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Thinking of Now and Tomorrow: Emerging Treatment Paradigms

Thinking of Now and Tomorrow: Emerging Treatment Paradigms. Pedro Cahn. Disclosures. Advisory boards : Merck, ViiV Healthcare Research funds : Abbvie , Merck, Richmond, ViiV Healthcare Speaker at educational activities : Abbvie , Gilead, Merck, ViiV Healthcare.

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Thinking of Now and Tomorrow: Emerging Treatment Paradigms

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  1. Thinking of Now and Tomorrow: Emerging Treatment Paradigms Pedro Cahn

  2. Disclosures Advisoryboards: Merck, ViiVHealthcare Researchfunds: Abbvie, Merck, Richmond, ViiVHealthcare Speaker at educationalactivities: Abbvie, Gilead, Merck, ViiVHealthcare

  3. FDA ARV Approvals 1987–2018 BIC IBA DOR DTG ETR TAF EVG RAL MVC RPV ENF ATV FTC FPV DRV TPV NFV DLV APV TDF LPV/r Number ARVs RTV IDV NVP EFV ABC 3TC SQV ddC d4T ddI AZT 2018 Year of FDA approval for ARV drugs used for the treatment of HIV ARV, antiretroviral; FDA, US Food and Drug Administration; HIV, human immunodeficiency virus

  4. 1996 2019 HAART Paradigms • CD4-guided ARV initiation • Six drugs available • HAART = three drugs • Only ARVs • One dose for all patients • Taken exclusively via the oral route • Daily dosage • Targets: RT, proteases • Treat all, regardless of CD4 counts • 32 antivirals, multiple combinations • Two 2DRs approved • Antivirals and bnAbs (under investigation) • Alternative dosing • Oral and injectables (Subcutaneous dosing, Intramuscular dosing [under investigation]) • Weekly, monthly, every other month dosing (under investigation) • Targets: RT, proteases, integrases, viral attachment, viral maturation, viral genes, capsid 2DR, two-drug regimen; bnAbs, broadly neutralizing antibodies; CD4, cluster of differentiation 4; HAART, highly active antiretroviral therapy; RT, reverse transcriptase

  5. Whatisthe Role of EFV in 2019? ACTG, AIDS Clinical Trials Group; CNS, central nervous system; DOR, doravirine; DTG, dolutegravir; EFV, efavirenz; RAL, raltegravir; RNA, ribonucleic acid; RPV, rilpivirine • RAL: superior at 5 years (exploratoryanalysis) • DTG: superior at 48 weeks (primaryendpoint) • RPV: non-inferior at 48 weeks (superior in patientswith BL pVL <100,000 c/mL) • DOR: non-inferior at 48 weeks and bettertolerated • Impactonthe CNS: • based on the ACTG meta-analysis of four studies • risk of suicidality • dyslipidemia • increasing rates of primary resistance

  6. Prevalence of NNRTI Resistance The pre-treatment prevalence of NNRTI resistance by sampling year Each circle represents a study and the size of the circle is proportional to the size of the study NNRTI, non-nucleoside reverse transcriptase inhibitor

  7. Simplification Strategies ART, antiretroviral therapy Reduce number of doses a day Reduce number of pills Reduce drugdosage Reduce number of drugs Reduce number of dayson ART Expanddosinginterval

  8. 12 Available STRs* (FDA) *According to the FDA (USA), indications vary by country; complete regimens only/c, cobicistat; ABC, abacavir; BIC, bictegravir; DRV, darunavir; EVG, elvitegravir; FTC, emtricitabine; HBV, hepatitis B virus; HLA-B, human leukocyte antigen class B; INSTI, integrase strand transfer inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; pVL, plasma viral load; STR, single-tablet regimen; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate

  9. DoseReduction ENCORE1: EFV 400 mg was non-inferior to approved 600 mg dose in ART-naïve adults*2 N = 302 N = 285 *Modified intention-to-treat analysis TB, tuberculosis; TLE400, fixed dose combination of efavirenz, lamivudine and tenofovir disoproxil fumarate (400 mg/300 mg/300 mg) ARV dose optimization/reduction may allow more patients to be treated for the same cost1 EFV was non-inferior at a lower dose vs originally approved higher dose1 Data on EFV 400 mg during 3rd trimester of pregnancy and anti-TB treatment co-administration are based on 2 small studies3,4

  10. Data Supporting Switch to Newer STRs Among Virologically Suppressed Patients BL, baseline; COBI, cobicistat; STR, single-tablet regimen Established non-inferior efficacy for switch vs BL regimens FDA approved to treat virologically suppressed patients

