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DAIDS IPCP-HTM

DAIDS IPCP-HTM. NIH/NIAID: 1 st IPCP on Rectal Microbicides Developments (2004-2011) Two Phase 1 Clinical Trials: RMP-01 : Topical UC781 (single & 7-day topical) RMP-02 / MTN-006 : Tenofovir (single oral, single & 7-day topical). Peter Anton, UCLA: PI

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DAIDS IPCP-HTM

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  1. DAIDS IPCP-HTM NIH/NIAID: 1st IPCP on Rectal Microbicides Developments (2004-2011) Two Phase 1 Clinical Trials: RMP-01: Topical UC781 (single & 7-day topical) RMP-02 / MTN-006: Tenofovir (single oral, single & 7-day topical) Peter Anton, UCLA: PI Ian McGowan, MWRI/University of Pittsburgh: co-PI NIH/NIAID: 2nd IPCP on Rectal Microbicides Developments (2009-2014) Ian McGowan, MWRI/University of Pittsburgh: PI

  2. NIH IP/CP Outline • Intent • Assays for use in RM trials • 1st Phase 1 RM Clinical Trial utilizing assays: RMP-01 (UC781) • 2nd Phase 1 RM Clinical trial: RMP-02/MTN-006 (Tenofovir) context

  3. NIH IP/CP Assay Optimization: selected for Phase 1 • Assay factors addressed prior to trial (some still to address) : • Apply to both vaginal and rectal samples • Anticipate effect of standard clinical trial / home use such as enemas/douches/gels (osm; pH; dilution effect) • Sequence of sample collection: inherent confounder • Multi-site trials: determine where samples (Flow, explants etc) collected versus where/when processed (fresh, frozen, O/N, batched: 1 lab?) • Semen/seminal fluid alter results/drug delivery? Same with sexual activity / trauma • Relevance for interpreting “biopsy infection” experiments • Compartment dilution effect on delivered drug concentrations? • Quantify [microbicide] likely exposed to tissue. Challenge much greater in rectal than cervicovaginal explants • NORMATIVE VALUES: to assess implications/actions of “out-of-range” values (and then: clinical relevance)

  4. McGowan et al, HPTN 056 JAIDS 2007 HPTN 056:Characterization of Baseline Mucosal Indices of Injury and Inflammation in Men for Use in Rectal Microbicide Trials Pre-Phase 1 rectal safety study: • normative ranges; inherent variability Primary Objective • Determine variability of mucosal immunological, virological and histopathological parameters in biopsies from 10cm & 30cm in the recto-sigmoid colon in 4 defined study groups (n=16): • HIV-/RAI- • HIV-/RAI+ • HIV+/RAI+: high PVL • HIV+/RAI+: high PVL Secondary Objective • Determine within group stability of defined measures over time (3 flexible sigs over 6 weeks) & biological variability between groups Assays • Histopathology (qual/quant); flow cytometry, tissue cytokine mRNA, rectal secreted Ig, tissue VL) Total: 48 procedures; 1,440 biopsies

  5. McGowan et al, HPTN 056 JAIDS 2007 HPTN-056: Data Analysis • Data analyzed by group means • Subject variability around means explored • Definitions: • Sig: within subject standard deviation • Tau: between subject standard deviation • Intra-class correlation (ICC) [ICC = Tau^2/ (Tau^2 + Sig^2)] • ICC thresholds • >0.75 shows strong stability • >0.5 shows moderate stability

  6. McGowan et al, HPTN 056 JAIDS 2007 Stability of Flow Cytometry Data ICC: Intra-class correlation >.75 shows strong stability

  7. McGowan et al, HPTN 056 JAIDS 2007 Stability of Cytokine Data ICC: Intra-class correlation >.75 shows strong stability

  8. NIH IP/CP Where to sample…”explants” • Colorectal (10cm) • Colonic (30cm) • Colorectal (higher than 10cm) • Upper intestinal tract (systemic delivery to targets) When to sample…explants • Real-life factors: bowel movements, prep, pre/post sexual prep, menses • Drug trial factors: how long post exposure, frequency, # samples Safe to sample…?

  9. X X NIH IP/CP Colorectal: Biopsy location

  10. NIH IP/CP Colorectal Biopsy safety and location

  11. ~10cm ~30cm Microbicide Failure Success HIV no effect? + effect? RM Clinical Relevance: Selection Site for Explants Concentration Anus Rectum Colon Ano-Rectal Distance Diagram courtesy: C Hendrix)

  12. Rectal Explant Model used in RM Clinical Trials: “ex vivo biopsy infection” experiments Explant media soaked collagen rafts HIV-1 infected and washed explants a) Explants transferred by transfer pipet to a dry petri-dish, cut-side down b)1 cm2 raft placed atop the explant and inverted. Media 100% exchanged q 3 daysfor ~2 weeks (D1/D4/D7/D11/D14) Supernatant frozen for batched p-24 ELISA (= qPCR of HIVRNA) Mounted explants transferred to well of 24-well plate containing 500ul of explant medium Fletcher et al AIDS 2006

