DREAM Developing Rectal Enema as Microbicide Behaviorally-Congruent Rectal Microbicides
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1 DREAM Developing Rectal Enema as Microbicide Behaviorally-Congruent Rectal Microbicides Craig W. Hendrix Wellcome Professor and Director Division of Clinical Pharmacology
2 Overview PrEP Achilles Heel - Adherence Behaviorally-congruent Rectal Microbicide Development Target product profile Luminal PK Dosing methods Tissue PK Intensive study design PK, PD, Safety, Acceptability DREAM Program Formulation enhancements Broader objectives
3 Adherence Response Formulation Changes in Development Phase III IIB/III II I Animal Periodic Dosing Periodic oral TDF/FTC dosing (Ipergay) Vaginal Ring (placebo-controlled) 1 month Dapivirine RCT (IPM & MTN-020) [CROI 2016] Oral v. Injectable Cabotegravir Phase 2B/3 HPTN 083 (planning) Periodic Dosing TFV/FTC oral event driven (HPTN 067) TFV rectal gel MTN-017 (CROI 2016) Injectable 2-3 month Rilpivirine q2 month HPTN 076 (ongoing) Cabotegravir q3 month HPTN 077 (ongoing) Behaviorally-congruent formulations medicate existing product used parasexually Episodic enema TFV/prodrug (TDF, TAF, CMX-157) DREAM U19 Manual rectal gel dosing as lubricant (Manual gel dosing JHU; Adonis MTN-033) Longer-acting Implantable TAF silicone/pva rod OCIS U19 Various ARVs Northwestern U UM1
4 Behaviorally-Congruent Lubricant & Enema/Douche Commonly Used in RAI Carballo-Dieguez A, Bauermeister J, Ventuneac A, Dolezal C, Balan I, Remien RH. The use of rectal douches among HIV-uninfected and infected men who have unprotected receptive anal intercourse: implications for rectal microbicides. AIDS Behav 2008;12: Carballo-Dieguez A, Bauermeister J, Ventuneac A, Dolezal C, Mayer K. Why rectal douches may be acceptable rectalmicrobicide delivery vehicles for men who have sex with men. Sex Trans Dis 2009;36(11) Galea JT, Kinsler JJ, Imrie J, Nureña CR, Sánchez J, Cunningham WE. Rectal douching and implications for rectal microbicides among populations vulnerable to HIV in South America: a qualitative study. Sex Transm Infect 2013;0:1-3. Javanbakht M, Stahlman S, Pickett J, LeBlanc M-A, Gorbach PM. Prevalence and types of rectal douches used for anal intercourse: results from an international survey. BMC Infectious Diseases 2014;14:95. Noor SW, Rosser BRS. Enema use among men who have sex with men: A behavioral epidemiologic study with implications for HIV/STI prevention. Arch Sex Behav 2013, Epub ahead of print.
5 Behaviorally-Congruent Rectal Microbicide Target Product Profile Behaviorally-congruent? Existing behavior & medicated product Enema/Douche Acceptable use? Neutral to Enjoyable Where? Rectal ~15-20 cm, coincident with HIV surrogate distribution How much? Enough to achieve 85 fmol TFV-DP/10 6 colon cells Sexual Lubricant How often? Single dose, episodic use How fast? 30 minutes to protection How long? 7 days protection (???)
