Clinical Pharmacology of HIV Pre-Exposure Prophylaxis (PrEP) Where are we now?

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Erika Mitchell
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1 Clinical Pharmacology of HIV Pre-Exposure Prophylaxis (PrEP) Where are we now? Pill Injection Implant Infusion Vaginal ring Gels Vaginal film Lube Douche Craig W. Hendrix, MD Wellcome Professor and Director, Division of Clinical Pharmacology Johns Hopkins University School of Medicine

2 Disclosures ViiV/GSK funded clinical trial managed through Johns Hopkins

3 Objectives Describe brief history of PrEP to date Limitations to daily oral PrEP Differential diagnosis vaginal product underperformance Innovations to broaden PrEP success Long-acting PrEP Vaginal microbicides Rectal microbicide

HIV Incidence/100 PY HIV PrEP Development 2001-2018 2001-2009 Vaginal microbicides 6 failed RCTs CAPRISA 004 Heterosexual Women TFV Vaginal Gel on demand 39% RRR 2010 Vaginal Tenofovir gel

4 HIV Incidence/100 PY HIV PrEP Development Vaginal microbicides 6 failed RCTs CAPRISA 004 Heterosexual Women TFV Vaginal Gel on demand 39% RRR 2010 Vaginal Tenofovir gel heterosexual women Modest protection, 3 RCTs (1 mitt, 2 post hoc) Clinical Pharmacology demonstrated concentration-response HIV PrEP Oral TFV + FTC MSM/TGW (N=3) modest to high level protection, snda Hetero women & men (N=2), high protection, snda PWID (N=1) protects Heterosexual women (N=2) failed to protect 2016 HIV Dapivirine intravaginal ring (N=2) Modest protection EMA NDA under review iprex MSM/TGW TDF/FTC oral 44% RRR TFV-DP (fmol/10 6 PBMCs) Abdool Karim Science 2010; Abdool Karim Lancet 2011; Grant NEJM 2010; Anderson STM 2012; Baeten NEJM 2012; Marrazzo NEJM 2015; van Damme NEJM 2012

5 Cumulative Probability of HIV Infection Cumulative Probability of HIV Infection HIV PrEP Development Vaginal microbicides 6 failed RCTs 2010 Vaginal Tenofovir gel heterosexual women Modest protection, 3 RCTs (1 mitt, 2 post hoc) Clinical Pharmacology demonstrated concentration-response HIV PrEP Oral TFV + FTC MSM/TGW (N=3) modest to high level protection, snda Hetero women & men (N=2), high protection, snda PWID (N=1) protects Heterosexual women (N=2) failed to protect 2016 HIV Dapivirine intravaginal ring (N=2) Modest protection EMA NDA under review Partners Discordant Couples TDF 0.67 ( ) TDF/FTC 0.75 ( ) Months VOICE Heterosexual Women TDF ( ) TDF/FTC ( ) TFV gel 0.15 ( ) Months Abdool Karim Science 2010; Abdool Karim Lancet 2011; Grant NEJM 2010; Anderson STM 2012; Baeten NEJM 2012; Marrazzo NEJM 2015; van Damme NEJM 2012

6 Vaginal PrEP Underperformance TFV Vaginal Gel mitt* Post Hoc Adherence Adjustment*** CAPRISA % RRR** VOICE gel 0% RRR FACTS 001 0% RRR Dapivirine IVR ASPIRE 27% RRR The Ring Study 31% RRR TDF/FTC Oral iprex 42% RRR Partners 75% RRR CDC TDF2 62% RRR 40-88% 75% % *mitt, modified intent to treat analysis; **RRR = relative risk reduction in HIV infection; ***assumes no microbiome effect

7 Differential Diagnosis Adherence doesn t completely account for oral-vaginal outcome differences Women practicing RAI certain, but variable effect If 1/20 HIV exposures is anal & 20x anal HIV transmission risk, max RRR is 50% Front door dose, no back door protection Vaginal microbiome may reduce TFV concentration with concomitant BV Polymorphic LOF kinase mutations impact NTP concentrations, but <10% [Tissue] v. [Systemic] relative contribution varies by route; unsettled Oral IM IV Systemic FGT or Colorectal Tissue Topical FGT or Colorectal Lumen

