ARVs in Development: Where do they fit?

Transcription

1 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

2 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

3 In Memorium Mark Wainberg ( )

4 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/

5 Success of current ART Substantial reduction in AIDS-related mortality Source: December 9, 2013; accessed September 3, 2014.

6 Adult life expectancy in rural South Africa Bor et al Science 2013

7 Why do we need new drugs? Side-effects of current therapies Potential long-term toxicities of current ART Resistance Need for less frequent dosing

8 New Drugs or Treatment and Prevention Tenfovir alafenamide (TAF) Bictegravir Doravirine Cabotegravir MK-8591 (EFdA)

9 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

10 Plasma and intracellular levels of tenofovir diphosphate Mills A et al ICAAC 2014 DRK/ICAAC/

11 Relative efficacy of TDF- and TAFcontaining ART Sax et al Lancet 2015

12 Effect of TDF and TAF on renal tubular function and bone density Sax et al Lancet 2015

13 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

14 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/

15 GS-US Study Design* Primary Endpoint Week 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 NCT ; egfr CG, estimated glomerular filtration rate by Cockcroft-Gault equation. 15

16 Virologic Outcome at Week 48 HIV-1 RNA < 50 copies/ml HIV-1 RNA <50 c/ml, % HIV-1 RNA < 50 copies/ml Virologic Outcome 1.0 HIV-1 RNA 50 copies/ml B/F/TAF (n=314) DTG/ABC/3TC (n=315) No Virologic Data Non-inferiority confirmed by pre-specified analyses for HIV-1 RNA < 50 copies/ml: 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 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

17 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 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

18 Results: Virologic Outcomes at Weeks 24 and 48 by FDA Snapshot HIV-1 RNA <50 copies/ml BIC + FTC/TAF Week 24 Week DTG + FTC/TAF % Treatment Difference (95% CI) Favors DTG + FTC/TAF Favors BIC + FTC/TAF Patients, % Virologic Virologic Success Failure n= No Data Virologic Virologic Success Failure No Data Wk 24 Wk 48-12% % No resistance to study medications was detected in either arm Sax PE et al CROI

19 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

20 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/

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24 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/

25 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

26 Cabotegravir nanosuspension

27 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

28 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

29 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

30 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

31 MK-8591 (EFdA) (NRTTI) Grobler JA et al CROI 2016

32 MK-8591: Phase 1b results Grobler JA et al CROI 2016 DRK/ICAAC/

33 MK-8591: extended release formulation Grobler JA et al CROI 2016 DRK/ICAAC/

34 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