ACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals

Transcription

1 ACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals ACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals

2 Are You Ready? New Drugs Are on the Way! Melanie Thompson, MD AIDS Research Consortium of Atlanta ACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals

3 Learning Objectives Upon completion of this presentation, learners should be better able to: Discuss the efficacy of D/C/F/TAF in naïve and treatment-experienced patients Describe the efficacy and resistance patterns of doravirine and DOR/TDF/3TC Explain the mechanism of action for 3 new drugs in phase II-III development ACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals

4 Faculty and Planning Committee Disclosures Please consult your program book. AIDS Research Consortium of Atlanta receives research funding from the following sources: Bristol-Myers Squibb, CytoDyn, Gilead Sciences, GlaxoSmithKline, Merck, Roche Laboratories, Taimed, ViiV Healthcare. Dr. Thompson does not receive any direct funding from pharma. Off-Label Disclosure The following off-label/investigational uses will be discussed in this presentation: All compounds discussed are investigational ACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals

5 D/C/F/TAF: First PI-based Single Tablet Regimen Darunavir/cobicistat/FTC/TAF combination regimen Studied in ART naïve persons (AMBER) Treatment-experienced, virologically suppressed persons (EMERALD) Expect FDA decision in July

6 AMBER Week 48: Phase 3, Randomized, Double-blind, International, Multicenter Trial Treatment-naïve adults (N=725) Screening plasma VL 1,000 copies/ml CD4 + >50 cells/mm 3 Genotypic susceptibility to DRV, FTC and TFV HBV/HCV negative 1:1 Double-blind treatment phase D/C/F/TAF + matching D/C + F/TDF placebo D/C + F/TDF + matching D/C/F/TAF placebo Baseline Week 48 Primary endpoint Single-arm phase D/C/F/TAF Roll-over phase Week 96 D/C/F/TAF Primary objective: Non-inferiority of D/C/F/TAF vs D/C + F/TDF (% patients with VL <50 copies/ml at 48 weeks) (Non-inferiority margin 10%; FDA-Snapshot algorithm) Stratification: screening VL />100,000 c/ml and CD4 + </ 200 cells/mm 3 Eron J, EACS

7 EMERALD Week 48: Phase III, Randomized, Open-Label, Multicenter Trial Screening phase Treatment phase Extension phase Roll-over phase 30 days prior to baseline Randomization * 2:1 N=1149 D/C/F/TAF Continue bpi + F/TDF D/C/F/TAF D/C/F/TAF Baseline Week 24 Week 48 Week 96 Interim analysis Primary endpoint Objective: Non-inferiority and safety of switching to D/C/F/TAF vs continuing bpi + FTC/TDF regimens in virologically suppressed HIV-1-infected adults at Week 48 Stratification: boosted PI at screening Key inclusion criteria: On a stable bpi + F/TDF regimen 6 mo Viral load (VL) <50 c/ml for 2 mo before screening; one 50 VL<200 c/ml w/in 12 mo prior to screening allowed Creatinine clearance (by Cockcroft-Gault) 50 ml/min Previous ART virologic failure (VF) allowed * Stratified by bpi (protease inhibitor boosted with low-dose ritonavir or COBI) at screening. Orkin C. IAS 2017, also Lancet HIV,

8 AMBER Week 48: Virologic Outcome at Week 48 (FDA Snapshot; VL<50 copies/ml) (ITT) Proportion of patients (%) % (n=331) 88.4% (n=321) VL (n=331) <50 copies/ml (n=321) 4.4% (n=16) D/C/F/TAF non-inferior to control Lower bound 95% CI > 10% D/C/F/TAF (N=362) Control (N=363) 3.3% (n=12) 4.1% (n=15) 8.3% (n=30) Virologic VL 50 c/ml No virologic data VL 50 copies/ml Stratified difference (95% CI) (D/C/F/TAF control) Favors control Favors D/C/F/TAF p< Percentage point difference p-value for non-inferiority at 10% NI margin Eron J, EACS

9 EMERALD Week 48: Rebound vs. FDA Snapshot (ITT) 1.2% ( 1.7% to 4.1%) Proportion of patients (%) % confirmed virologic rebound cumulative through Wk % (95% CI: 1.5%, 2.2%*) FDA-Snapshot analysis at week 48 (<50 copies per ml) D/C/F/TAF (N=763) *Upper bound 95% CI <4.0% (p<0.0001) No discontinuations for efficacy reasons Last VL in W48 window 50 c/ml, or discontinuation for efficacy reasons, or premature discontinuations ( efficacy/ae/death), with last (single) VL 50 c/ml Most rebounders (12/19 D/C/F/TAF and 4/8 control) resuppressed (<50 c/ml) at Week 48) D/C/F/TAF was Non-inferior to Control at Week 48 Orkin C. IAS 2017, also Lancet HIV,