8 Long-Acting Formulations

PA-IC 90 Men Women Target Dosing based on Animal Model Cohort 2 Injection every 2 months Confidence bolstered by Treatment

9 Adherence: CAB-LA (2 months) Cohort 1 Injection every 3 months Problem being solved is daily oral adherence Solution requires some daily oral adherence Oral lead-in may be dropped with data Long tail may be inconsequential for resistance 8x PA-IC 90 4x PA-IC 90 1x PA-IC 90 Men Women Target Dosing based on Animal Model Cohort 2 Injection every 2 months Confidence bolstered by Treatment Effectiveness But tissue concentrations poor relative to plasma HPTN 083/084 greatly inform target concentration issue 8x PA-IC 90 4x PA-IC 90 1x PA-IC 90

10 Adherence: bnmabs (2 6 months) Neutralize virus (Env) & recruit effector cells to kill HIV infected cells Rare elite neutralizers: evolve nabs which neutralize within & across clades Engineering improvements increase coverage, potency, and half-life Passive immunoglobulin low potency, narrow breadth Early bnmabs (from elite neutralizers) increase potency & breadth Combinations broadens coverage (move up) FcRn substitution increases half-life (move right) Treatment Clinical transiently reduces viral load (VRC01) Prevention High level SHIV vaginal/rectal protection macaques 2 RCTs underway with VRC01 infusion Expensive vs. other approaches Sok D. Immunity 2016;45(5): (Figure 1)

11 Adherence: Subdermal Implant Designs (1 year) TAF Oak Crest (removable) TAF RTI (biodegradable) TAF or CAB SLAP-HIV (removable) Gunawardana et al., AAC, 2015 van der Straten LEAP 2018 Hope/Kiser SLAP-HIV Courtesy Marc M. Baum, Oak Crest Institute of Science; Gunawardana et al., AAC, 2015; Ariane van der Straten LEAP 2018; Thomas Hope SLAP-HIV.

12 Vaginal Microbicide Formulations

channels size Flexible drug combinations unlike matrix of single reservoir rings Phase I, 3

13 Adherence: Pod-IVR Design (1 month) <10 Polymer-coated drug pods An un-medicated, torus-shaped elastomeric support holds the pods Release rate controlled through delivery channels size Flexible drug combinations unlike matrix of single reservoir rings Phase I, 3 ARV study under review MPT (contraception/arv) pre-clinical Marc Baum & John Moss, Oakcrest Institute of Science

Front Door-Back Door: Pod-IVR Day 7 Rectal Fluid Concentrations P = 0.002 ** Vincent K, et al.

MVC TFV <0.5 2.2 3.9 BLQ FTC <0.6 <0.35-81.0 0.81 MVC <0.006 <0.013 - - 1.

14 Front Door-Back Door: Pod-IVR Day 7 Rectal Fluid Concentrations P = ** Vincent K, et al. PLOS One (in review) In Vitro (mm) Pod-IVR (clinical : in vitro) ARV IC 50 IC 90 Pod-IVR D7 TDF TDF FTC TDF FTC MVC TFV < BLQ FTC <0.6 < MVC <0.006 < Combinations complex Rectal fluid may provide protective levels Future Work. - Rectal tissue cell active drug - Anterior & posterior colon wall - Relevant distance

15 Multipurpose Prevention Technologies (MPT) MPT: PrEP & (Other STI* +/or Contraception) Complicated design, development, & partnerships Balances limiting attributes of optimized single drug platforms with improved adherence with one device, two purposes Product pipeline (22 products) Intravaginal ring 4 pregnancy, 5 STI Vaginal Gels 3 pregnancy, 4 STI Vaginal films 2 STI Fast dissolve insert 3 STI Barrier - 1 pregnancy/sti Addressing twin issues of HIV & high birth rate in Africa *Most STIs are HIV in combination with HSV-2 +/or HPV, 2 products also cover chlamydia

FAME On Demand, Portable: Tenofovir Film Plasma TFV (ng/ml) 14 12 10 8 6 4 2 Plasma Cervical Tissue Homogenate Ex vivo HIV Tissue Challenge Film Gel TFV ng/mg 10 4 Exo Film Exo Gel Fnx Film 10 3 Fnx

