Joseph J. Eron Jr, MD - PowerPoint Presentation

Joseph J. Eron Jr, MDProfessor of MedicineUniversity of North Carolina at Chapel HillChapel Hill, North Carolina Antiretroviral Therapy New Drugs: The Only Thing That Stays the Same is Change FORMATTED: 04/19/2016 San Francisco, California: May 6, 2016 From JJ Eron , Jr, MD , at San Francisco, CA : May 6 , 2016, IAS-USA.

Learning ObjectivesAfter attending this presentation, participants will be able to: Discuss reasons for new ARV agents List advantages of recently approved agents Describe new mechanisms of action of ARV that are in development

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

Published July 20, 2015 a t 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 pregnancyTherapy 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 treatedStigma, substance use, mental health, access to clinics, transportation, clinic capacity, country stocks, availability of 3rd line therapyHIV-1 resistance will always be with us

Continued ImprovementCurrently Available ART Classes Tenofovir alafenamide fumarate (NtRTI)Similar efficacy to TDF, less bone toxicity and renal tubular effects Smaller mg dosing (25 mg), Use in renal dysfunction (CrCl down to 30 cc/min)Activity against NRTI-resistant variants (?)Doravirine (NNRTI)Limited CNS side effectsNo food requirement or PPI interactionPhase III underway GS-9883 (integrase inhibitor)No boosting required, co-formulated with TAF and FTCPhase III underwayTwo drug therapyLess expensive, fewer toxicities?

How will you manage your patients who are currently on TDF containing regimens? I will continue TDF in those who are stable without side effectsI will switch all my TDF patients to TAF-containing regimens I will prioritize specific patients (e.g. older, those with co-morbidities like HTN and DM, osteopenia)Not sure 1

Mills et al, Lancet Infect Dis 2016; 16: 43–52. See Abstract 29 Gallant et al ART to Decrease Long-term Toxicity Switch from Tenofovir DF to Tenofovir alafenamide–containing therapy in patients with suppressed plasma HIV RNA levels.Improvements in proximal renal tubular function

Study 112: Week 96 Changes After Switch to E/C/F/TAF in Patients With Renal Impairment Median eGFR change after E/C/F/TAF switchCDK-EPI Cr: 1.0 mL/min (n=158)CDK-EPI CysC: 3.9 mL/min (n=157) Significant improvements (P<0.05)ProteinuriaRenal tubular functionSpine and hip bone mineral densityMaintained HIV RNA <50 copies/mL: 88%Virologic failure: 2% (5/242)No virologic data: 10% (23/242)5 discontinuation due to increasing eGRFAll 5 had HTN and 2 had DMNo discontinuations due to tubular injury Post FA, et al. 23 rd CROI. Boston, 2016. Abstract 680. Median Change in eGFR (CDK-EPI Cr) Median eGFR (mL/min) 0 24 48 72 96 Baseline eGFR (mL/min) >60 (n=76) 31-40 (n=24) 51-60 (n=78) < 30 (n=10) 41-50 (n=54) Week

Doravirine 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 48Doravirine 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% 7 4% < 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

DOR 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.

Have you used two drug therapy (like a boosted PI or dolutegravir plus 3TC or FTC) as initial therapy or as maintenance therapy? YesNoWhat are you talking about? 1

Two drug ART to Achieve and Maintain SuppressionDolutegravir plus 3TC 24 week data: PADDLE Study # SCR BSL DAY 2 DAY 4 DAY 7 DAY 10 W.2 W.3 W.4 W.6 W.8 W.12 W.24 1 5.584 10.909 3.701 383 101 71 < 50 < 50 < 50 < 50 < 50 < 50 < 50 2 8.887 10.233 5.671 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 3 67.335 151.569 37.604 1.565 1.178 266 97 53 < 50 < 50 < 50 < 50 < 50 4 99.291 148.370 11.797 3.303 432 179 178 55 < 50 < 50 < 50 < 50 < 50 5 34.362 20.544 4.680 1.292 570 168 107 < 50 < 50 < 50 < 50 < 50 < 50 616.02414.4993.7541.634162< 50< 50< 50< 50< 50< 50< 50< 50737.60418.5972.94881961< 50< 50< 50< 50< 50< 50< 50< 50825.07124.3686.2641.377Not done268105< 50< 50< 50< 50< 50< 50914.70710.832Not done516202< 50< 50< 50< 50< 50< 50< 50< 501010.6797.9785.671318< 50< 50< 50< 50< 50< 50< 50< 50< 501150.089273.676160.97468.1293.8802.247784290288147< 50< 50< 501213.50864.1033.4963.2961353513518467< 50< 50< 50< 501328.09333.82937.35026.34353926861< 50< 50< 50< 50 < 50< 501415.34815.1513.99479119898< 506164< 50< 50< 50< 501523.18523.50015.8304.21719269< 50< 50< 50Not done< 50< 50< 501611.3773.91037097143< 50< 50< 50< 50< 50< 50< 50< 501739.10025.82811.8791.97046014752< 50< 50< 50< 50 < 50< 501860.77173.06931.1702.174692358156< 50< 50< 50< 50< 50< 501982.803106.32035.5172.90289735216876< 50< 50 < 50< 50< 50205.1907.3683.43314756< 50< 50< 50< 50< 50< 50 < 50< 50 From week 8 onwards all patients had pVL < 50 copies/mL Figueroa et al (Pedro Cahn) 15 th European AIDS Conference 2015

Two Drug ART Maintains SuppressionLatte: Cabotegravir (InSTI) + rilpivirine maintenance vs. EFV-based therapy Margolis DA, et al Lancet Infect Dis 15;1145 2015

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

Cabotegravir LA and Rilpivirine LA Nanosuspensions Drug 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.