10 Resistance Analysis Through Week 48 AMBER: 1 patient on D/C/F/TAF had K103N at screen and M184V emerged at virologic failure EMERALD: 1 rebounder (D/C/F/TAF) and 3 rebounders (control) No DRV, primary PI, TFV or FTC resistance mutations observed Eron J, EACS 2017 Orkin C. IAS 2017, also Lancet HIV,

11 Adverse Event Summary AMBER Slightly higher diarrhea (11% vs 8.6%) and nausea (9.9% vs 5.5%) in control arm Slightly higher rash in D/C/F/TAF arm (6.1% vs 3.9%) EMERALD Slightly higher diarrhea (8% vs 4%) and headache (8% vs 4%) in D/C/F/TAF arm Both Studies Renal, bone, and lipid changes as expected for TAF vs TDF Eron J, EACS 2017 Orkin C. IAS 2017, also Lancet HIV, 2017

12 Doravirine: A New NNRTI and an NNRTI-based STR DRIVE-FORWARD = doravirine (DOR) vs darunavir/r (each with either TDF/FTC or ABC/3TC according to preference) DRIVE-AHEAD = single tablet regimen DOR/TDF/3TC vs EFV/TDF/FTC First new product coformulated with a generic (3TC and TDF) Characteristics of DOR Once daily, no food restrictions Fewer drug-drug interactions than EFV or RIL Resistance profile: active against many not all NNRTI mutations K103N, Y181C, G190A, K103N/Y181C, E138K

13 DRIVE-FORWARD: ART Naïve Patients DOR + 2NRTI is non-inferior to DRV/r + 2NRTI at Week 48 Molina J, CROI 2017, Abstract 45 LB

14 DRIVE-AHEAD: Virologic Outcome at Week 48 (FDA Snapshot Approach) DOR/3TC/TDF EFV/FTC/TDF Percentage of Participants DOR/3TC/TDF is non-inferior to EFV/FTC/TDF at Week HIV-1 RNA <50 copies/ml HIV-1 RNA 50 copies/ml No data in window Molina J, IAS 2017, Abstract TUAB0103LB

15 Adverse Event Summary DRIVE-FORWARD More diarrhea in DRV/r arm (22% vs 14%) Neuropsychiatric events similar (13% DRV/r vs 11% DOR) DRIVE-AHEAD All drug-related AEs: 64% EFV/TDF/FTC vs 31% DOR/TDF/3TC Neuropsychiatric AEs more common on EFV/TDF/3TC

16 DRIVE-AHEAD: Most Common Adverse Events ( 10% in Either Group) DOR/3TC/TDF (N=364) n (%) EFV/FTC/TDF (N=364) n (%) Difference in % estimate (95% CI) a Headache 47 (13%) 45 (12%) 0.5 (-4.3, 5.4) Diarrhea 39 (11%) 49 (14%) -2.7 (-7.6, 2.0) Nasopharyngitis 39 (11%) 31 (9%) 2.2 (-2.1, 6.6) Dizziness 32 (9%) 135 (37%) (-34.0, -22.5) Nausea 28 (8%) 39 (11%) -3.0 (-7.3, 1.2) Abnormal dreams 17 (5%) 42 (12%) -6.9 (-11.0, -3.0) Rash 17 (5%) 44 (12%) -7.4 (-11.6, -3.5) a 95% CIs were calculated using Miettinen and Nurminen s method Molina J, IAS 2017, Abstract TUAB0103LB IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved

17 DRIVE-AHEAD: Proportion of Participants with Predefined Neuropsychiatric Adverse Events at Week 48 Molina J, IAS 2017, Abstract TUAB0103LB IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved

18 DRIVE-AHEAD: Fasting Lipids: Change from Baseline at Week 48 Molina J, IAS 2017, Abstract TUAB0103LB IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved

