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Joseph J. Eron, Jr, MD Joseph J. Eron, Jr, MD

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Joseph J. Eron, Jr, MD - PPT Presentation

Joseph J Eron Jr MD Professor of Medicine and Epidemiology The University of North Carolina at Chapel Hill Chapel Hill North Carolina Future Directions Investigational Approaches to Antiretroviral Therapy ID: 764405

therapy hiv 2016 bms hiv therapy bms 2016 drug abstract rna phase antiretroviral iii croi 955176 663068 study maturation

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Joseph J. Eron, Jr, MDProfessor of Medicine and EpidemiologyThe University of North Carolina at Chapel HillChapel Hill, North Carolina Future Directions: Investigational Approaches to Antiretroviral Therapy Washington, DC: August 24, 2016

Future Directions: Investigational Approaches to Antiretroviral Therapy Joseph J. Eron, Jr, MD Professor of Medicine and Epidemiology UNC Chapel Hill August 2016

Financial Relationships With Commercial EntitiesDr Eron has received research grants awarded to his institution from AbbVie, Bristol-Myers Squibb, Merck & Co, Inc, and ViiV Healthcare. He has served as a consultant to AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc, GlaxoSmithKline, Janssen Therapeutics, and ViiV Healthcare. (Updated 08/16/16)

Learning ObjectivesAfter attending this presentation, participants will be able to: Describe why new antiretroviral approaches are needed List mechanisms of action of investigational antiretroviral drugs Describe how these new drugs and formulations might be incorporated into clinical practice

Goals of Antiretroviral TherapyMaintain or restore the health of people living with HIV-1 (PLWHIV) through suppression of HIV-1 replicationMinimize or eliminate short and long-term adverse effects of the therapyHave therapies that are accessible to all PLWHIVPrevent transmission of HIV-1 to others via any route of exposure

Published July 20, 2015 at NEJM.org

Why Do We Need New Antiretroviral Agents?A 25 year old started on therapy today may need treatment for 6 decades! An infected infant – 8 decadesTherapy must be incredibly safe, maximally tolerated and include a range of choicesRenal, cardiovascular, liver and bone toxicitySafety of ART in pregnancy Therapy options for infants and childrenAdherence, life chaos, treatment fatigue, tolerabilityAging and drug interactions (e.g. CYP 3A4 inhibition) TREATMENT GAP -Not all PLWHIV in care are treated Stigma, substance use, mental health, access to clinics, transportation, clinic capacity, country stocks, availability of 3 rd line therapyHIV-1 resistance will always be with us

Continued Improvement in Currently Available ART ClassesDoravirine (NNRTI)Fewer side effects (?) and no food or PPI requirementsPhase III in naïve patients RaltegravirOnce daily Bictegravir (GS-9883; integrase inhibitor) Single tablet, unboosted, TAF-basedPhase III in naïve and switchIntegrase-based two drug therapy Phase III in switch (DTG or CTG plus RPV) Phase III in naïve in development (DTG plus 3TC) MRK-8591 (eFdA – NRTI)Long acting oral and injectable (?)

New NNRTIDoravirine Versus Efavirenz in ART-Naïve PatientsPhase 2b study (n=216)HIV RNA >1000 copies/mLCD4 >100 cells/mm3Randomized armsDOR 100 mg or EFV 600 mg + FTC/TDF Non-success at week 48 Doravirine arm (n=18) Efavirenz arm (n=14)Discontinuations due to AEDoravirine arm: 3%Efavirenz arm: 6% Overall (NC=F) HIV RNA <40 Copies/mL (Week 48) Patients (%) 78% Doravirine Efavirenz 79% 87% 74% < 100K (OF) Gatell J-M, et al. 23 rd CROI. Boston, 2016. Abstract 470. >100K (OF) Baseline HIV RNA (copies/mL) 87% 84% NC=F: non-completer=failure; OF: observed failure

New NNRTIDOR vs. EFV: Clinical Adverse Events Gatell JM, et al. CROI 2016. Abstract 470. Clinical AEs, [1] % DOR + TDF/FTC (n = 108) EFV + TDF/FTC (n = 108) ≥ 1 AE 87.0 88.9 Serious AEs 6.5 8.3 Discontinued for AEs 2.8 5.6 Drug-related AEs* 31.5 56.5 Diarrhea 0.9 6.5 Nausea 7.4 5.6 Dizziness 6.5 25.9 Headache 2.8 5.6 Abnormal dreams 5.6 14.8 Insomnia 6.5 2.8 Nightmares 5.6 8.3 Sleep disorder 4.6 6.5 *Specific AEs occurring in ≥ 5% of pts included.

Raltegravir once dailyIn treatment naïve patients

New Integrase InhibitorBictegravir – 10 d Monotherapy4 participants in each groupGallant et al ASM Microbe 2016 100 mg daily dose: Half life ~ 20 hours pa IQ = 25Peak VL decline = 2.9 log10 Single tablet combination with FTC and TAFPhase III studies in naïve patients vs. DTG plus TAF/FTC or DTG/ABC/3TC fully enrolledSwitch study from DRV/r or ATV/r also fully enrolled

InSTI based 2-drug therapyDolutegravir plus 3TC 48 week data: PADDLE Study Cahn et al WAC Durban 2016 PDVF = HIV RNA 99 (wk 36, 246 retest, 61 wk 48, then BDL) ACTG single arm (N = 120) underway (HIV RNA up to 500,000) Phase III comparative trial in development

Maintaining therapy for Life in all PLWHIVAdherenceHard to reach populations, substance use, depression, children, adolescents …….Life ChaosTravel, dislocation for work or safety, surgery, drug interactions, pill fatigue, patient preference ……Long acting antiretroviral Therapy!