6 Selecting Luminal Distribution Targets Localizing Cell-free & Cell-Associated HIV Targets Cell-free HIV Surrogate 99m Tc-Sulfur Colloid Cell-Associated HIV Surrogate 111 In-Lymphocytes Rectal Challenge
7 SPECT Image Analysis SPECT Emission Image Tube-Fitting Algorithm PK-Distance Parameters 99m Tc-DTPA Distribution 1 Cao, et al, BrJCP 2012 Fit 3-D centerline curve (red) Move disc along centerline Plot concentration v. distance D min distance to most distal signal DC max distance to max concentration D ave distance to average concentration D max distance to most proximal signal
8 Assessing Luminal Vehicles Comparing Luminal Drug & HIV Kinetics Microbicide ( 111 In-DTPA) HIV ( 99m Tc-SC) in Ejaculate Concentration-Distance-Time Dual Isotope Imaging (SMW) 99m Tc-SC HIV Surrogate 111 In-DTPA Microbicide ARV Surrogate AUC adjusted "Concentration" Centimeters from Point Source Hours after Dosing Rectal TFV gel (0h), simulated sex/ejaculation (1h), SPECT/CT (2h) 85-90% HIV (2.5 ml) covered by Microbicide volumes (10 ml gel, 125 ml enema) tested to date
9 Assessing Luminal Vehicles Rectal Formulations Luminal Distribution Study CDC Imaging 1 P5-Aim2 2 P5-Aim 2 2 Manual Gel 3 P5-Aim 1 4 Formulation Gel Gel Fluid Gel Enema Volume 10 ml 10 ml 10 ml 10 ml 125 ml Dose Method Applicator Applicator Applicator Manual/Phallus Applicator Osmolality Hyper-osmolar Iso-osmolar Iso-osmolar Iso-osmolar Iso-osmolar Post-dose 4h 4h 4h 4h 4h D max 14.0 (9.0 63) 12.9 (11.6, 20) 23.1 (14.9, 25.1) 8.5 ( 8.5, 10.4) 38.6 (23.8, 41.7) DC max 6.0 (2.0 14) 5.1 ( 2.0, 8.3) 5.3 ( 3.3, 7.2) 4.3 ( 2.3, 7.7) 17.5 ( 8.2, 24.1) D ave 6.7 (3.2 29) 6.4 ( 4.7, 7.5) 6.8 ( 4.7, 10.2) 0.9 ( 0.5, 3.4) 19.6 ( 9.8, 23.6) D min (-3.5, 0.8) -3.8 ( -3.8, -3.5) 0.0 (-0.1, 1.0) 2.0 ( ) median and range for CDC Imaging (BJCP 2012), IQR for all others. D max, greatest proximal distance at which radiolabel is detected DC max, distance at which greatest radiolabel concentration is detected D ave, mean residence distance (similar to mean residence time) D min, most distal location of radiolabel All distances are relative to coccyx 1 Cao, et al, BrJCP 2012; 2 Leyva, et al. ARHR 2015; 3 Shieh, et al. CROI 2016; 4 Leyva, et al. ARHR 2013 Rectal HIV ~15 cm
10 Dosing Method Applicator >> Manual Intraluminal Dosing Efficiency Not Well Liked Gel (HEC) via HTI Intrarectal 3.5 ml Behaviorally-Congruent Wet TM Gel Lubricant Manual/Phallus 10 ml Behaviorally-Congruent Enema (Normosol-R) Intrarectal 125 ml intraluminal Retention 88% (86%, 90%) Volume Delivered 3.1 (3.1, 3.1) Retention 3.6% (1.0%, 27.4%) Volume Delivered 0.3 (0.3, 0.4) Requires TFV 10% for equivalence to 3.5 ml TFV 1% gel Retention 60% Volume Delivered 75 ml
11 Colon Pharmacology Time to Protection Oral vs. Rectal Dosing TFV-DP Targets 30 Minutes Post-Dose Rectal Tissue Cell TFV-DP (fmol/m cells) Single Oral TDF Single Rectal VF Multiple Rectal VF Single dose TFV 1% rectal gel appears 30 v. 5d. w/ daily oral Steady-state accumulation ~5-fold (daily rectal dosing) Large variability in colon tissue RMP-02/MTN-006 Yang, et al. PLOS One 2014
