Investigational Approaches to Antiretroviral Therapy

Transcription

1 Investigational Approaches to Antiretroviral Therapy Rajesh T. Gandhi, MD Massachusetts General Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts Learning Objectives After attending this presentation, learners will be able to: Discuss the appropriate use of novel antiretroviral agents Identify new approaches for treating people with HIV infection Slide 3 of 4 Investigational Approaches to Antiretroviral Therapy Are there any new options for initial treatment of HIV? Are two antiretrovirals as good as (or better than) three? Updates on 2- drug therapy What are the options in someone who has difficulty taking daily drugs? Long-acting agents in development What are new medicines for treating someone with multi-drug resistant HIV? What s on the horizon? Slide 4 of 4

2 Slide 7 of 4 New Antiretroviral Drugs New medications in current classes Bictegravir (INSTI) (approved Feb 218) Doravirine (NNRTI) Bictegravir (BIC) Unboosted integrase inhibitor; high in vitro genetic barrier to resistance, low potential for drug interactions Phase 3 trials in treatment naïve people: BIC/FTC/TAF vs DTG/ABC/3TC; BIC/FTC/TAF vs. DTG + FTC/TAF BIC non inferior to DTG in terms of virologic suppression; no resistance 1,2 As compared to DTG/ABC/3TC, similar changes in estimated GFR, tubular proteinuria, bone mineral density and lipids Randomized switch studies in virologically suppressed persons: Switching to BIC/FTC/TAF non-inferior to continuing boosted PI 3 or a DTG, ABC, 3TC-containing regimen 4 Slide 8 of 4 1 Gallant J et al, Lancet 217; 2 Sax P et al Lancet 217; 3 Daar E et al IDWeek Molina J-M et al, CROI 218 abstract 22 Bictegravir/FTC/TAF: Treatment Naïve Trials Study ,2 Study 149 3,4* -.6% -3.5% (-4.8 to 3.6%) (-7.9 to 1.%) Proportion of Participants, % HIV-1 RNA < 5 c/ml 1 B/F/TAF (n=314) ABC/3TC/DTG (n=315) HIV-1 RNA No HIV-1 RNA 5 c/ml Data HIV-1 RNA < 5 c/ml B/F/TAF (n=32) DTG + FTC/TAF (n=315) HIV-1 RNA No HIV-1 RNA 5 c/ml Data Slide 9 of 4 Bictegravir/FTC/TAF has non-inferior efficacy vs DTG-containing regimens in treatment-naïve populations at Week 48 Gallant J et al, Lancet 217; Sax P et al Lancet 217

3 Slide 1 of 4 Bictegravir/FTC/TAF Indications: Initial treatment of adults with HIV Replacement for regimen in persons who are virologically suppressed and have no history of treatment failure or known resistance to its components Pharmacology and dosing: One-pill, once a day, with or without food. Not recommended if estimated CrCL <3 ml/minute Drug resistance: Active in vitro against HIV isolates that carry some integrase resistance mutations Efficacy in people with prior INSTI failure or resistance is unknown Bictegravir/FTC/TAF Drug interactions: Rifampin contraindicated; other rifamycins not recommended. Metformin AUC increased 39%; no effect on glucose 1 ; assess benefit/risk BIC chelated by polyvalent cations; time doses according to label Pregnancy: Not recommended -- insufficient safety data Side effects: Diarrhea, nausea and headache Increase in serum creatinine (median.1 mg/dl) because of inhibition of tubular secretion Slide 11 of 4 1 Custodio J et al ID Week 217, 1386 Doravirine (DOR): Investigational NNRTI Active in vitro against HIV that is resistant to first-generation NNRTI (isolates with K13N, Y181C, G19A, E11K, E138K, K13N/Y181C) 1 Once daily without regard to food Low potential for drug interactions In phase 3 clinical trial (DRIVE- FORWARD) 2, DOR non-inferior to darunavir/r in terms of virologic suppression with superior lipid profile 1 Lai AAC 214;58: Molina JM, et al, CROI 217, Abstract 45LB Slide 12 of 4

