 + NRTI subjects with a W20 HIV-1 RNA <50 c/mL simplified to 744 + RPV at W24. Oral Induction Phase Oral Maintenance Phase HIV ART-naive 744 10 mg + 2 NRTIs* 744 10 mg + RPV 25 mg HIV-1 RNA ≥1000 c/mL CD4 ≥200 cells/mm3 744 30 mg + 2 NRTIs 744 30 mg + RPV 25 mg 1:1:1:1 Randomization Stratified by VL and NRTI 744 60 mg + 2 NRTIs 744 60 mg + RPV 25 mg EFV 600 mg + 2 NRTIs *ABC/3TC or TDF/FTC
D1 Week 16 20 24 48 72 96
• Primary endpoint: % HIV-1 RNA <50 c/mL at 48 weeks (FDA “Snapshot”). Intent-to-treat exposed (ITT-E)-received at least one dose of Investigational Product (IP). Intent-to-treat maintenance exposed (ITT-ME)-received at least one maintenance dose.
21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA Baseline Characteristics – ITT-E
744 744 744 EFV 10 mg 30 mg 60 mg 600 mg n=60 n=60 n=61 n=62
Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA Subject Disposition - ITT-E
Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA Primary Endpoint Virologic Success: HIV-1 RNA <50 c/mL by FDA Snapshot (ITT-E)
744 overall EFV
Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA Secondary Endpoint - Maintenance Population Virologic Success: HIV-1 RNA <50 c/mL by Snapshot (ITT-ME)
744 10 mg (n=52) 744 30 mg (n=53) 744 60 mg (n=55) EFV (n=47)*
Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA Treatment Outcomes - Maintenance Population HIV-1 RNA <50 c/mL by Snapshot (ITT-ME)
• Similar response rate for 744 + RPV, relative to continuing EFV + NRTIs • Similar response across 744 doses
744 744 744 744 EFV 10 mg 30 mg 60 mg Total 600 mg n=52 n=53 n=55 n=160 n=47*
Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA Protocol-Defined Virologic Failure
744 total EFV n=181 n=62
744 total EFV n=160 n=47
Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA Adverse Events
• Neuropsychiatric AEs more commonly seen with EFV. • Headache was more commonly seen with 744 (22%) than EFV (11%). Predominantly Grade 1 and 2; no withdrawals due to headache.
744 744 744 EFV 10 mg 30 mg 60 mg 600 mg n=60 n=60 n=61 n=62
21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA Outcomes at 96 weeks (72 weeks of simplification)
CAB 76%
EFV 63% CAB EFV total 600 mg n=160 n=47* Protocol-Defined Virologic Failure
Induction Phase: • Seven subjects total: CAB 10 mg, n=1 Week 8; 30 mg, n=1 Week 4; 60 mg, n=1 Week 8; EFV 600 mg, n=4 Weeks 4 (n=2), 8 and 16
• No treatment-emergent genotypic or phenotypic resistance.
Maintenance Phase: • Five subjects total: CAB 10 mg, n=2 Weeks 48 and 72; CAB 30 mg, n=1 Week 36; EFV 600 mg, n=2 Weeks 36 and 60. Treatment-Emergent Resistance: • CAB 10 mg – NNRTI (E138Q) and IN (Q148R) in one subject with PDVF at Week 48. CAB FC = 3; RPV FC = 2. CAB and RPV exposures <50% of predicted concentrations at PK assessments.2 • CAB 10 mg – NNRTI K101K/E and E138E/A in one subject with PDVF at Week 72 with RPV FC = 4.6. No treatment-emergent integrase resistance. • One additional subject on CAB 10 mg + RPV with suspected virologic failure (without confirmatory lab draw; lost to follow-up) developed treatment-emergent NNRTI K101K/E and E138E/K at Week 48. RPV FC = 2.18. Tables
Table 1. Fold Change in IC50 Compared With WT for CAB, DTG, RAL and EVG Against Site-Directed Mutant HIV-1
Table 2. Half-Life (Hours) of Dissociation for WT and SDM Integrases at 37°C LATTE Study - Week 48 Analysis Conclusions
• Following induction therapy, oral 744+RPV maintained virologic suppression at a rate similar to EFV+NRTIs. • Primary Endpoint: 82% of 744+RPV and 71% of EFV+NRTIs subjects had HIV-1 RNA <50 copies/mL. • Secondary Endpoint (ITT-ME): 93% of 744+RPV and 94% of EFV+NRTIs subjects had HIV-1 RNA <50 copies/mL. • Similar response rate across 744 10mg, 30mg, and 60mg arms. One subject, with persistently low 744 and RPV drug concentrations, developedtreatment emergent INI and NNRTI mutations. • 744+RPV was well tolerated, with few drug related AEs leading to withdrawal. • Long-term data needed, however, these regimen POC results support evaluation of long-acting injectable regimen of 744 LA + TMC278 LA as maintenance therapy.
Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA Conclusions
• Following induction therapy, oral CAB + RPV maintained virologic suppression at a ratesimilar to EFV + NRTIs through 96 weeks. Primary endpoint: 76% of CAB + RPV and 63% of EFV + NRTIs subjects had HIV-1 RNA <50 c/mL. Secondary endpoint (ITT-ME): 86% of CAB + RPV and 83% of EFV + NRTIs subjects had HIV-1 RNA <50 c/mL. Numerically lower response rate of CAB 10 mg and 30 mg, relative to 60-mg arm is largely due to non-virologic discontinuations, with a low PDVF rate across all arms. • CAB + RPV was well tolerated, with few drug-related AEs leading to withdrawal. • CAB 30-mg once-daily dose was selected for further oral development. • These regimen POC results support evaluation of long-acting injectable regimens of CAB LA + RPV LA as maintenance therapy.