12 Colon Pharmacology Duration of Protection TFV-DP Kinetics in Colon Tissue TFV-DP (fmol/million cells) Single Oral Dose ( 14 C-TDF Study) Days PBMC CD4 iprex EC90 Half-life estimates enable PK modeling Daily TDF 1 week Rectal TFV 1% gel c/w 1 week protection Anatomic Location Moiety Units Terminal Half-life Median (IQR) Plasma TFV ng/ml 69 (55, 77) PBMC TFV-DP fmol/m 48 (38, 76) Blood CD4+ Cells TFV-DP fmol/m 112 (100, 118) VT TFV ng/gm 47 (38, 53) VT TFV-DP fmol/gm 53 (45, 68) VT Total Cells TFV-DP fmol/m 66 (43, 202) VT CD4+ Cells TFV-DP fmol/m 139 (121, 167) CVL** TFV ng/ml 40 (38, 43) CVL Cells TFV-DP fmol/m - CT TFV ng/gm 31 (24, 36) CT TFV-DP fmol/gm 34 (21, 40) CT Total Cells TFV-DP fmol/m 82 (43, 89) CT CD4+ Cells TFV-DP fmol/m 60 (52, 72) Colon Brush TFV ng/ml 20 (20, 21) Louissaint ARHR 2013
13 Intensive Multi-Domain Design Enema Safety, PK, Acceptability Toxicity Distribution Acceptability ISO HYPER ISO MIP Coronal SPECT/CT 9 men, single dose cross-over Hyper-, iso-, hypo-osmolar enema Luminal PK, histology, acceptability favor iso-osmolar Leyva, et al. ARHR 2013
14 Intensive Multi-Domain Design Rectal TFV 1% Gel Comparison CHARM 01 & 02 Single dose TFV 1% gel comparison, N=14, 9 VF 3,111 mosm/kg (MTN-006) RGVF 836 mosm/kg (MTN-017) RF 479 mosm/kg Plasma TFV (C max, AUC) VF > RGVF > RF &SURAI v. No SURAI No difference Colon Tissue MMC TFV-DP (CHARM 01) TFV-DP VF > RGVF = RF All products exceed tissue cell targets PD all formulations demonstrate ex vivo protection Luminal Distribution D max, D ave VF > RGVF = RF SURAI neutralized these differences Dual Isotope HIV v. Drug Distribution 86% (SD 19%) HIV c/w Microbicide No SURAI Med (IQR) VF RGVF RF Microbicide ( 111 In-DTPA) HIV ( 99m Tc-SC) in Semen Rectal TFV gel (0h), SURAI (1h), SPECT/CT (2h) McGowan PLOS One 2015; Hiruy H, et al., ARHR 2015
15 DREAM: Enema Formulation Development Single dose enhanced tenofovir enema for behaviorally-congruent PrEP TFV-DP fmol/million colon CD4+ cells Bioavailability Enhanced TFV 4-Mixture Sustained Release-TFV + Bioavailability Enhanced-TFV 1-TFV (MTN-017 equivalent dose) 3-Mixture Sustained Release-TFV + TFV 4/w TDF 2/w TDF Hours TFV enema PK Enhancements Bioavailability Enhancement (F) o Hypotonic vehicle Absorption Rate Enhancement (k a ) o TFV analogs (TDF, TAF, CMX-157) Sustained release (macaque only during DREAM Project) o Nanoparticle o Gelling agent Reference Targets iprex PK/PD analyses (4 TDF doses per week, 4/w TDF ) Bridging iprex to PK studies Colon MMC/CD4+ cell TFV-DP
16 DREAM: Clinical Studies DREAM 01: Single dose, dose escalation, 3 formulations (1x, 3x, 9x), one week PK luminal distribution, blood/tissue/lumen PD ex vivo tissue HIV challenge Safety clinical, laboratory, transcriptomics/proteomics Acceptability DREAM 02: Sequence effect (enema semen vs. semen enema) DREAM 01 PK readouts DREAM 03: Optimal TFV (DREAM 01) v. Optimal TFV prodrug (pre-clinical) DREAM 01 Readouts
17 DREAM: Program Targeted Outcomes Clinical Best naked TFV or TFV prodrug enema Macaque Best hypotonic nanoparticle thermoreversible enema Topical Dosing 3-D drug penetration model (tissue MALDI) Microbicide development PK/PD surrogates Allometric PK & PD scaling (human, macaque, mouse) Adherence Quantitative rectal dose adherence monitoring Rectal microbicide clinical trial simulation
18 Thank You! Research Participants DREAM Team (U19) Drug Development Unit Clinical Pharmacology Analytical Lab NIH/DAIDS Microbicide Trials Network (UM1) Integrated Pre-clinical/Clinical Topical Microbicide Development (U19) Hopkins Center for AIDS Research (P30)
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