  11. 2DR: SWORD-1 and -2: Viral Replication With HIV-1 RNA <50 c/mL • Similar rate of post-BL TD and TND categories by BL category across arms • Qualitative viremia by TD more common with BL TD vs BL TND • No difference between arms in virologic success by TND at Week 48 (FDA Snapshot) • DTG + RPV 84% vs continued BL ART 80% (adjusted difference: 3.1%; 95% CI: -2.2% to 8.3%) Patients with TND at BL who maintained TND,% TD, target detected; TND, target not detected Week The analysis used viral load assay that reports qualitative TD or TND for HIV-1 RNA <40 c/mL Patients with TND at BL: 78% for DTG + RPV arm, 83% for continue BL ART arm

  12. GEMINI-1 and -2: DTG + 3TC vs DTG + FTC/TDF in Treatment-Naïve Patients Primary analysis Week 48 Stratified by HIV-1 RNA (≤ vs > 100,000 c/mL), CD4+ cell count (≤ vs > 200 cells/mm³) Week 144 Continuation of DTG + 3TC permitted ART-naïve adults with HIV-1 RNA 1,000–500,000 c/mL, ≤10 days on previous ART, no major resistance associated mutation, no HBV infection or HCV requiring therapy (N = 1,433) DTG + 3TC PO QD (n = 716) DTG + FTC/TDF PO QD (n = 717) Screening within 28 days of study start; studies double-blinded until Week 96, open label until Week 148 HCV, hepatitis C virus • Parallel, international, randomized, double-blind phase III non-inferiority studies • Primary endpoint: HIV-1 RNA <50 c/mL at Week 48 (FDA Snapshot) (non-inferiority margin: –10%) • DTG + 3TC vs DTG + FTC/TDF: 91% vs 93% (difference: –1.7%; 95% CI: –4.4% to 1.1%) • no treatment-emergent INSTI or NRTI mutations in patients with VF in either arm

  13. GEMINI-1 and -2: Snapshot Analysis by Visit: Pooled ITT-E Population Snapshot analysis Adjusted treatment difference (95% CI) at Week 48† DTG + TDF/FTC DTG + 3TC ITT-E –1.7 –4.4 1.1 Per protocol –1.3 1.2 –3.9 DTG + 3TC is non-inferior to DTG + TDF/FTC with respect to proportion achieving HIV-1 RNA <50 c/mL at Week 48 (Snapshot, ITT-E population) in both studies *Calculated from a repeated-measures model adjusting for study, treatment, visit (repeatedfactor), BL plasma HIV-1 RNA, BL CD4+ cellcount, treatment and visitinteraction, and BL CD4+ cellcount and visitinteraction. †Based on Cochran-Mantel-Haenszelstratifiedanalysisadjusting for the following BL stratificationfactors: plasma HIV-1 RNA (≤100,000 vs >100,000 c/mL) and CD4+ cellcount (≤200 vs >200 cells/mm3). ITT-E, intention-to-treat exposed

  14. GS-1490: BIC/FTC/TAF vs DTG + FTC/TAF in Treatment-Naïve Adults at Week 96 Primary analysis Week 48 Week 144 Stratified by HIV-1 RNA (≤100,000 or >100,000 to ≤400,000 or >400,000 c/mL), CD4+ cell count (<50 or 50–199 or ≥200 cells/mm3), geographic region (US or ex-US) Current analysis Week 96 BIC/FTC/TAF QD + DTG + FTC/TAF placebo QD (n = 320) Treatment-naïve adults with HIV-1 RNA ≥500 c/mL, eGFRCG≥30 mL/min (N = 645) DTG + FTC/TAF QD + BIC/FTC/TAF placebo QD(n = 325) eGFRCG, estimated glomerular filtration rate by Cockcroft-Gault equation; US, United States • Multicenter, randomized, double-blind, active-controlled non-inferiority phase III trial1 • Primary endpoint: HIV-1 RNA <50 c/mL at Week 48 (non-inferiority margin: –12%)2 • BIC/FTC/TAF vs DTG + FTC/TAF: 89% vs 93.0% (difference: –3.5%; 95% CI: –7.9% to 1.0%; p=0.12) • no treatment-emergent resistance in either treatment arm

  15. GS-1490: Virologic Outcomes at Week 96 % Treatment difference (95% CI) Virologic outcome 100 89.8 87.9 BIC/FTC/TAF (n = 314) Favors DTG/ABC/3TC Favors BIC/FTC/TAF 80 DTG/ABC/3TC (n = 315) 60 Patients,% -1.9 40 -6.9 3.1 11.5 20 7.9 2.2 0.6 0 HIV-1 RNA <50 c/mL HIV-1 RNA ≥50 c/mL No virologic data -12 -5 0 5 12 276/314 283/315 2/ 314 7/ 315 36/ 314 25/ 315 n/N = Non-inferiority of BIC/FTC/TAF vs DTG/ABC/3TC confirmed in additional analyses No treatment-emergent resistance detected in any patient through Week 96