19 Molina J, CROI 2017, Abstract 45 LB DRIVE-FORWARD: ART Naïve Patients

20 DRIVE-AHEAD: Treatment Experienced Resistance Data at Week 48 DOR/3TC/TDF NNRTI mutations: Y188L; V106I, F227C; V106V/I, H221H/Y, F227C; F227C; V106A, P225H, Y318Y/F; V106M/T, F227C/R DOR/3TC/TDF (N=364) EFV/FTC/TDF (N=364) Participants with PDVF, a n (% of N) 22 (6.0%) 14 (3.8%) Non-responder Rebounder Non-responder Rebounder Participants discontinued without PDVF, n (% of N) 35 (9.6%) 50 (13.7%) Genotype test successfully performed, n Primary NNRTI resistance, n (% of N) 6 (1.6%) b 12 (3.3%) c Primary NRTI resistance, n (% of N) 5 (1.4%) b 5 (1.4%) c NRTI mutations: M41L, M184V; a Protocol-defined virologic failure (PDVF): - Confirmed HIV-1 RNA 50 copies/ml after initial response of HIV-1 RNA <50 copies/ml; OR - Confirmed HIV-1 RNA 200 copies/ml at Week 24 or Week 36; OR M184V; - Confirmed HIV-1 M184V; RNA 50 copies/ml at K65R; Week 48 K65K/R, M184V b In the DOR/3TC/TDF group, NNRTI mutations were RT: Y188L; V106I, F227C; V106V/I, H221H/Y, F227C; F227C; V106A, P225H, Y318Y/F; V106M/T, F227C/R Nucleoside reverse transcriptase inhibitors (NRTI) mutations were RT: M41L, M184V; M184V; M184V; K65R; K65K/R, M184V c In the EFV/FTC/TDF group, NNRTI mutations were RT: K103N; K103N, E138E/G; K103N; G190E; K103N; K103N, M230L; G190E; K103N, V108V/I, T369T/A/I/V; K103N; K103N; K101K/N, K103N, P225P/H NRTI mutations were RT: V118I, M184V; M184V; M184V; M184V, K219K/E; K65K/R, M184M/I EFV/FTC/TDF NNRTI mutations: K103N; K103N, E138E/G; K103N; G190E; K103N; K103N, M230L; G190E; K103N, V108V/I, T369T/A/I/V; K103N; K103N; K101K/N, K103N, P225P/H NRTI mutations: V118I, M184V; M184V; M184V; M184V, K219K/E; K65K/R, M184M/I Molina J, IAS 2017, Abstract TUAB0103LB IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved

21 Dolutegravir/3TC: Two Drug Single Tablet Regimen GEMINI 1 and 2: Registrational trials in treatment-naïve patients Other trials: Study Treatment Setting Est. Sample Size Study Design TANGO Suppressed Switch 600 RCT ASPIRE Suppressed Switch 90 RCT LAMIDOL Suppressed Switch 100 Prospective Cohort PADDLE Treatment Naive 20 Single arm, Pilot ACTG 5353 Treatment Naive 125 Single arm

22 Gemini-1 and -2: Dolutegravir/3TC Single Tablet Regimen Objective: Demonstrate non-inferiority of DTG + 3TC QD compared with DTG+TDF/FTC over 48 weeks in HIV-1-infected ART-naïve subjects Primary endpoint: % with HIV-1 RNA <50 c/ml at Week 48 by FDA snapshot algorithm (missing, switch or discontinuation = failure) non-inferiority margin: 10% 1,2 HIV treatment-naïve VL >1000 c/ml VL <500,000 c/ml Randomisation 1:1 N=700 DTG + TFD/FTC DTG + 3TC Baseline Week 24 Week 48 Week 96 Week 144 North America + EU + international Interim analysis Primary endpoints Secondary endpoints

23 Long Acting Cabotegravir and Rilpivirine Cabotegravir = integrase inhibitor; rilpivirine = NNRTI First long-acting nanoparticle injectables studied for treatment, given every 4 or 8 weeks after induction with oral medications LATTE (naïve), FLAIR (naïve), ATLAS (maintenance) studies in progress Half-life of LA cabotegravir = days Half-life of LA rilpivirine = days LA cabotegravir also being studied for HIV prevention FDA action not expected until 2019 for treatment

24 Cabotegravir LA + Rilpivirine LA: LATTE-2 Induction period Maintenance period a CAB 400 mg IM + RPV 600 mg IM ; Q4W (n=115) CAB 30 mg + ABC/3TC for 20 weeks CAB loading dose at Day 1 CAB 600 mg IM + RPV 900 mg IM; Q8W (n=115) CAB loading doses at Day 1 and Week 4 CAB 30 mg + ABC/3TC PO QD (n=56) Add RPV 4 weeks Day 1 Randomization 2:2:1 Week 32 Primary analysis Dosing regimen selection Week 48 Analysis Dosing regimen confirmation Week 96 b Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.

