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an NIH IP/CP for Topical Microbicides

"Beginning to Cross the Rectal Rubicon" Clinical Trials with UC781 & Tenofovir Peter A. Anton MD NIAID IP/CP U19 UCLA / University of Pittsburgh / CONRAD / MTN. an NIH IP/CP for Topical Microbicides. NIH IP/CP. Overview.

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an NIH IP/CP for Topical Microbicides

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  1. "Beginning to Cross the Rectal Rubicon" Clinical Trials with UC781 & Tenofovir Peter A. Anton MD NIAID IP/CP U19 UCLA / University of Pittsburgh / CONRAD / MTN an NIH IP/CP for Topical Microbicides NIH IP/CP

  2. Overview • MDP: U19 funded (5 years) 8/04-7/09 for topical rectal microbicide work • Structure: 4 Projects, 4 Cores • Project 1: Preclinical/NHP • Project 3: Behavioral/Acceptability • Project 4: Pre/Phase 1 Human trials • Project 5: Human Pharmacodymanics and Rectal Formulations • Core A: Administrative • Core B: Regulatory • Core C: Data Management and Biostatistics • Core D: Formulation Science • Plans: new U19 submission (5 years) 7/08 to hopefully start 7/10 • Today: Review mainly Phase 1 Trials and future plans NIH IP/CP

  3. Related MDP achievements with UC781 & Tenofovir • Project 1: explant data: alone and in combination • Project 1: exciting macaque prevention data • Core D: developing formulations miscible with UC781, tenofovir • Project 3: acceptability data will help guide carrier • Project 4: acceptability data helps with formulations and carrier • Project 5: test various formulations for distribution, permeability NIH IP/CP

  4. PMPA/UC781 combinations are more active than the individual compounds 1- In cellular models (luciferase reporter cell line TZM-bl and activated PBMCs) the IC50 values for PMPA and UC781 were reduced, on average, by 65.55 % and 55.90 %, respectively, when used in combination against a panel of R5 and X4 HIV-1 isolates. 2- In the colorectal explant model the PMPA/UC781 combination was also more active than the individual compounds with reductions of 82.86 % for PMPA and 36.88 % for UC781 of the IC50 values. 3- The PMPA/UC781 combination was active against - an NNRTI-escape mutant, A17, fully resistant to UC781, and - an NRTI-resistant isolate with the K65R mutation when tested in cellular and colorectal explant models. NIH IP/CP

  5. Clinical Trials RMP-01: A PHASE 1 SAFETY AND ACCEPTABILITY STUDY OF THE UC781 MICROBICIDE GEL APPLIED RECTALLY IN HIV SERONEGATIVE ADULTS RMP-02 / MTN-006: A TWO-SITE, PHASE I, DOUBLE- BLIND, PLACEBO-CONTROLLED SAFETY AND PHARMACOKINETIC TRIAL OF TOPICAL, VAGINALLY-FORMULATED 1% TENOFOVIR GEL APPLIED RECTALLY IN HIV SERONEGATIVE ADULTS NIH IP/CP

  6. NIH IP/CP Always more questions than answers • New? • definition of ‘safety’? what to compare to? What’s “normal” • first populations to study? • where to look: anus, rectum, rectosigmoid, colon, SI?? • what assays? • how to interpret changes that have clinical relevance?

  7. NIH IP/CP Pivotal: HPTN 056 • first effort to try to define these normative ranges…“immnuotoxicity” • for primarily financial and some scientific reasons, limited to men • HPTN 056 (McGowan PI) attempted to quantify these ranges in 4 groups (N = 4/group); each subject seen every 2 weeks for 6 weeks to evaluate reproducibility and stability of readouts. • Groups: HIV- men, no hx of RAI HIV- men, + hx RAI HIV+ men, undetectable PVL HIV+ men, PVL >5000 copies/ml • Indices…at 2 sites (10cm and 30 cm): • Histology (quantitative & qualitative) • secreted IgG and IgA • cytokine mRNA from tissue • MMC phenotypes • not endoscopic appearance McGowan et al JAIDS 2007

  8. NIH IP/CP What did we learn from HPTN 056? • at least at this stage, not a huge difference in readouts between 10cm and 30cm (being tested in RMP-01) • quantitative histology far too variable in health • HIV+ have some (predictable) baseline differences from HIV- • HIV- with/without RAI no different (? frequency) • rectal Ig readouts have large intra-subject, intra-group variability • cytokines and cell phenotypes quite stable • caveats to 056: not very sexually-active population, older, men • GOAL: to continue weaning/assessing mucosal assays