4 Slide 13 of 4 DRIVE-AHEAD: Doravirine/3TC/TDF in Treatment-Naïve Persons With HIV Infection Phase 3 Double-blind Treatment-naïve HIV RNA 1 copies/ml Stratified by HIV RNA HCV or HBV allowed Doravirine/3TC/Tenofovir DF (n=364) Efavirenz/FTC/Tenofovir DF (n=364) Week Primary outcome: HIV RNA <5 copies/ml (FDA snapshot algorithm). Primary Endpoint Non-inferiority: -1%. HIV RNA <5 copies/ml Baseline demographics: Male: 85%. Age: 3-32 years. White: 48%. History of AIDS: 14%. HIV RNA: log 1 copies/ml. CD4: cells/mm 3. Squires KE, et al. J Int AIDS Soc. 217;2(suppl 4): Abstract TUAB14LB DRIVE-AHEAD: Doravirine/3TC/TDF in Treatment-Naïve Persons With HIV Infection DOR/3TC/TDF non-inferior to EFV/FTC/TDF at Wk 48 in terms of virologic suppression HIV RNA >5: ~1% in each arm Virologic failures in DOR arm (6%) Primary NNRTI resistance: 1.6% Primary NRTI resistance: 1.4% DOR superior to EFV in terms of lower incidence of neuropsychiatric adverse events; more favorable changes in lipids New drug applications for DOR/TDF/3TC and for DOR alone submitted to FDA in Jan 218; PDUFA date: Oct 218 Patients (%) HIV RNA <5 Copies/mL Doravirine/3TC/TDF Difference (%): 3.5 (-2., 9.) 1 91% 91% 84% 81% Overall ITT (n=364/364) 1K (n=277/258) Efavirenz/FTC/TDF 81% 81% >1K (n=69/73) HIV RNA (copies/ml) (Observed Failure Approach) Slide 14 of 4 Squires KE, et al. J Int AIDS Soc. 217;2(suppl 4): Abstract TUAB14LB; Orkin C et al, CROI 218, abstract 491 OR FEW Slide 16 of 4

5 Slide 17 of 4 Current NRTI-limiting Regimens for Initial Therapy LPV/r + 3TC (GARDEL) 1 Non-inferior to LPV/r + 2 NRTI Disadvantages: high pill burden, toxicities DRV/r + RAL (NEAT1) 2,3 Non-inferior to DRV/r + TDF/FTC CD4 <2: DRV/r + RAL inferior to DRV/r + 2 NRTI VL >1 K: more failures with DRV/r + RAL 1 Cahn P et al, Lancet ID 214; 2 Raffi F et al, Lancet, 214; 3 Lambert-Niclot S et al, J Antimicrob Chemother, 216; 4 Figueroa MI et al, 15 th EACS, 215 Dolutegravir + 3TC for Initial Therapy PADDLE: single arm study 2 pts with VL <1K: HIV RNA <5 in 9% at wk 48 ACTG A5353: Phase 2 single-arm study HIV RNA 1 to <5, 12 participants enrolled Week 24, HIV RNA <5 in 9% Virologic failure (n=3); suboptimal adherence 1 person: R263RK and M184V ACTG A5353 Wk 24 Virologic Outcomes Baseline HIV RNA GEMINI-1 and -2: ongoing phase 3 trials; results anticipated this year Figueroa MI et al, 15 th EACS, 215. Taiwo BO et al, Clin Infect Dis, 217. >1K (n=37) 1K (n=83) VL <5 (%) 89 9 Virologic non-success (%) HIV RNA >5 copies/ml Other reasons 8 2 Slide 18 of 4 DRV/r + 3TC for Initial Therapy Randomized trial (ANDES) DRV/r + 3TC (n=75) DRV/r + 3TC/TDF (n=7) VL <5 at wk 48: 93 94% Baseline VL >1K: high response rate Dual therapy non-inferior to triple therapy at wk48 Promising results; larger trial ongoing Patients (%) HIV RNA <5 (ITT) Darunavir/r +: 3TC 3TC + tenofovir DF Difference (%): -1.% (-7.5 ; 5.6%) 93% 94% 1 91% 92% Overall (n=7/66) Baseline HIV RNA >1K Copies/mL (n=2/12) Slide 19 of 4 Figueroa et al, CROI 218, Abstract 489

