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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

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


Daids ipcp htm

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


Daids ipcp htm

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)


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    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


  • Hptn 056 data analysis

    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


    Stability of flow cytometry data

    McGowan et al, HPTN 056 JAIDS 2007

    Stability of Flow Cytometry Data

    ICC: Intra-class correlation >.75 shows strong stability


    Stability of cytokine data

    McGowan et al, HPTN 056 JAIDS 2007

    Stability of Cytokine Data

    ICC: Intra-class correlation >.75 shows strong stability


    Where to sample explants

    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…?


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    X

    X

    NIH IP/CP

    Colorectal: Biopsy location


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    NIH IP/CP

    Colorectal Biopsy safety and location


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    ~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)


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    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


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    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


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    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


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    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


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    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)


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    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


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    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


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    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


    Daids ipcp htm

    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


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    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


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    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


    Daids ipcp htm

    p=0.002

    p=0.002

    p=0.001

    p=0.10

    Safety

    Clinical Grade 3 Events


    Acceptability

    Acceptability

    75% likely to use TFV in the future

    if they felt it might be helpful,

    despite relatively more dislike and discomfort.


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    DAIDS IPCP-HTM

    Mucosal Injury Indices


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    PK: TFV Exposure in Plasma

    • With RECTAL dosing: plasma TFV Cmax & AUC: 2% of ORAL

    • ‘7-day’ RECTAL dosing: no TFV accumulation in plasma


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    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


    Daids ipcp htm

    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)


    Daids ipcp htm

    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


    Daids ipcp htm

    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.


    Daids ipcp htm

    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.


    Daids ipcp htm

    DAIDS IPCP-HTM

    QUESTIONS ?


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