  9. NIH IP/CP 1st trial: UC781 RM (MDP-01) • first effort: as first RM trial, many potholes to avoid • first effort, interventional test of HPTN 056 indices • preferential assays for ‘safety’? Others (calprotection, fluid cytokines)? • how interpret findings without “positive control”? • IND study; great collaboration with Biosyn, now CONRAD • Pre-PSRC very helpful in preparation for PSRC • Critical first steps by NIAID to adapt toxicity tables for AE reporting to enable efforts to distinguish anticipated procedure-related findings

  10. A PHASE 1 SAFETY AND ACCEPTABILITY STUDY OF THE UC781 MICROBICIDE GEL APPLIED RECTALLY IN HIV SERONEGATIVE ADULTS: A SAFETY REPORT AT 100% COMPLETION (!!!) P Anton, T Saunders, A Adler, C Siboliban, E Khanukhova, C Price, J Elliott, K Tanner, D Cho, EJ Johnson, J Klein, A Dominquez, S Watson, Ana Ventuneac,Alex Carballo-Dieguez, J Boscardin, Y Zhao, AM Corner, C Mauck, I McGowan UCLA, NIH, CONRAD an NIH IP/CP for Topical Microbicides

  11. 1st Rectal Microbicide IND Trial • blinded analysis at 100% completion of safety data only • Sponsored by Biosyn, now CONRAD with NIAID’s U19 IP/CP • Single site: UCLA • NNRTI: UC781 evaluated in 36 seronegatives (men & women) • 3 Groups: 0.1% gel vs. 0.25% gel vs. placebo gel (Universal, not excipient; same as vaginal trials) • Single and 7d exposures (subset enrolled in 24 hour pK) • Using: vaginal formulation of the reverse-transcriptase inhibitor • UC781 gel applied rectally with vaginal applicator NIH IP/CP

  12. Trial Objectives and Indices • Primary Objective: • To evaluate the safety and acceptability of 0.1% and 0.25% UC781 vaginal microbicide gel versus placebo when applied rectally. • Indices: • Frequency of ≥Grade 2 adverse events • Acceptability assessments NIH IP/CP

  13. Trial Objectives and Indices • Secondary Objectives: Using very detailed, sensitive assays, to determine whether use is associated with rectal mucosal damage (immunotox): • Epithelial sloughing • Histopathology • Mucosal mononuclear cell phenotype (flow) • Mucosal cytokine mRNA (tissue) • Mucosal cytokines (secreted) • Mucosal immunoglobulins • Fecal calprotectin • Explants- ex vivo susceptibility to HIV infection *(Many compared to baselines established in HPTN 056..McGowan JAIDS 2007) NIH IP/CP

  14. NEW: Amended Toxicity Tables for AE (1° endpoint) • DAIDS EAE Reporting Manual and DAIDS Toxicity Tables • Clarifications/Additions to avoid inaccurate AE reporting: “diarrhea” “hematochezia” (from NCI, not in DAIDS) “bloody diarrhea” “Proctitis” (stricter definition than DAIDS; used by NIDDK) “bruising” (to cover AE related to applicator injury)(NCI) • Protocol team to review q 2-4 weeks; DSMB on call • Trial suspended if 2 or more subjects have ≥ Grade 3 NIH IP/CP

  15. NIH IP/CP Applicator (vaginal form) issues • Not optimal for rectal application, but tolerated. • Acceptability portion of UC781 trial asking lots of questions regarding applicator; pilot amFAR study underway with prototype

  16. Study Outline • Study Population: HIV negative men and women with a history of RAI (in order to give context to applicator use and acceptability assessments) • Study Size: 36 participants (men and women) in 3 arms • Accrual: 9-12 months • Duration: 14 months (First subject screened on 12/20/07 and the last subject completed study on 04/03/08 NIH IP/CP

