The picture can't be displayed. ARVs in Development: Where do they fit? Daniel R. Kuritzkes, M.D. Division of Infectious Diseases Brigham and Women s Hospital Harvard Medical School
Disclosures The speaker is a consultant and/or has received speaking honoraria and/or grant support from the following companies relevant to this talk: Gilead GlaxoSmithKline Janssen (J&J) Merck ViiV
In Memorium Mark Wainberg (1945-2017)
FDA-Approved Antiretroviral Agents and Fixed-dose Combinations NRTI Zidovudine Didanosine Stavudine Lamivudine Abacavir Tenofovir* Emtricitabine ZDV/3TC ABC/3TC FTC/TDF FTC/TAF ZDV/3TC/ABC NNRTI Nevirapine Efavirenz Etravirine** Rilpivirine EFV/FTC/TDF RPV/FTC/TDF RPV/FTC/TAF *Nucleotide RT inhibitor **Approved only for treatment-experienced patients Protease Inhibitors Saquinavir Ritonavir Indinavir Nelfinavir Fosamprenavir Lopinavir/ritonavir Atazanavir Atazanavir/cobicistat Tipranavir** Darunavir Darunavir/cobicistat Fusion Inhibitors Enfuvirtide (T-20)** CCR5 antagonists Maraviroc Integrase inhibitors Raltegravir Elvitegravir/cobicistat/FTC/TDF E/C/F/TAF Dolutegravir Dolutegravir/ABC/3TC DRK/ICAAC/9.12.13
Success of current ART Substantial reduction in AIDS-related mortality Source: www.cdc.gov December 9, 2013; accessed September 3, 2014.
Adult life expectancy in rural South Africa Bor et al Science 2013
Why do we need new drugs? Side-effects of current therapies Potential long-term toxicities of current ART Resistance Need for less frequent dosing
New Drugs or Treatment and Prevention Tenfovir alafenamide (TAF) Bictegravir Doravirine Cabotegravir MK-8591 (EFdA)
Tenofovir Alafenamide Fumarate (TAF) O P HO OH O N N NH 2 N N O O O O P O O O O N N NH 2 N N O O O P N H O O N N NH 2 N N TFV Tenofovir O O TDF Tenofovir Disoproxil Fumarate TAF Tenofovir Alafenamide Gut TFV TDF TAF Plasma TDF/TFV TAF Lymphoid Cells TAF Cathepsin A TFV TFV-MP Zolopa A, et al, 20 th CROI, Atlanta, 2013 TFV-DP
Plasma and intracellular levels of tenofovir diphosphate Mills A et al ICAAC 2014 DRK/ICAAC/9.12.13
Relative efficacy of TDF- and TAFcontaining ART Sax et al Lancet 2015
Effect of TDF and TAF on renal tubular function and bone density Sax et al Lancet 2015
TAF and rifampicin TAF is a substrate of several drug transporters P-glycoprotein, OATP1B1, OATP1B3 and BCRP Rifampicin induces CYP3A4, P-gp and BRCP, but inhibits OATP1B1 and OAT1B3 Net effect is a significant reduction in plasma TFV concentrations New data suggest twice daily administration of TAF overcomes RIF effect Aligns nicely with need to administer DTG twice daily when co-administered with RIF Custodio JM et al. 16 th EACS, Milan, 2017
Bictegravir (GS-9883) Novel, once-daily, INSTI Potent in vitro activity against wild-type and most INSTI-resistant variants BIC plasma half-life approximately 18 hours No requirement for boosting DRK/ICAAC/9.12.13
GS-US-380-1489 Study Design* Primary Endpoint Week 0 48 96 144 Treatment-Naïve Adults HIV-1 RNA 500 c/ml egfr CG 50 ml/min 1:1 n=314 B/F/TAF QD DTG/ABC/3TC Placebo QD HLA B*5701 negative Negative for chronic HBV n=315 DTG/ABC/3TC QD B/F/TAF Placebo QD Phase 3, randomized, double-blind, active-controlled study Stratified by HIV-1 RNA, CD4 cell count, geographic region North America and Europe Primary endpoint: proportion with HIV-1 RNA <50 copies/ml at Week 48 Noninferiority margin of 12% based on FDA snapshot algorithm *ClinicalTrials.gov NCT02607930; egfr CG, estimated glomerular filtration rate by Cockcroft-Gault equation. 15
Virologic Outcome at Week 48 HIV-1 RNA < 50 copies/ml HIV-1 RNA <50 c/ml, % 100 80 60 40 20 0 92.4 HIV-1 RNA < 50 copies/ml 290 314 93.0 293 315 Virologic Outcome 1.0 HIV-1 RNA 50 copies/ml 3 314 8 315 B/F/TAF (n=314) DTG/ABC/3TC (n=315) 2.5 6.7 4.4 No Virologic Data 21 314 Non-inferiority confirmed by pre-specified analyses for HIV-1 RNA < 50 copies/ml: 14 315 Per protocol: B/F/TAF 99.3% vs DTG/ABC/3TC 98.6% (p=0.43) Missing=Failure: B/F/TAF 92.4% vs DTG/ABC/3TC 93.3% (p=0.65) Favors DTG/ABC/3TC Missing=Excluded: B/F/TAF 99.3% vs DTG/ABC/3TC 97.7% (p=0.10) % Treatment Difference (95% CI) -0.6 Favors B/F/TAF -4.8 3.6-12 -8-4 0 4 8 12 Mean CD4 increase from baseline at Week 48: B/F/TAF +233 cells/µl vs DTG/ABC/3TC +229 cells/µl (p=0.81) 16
