Craig W. Hendrix, MD Johns Hopkins University DREAM Program On Demand, Behaviorally-Congruent Rectal Microbicide Douche Craig W. Hendrix, MD Johns Hopkins University

Outline Rectal microbicide need & feasibility Rectal microbicide history (tenofovir) DREAM Program Mouse & macaque development Human development Future Studies

Rectal Microbicide Feasibility Oral PrEP not for everyone Product options improve adherence On demand oral TDF/FTC & vaginal PrEP works Rectal TFV gel high adherence Behaviorally-congruent formulations “piggy- back” onto commonly used sex products

Rectal Microbicide Development Are rectal douches acceptable to those at risk? Can tenofovir be delivered safely by douche? Can douches provide protective concentrations? Can a rectal douche prevent HIV?

TFV Rectal Microbicide Development Methods/Vehicle Development JHU “HIV” surrogate distribution 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 Lube dosing feasibility Phase I Phase II Phase III Drug Product Development Vaginal Formulation (VF) 3,111 mOsm/kg TFV 1% Reduced Glycerin (RGVF) 836 mOsm/kg Rectal Formulation (RF) 479 mOsm/kg Douche Formulation (DF) Hypo-osmolar RMP-02/MTN-006 No Phase II Safety/AEs MTN-017 No Phase III Applicator (Safety) MTN-007 CHARM 01/02 Future RCT ? On Demand Lube Phase I-II ? TFV 10% RF Lube Safety/Accept Future RCT ? On Demand Douche Phase II ? TFV Douche Safety/Accept DREAM 01-03

DREAM Program Background Objective Process Adherence & choice greatest PrEP needs On demand, behaviorally congruent product desired Douche behaviorally-congruent (80% RAI MSM) Objective Single dose TFV (prodrug) enema, 1 week protection Process Sequential mice, macaque, human evaluation Select best of 4 tenofovir-related drugs Optimize formulation

Grindr Survey 4,751 Took Grindr Survey (OCT-NOV 2017) 78% RAI last 3 months 80% douche before RAI 27% douche after RAI (independent of above) Likelihood of using a microbicide douche (currently douche) Likelihood of using a microbicide douche (currently do not douche) Top supportive of RM douching partner Alex Carballo-Dieguez & Rebecca Giguere (DREAM U19 Project 1)

Douche Vehicle Evaluation MIP Coronal SPECT/CT ISO ISO & HYPO HYPER Toxicity Distribution Acceptability Leyva, et al. ARHR 2013 9 men, single dose of 3 different douches Hyperosmolar (Fleet), Iso-osmolar (Saline-like), hypo-osmolar (tap water) Luminal distribution, histology, acceptability favor iso- & hypo-osmolar

Speeding Tissue Absorption Iso-osmolar Hypo-osmolar Iso Hypo Osmolarity Fluorescent particle distribution in mouse vagina 10’ post-dose Administered in isotonic (left) or hypotonic (right) fluid Hypo-osmolar best mucosal surface coverage Ensign, et al., Biomaterials 2013 & Sci Trans Med 2012

Mouse TFV Prodrug Comparison Target Hypo-osmolar better for some TFV prodrugs Variability significant Target achieved by median of TFV & all prodrugs Ensign et al 2017 (in review); Xiao et al AAC 2017

Interspecies comparisons Interspecies TFV-DP Comparisons Interspecies comparisons TFV-DP Target TFV-DP active form of tenofovir Hypo-osmolar best >5x increases in tissue TFV-DP in macaques Variability high (2 log10 range common) Target exceeded by median low & high doses Xiao et al AAC 2017

NHP Oral TDF v. TFV Douche PK Plasma similar TFV with oral & rectal dosing Colon TFV-DP far higher with rectal dosing Controversy whether blood or tissue is more important Francois Villinger, University of Louisiana (Lafayette) CROI LB 2018