  13. A PHASE 1 SAFETY AND ACCEPTABILITY STUDY OF THE UC-781 MICROBICIDE GEL APPLIED RECTALLY IN HIV SERONEGATIVE ADULTS: RMP-01 P Anton, T Saunders, A Adler, C Siboliban, E Khanukhova, C Price, J Elliott, K Tanner, Ana Ventuneac, Alex Carballo-Dieguez, J Boscardin, Y Zhao, W Cumberland, AM Corner, C Mauck, I McGowan UCLA, NIH, CONRAD submitted

  14. Rectal Biopsy Infections ex vivo: RMP-01 • Samples acquired endoscopically (large-cup forceps): 14 biopsies at each site (10cm and 30cm) • NO DRUG ADDED TO EXPLANTS (except at V2): all drug applied in vivo • To laboratory and set up within 2 hours • HIV (pre-determined strain, titers) applied to explants, incubated 2 hrs • Biopsies washed (>3-5 times), then mounted on gelfoam, placed in well of 24-well plate; incubated for 12-14 days. • Controls: media (uninfected control); UC781 at baseline visit only to demonstrate in vitro efficacy • Supernatants for p24 taken every 3 days (100%); each time point is mean of 2 biopsies pooled; cumulative p24 graphed NIH IP/CP

  15. HEC Placebo UC781 0.10% UC781 0.25% 10cm 30cm NIH IP/CP Confidence from RMP-01 UC781 RM trial (n=36; 3 arms) (V2 = baseline) (V3 = single topical application UC781) Bx infection data (V2 vs V3)104 virus titer in vivo exposed ex vivo infected

  16. HEC Placebo UC781 0.10% UC781 0.25% 10cm 30cm NIH IP/CP RMP-01 UC781 RM trial: now 102 virus titer Baseline variability looks same…. but only 60% infected with this titer (V2 = baseline) (V3 = single topical application UC781)

  17. Lessons learned thus far for these types of trials:Do infectibility results from 30cm and 10cm differ: NONeed infectibility of ‘all’ baseline sample explants: YES NIH IP/CP Baseline infectibility No difference seen when using 36 subjects’ baseline data: “OK” to use 1 site in next trial Use higher titer virus for explant infection studies

  18. DAIDS IPCP-HTM RMP-02/MTN-006: A Phase 1, Placebo-Controlled Trial of Rectally Applied 1%Vaginal Tenofovir Gel with Comparison to Oral Tenofovir Disoproxil Fumarate P Anton1, R Cranston3, A Carballo-Dieguez4, A Kashuba5, E Khanukhova1, J Elliott1, L Janocko6,8, N Richardson-Harman7, W Cumberland9, C Mauck10, C Hendrix2,8, I McGowan6,8 UCLA: Dept. of Medicine1 & School of Public Health9, Johns Hopkins University2, University of Pittsburgh: Dept. of Medicine3 & Magee-Womens Research Institute6, Columbia University4, UNC CFAR & School of Pharmacy5, Alpha StatConsult LLC7, MTN8, CONRAD10 Presented: CROI 2011, Boston, MA

  19. Study Rationale • Rectal intercourse is commonly practiced by men and women • HIV transmission during receptive anal intercourse (RAI) is significantly greater per sexual act • CAPRISA 004 demonstrated 39% reduction in HIV infection using 1% tenofovir gel formulated for vaginal use • Given the prevalence of RAI and the success of this agent, this Phase 1 trial aimed to evaluate safety of the hyper- osmolar, vaginally formulated 1% tenofovir gel when used rectally; in addition, aims were to investigate acceptability, mucosal injury and multi-compartment PK

  20. Safety, PK / PD, acceptability Single rectal tenofovir (N = 18) 2:1 7 Day Rectal tenofovir (N = 18) 2:1 Open label Oral tenofovir (N = 18) Baseline Evaluation RMP-02/MTN-006 Study Design • 3 stage trial at 2 sites (UCLA/MWRI): open label TDF (oral) followed by 2:1 randomization of tenofovir: HEC placebo (for single rectal topical dose; 7-day rectal topical dosing) • Each dosing stage with 2 weeks of sampling (then: 2 weeks wash-out/healing) • Product: Tenofovir Disoproxil Fumarate (TDF) 300mg tablet, Tenofovir 1% gel (vaginal formulation/applicator) or HEC placebo gel • 8.5 months; 3.5 months/participant • all 18 enrolled → completed. 100% retention (78% male; 22% female) Each participant completed 12 visits with 8 flexible sigmoidoscopies in 3.5 months → ~2300 bx >10,000 study samples