  17. Inclusion Criteria Men who meet the following 10 criteria and women who meet the following 12 criteria are eligible for inclusion in the study: 1. Age of 18 2.HIV-1 status antibody negative as documented at screening 3.Understands and agrees to local STI reporting requirements 4.Able and willing to communicate in English 5.Able and willing to provide written informed consent to take part in the study 6.Able and willing to provide adequate information for locator purposes 7.Availability to return for all study visits, barring unforeseen circumstances 8.A history of consensual RAI at least once in lifetime* *Required to assure that subjects have a context for the acceptability assessments. 9.Willing to abstain from insertion of anything per rectum other than the study gel for the 1 week prior to treatment, 1 week prior each flexible sigmoidoscopy (i.e. during week of study gel use), and 1 week after each flexible sigmoidoscopy. 10.Willing to use condoms for the duration of the study In addition to the criteria listed above, female participants must meet the following criteria: 11.Negative pregnancy test 12.Post-menopausal or using an acceptable form of contraception.

  18. Exclusion Criteria 1.HIV positive at baseline 2.History of inflammatory bowel disease 3.Active inflammatory condition of the GI tract at baseline 4.Active rectal infection at baseline 5.≥Grade 2 laboratory abnormality at baseline 6.Allergy to methylparaben, propylparaben, sorbic acid 7.History of alcoholism or IV drug abuse 8.Unwillingness to refrain from chronic use of aspirin and NSAIDs. 9.Use of warfarin or heparin 10.Use of systemic immunomodulatory medications within 4 weeks of Visit 2 11.Use of rectally administered medications, with the exception of over the counter enemas, within 4 weeks of Visit 2 12.Use of product containing nonoxynol-9 rectally within 4 weeks of Visit 2 13.Use of any investigational products within 4 weeks of Visit 2 14.Any other clinical condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for the study. In addition to the criteria listed above, female participants will be excluded if they meet any of the following criteria: 15.Pregnancy 16.Breastfeeding 17. Female of child-bearing potential unwilling to use acceptable form of contraception

  19. Randomization: 0.1% UC781, 0.25% UC781, or placebo  1 wk  1 wk <4 wk flex flex flex Week 0 Week 2 Week 5 Week 6 Week 8 ~ 8 days Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Safety; Given 7 daily doses Screening 7-day exam Phone interview Single-dose exam Baseline Baseline Behav Questionnaire In depth tel interview Acceptability questionnaire RM Phase 1 Trial Design NIH IP/CP

  20. ‘post-biopsy’ appearance UCLA IRB # 02-05-001; approved for 30 bx per visit Multiple publications, Near 100% adherence No AE

  21. NIH IP/CP Indices/Assays used in UC781 RM safety trial • “routine” clinical sn/sx and laboratories • rectal swabs for STI, microflora • rectal sponges for secreted IgG, IgA and cytokines * • stool calprotectin * • rectal lavage for epithelial sloughing * • tissue at 10cm and 30cm for: • Histology (qualitative)(quantitative dropped) • Cytokine mRNA • MMC for phenotype by FACS • Explant infection studies * • plasma pK (to 24 hours) * Not in HPTN 056

  22. Clinical Results at 100% Completion: Blinded • Recruit/Enroll: CFAR/IPCP Trial Registry has helped. • 146 volunteers • 55 screened • 36 enrolled (entered V2) • 36 completed • 26 men (72%) and 10 women (28%) • no withdrawals (including due to procedures) • average of 80 phone calls/emails to get each subject recruited and through trial • 1 year, 3 months NIH IP/CP

  23. Safety Conclusions at 100% completion • Appears safe and well-tolerated • Subjects highly compliant with demanding protocol • Procedures well tolerated • No Drop outs/withdrawals • No Grade 3 or 4 AE • No procedure related AE • 84 Grade 1 AE reported • 8 Grade 2 AE reported in 5 of 36 individuals completing (4 from one individual at V3; not at V5) • New NIAID RM toxicity tables are useful in RM clinical trials where biopsy procedures produce findings that might otherwise be reported as “possibly-related’ • 36 subjects completed from 55 screened (66%) NIH IP/CP

  24. Ex Vivo HIV-challenge of in vivo exposed colorectal explants may be an important predictor of microbicidal effectiveness Explant infectivity results from a Phase 1 Rectal Microbicide Trial of UC781 (blinded data from 75% completed) an NIH IP/CP for Topical Microbicides

  25. Explants: process • Samples acquired (large-cup forceps): 14 biopsies at each site (10cm and 30cm) • NO procedure-related AE; no withdrawal / loss to follow-up • NO Microbicide DRUG ADDED (except at V2): all drug is applied IN VIVO • To laboratory and set up within 2 hours max. • HIV applied and left incubating for 2 hours: all washed and then 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; each time point is mean of 2 biopsies pooled; cumulative profile graphed NIH IP/CP