Cabotegravir LA and Rilpivirine LA NanosuspensionsDrug nanocrystal suspended in liquid = nanosuspensionNanomilled to increase surface area and drug dissolution rate Allows ~100% drug loading vs. matrix approaches for lower inj. volumes R H. Müller, et al. European Journal of Pharmaceutics and Biopharmaceutics 78 (2011) 1-9 Component Function GSK1265744 (d50 ~200 nm) Active Mannitol Tonicity agent Surfactant System Wetting/Stabilizer Water for Injection Solvent GSK744 200mg/mL TMC278 300mg/mL Component Function TMC278 (d50 ~200 nm) Active Glucose Tonicity agent Surfactant System Wetting/Stabilizer Water for Injection Solvent Spreen et al. IAS 2013; Kuala Lumpur. Abstract WEAB0103.

Margolis et al WAC Durban 2016

Grobler et al CROI 2016

Antiretroviral Therapy: The Next Generation? Implantable (and removable) combination antiretroviralsVectored delivery of combinations of antibody-based therapy or protein based therapy

Resistant HIV-1 will always be with usFour to eight decades of therapy!Previous exposure to suboptimal treatment in the developed world Limited monitoring of virologic response world-wideTransmitted drug resistance

Viremic patients with multi-drug resistant HIV-1 Patients currently suppressed on therapy That have multi-drug resistant HIV-1 Settings with Viral load Monitoring and Multiple Treatment Options and Past Sub-optimal ART

New Agents for Resistant HIV-1Integrase InhibitorsBictegravirN(t)RTITAF (approved)EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine)(Phase I-II)NNRTIDoravirine (Phase III) Maturation InhibitorsBMS 955176 (Phase II)Attachment inhibitorsBMS 663068 -> 626529 (Phase III) Monoclonal antibodies Broadly virus neutralizing Targeting entry receptorsIbalizumabPRO140 New Targets: e.g. LEDGF, combination entry, additional maturation sites, HIV-1 RNA processing

Integrase Inhibitor Activity Against Resistant Variants in VitroKirsten White, Tomas Cihlar and Michael D. Miller ASM Microbe 2016

Activity of NRTI vs. Resistant variantsFold changeGrobler et al ASM Microbe 2016

Maturation Inhibitors (MIs):BMS-955176 Mode of Action Gag polyprotein Lataillade et al. CROI 2015, Abstract 114LB

Gag polyproteinProtease Untreated Maturation Maturation Inhibitors (MIs): BMS-955176 Mode of Action Mature virus Lataillade et al. CROI 2015, Abstract 114LB

Gag polyproteinImmature virus Maturation Inhibitors (MIs): BMS-955176 Mode of Action Untreated BMS-955176 MaturationInhibitor BMS-955176 inhibits the last protease cleavage event between capsid (CA) protein p24 and spacer peptide 1 (SP1) in Gag, resulting in the release of immature, non-infectious virions Adamson et al. Expert Opin Ther Targets 2009; 13:895–908 Sundquist et al. Cold Spring Harb Perspect Med 2012; 2:7. Protease Maturation Mature virus Protease Treated with BMS-955176 Lataillade et al. CROI 2015, Abstract 114LB

BMS-955176: Median Change in HIV-1 RNA over Time Median change in HIV-1 RNA from baseline to Day 11 reached ~-1.4 log10 c/mL Median change in HIV-1 RNA from baseline , log 10 copies/mL Study days Dosing period Lataillade et al. CROI 2015, Abstract 114LB See Abstract 425, 464

HIV Entry Inhibitors Virus-Cell Fusion Adapted from Moore JP, PNAS 2003;100:10598-10602. gp41 gp120 V3 loop CD4 Binding CD4 Cell Membrane Coreceptor Binding CCR5/CXCR4 (R5/X4) CCR5 Inhibitors maraviroc enfuvirtide BMS 663068

AI438011: BMS-663068 Attachment Inhibitor Monotherapy Substudy: Mean Change in HIV-1 RNA from Baseline* *Error bars represent standard error of the mean. Lalezari et al CROI 2014 abstract 86 Abstract 472

Attachment Inhibitor – Clinical DevelopmentBMS-663068 HIV-1 variants have a range of susceptibilityIn Phase IIB study 6% had a BMS-626529 IC50 >100 nM at screening Phase IIB study in participants with limited resistanceAttachment Inhibitor (over a range of doses) plus RAL and TDF had similar activity over 48 weeks to ATV/r plus RAL plus TDF Phase III study: highly ARV-experienced pts with MDR HIV If at least one fully active ARV then BMS-663068 600 mg or placebo BID for 8 days with no change in background ART followed by BMS-663068 600 mg BID for 48 weeks or longer with optimized backgroundIf no fully active ARV thenBMS-663068 600 mg BID for 48 weeks or longer with optimized background therapy

Broadly Neutralizing antibodiesCan they be harnessed as therapy?

Combined Antibodies: Improved Potency and Breadth Kong, Montefiori Korber et al. J. Virol (2015) 2 mAbs > 98% coverage

HIV-1 discovered ZDV monotherapy ZDV/3TC Triple Drug Therapy Single Tablet Regimens The Integrase Era Long Acting Injectable? ????? 1983 1987 1995 1996 2006 2012-13 2017 2020 Antiretroviral Therapy: The Future

Joseph J. Eron, Jr, MDProfessor of Medicine and EpidemiologyThe University of North Carolina at Chapel HillChapel Hill, North Carolina Future Directions: Investigational Approaches to Antiretroviral Therapy Washington, DC: August 24, 2016