25 LATTE-2 Week 96 Results HIV-1 RNA <50 c/ml by Snapshot (ITT-ME) Oral CAB induction period (ITT-ME population) Maintenance period Adverse Events Low frequency and generally balanced across arms Slightly more pyrexia and flu-like illness in IM arms Injection-site reactions: mild-moderate severity, rapidly resolved BL, baseline; CAB, cabotegravir; ITT-ME, intent-to-treat maintenance exposed; Q4W, every 4 weeks; Q8W, every 8 weeks. Eron et al. IAS 2017; Paris, France. Slides MOAX0205LB.

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27 NEW!! Expanded Access CAB/RPV LA Inability to construct a viable ARV regimen with commercially available medications Demonstrated need for a long acting, injectable antiretroviral including, but not limited to malabsorption or inability to achieve adequate drug levels via oral route. NOTE: Poor/incomplete adherence to oral meds is not a sufficient rationale for inclusion. Females: willing to abstain or use birth control for 2 weeks before, during, and 52 weeks after last dose GSKClinicalSupportHD@gsk.com;

28 Fostemsavir: An Attachment Inhibitor Prodrug of temsavir, which binds to gp120, causing a conformational change that blocks CD4 binding Reduced HIV-1 RNA by 1.37 or 1.47 log 10 at day 8 of monotherapy 800mg BID or 1200mg QD, respectively In Phase III: heavily treatment experienced patients 8 day placebo-controlled randomized phase --> open label 600mg BID with optimized background Mean change in HIV-1 RNA at day 8 = log 10 Non-randomized cohort for patients with no fully active drugs available: open label 600mg BID; ibalizumab allowed

29 Fostemsavir; Virologic Response through Week 24 (Observed Analysis)* Randomised Cohort Non-randomised Cohort % of Participants % 80% 85% 77% 72% 79% 75% 75% 70% 57% 59% 52% 51% 44% 32% % of Participants % 54% 54% 50% 53% 50 53% 50% 49% 40 47% 51% 42% 30 38% 30% 36% 20 17% 10 0 n=272 n=262 n=256 n=248 n=248 n=247 n=99 n=98 n=93 n=92 n=90 n=89 Baseline Week 4 Week 8 Week 12 Week 16 Week 24 Baseline Week 4 Week 8 Week 12 Week 16 Week 24 <40 c/ml <200 c/ml <400 c/ml <40 c/ml <200 c/ml <400 c/ml *Change in OBT for efficacy reasons were not considered virologic failures in this analysis. Kozal et al. EACS 2017; Milan, Italy. Oral PS8/5.

30 PRO 140: A CCR5-Directed Monoclonal Antibody Humanized IgG4 monoclonal antibody that blocks HIV-1 from entering entering and infecting healthy immune cells High genetic barrier to virus resistance Active against multidrug resistant viruses, including those resistant to maraviroc With single dose, HIV-1 RNA reduction to 1.83 log Administered weekly by SC injections Being studied in treatment-experienced patients Mean Log 10 Change in HIV RNA resistant Placebo 162mg weekly 324mg biweekly 324mg weekly Jacobsen J, et al. J Infect Dis 2010; May 15;201(10):1481-7; St udy Day

31 MK 8591 for Treatment and Prevention New class: nucleoside reverse transcriptase translocation inhibitor (NRTTI) Blocks translocation and terminates the DNA chain Also has delayed chain termination effect after incorporation Also known as EFdA (4 ethynyl-2 fluoro-2 deoxyadenosine) Very potent: dose as low as 0.25mg may be possible for treatment Very long half-life of triphosphate form: hours MK 8591-TP levels remain above pharmacokinetic target for 30 days after last dose Weekly dosing likely possible Being studied with doravirine in Phase II Promising studies in macaques for prevention Matthews R, CROI 2018; Markowitz M, CROI 2018

32 Other New Drugs on the Horizon Capsid inhibitors Combinectin Maturation inhibitors Toll like receptor 7 agonists being studied in cure research Broadly neutralizing antibodies (bnabs) As well as new drugs in old classes NRTI, PI, INI STAY TUNED! COME BACK NEXT YEAR!

33 Acknowledgements Slides and Data Kimberley Brown Janssen Kush Dhody - CytoDyn Barbara Mungin, Mike Robinson, Kathleen Squires - Merck Mark Shaefer - ViiV Healthcare Patients who participated in the trials and clinical site staff who conducted them!

34 ACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals