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DREAM Program On Demand, Behaviorally-Congruent Rectal Microbicide Douche

This outlines the need and feasibility of rectal microbicides for HIV prevention, including a history of tenofovir, the DREAM Program, mouse and macaque developments, and future studies. It discusses the potential of behaviorally-congruent formulations to enhance adherence and prevent HIV transmission. The text details methods, drug product development phases, vehicle development, and safety assessments, highlighting the progress and challenges in the field. The Grindr survey results, douche vehicle evaluation, and clinical studies like DREAM-01 are also summarized, paving the way for innovative prevention strategies.

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DREAM Program On Demand, Behaviorally-Congruent Rectal Microbicide Douche

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

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

  3. 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-congruentformulations “piggy-back” onto commonly used sex products

  4. 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?

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

  6. DREAM Program • Background • 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

  7. 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 do not douche) Likelihood of using a microbicide douche (currently douche) Top supportive of RM douching partner Alex Carballo-Dieguez & Rebecca Giguere (DREAM U19 Project 1)

  8. Douche Vehicle Evaluation Acceptability Distribution Toxicity ISO • 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 HYPER MIP Coronal SPECT/CT ISO & HYPO Leyva, et al. ARHR 2013

  9. Speeding Tissue Absorption Iso-osmolar Hypo-osmolar • 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 Iso Hypo Osmolarity

  10. Mouse TFV Prodrug Comparison Target • Hypo-osmolarbetter for some TFV prodrugs • Variability significant • Target achievedby median of TFV & all prodrugs Ensign et al 2017 (in review); Xiao et al AAC 2017

  11. Interspecies TFV-DP Comparisons Interspecies comparisons TFV-DP Target • TFV-DP active form of tenofovir • Hypo-osmolarbest >5x increases in tissue TFV-DP in macaques • Variability high (2 log10range common) • Target exceeded by median low & high doses Xiao et al AAC 2017

  12. 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

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

  14. 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

  15. Safety AE: None > Grade 2 Histology: No Change from Baseline Product C not shown No adverse events due to douche product No colon tissue damage

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

  17. 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

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

  19. 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

  20. DREAM-03: Multiple Douche Impact • Do multiple douches increase tissue drug concentration? • Do non-medicated douches reduce tissue concentration? • DREAM-03 Design

  21. 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

  22. 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

  23. 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

  24. Thank You!

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