16 FAME On Demand, Portable: Tenofovir Film Plasma TFV (ng/ml) Plasma Cervical Tissue Homogenate Ex vivo HIV Tissue Challenge Film Gel TFV ng/mg 10 4 Exo Film Exo Gel Fnx Film 10 3 Fnx Gel Mid Film Mid Gel RF Film 10 2 RFl Gel VT Film VT Gel CUM P24 Antigen (pg/mg) Hours Hours 10-2 BL D1 5hr D3 72hr BL D1 5hr D3 72hr Film Sampling Day Gel T max Film > Gel; C Film> Gel 8+ hrs Film > Gel (except RF, Plasma) BL v 5h NS; Film v. Gel any time NS FAME Program: Robinson JAIDS 2018, Bunge JAIDS (in review); Also Dapivirine Bunge JAIDS 2016; Robinson ARHR 2016

17 Systemic v. Tissue & Oral v. Topical Dosing Study N Regimen Duration Include Pod-IVRs MTN-001 oral & VF MTN-014 HPTN 066 Serum or Plasma TFV ng/ml VT TFV-DP fmol/mg MTN-001 TFV 1% VF* 144 Gel QD x 42d 0.67 (BLQ, 2.09) C 24 1,807 (591, 5,860) MTN-014 TFV 1% RGVF 14 Gel QD x 14d DOD 0.58 (BLQ, 1.3) C (37, 2,377) Criteria Start to with advance MTN-014 product? table Vaginal tissue TFV-DP? (vaginal dosing) Show VT TFV-DP PBMC Show TFV-DP? Plasma/Serum (oral TFV dosing) Both? In what combination? Pod-IVR TDF (OCIS) 6 IVR x 7d BLQ (<0.31) C ss 303 (277,938) Pod-IVR TDF-FTC (OCIS) 6 IVR x 7d BLQ (<0.31) C ss 289 (110, 603) Pod-IVR TDF-FTC-MVC (OCIS) 6 IVR x 7d BLQ (<0.31) C ss 302 (177, 824) Reservoir IVR (Einstein) 15 IVR x 14d 1.9 (1.2, 2.4) C max 120 (90, 550) TFV Film 40 mg SD (FAME) 10 Film once 10.4 (3.9, 13.6) C max 160 ( 27, 485) 5hr TFV Film 40 mg MD (FAME) 15 Film QD x (0.46, 2.81) C ( 56, 1456) 2hr How Long? (on demand vs. IVR ) MTN-001 TDF oral* 144 PO QD x 42d 65 (14, 103) C 24 BLQ (BLQ, BLQ) HPTN-066 TDF oral* 13 PO QD x 35d DOD 52 (49, 56) C 24 BLQ, 41 (2/2) *proven product effectiveness in primary (oral TDF 65% RRR) or post hoc (oral >90% RRR; vaginal 60-88% RRR)

18 Evolving Thoughts on Target Concentration TDF/FTC Rx dose (conc n) same for PrEP refuted by protective doses in MSM v. women [Tissue] a/w successful oral PrEP predicts topical dosing target refuted by vaginal gel underperformance despite high TFV [tissue] At least a [2-site] problem, [systemic] & [tissue] contribute, but in different proportion depending on dosing route Supported by plasma conc n-response PK/PD model fit Improved by [tissue] & route of risk adjustment of [systemic] data What is DEC90 for oral vs. Topical? Any resolution short of oral v. topical RCT?

19 Rectal Microbicide Formulations

20 On Demand Rectal Microbicide Feasibility On demand oral PrEP (Truvada) efficacy high Ipergay 86 % risk reduction On demand vaginal tenofovir efficacy modest CAPRISA 004, FACTS 001 ~60% with good adherence NHP Protection: Single dose rectal TFV protects rectal SHIV challenge Behaviorally-congruent formulations ARV-medicated sex lubricant or douche piggy-back onto very common sex practices less demanding of behavior change

21 TFV Rectal Microbicide Development Methods/Vehicle Development JHU HIV surrogate distribution JHU Tissue pharmacology CDC/NIH Luminal PK-D imaging NIH PD Surrogates: Explant, BLT, NHP MDP 2/2b RF vehicle development MDP 1 Enema vehicle development JHU Lube dosing feasibility