Mean Plasma cabotegravir Concentration-Time Profiles Following Single 100-800 mg LAP Doses (200mg/mL nanosuspension) Differences observed between split and unsplit dosing Spreen et al. IAC 2012; Washington, DC. Abstract TUPE040 .

4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA)MK8591 EFdA (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI)Sub-nanomolar potency in vitro1 and prolonged suppression of SIV in macaque model2Prolonged persistence of triphosphate form in PBMC and macrophagePotential for once weekly dosing Long-acting formulations under development 1 Michailidis et al J Biol Chem 284: 35681-91; 2009 2 Murphey-Corb et al AAC 56:4707-12; 2012

MK-8591: Reduction in HIV RNA for at Least 10 Days After Single Oral Dose Open-label study (n=6)Treatment-naïve malesCD4 >500 cells/mm3 MK-8591 (NRTI)Single, 10-mg oral doseIntracellular MK-8591-TP in PBMCT1/2 (geometric mean): 103 hoursNo evidence of resistance out to day 10 HIV RNA reduction (log10 copies/mL)Day 7: 1.67Day 10: 1.78Generally well tolerated Friedman E, et al. 23 rd CROI. Boston, 2016. Abstract 437LB. HIV RNA After Single Dose Mean Change in Log 10 Copies/mL 0 50 100 150 200 250 Time (hours)

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

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

How often in your practice do you see patients with virologic rebound and resistance to one or more drugs in three or more classes? Once a weekOnce a monthOnce every 6 months Almost never 1

In the next 5 years how many patients in your practice will need a new drug from a new class to treat resistant HIV-1? I am not sure I will see even one1 to 5 patients 5 to 10 patients10 to 25 patientsMore than 25 patients 1

8,746 patients in UK CHIC study who initiated TDF-based first-line ART between 1998 and 2012 VF defined as 2 consecutive viral loads >200 copies/ml Considered major IAS-USA mutations from resistance tests at time of initial failure Multiple imputation used to account for missing resistance tests (56 %)Analysis ignores treatment switches/interruptionsVirologic failure and resistance emergence on current first-line regimens is RARE Courtesy of Ellen White, David Dunn and colleagues

Resistance in Developing WorldSecond-line study: NNRTI/NRTI first line virologic failure – 15 countries – majority of participants from Africa or Asia Baseline resistance - 492 participant samples97% had resistance and almost all had both NRTI and NNRTI mutation61% had at least 2 NRTI mutations15% K65R or K70E and 13.4% had multi-nucleoside mutations (69 insertion or 151 complex) Boyd, M et al Lancet 2013; 381: 2091–99 The TenoRes Study Group Lancet Infect Dis 2016 Published Online January 28, 2015 – Abstract 503

New Agents for Resistant HIV-1Integrase InhibitorsDolutegravir (approved)GS-9883 (Phase III) N(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) Broadly neutralizing monoclonal antibodiesNew Targets: e.g. LEDGF, combination entry, additional maturation sites, HIV-1 RNA processing

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

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

Gag polyprotein Immature virus Maturation Inhibitors (MIs):BMS-955176 Mode of Action Untreated BMS-955176 Maturation Inhibitor 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

BMS-955176 + ATV ± RTV vs. TDF/FTC plus ATV/r Small Pilot study in Treatment Naïve Pts Hwang et al EACS 2015. TDF/FTC 300 mg/200 mg + ATV 300 mg + RTV 100 mg N=4 BMS-955176 40 mg + ATV 300 mg + RTV 100 mg N=8 BMS-955176 40 mg + ATV 400 mg N=8 BMS-955176 80 mg + ATV 400 mg N=8 –2.5 –2 –1.5 –1 –0.5 0 0.5 1 Median change in HIV-1 RNA (log 10 c/mL) from baseline Study day 10 15 20 25 30 35 40 45 50 5 0 Dosing period

BMS-626529 Attachment Inhibitor: Proposed Mechanism of Action 1. Langley DL et al. Manuscript in development.

AI438011: BMS-663068 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 IC 50 >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 HIVIf at least one fully active ARV thenBMS-663068 600 mg or placebo BID for 8 days no change in background ART then BMS-663068 600 mg BID for 48 weeks or longer with optimized background If no fully active ARV then BMS -663068 600 mg BID for 48 weeks or longer with OBT

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

Broadly Neutralizing Antibodies as TherapyCan they be used successfully as therapy? Single antibodies lack needed breadthCombinations of antibodies with differing targetsModifiable to increase half-life Bispecific antibodiesAntibody-like inhibitors (e.g. eCD4-Ig)In combination with long-acting antiretrovirals?But…Cumbersome delivery, increasing potency = decreasing doseVirus escape – frequency of monitoringAnti-idiotype or other inhibitory antibodies Advantages over antiretrovirals – other than being sexy?Caskey et al Nature 2015; Lynch et al Sci Transl Med 2015; Bar et al Abstract 32LB; Chun et al Abstract 311LB

HIV-1 discovered ZDV monotherapy Triple Drug Therapy Single Tablet Regimens The Integrase Era Long Acting Therapy? ????? 1983 1987 1996 2006 2012-13 2020 2025 Antiretroviral Therapy: The Future