6 Slide 2 of 4 Switching to NRTI-limiting regimens after virologic suppression (maintenance) LPV/r + 3TC/FTC (OLE) 1 ATV/r + 3TC (SALT, ATLAS-M) 2-3 DRV/r + 3TC (DUAL) 4 DRV/r + RPV (small trial, n=6) 5 DRV/r + DTG (DUALIS) being studied DTG + 3TC (LAMIDOL, ASPIRE favorable results 6,7 ; TANGO large RCT just launched 8 ) 1 Arribas JR et al, Lancet ID, 215; 2 Perez-Molina JA et al, Lancet ID, 215; 3 Di Giambenedetto S et al, J Antimicrob Chemother 217; 4 Pulido T HIV Drug Therapy 216 Glasgow, O331; 5 Maggiolo F, JAIDS, 216; 6 Joly V et al CROI 217, abstract 458; 7 Taiwo B et al CID, 217 ; 8 Switching to DTG + RPV in Virologically Suppressed Patients: SWORD-1 and -2 Pts on stable 1 st or 2 nd ART (no change due to VF) and VL <5 for >12 mo. Randomized 1:1 to continue antiretroviral regimen (CAR) or switch to DTG + RPV DTG + RPV non-inferior to CAR DTG/RPV single pill regimen available Food, acid lowering therapy, cation considerations Slide 21 of 4 HIV RNA <5, % Virologic outcomes at wk DTG + RPV (n=513) CAR (n=511) 5 4 <1 1 <1 1 Virologic Virologic No virologic success non-response data Llibre JM et al. CROI 217; Abstract 44LB.; Llibre JM et al, Lance 218 LATTE-2: Long-Acting Cabotegravir + Rilpivirine as Maintenance Therapy Cabotegravir (integrase inhibitor) and rilpivirine (NNRTI): long-acting formulations 1,2 LATTE-2: Phase 2a 3 Open-label 18 years of age ART-naïve CD4 2 Creatinine clearance 5 No HBV or ALT 5x ULN Slide 23 of 4 *In virologically suppressed patients, oral RPV added during last 4 weeks of induction phase. Qualification for maintenance phase: HIV RNA <5 between wk -4 and day 1. Baseline characteristics: Median age: 35 years. Male: 92%. Median HIV RNA: 4.4 log 1 copies/ml. HIV RNA >1K copies/ml: 18%. Median CD4: 489 cells/mm Spreen HIV Clin Trials 213;14: Spreen JAIDS 214;67: Margolis DA, et al. Lancet. 217Jul 21. [Epub ahead of print].

7 LATTE-2: Virologic Outcomes With LA Cabotegravir + Rilpivirine as Maintenance Therapy HIV RNA <5 Copies/mL (%) % 87% 94% Week 96 Results Oral cabotegravir + 3TC/ABC daily (n=56) IM cabotegravir + IM rilpivirine Every 4 weeks (n=115) Every 8 weeks (n=115) 4% 2% % 2% Success Failure No Virologic virologic failure: q8 week 8 [no resistance]) [INI + NRTI Data Protocol-defined weeks (n=2 at weeks 4 and 48 resistance]) and oral cabotegravir (n=1 at 14% Injection site reactions: mild/moderate; transient High participant satisfaction Ongoing phase 3 trials (FLAIR, ATLAS): every 4-wk dosing; results in 218 ATLAS-2M: every 8-wk dosing; results in % Slide 24 of 4 Eron J, et al. J Int AIDS Soc. 217;2(suppl 4): Abstract MOAX25LB. Margolis DA, et al. Lancet. 217Jul 21. [Epub ahead of print]. Long-acting NRTI: MK-8591 (EFdA) Slide 25 of 4 Nucleoside RT translocation inhibitor (NRTTI) Half life of active anabolite: 8-13 hr Humans: single oral dose as low as.5 mg suppressed HIV RNA for >7 day Study in healthy volunteers: multiple daily doses as low as.25 mg expected to lead to HIV suppression Phase 2b trial in people with HIV, in combination with DOR and 3TC, has started (DRIVE2Simplify) Daily dosing Phase 1b, single-dose, monotherapy study Study population: ART naïve (N=3) Grobler CROI 217 #435 Matthews IAS 217 #TUPDB22LB Matthews RP CROI 218 #26 Long-acting NRTI: MK-8591 (EFdA) Animals: drug accumulates in lymph nodes, vagina, rectum Oral MK-8591, even at low doses, protects monkeys from rectal SHIV challenge Parenteral dosing: 6-12 months Supports possible role in PrEP Grobler CROI 216 #98 Friedman CROI 216 #437LB Grobler CROI 217 #435 Markowitz IAS 217 #MOAX23LB Markowitz CROI 218, #89LB Adapted from slide by Trip Gulick, MD Slide 26 of 4