  26. Endoscopic biopsies + Absorbable gelatin sponge = Happy Explants Colorectal explants (10 cm and 30 cm) NIH IP/CP

  27. Explants: (i) prior experience with UC781 (ii) specifics of design plan • EXPLANTS are proven/published model: • Margolis et al. J Clin Invest 1998 • Fletcher et al. J Virol. 2005 • Fletcher et al. AIDS 2006 • UC781 has been shown to suppress/reduce explant HIV infection in vitro, ex vivo: • Fletcher et al. J Virol. 2005 (UC781 inhibits infection in cervical explant model) • Abner et al. J Infect Dis. 2005 (UC781 inhibits infection in cervical explant model) • Gupta et al. AIDS Res Hum Retroviruses. 2006 (frozen/fresh explants with UC781) • Van Herrewege et al. Antiviral Res. 2007 (cell line/chamber model with UC781) • Cummins et al. Antimicrob Agents Chemother. 2007 (cervical explant model: inhibition with UC781) • Explants from 2 sites (10 cm and 30 cm) • Explants from 3 visits: Baseline, post single exposure, post 7-day exposure • Each exposed to same laboratory viral strain: only R5 HIVbal • Two viral concentrations used to ensure infectivity and assess threshold: • TCID50: 104 and 102 • CONTEXT: in our hands, 104 always causes infection (no intra-subject variability) while 102 can vary NIH IP/CP

  28. Presentation Focus • Due to short presentation time AND still blinded nature of data: • Only most controlled data will be presented now. • Data at 10 cm (clinically relevant) • Data at Visit 3: single dose exposure (controlled) • Data from 104 viral infection ex vivo (ensure baseline infection) NIH IP/CP

  29.  1 wk  1 wk <4 wk Week 0 Week 2 Week 5 Week 6 Week 8 RM Phase 1 Trial Design Randomization: 0.1% UC781, 0.25% UC781, or placebo flex flex flex ~ 8 days Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Screening Baseline 7-day exam Phone interview Single-dose exam Safety NIH IP/CP

  30. At Baseline (V2), 26/27 of subject’s explants infectible with HIVBaL104 TCID50 (10 cm) NB: All data recoded so PI/Team blinded from Laboratory identification NIH IP/CP

  31. Explant infectibility at each visit NIH IP/CP

  32. Visit 3 Results (single dose; samples acquired at 30’) • 18/27 (66%) subject’s explants infectible, to some degree, with HIVBaL104 TCID50 • 9/27 (33%) subject’s explants unable to establish infection with HIVBaL104 TCID50 • One subject (#19) never established infection (FACS shows +CCR5) NIH IP/CP

  33. Visit 3 Results (single dose; samples acquired at 30’) • 33% with NO INFECTION • 33% with NO CHANGE • 33% in MIDDLE BLINDED 1 non-responder in “NO infection” group NIH IP/CP

  34. BLINDED Data UC781 RM Trial: Expanded view of 33% subjects showing “No infection” and 33% subjects showing “No change” (Visit 3) A B NIH IP/CP

  35. No differences appreciated at Baseline between the 33% “no infection”and the 33% “no change” groups NIH IP/CP

  36. Following 7 days of daily dosing (V5), no emerging pattern of response yet evident. NIH IP/CP

  37. Interpretations • Data (75% reported here) all still blinded • Nearly all explants infectible at Baseline (26/27; 96%) • 3 study groups: placebo, high-dose UC781, low-dose UC781 • Important observation: Not all results the same after single exposure • Convenient to anticipate that high drug dose are group that showed no response to 104 HIV infection ex vivo; even MIDDLE group demonstrated some reduction in infection…need to await unblinding. • If so: (i) potentially important biomarker, especially for Phase 1 trials • (ii) remarkable that a “clinically-safe”, in vivo rectally-applied drug dose could retain efficacy in assay of ex vivo tissue infection, using clinically excessive doses of laboratory viral strain (R5 only) NIH IP/CP