  21. DAIDS IPCP-HTM Subject’s Samples Workflow: ‘chain of custody’ Clinical Unit Blood Urine Vaginal Sponge Rectal Swabs Rectal Sponges Stool Sample Rectal Lavages Biopsies UCLA/MG Cytokines UCLA/MG Magee NAAT GC/CT UCLA/MG UCLA/MG UCLA/MG (Sloughing Assay) UCLA/MG Clin Lab (Safety labs, HIV, RPR HSV 1 & 2) UCLA/MG Beta HcG & U/A Magee NAAT GC, CT MTN PK Lab UCLA/MG Plasma PBMC MTN Micro (rectal microflora) Genova (calprotectin) UCAL/MG (Explant Culture, Immunophenotyping PK processing UCLA Research Pathology (Qualitative) MTN PK Lab MTN PK Lab Magee-WRI (gram stain,pH) MTN PK Lab

  22. Study Endpoints • Primary Objective:Safety of 1% vaginally-formulated tenofovir gel, applied rectally • Endpoint:≥ Grade 2 AE • Secondary Objectives:Acceptability, Mucosal Immunotoxicity, PK • Endpoints - Acceptability: - % of those at last visit liking product • - likely to use the candidate in the future if helps • Endpoints - Mucosal Injury: - fecal calprotectin • - rectal microflora • - secreted rectal cytokines • - rectal epithelial sloughing • - rectal histology • - rectal mucosal CD4+ T cell phenotype/activation • Endpoints - PK:Tenofovir/diphosphate concentrations (9-10 compartments): • Blood: plasma, PBMC, PBMC subsets (CD4+/CD4-) • Fluids: rectal fluid, vaginal fluid (sponges) • Tissue: Whole biopsy homogenates, isolated mucosal mononuclear cells (MMC) & CD4+/CD- subsets • Exploratory Objective:ex vivo infectibility of in vivo exposed rectal tissue biopsies • Endpoint: cumulative HIV-1 p24 levels in colorectal explant supernatants at 14d

  23. p=0.002 p=0.002 p=0.001 p=0.10 Safety Clinical Grade 3 Events

  24. Acceptability 75% likely to use TFV in the future if they felt it might be helpful, despite relatively more dislike and discomfort.

  25. DAIDS IPCP-HTM Mucosal Injury Indices

  26. PK: TFV Exposure in Plasma • With RECTAL dosing: plasma TFV Cmax & AUC: 2% of ORAL • ‘7-day’ RECTAL dosing: no TFV accumulation in plasma

  27. 7/18 10/12 12/12 PK: TFV-DP in Rectal Tissue (30 minutes post dose) Single ORAL: (i) TFV DP Tmax ≥ 24h post-dose. (ii) At 10 days, TFV DP detectable in 55% subjects Single RECTAL dose: (i) Tissue TFV DP Cmax was 112x > single ORAL and AUCall was 1.5x > single ORAL. (ii) At 10 days, TFV DP detectable in 80% ‘7-day’ RECTAL dosing: Tissue TFV DP accumulated: Cmax was 5x > singleRECTAL dose

  28. ANCOVA p=0.005 Biopsy Infection ex vivo of 7-day RECTAL dosing in vivo: Significant suppression seen (HIV-1BaL TCID50=104at ~10 cm) effect size: 0.80 Single ORAL dosing: no significant changes (p=0.65) Single RECTAL dosing: no significant changes (p=0.12)

  29. Dose-Response Relationship: rectal tissue TFV DP with rectal biopsy infectibility • Virus inhibition correlated with increasing tissue TFV-DP, even with small study n • Feasible to assess both dose and response following in vivo exposure to drug

  30. CONCLUSIONS • The vaginal formulation of 1% TFV gel was sub-optimal for clinical safety and acceptability when rectally applied. • Despite extensive mucosal indices of injury, none were seen with product use. • Consistent with other studies, the systemic absorption of rectally-delivered TFV was ~2% of oral dose. • Rectal dosing was associated with 100x more active TFV-DP in the target mucosa than oral dose. • Rectal tissue biopsy infection ex vivo was significantly reduced compared to control; may be a potential biomarker of efficacy. • PK/PD:Dose/response correlations were evaluable and significant in this intensive small trial.

  31. DAIDS IPCP-HTM Acknowledgments • U19 Integrated Preclinical-Clinical Program for HIV Topical Microbicides (IPCP-HTM) grant funded by DAIDS, NIAID, NIH grant (AI060614) • Participants • Study Teams at each site: UCLA MWRI, University of Pittsburgh • NIH/DAIDS • MTN Network Support • MTN Microbiology Laboratory • MTN Clinical Pharmacology Analytical Lab at JHU • CONRAD • Gilead • Alpha StatConsult LLC • Support from MTN: funded by NIAID (5U01AI068633), NICHD, NIMH, all of NIH.

  32. DAIDS IPCP-HTM QUESTIONS ?

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