Analysis Concentration-Distance-Time Dual Isotope Imaging (SMW) D

06 DC max 0.05 AUC adjusted "Concentration" 0.04 D min 0.03 0.

22 Does RM Outdistance & Outlast HIV? Microbicide ( 111 In-DTPA) HIV ( 99m Tc-SC) in Ejaculate Image Analysis Concentration-Distance-Time Dual Isotope Imaging (SMW) D max 99m Tc-SC HIV Surrogate 111 In-DTPA Microbicide ARV Surrogate 0.06 DC max 0.05 AUC adjusted "Concentration" 0.04 D min Rectal TFV gel (0hr), simulated sex/ejaculation (1hr), SPECT/CT (2hr) DC max D min D max Centimeters from Point Source Hours after Dosing Hiruy, et al. ARHR 2015 Cao, et al. BrJCP 2012 Hendrix, et al. CPT 2008

23 TFV Rectal Microbicide Development Methods/Vehicle Development Drug Product Development Phase I Phase II Phase III JHU HIV surrogate distribution JHU Tissue pharmacology Vaginal Formulation (VF) 3,111 mosm/kg TFV 1% RMP-02/MTN-006 No Phase II Safety/AEs CDC/NIH Luminal PK-D imaging NIH PD Surrogates: Explant, BLT, NHP MDP 2/2b RF vehicle development Reduced Glycerin (RGVF) 836 mosm/kg TFV 1% Rectal Formulation (RF) 479 mosm/kg TFV 1% MTN-007 CHARM 01/02 TFV 10% RF Lube MTN-017 Safety/Accept No Phase III Applicator (Safety) Future RCT? On Demand Lube MDP 1 Enema vehicle development JHU Lube dosing feasibility Enema Formulation (EF) Dose escalation Iso- or hypo-osmolar

24 Is Gel as Lube Feasible? Douche Saline-like 125 ml Applicator Gel HEC 10 ml Manual Lube Application Wet TM 10 ml intraluminal How much product is delivered? Where is the gel distributed?

25 Is Gel as Lube Feasible? Douche Saline-like 125 ml Applicator Gel HEC 10 ml Manual Lube Application Wet TM 10 ml intraluminal Retention: 60% 95% 10% (3.5 ml gel) Distribution: 60 cm cm cm

26 TFV Rectal Microbicide Development Methods/Vehicle Development Drug Product Development Phase I Phase II Phase III JHU HIV surrogate distribution JHU Tissue pharmacology Vaginal Formulation (VF) 3,111 mosm/kg TFV 1% RMP-02/MTN-006 No Phase II Safety/AEs CDC/NIH Luminal PK-D imaging NIH PD Surrogates: Explant, BLT, NHP MDP 2/2b RF vehicle development Reduced Glycerin (RGVF) 836 mosm/kg TFV 1% Rectal Formulation (RF) 479 mosm/kg TFV 1% MTN-007 CHARM 01/02 TFV 10% RF Lube MTN-017 Safety/Accept No Phase III Applicator (Safety) Future RCT? On Demand Lube MDP 1 Enema vehicle development JHU Lube dosing feasibility Enema Formulation (EF) Dose escalation Iso- or hypo-osmolar DREAM Safety/Accept Future RCT? On Demand Douche

Grindr Survey Especially with sex product, Essential to build around user experience 4,751 Took Grindr Survey o 78% RAI last 3 months 80% douche before RAI 27% douche after RAI Likelihood of using a

27 Grindr Survey Especially with sex product, Essential to build around user experience 4,751 Took Grindr Survey o 78% RAI last 3 months 80% douche before RAI 27% douche after RAI Likelihood of using a microbicide douche (currently douche) 98% 1% 1% 28% 70% Likelihood of using a microbicide douche (currently do not douche) 94% 4% 2% 36% 58% Insertive partner supportive of RM douching partner 96% 1% 4% 95% Alex Carballo-Dieguez et al AIDS Behav (In Review) Definitely Yes Probably Yes Probably Not Definitely Not Supportive Opposed Neither Generally much higher than similar survey research for vaginal products

increase tissue TFV-DP Interspecies comparisons Significant variability (1-2 log 10 range) Colorectal tissue [TFV-DP] target