8 Slide 27 of 4 6 yo F diagnosed with HIV in 199. Multiple previous regimens HIV RNA 2,; CD4 cell count 15 HIV phenotype: resistance to NRTI, NNRTI, PIs. Sensitive to INSTI Which of the following classes of drugs is in phase 3 clinical trials? 1. Entry/attachment inhibitors 2. Maturation inhibitors 3. Capsid inhibitors 4. Broadly neutralizing antibodies Case Scenario New Medications for Multi-drug Resistant HIV in Phase 3 trials Ibalizumab Fostemsavir Slide 28 of 4 HIV Entry Inhibitors CD4 Binding Coreceptor Binding Virus-Cell Fusion fostemsavir ibalizumab gp41 gp12 V3 loop CCR5 Inhibitors maraviroc* enfuvirtide* CD4 Slide 29 of 4 Cell Membrane * = FDA approved CCR5/CXCR4 (R5/X4) Slide courtesy of Trip Gulick, MD; Adapted from Moore JP, PNAS 23;1:

9 A Approved 3 Slide 3 of 4 Humanized monoclonal Ab: binds CD4 on host cells; blocks HIV entry (post attachment inhibitor) 1 Active against CCR5 and CXCR4 tropic HIV No cross resistance with other ARVs 2 IV infusion: 2, mg loading dose then 8 mg every 2 wks Duration of infusion: 15-3 min Ibalizumab 1 Emu B et al, Abstract 1686, IDWeek 217; 2 Weinheimer S et al, CROI 218 Ibalizumab in Persons with Multi-Drug Resistant HIV Slide 31 of 4 Phase 3 trial: 4 heavily treatment experienced pts with 3-class ARV resistance Primary endpt: VL drop >.5 log 1 c/ml: 3% during control period 83% after loading dose After loading dose, regimen optimized to include 1 active drug Wk 24: VL <2 in 5% Expanded access: viral suppression to wk 48 March 6, 218 Emu B et al, Abstract 1686, IDWeek Fostemsavir (FTR): Oral HIV Attachment Inhibitor Prodrug of temsavir: binds to gp12, inhibits HIV attachment to CD4 Phase 3 trial in heavily treatment experienced patients with virologic failure (BRIGHTE) Kozal M et al, 16th EACS, 217 Slide 32 of 4

10 Slide 33 of 4 Fostemsavir (FTR): Phase 3 Trial (BRIGHTE) Adjusted Mean (95% CI) Mean VL Change at day 8 N=69 N=21 Placebo FTR 6mg BID Difference (95% CI) = (-.81, -.441) P<.1 Virologicresponse through wk 24 (observed analysis) Kozal M et al, 16th EACS, 217 Regulatory submissions are currently anticipated to take place in the 219/22 timeframe At wk 24, 54% of randomized and 36% of non-randomized ppts who received FTR + OBR achieved VL <4 Monoclonal Antibody against CCR5: PRO 14 Weekly subcutaneous injection Single drug maintenance of suppression study 1 : 1 pts had virologic suppression for 2 yr (out of 31 who entered) One week randomized placebo controlled phase 2b/3 trial in combination with existing ART in people failing current ART 2 N=52; CCR5 tropic HIV Resistance to 3 ARV classes or 2 or more classes with limited treatment options At 1 week, statistically significant reduction in HIV RNA of >.5 log 1 c/ml with PR 14 vs placebo Participants continuing for additional 24 weeks with weekly PRO 14/optimized ART Slide 34 of 4 1 Lalezari J et al, CROI 217, abstract 437; 2 HIV Maturation Inhibitors (MI) Slide courtesy of Trip Gulick, MD Treated with maturation inhibitor Immature virus Slide 35 of 4 Morales-Ramirez IAS 217 #MOAB13:BMS /GSK development halted due to GI toxicity

11 36 On the Horizon Broadly neutralizing antibodies Other novel agents Slide 36 of 4 Broadly Neutralizing Antibodies against HIV Slide 37 of 4 Slide courtesy of Pablo Tebas, MD Scheid J et al, Nature, 216 Slide 38 of 4 Similar results with VRC1. Bar K et al, NEJM 216 Combination bnab, long-acting bnab being studied for treatment, prevention

12 Slide 39 of 4 Other investigational drugs in the pipeline: Investigational Approaches to Antiretroviral Therapy Slide 4 of 4 New options for initial treatment: Bictegravir/FTC/TAF approved; Doravirine (NNRTI) under FDA review Two-drug therapy advancing: DTG + 3TC and DRV/r + 3TC being studied for initial therapy; DTG/RPV approved for maintenance What are the options in someone who has difficulty taking daily drugs? Long-acting agents in development: LA-CAB/LA-RPV in phase 3 trials; MK-8591 (EFdA); others What do you give to someone with highly drug resistant HIV? Ibalizumab approved; fostemsavir completed phase 3; PRO 14, other agents being developed What s on the horizon? broadly neutralizing antibodies, and many others!!