Study Design Primary endpoint Secondary endpoint Treatment-naïve HIV-1 RNA 1,000 c/ml HBV and HCV negative CD4 200/µL 2:1 Randomization Week 0 24 48 n=65 n=33 BIC + FTC/TAF QD DTG Placebo QD DTG + FTC/TAF QD BIC Placebo QD Randomized, double-blind, active-controlled study Primary Endpoint: proportion with HIV-1 RNA <50 copies/ml at Week 24 After Week 48, all patients who completed the double-blind phase entered an extension phase and received open label BIC/FTC/TAF Sax PE et al CROI 2017 17
Results: Virologic Outcomes at Weeks 24 and 48 by FDA Snapshot HIV-1 RNA <50 copies/ml 100 80 97 94 BIC + FTC/TAF Week 24 Week 48 97 91 DTG + FTC/TAF % Treatment Difference (95% CI) Favors DTG + FTC/TAF Favors BIC + FTC/TAF Patients, % 60 40 20 0 3 6 0 Virologic Virologic Success Failure n= 63 65 31 33 2 65 2 33 0 No Data 0 65 0 33 Virologic Virologic Success Failure 63 65 30 33 2 6 2 3 1 65 2 33 No Data 1 65 1 33 Wk 24 Wk 48-12% 2.9-8.5 14.2 6.4-6 18.8 0 12% No resistance to study medications was detected in either arm Sax PE et al CROI 2017 18
Bictegravir/FTC/TAF pros and cons PROS Potent, well-tolerated STR No boosting required Avoids abacavir, TDF Low risk of resistance No dosing restriction regarding food No limitation regarding baseline CD4 count, virus load CONS Cannot be co-administered with rifampicin Cost (at present) Limited (no) data on safety in pregnancy
Doravirine Novel, next-generation NNRTI Unique resistance profile Active against HIV with common NNRTI resistance mutations (K103N, Y181C, G190A, K103N/Y181C, E138K) Not a CYP3A4 inducer or inhibitor Once-daily dosing without regard to food DRK/ICAAC/9.12.13
Doravirine: strengths and weaknesses Strengths Potent NNRTI No known restrictions regarding food or PPI Co-formulated as STR Potential cost advantage over other STRs (assuming generic pricing of TDF and 3TC components) Weaknesses Co-formulated with TDF Limited resistance data from clinical trials to date Limited (no) data in pregnancy Substantial impact of rifampicin on DOR trough concentrations (cannot be co-administered) DRK/ICAAC/9.12.13
Long-acting ARVs Less frequent dosing of ARVs could improve adherence to and effectiveness of ART Potentially amenable to DOT Several approaches currently in development
Cabotegravir nanosuspension
LATTE-2 Cabotegravir (CAB) is an HIV-1 integrase inhibitor Oral 30 mg tablet (t ½, ~40 hours) IM LA injection 200 mg/ml (t ½, ~20-40 days) Rilpivirine (RPV) is an HIV-1 NNRTI Oral 25 mg tablet (t ½, ~50 hours) IM LA injection 300 mg/ml (t ½, ~30-90 days) Oral 2-drug CAB + RPV proof of efficacy established through Week 144 in LATTE-1 LATTE-2 Week 48 data supported the decision to evaluate the Q4W CAB LA + RPV LA IM regimen in phase III studies (FLAIR and ATLAS; ongoing) Q8W dosing remains under long-term evaluation within LATTE-2 Eron et al 9 th IAS Conf on HIV Science, Paris, 2017
LATTE-2 Week 96 Results HIV-1 RNA <50 c/ml by Snapshot (ITT-ME) Oral CAB induction period (ITT-ME population) Maintenance period BL, baseline; CAB, cabotegravir; ITT-ME, intent-to-treat maintenance exposed; Q4W, every 4 weeks; Q8W, every 8 weeks. Eron et al 9 th IAS Conf on HIV Science, Paris, 2017
Protocol-Defined Virologic Failure (PDVF) Through 96 Weeks 2 PDVFs Q8W 1 without treatment emergent resistance (Week 4) b 1 with INI + NNRTI mutations (Week 48) c No PDVFs Q4W 1 PDVF Oral CAB + NRTIs (Week 8) No treatment emergent resistance No additional PDVFs occurred after Week 48 in any arm Eron et al 9 th IAS Conf on HIV Science, Paris, 2017
Ongoing studies of LA cabotegravir FLAIR and ATLAS Phase 3 trials in combination with LA rilpivirine HPTN 083 and 08 Phase 3 trials for PrEP ACTG A5359 Phase 2b/3 trial in combination with LA rilpivirine in patients with prior non-adherence
MK-8591 (EFdA) (NRTTI) Grobler JA et al CROI 2016
MK-8591: Phase 1b results Grobler JA et al CROI 2016 DRK/ICAAC/9.12.13
MK-8591: extended release formulation Grobler JA et al CROI 2016 DRK/ICAAC/9.12.13
LA formulations: Pros and Cons PROS Allow monthly dosing Tolerated well to date More convenient Less stigma May promote adherence Potential for DOT? CONS Some require i.m. injection Long-term tolerability? Very long terminal ½-life Cannot be self-administered Potential for resistance in non-adherent patients