  38. Data Presentation: Other assays • Blinded data presented with laboratory numbers recoded to maintain blind…numerical sequence # • Data presented as box plot showing 25-75% range (Interquartile range=IQR) with median identified; ‘whiskers’ reflect 1.5xIQR. “Outliers” are small circles • Data presented as “grouped” at each visit • Data next presented according to explant ‘responders’, ‘non-responders’ or ‘middle’ • When available, HPTN 056 data presented to give context and evidence of reproducibility at baseline NIH IP/CP

  39. MMC phenotypes by FACS: Does CCR5 on CD4 change? CCR5 expression on CD4+ MMC does not seem to change in group as a whole after single or 7-day exposure; Subset analysis based on explant responders: no changes. Mean similar to HPTN 056 NIH IP/CP

  40. MMC phenotypes by FACS: Do ‘double +s’ on CD4 change? CCR5/CXCR4 dual expression on CD4+ MMC does not seem to change in group as a whole after single or 7-day exposure; Subset analysis based on explant responders: no changes. Mean similar to HPTN 056 NIH IP/CP

  41. MMC phenotypes by FACS: Does activation on CD4 change? While trends in CD38 and HLA-DR on CD4 MMC may be suggested, there is no difference over time compared to baseline changes. HPN 056 data not immediately available. NIH IP/CP

  42. Collection of rectal secretions for cytokines/chemokines with surgical sponges

  43. Boxplots of IL-1b Boxplots of IL-6 100 100 100 100 U19 (All) U19 (NON) U19 (Med) U19 (RESP) U19 (All) U19 (NON) U19 (Med) U19 (RESP) (n=27) (n=9) (n=9) (n=9) (n=27) (n=9) (n=9) (n=9) 80 80 80 80 60 60 60 60 IL-1b IL-6 40 40 40 40 20 20 20 20 0 0 0 0 V2 V3 V5 V2 V3 V5 V2 V3 V5 V2 V3 V5 V2 V3 V5 V2 V3 V5 V2 V3 V5 V2 V3 V5 Group Group Luminal cytokines by Luminex™: IL-1b or IL-6 No appreciable differences over time or within subgroups of IL-1b or IL-6. In general, IQR reasonably tight for whole group at baseline.

  44. Luminal cytokines by Luminex™: IL-12 or IFN-g No appreciable differences over time or within subgroups of IL-12 or IFN-g. IQR reasonably tight for IL-12; broad for IFN-g.

  45. Luminal cytokines by Luminex™: TNF-a or RANTES No appreciable differences over time/within subgroups of TNF-a or RANTES. IQR reasonably tight for TNF-a; broad for RANTES.

  46. Luminal cytokines by Luminex™: MIP-1a No appreciable differences over time or within subgroups of MIP-1-a. In general, more variable IQR.

  47. “Blinded” Interpretations • MMC phenotypes: Based on FACS data, there appears to be no difference among the all subjects in the 3 groups (placebo, high- does, low-dose) over all visits on co-receptor expression or activation status. • Rectal fluid cytokines: Using Luminex™ data from rectal sponges eluates, there does not appear to be any trend/significant differences among 7 measured cytokines/chemokines after single or 7 day exposure. • Based on these still blinded data, if these assays (MMC phenotype and ‘secreted’ cytokines) are relevant and sensitive enough to assess early/mild immunoreactive changes to topical UC781 exposure, we are not detecting such changes NIH IP/CP

  48. 350000 HPTN056 (n=8,v=24) 250000 150000 50000 0 NIH IP/CP Boxplots comparing range of IgA at UC781 baseline (V2) with HPTN 056 Boxplots of IgA 350000 UC-781 (All) U19 (Low) U19 (Med) U19 (High) (n=27) (n=9) (n=9) (n=9) 250000 IgA (ng/ml) 150000 50000 0 V2 V3 V5 V2 V3 V5 V2 V3 V5 V2 V3 V5 Group

  49. NIH IP/CP Boxplots comparing range of IgG at UC781 baseline (V2) with HPTN 056

  50. NIH IP/CP Findings thus far in UC781..still blinded • safe • intensive recruiting/scheduling (~80 phone calls/emails per subject): HIGH adherence • no significant AE or procedure problems • most immunoassays: no difference seen across 36 • explant data: exciting. May be potential bio-indicator • lessons from blinded results that have guided next trial: • no apparent difference between 10cm and 30cm; therefore, only 10cm in next trial. Can anal bx with stool and sponges suffice? • Ig variabilty even greater in this trial that in HPTN 056..therefore, dropped as future immunotox/safety assay in next trial

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