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DREAM Program On Demand, Behaviorally-Congruent Rectal Microbicide Douche

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.

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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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