  16. Investigational ARVs Fusion inhibitors Attachment inhibitors CCR5 co-receptor antagonists Monoclonal antibodies NRTIs NRTIs NNRTIs Rev inhibitors INSTIs Capsid inhibitors PIs Maturation inhibitors CCR, C-C chemokinereceptor

  17. CCR5 antagonist Maraviroc Enfuvirtide Entry Inhibitors gp120 binding Coreceptor binding Virus-cell fusion CD4 binding Fostemsavir Ibalizumab gp41 gp120 V3 loop CD4 Cell membrane CCR5/CXCR4 (R5/X4) * = FDA approved

  18. BRIGHTE: Fostemsavir in Heavily Treatment–Experienced Adults at Week 96 BRIGHTE is an ongoing phaseIIIrandomized, placebo-controlled, double-blind trial Randomizedcohort*: HTE participants failing current regimen with confirmed HIV-1RNA ≥400 c/mLand: Blinded FTR 600mg BID +failing regimen Open label FTR 600 mg BID +OBT Randomized 3:1 • 1 or 2 ARV classesremaining and≥1 fully active and available agent perclass • Unable to construct viable regimen from remainingagents Blinded placebo+ failing regimen Day 1 Day 8–primaryendpoint Day 9 –open label FTR +OBT Week24† Week48† Week 96† End of study‡ Non-randomizedcohort*: HTE participants, failing current regimen with confirmed HIV-1RNA ≥400 c/mLand: Open label FTR 600 mg BID +OBT Non-randomized • 0 ARV classes remainingand no remaining fully active approvedagents§ Day1 Week24 Week48 Week 96 End of study‡ *There was no screening FTR IC50 criteria†Measured from the start of open label FTR 600 mg BID + OBT‡The study is expected to be conducted until an additional option, rollover study or marketing approval is in place§Use of investigational agents as part of OBT was permittedFTR, fostemsavir; HTE, heavily treatment-experienced; IC50, 50% inhibitory concentrations ; OBT, optimized background therapy

  19. BRIGHTE Study: Results • *At baseline 8 participants had HIV-1 RNA <400 copies/mL, 5 had HIV-1 RNA <200 copies/mL, and 1 had HIV-1 RNA <40 copies/mL.†At baseline 5 participants had HIV-1 RNA <400 copies/mL, 4 had HIV-1 RNA <200 copies/mL, and 1 had HIV-1 RNA <40 copies/mL.

  20. New Drugs NNRTI, NRTTI, Capsid Inhibitors Islatravir (MK-8591) (phase II)2 • Potent at low concentrations (0.05 pmol/106 cells) • 3 panels of 12 adults each received multiple daily doses in a phase II study (figure) GS-CA1 (pre-clinical)3 • Highly selective and potent • Plasma levels after 1 dose were maintained >10 weeks in rats • Potential for monthly or longer intervals in dosing Doravirine (phase III)1 • Reduced plasma HIV-1 RNA to <50 c/mL in 84% patients at Week 48 • Non-inferior to darunavir and efavirenz Patients with HIV-1 RNA <50 c/mL at Week 48 • VL decline with islatravir-TP GS-CA1 plasma concentrations following single SC dose in rats Dose (mg) 0.5 1 2 10 30 Proportion of patients Change in placebo-corrected VL NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTTI, nucleoside reverse transcriptase translocation inhibitor; paEC95, protein-adjusted concentration producing 95% maximal effect; SC, subcutaneousTP, triphosphate; VL, viral load

  21. GS-6207 (Phase I) • GS-6207, an analog of GS-CA1, is a novel, selective and highly potent inhibitor of HIV capsid function1,2 • Potential for quarterly or less frequent dosing2 • Measurable concentrations for at least 24 weeks • Plasma concentrations after one dose (≥100 mg) support dosing interval of ≥12 weeks • Well-tolerated following single SC doses of up to 450 mg in healthy subject2 • Ongoing phase I study in patients with HIV-12

  22. Why Investigate LA/ER? Advantages • Infrequent dosing • A long apparent T½ • Lower drug dose needed (nanoformulation) • Prevents poor adherence • Possibility of directly observed therapy • Tissue targeting (LN/macrophage uptake) • Use in patients with pill fatigue • Better protection of health privacy • Avoids treatment-related HIV stigma Disadvantages • Injection site reactions • More frequent visits to the clinic • Increased HCP workload • Long tail, in case of unexpected toxicities • No chelation available, in case of urgent need ER, extended release; HCP, healthcare provider; LA, long-acting; LN, lymph node