Macaque Virus Challenge Weekly rectal monkey HIV (SHIV) challenge Measure SHIV in plasma Hypo-Osmolar Iso-Osmolar Rectal hypo-osmolar dosing Highly protective Superior to oral dosing Francois Villinger, University of Louisiana (Lafayette) CROI LB 2018

Clinical Study: DREAM-01 Design: Phase I, single ascending dose study Goal: Find dose safely achieving colon TFV-DP target Objectives: Safety, drug concentration, & acceptability Products (125 mL): A: TFV 1.76 mg/mL (normal saline) B: TFV 5.28 mg/mL (normal saline) C: TFV 5.28 mg/mL (half-normal saline) Subjects: 18 MSM receive all 3 products sequentially

Epithelial Denudation Lamina propria Hemorrhage Safety AE: None > Grade 2 Product Time Overall Grade (0-5) Epithelial Denudation (0-3) Lamina propria Hemorrhage Baseline Pre-Dose 0.5 1.0 0.0 Product A 1 or 3 hrs   24 hrs 3.0 72 hrs Product B Histology: No Change from Baseline Total Product A Product B Participants who experienced an AE Grade 1 3 1 Grade 2 2 6 5 Total # of AE’s Reported 9 8 12 10 Product C not shown No adverse events due to douche product No colon tissue damage

Colonic Luminal Distribution Desired Distribution in Colon Distribution variable 1 hr Product A Product B J001 J002 J003 J004

Human vs. Macaque Blood TFV Human Plasma TFV Macaque Plasma TFV Macaque greater than human blood exposure Human rectal douche greater than vaginal TFV gel

Human > Macaque Colon TFV-DP Douche B Douche C Human

DREAM-02: Douche & Semen/HIV Distribution “Microbicide”(111In-DTPA) “HIV” (99mTc-SC) in Ejaculate Does douching after sex worsen HIV distribution? Compare sequences – Douche then sex – Sex then douche Example of SPECT/CT Distribution of product (left) And HIV surrogate (right) Rectal TFV gel (0h), simulated sex/ejaculation (1h), SPECT/CT (2h) Amber bones, Color product or “HIV” Hiruy, et al. ARHR 2015

DREAM-03: Multiple Douche Impact Do multiple douches increase tissue drug concentration? Do non-medicated douches reduce tissue concentration? DREAM-03 Design Sequence 1st douche 2nd douche 3rd douche A TFV B Half-Saline C

TFV Advanced Development Pharmaceutics Sachet packaging In line hose attachment Mouse TFV nanoformulation douche TFV thermoreversible gelling douche Macaque PK & SHIV challenge w/ optimized nano/gelling form

Summary Grindr survey: behavioral congruence sound DREAM Pre-Clinical Hypo-osmolar formulations increase tissue TFV-DP Douche better than oral in NHP SHIV challenge DREAM-01 Clinical No toxicity seen TFV-DP colon “target” exceeded by 2-3log10 in 1-3 hrs Plasma TFV below & colon TFV-DP above NHP Multiple dose & packaging studies planned RCTs needed to demonstrate HIV protection

Acknowledgements Study Volunteers NIH/DAIDS IP/CP-HTM Program - Jim Turpin, Hans Spiegel, Cherlynn Mathias, Jeanna Piper, James Cummins, Anabel Lowry Johns Hopkins - Mark Marzinke, Namandje Bumpus, Edward Fuchs, Ethel Weld, Rahul Bakshi, Laura Ensign, Justin Hanes, Richard Cone University of Pittsburgh - Ian McGowan, Lisa Rohan, Ken Ho, Lin Wang, Cindy Jacobsen, Jarrett Engstrom, Rhonda Brand UCLA- Peter Anton, Julie Elliott, Terry Sanders Columbia - Alex Carballo-Dieguez, Rebecca Giguere University of Louisville (Fayette)- Francois Villinger, Xiao Peng Emory - Sanjeev Gumber Duke - David Katz UCSF - Rada Savic CONRAD- -Tim McCormack SAB -Jim Pickett, Tom Moench, Florian Hladik, Jose Romero

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