28 Interspecies TFV-DP Comparisons TFV, TDF, TAF, CMX-157 Comparison Doses selected to achieve clinical target No large differences in mice or NHP Advance TFV to Clinical development Flexible formulations Hypo-osmolar formulation NHP ~10-fold increase tissue TFV-DP Interspecies comparisons Significant variability (1-2 log 10 range) Colorectal tissue [TFV-DP] target (iprex reference) exceeded by all doses in NHP Douche A Douche B Douche C Xiao et al AAC 2017; Ensign et al Eur J Pharm Biopharm 2018

29 Plasma TFV (ng/mg) Rectal Tissue TFV-DP (fmol/mg) TFV Douche: Macaque SHIV Challenge Pharmacodynamics: SHIV Rectal Challenge Daily oral TDF vs. weekly rectal TFV Weekly intrarectal SHIV challenge (10 3 TCID50) Weekly plasma viral RNA by qpcr Infected = 2 vrna values > 250/mL x 2 wks Single Dose PK: Oral TDF v. Rectal TFV (Douche C) (Douche B) Steady-state oral PK & Challenge Ongoing; Oral-Topical [target] conversion remains unclear

30 Phase I: Douche PK in NHP & Human Macaque PK Colon Cell TFV-DP Human PK Colon Cell TFV-DP DREAM-01 Douche B Douche C Daily Oral 7/wk 4/wk 2/wk Clinical Study Single dose TFV Douche 3 Dose levels Colon & 24hr (6 of 18 total) Douche Douche Douche A B C

31 Cell-free HIV Surrogate Cell-Associated HIV Surrogate Colon Luminal HIV & Product Distribution Define HIV Distribution Compare to Product Distribution J001 J002 J003 J004 Product A 1 hr 99m Tc Cell-free 111 In Cell-assoc Louissaint JID 2012 HIV surrogates (SPECT, color) & anatomy (CT, grayscale) P value* Product B DREAM-01 Clinical Study Single dose TFV Douche SPECT/CT Sacnning Median (IQR) Median (IQR) 1 hr 7 (5, 8) 6 (5, 9) hr 6 (5, 9) 5 (4, 7) hr 6 (3, 7) 7 (6, 8) 0.19 *Sigmoidoscope distance adds 4 cm Weld IAS 2017 DREAM-01

32 TFV Douche Development Phase I DREAM-01 SAD (>90% complete) DREAM-03 MAD (NIH & FDA review) DREAM-02 Douche + sex sequencing (in development) Phase II/III Extended safety convert to efficacy Clinical trial simulation NDA & Market Planning Negotiating with corporate partners

33 Summary Long-Acting Injectables RCTs, limits AEs, oral lead-in, long tail Infusion bnmabs RCTs, future SC dosing?, less AEs, COST Implantables Pre-clinical, less frequent dosing, retrievable, bnmab suitable Vaginal Microbicides Vaginal gel & IVR underperformed in RCT Novel formulations may enhance adherence, front-door back door issues Uncertain cervicovaginal tissue concentration targets Rectal Microbicides Behaviorally-congruent strategies - Lube feasible? Douche acceptable & exceeds [target]? Uncertain rectal dosing target tissue concentration uncertain Model building & Clinical Trial Simulation underway

34 Acknowledgements Angela Kashuba Pete Anderson Partners, Collaborators, Muses Ed Fuchs, Drug Development Unit, JHU Mark Marzinke, Clinical Pharmacology Analytical Laboratory, JHU Peter Anton, UCLA Ian McGowan, University of Pittsburgh Bill Spreen & Parul Patel, ViiV/GSK Raphael Landovitz, UCLA Marc Baum, Oak Crest Institute of Science Ariane van der Straten, Research Triangle Institute Pat Kiser, Northwestern University Funders - CDC, NIH/DAIDS, JHU CFAR

35 Questions?

Beyond Oral PrEP: Promise and Challenges of Alternative Antiviral Dosing Methods for PrEP

Beyond Oral PrEP: Promise and Challenges of Alternative Antiviral Dosing Methods for PrEP Pill Injection Implant Infusion Vaginal ring Gels Vaginal film Lube Douche Craig W. Hendrix, MD Wellcome Professor