  23. ATLAS Virologic Snapshot Outcomes at Week 48 for ITT-E: Non-Inferiority Achieved for Primary and Secondary Endpoints CAB LA + RPV LA CAR Virologic outcomes Adjusted treatment difference (95% CI)* Primary endpoint: LA non-inferior to CAR (HIV-1 RNA ≥50 c/mL) at Week 48 0.6 6% NImargin -1.2 2.5 CAR CAB LA + RPV LA Difference,% Virologic success (<50 c/mL) No virologic data Virologicnon-response (≥50 c/mL) Key secondary endpoint: LA non-inferior to CAR (HIV-1 RNA <50 c/mL) at Week 48 -3.0 -10% NI margin -6.7 0.7 Difference,% *Adjusted for sex and BL third agent class CAR, current antiretroviral; NI, non-inferiority

  24. FLAIR Virologic Snapshot Outcomes at Week 48 for ITT-E:Non-Inferiority Achieved for Primary and Secondary Endpoints CAB LA + RPV LA DTG/ABC/3TC Virologic outcomes Adjusted treatment difference (95% CI)* Primary endpoint: LA non-inferior to DTG/ABC/3TC (≥50 c/mL) at Week 48 -0.4 -2.8 2.1 6% NImargin DTG/ABC/3TC CAB LA + RPV LA Difference,% Virologic success (<50 c/mL) No virologic data Virologicnon-response (≥50 c/mL) Key secondary endpoint: LA non-inferior to DTG/ABC/3TC (<50 c/mL) at Week 48 0.4 −10% NI margin -3.7 4.5 Difference,% *Adjusted for sex and BL HIV-1 RNA (< vs ≥100,000 c/mL) 3TC, lamivudine; ABC, abacavir; CAB, cabotegravir; CI, confidence interval; DTG, dolutegravir; ITT-E, intention-to-treat exposed; LA, long-acting; NI, noninferiority; RPV, rilpivirine

  25. Long-Acting ARV Implants PK, pharmacokinetic • Potential advantages over injectable therapy • Removable • More consistent and predictable drug release • PK not dependent on injection site • May remain in place for years (inert, non-degradable SC versions) • Potential disadvantages over injectables • Specialized device required for insertion • Minor surgical procedure to remove • Regulated as both a drug and a device • Potential difficulties moving to a generic marketplace

  26. Islatravir: NRTI and Translocation Inhibitor • Islatravir-TP concentration time profile with QD dosing • Islatravir administered at low doses exhibits substantially higher inhibitors quotients than marketed NRTIs 10 • 0.25 mg Islatravir • 0.75 mg Islatravir • 5 mg Islatravir • [Islatravir-TP]PBMC (pmol/106cells) 1 100 0.1 Ctroughinhibitory quotient 0 10 20 30 40 10 Time,days • Islatravir-TP concentration time profile with QW dosing n=9 n=9 n=6 n=68 n=64 n=160 n=63 1 Week 1 Week 3 FTC 200 mg QD TAF 25 mg QD TDF 300 mg QD 3TC 150 mg BID/300 mg QD 100 100 • Islatravir0.75 mg QD • Islatravir 10 mg QW • Islatravir0.25 mg QD 10 10 • [Islatravir-TP]PBMC (pmol/106cells) 1 1 0.1 0.1 QW, weekly 0 2 4 6 0 2 4 6 8 10 12 14 Time,days Time,days 10 mg QW 30 mg QW 100 mg QW

  27. BroadlyNeutralizing Monoclonal Antibodies 50% of individuals infected with HIV-1 produce antibodies capable of neutralizing circulating diverse viral strains1 1% of individualproduce antibodies capable of neutralizing more than 80% of circulating diverse viral strains, these individuals are called elite neutralizers2 bnMAbs3 bnMAb, broadly neutralizing monoclonal antibodies

  28. EarlyTreatmentWithbnMAbsInterferesWith Viral Seeding Hyperacute infection (0–14 days) DNA, deoxyribonucleic acid; NmAb, neutralizing monoclonal antibody; PBMC, peripheral blood mononuclear cell; SIV, simian immunodeficiency virus

  29. A Timeline into the Future ????? Long acting 2DR bnMAbs The integrase era STRs 3DRs AZT/3TC AZT monotherapy HIV-1 discovered 2012–13 2017 1996 2006 19972 1983 19871

  30. Conclusions Thefuture looks reallyexciting! • Theeffectiveness of ART isalreadyveryhigh • Theguidelines lean towardsINSTIs • Otherclasseshave new combinations (TAF/FTC/DRV/c and TDF/3TC/DOR) • Patientsrequestsimplertreatments • There are differentstrategies in development • 2DRs (alreadyapprovedby FDA and EMA) • Long-actingdrugs • Experimental: • weekly oral doses • monthlyinjectables • implants • b-nMabs

  31. Thankyouforyourattention! pedro.cahn@huesped.org.ar

  32. Thank you.

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