an NIH IP/CP for Topical Microbicides

1. A PHASE 1 SAFETY AND ACCEPTABILITY STUDY OF THE UC-781 MICROBICIDE GEL APPLIED RECTALLY IN HIV SERONEGATIVE ADULTS: AN INTERIM SAFETY REPORT AT 50% 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

2. Relevant Clinical Context • Any microbicides demonstrating efficacy in vaginal trials will likely require demonstration of rectal safety • Receptive anal intercourse (RAI) is main risk for MSM but also significant contribution to heterosexual transmission • By numbers alone, more RAI in heterosexuals; not well quantified in higher risk settings • Rectosigmoid: Increased vulnerability/risk per sexual act • Rectal compartment very different than cervicovaginal • The first rectally-focused NIH IP/CP microbicide effort • Longer goal: development of an acceptable, effective, affordable, rectally-formulated microbicide NIH IP/CP

3. Epithelia Compartment Difference: Rectum NIH IP/CP

4. 1st Rectal Microbicide IND Trial • interim, blinded analysis at 50% completion of safety data only • next 2 presentations report on blinded interim data analyses • Sponsored by Biosyn, now CONRAD with NIAID’s U19 IP/CP • Single site: UCLA • NNRTI: UC-781 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 • UC-781 gel applied rectally with vaginal applicator NIH IP/CP

5. Applicator (vaginal form) • Participants apply small amount of lubricant to applicator for insertion. • Not to use OTC lubricants as they may cause toxicity and interact with the study product. NIH IP/CP

6. Trial Objectives and Indices • Primary Objective: • To evaluate the safety and acceptability of 0.1% and 0.25% UC-781 vaginal microbicide gel versus placebo when applied rectally. • Indices: • Frequency of ≥Grade 2 adverse events • Acceptability assessments NIH IP/CP

7. 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

8. 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

9. 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: 18 months (last subject already enrolled; completion date for entire study: mid 3/08) NIH IP/CP

10. 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.

11. 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

12. Randomization: 0.1% UC-781, 0.25% UC-781, 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

13. ‘post-biopsy’ appearance UCLA IRB # 02-05-001; approved for 30 bx per visit

14. Clinical Results at 50% Completion: Blinded • Recruit/Enroll: CFAR/IPCP Trial Registry has helped. • 92 volunteers • 36 screened • 22 enrolled (entered V2) • 19 completed • 13 men (72%) and 5 women (28%) • no withdrawals (including due to procedures) • average of 80 phone calls/emails to get each subject recruited and through trial NIH IP/CP

15. Clinical Results at 50% Completion: Blinded • Adverse events: • No Grade 3 or 4 AE • 64 total AE reported: • 7 Grade 2 AE (in 4 of 19 subjects completing) • 4/7 from 1 individual at V3 (fever, cramps, flatulence, diarrhea; none on 7 day exposure): “possibly related” • 2 with limited diarrhea (resolved): “possibly related” • 1 transient thrombocytopenia: “not related” • NO procedure related AE NIH IP/CP

16. Conclusions at 50% 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 • 7 Grade 2 AE reported in 4 of 19 individuals completing (4 from one individual at V3; not at V5) • New NIAID RM toxicity tables are useful in clinical trials where biopsy procedures produce findings (blood, diarrhea, urgency) that otherwise would have been reported as AE, “possibly-related’ to product. NB: Findings not much different at 75% completion NIH IP/CP

17. NIH NIAID U19 IP/CP #AI060614: “Microbicide Development Program” UCLA Ian McGowan (U Pitt) Chomchay Siboliban Amy Adler Terry Saunders Elena Khanukhova Charlie Price Julie Elliott John Boscardin Ying Zhao Daniel Cho Karen Andrews Elizabeth Johnson Alexis Dominguez Julia Klein Biosyn, Inc Anne Marie Corner Linda Knapp Linda Kristekas NIH Jim Turpin Jeanna Piper Cherylnn Mathias Grace Chow CONRAD Henry Gabelnick Christine Mauck Tim McCormick Marianne Callahan Consultants Alex Carballo-Dieguez Ana Vetuneac VOLUNTEERS! an NIH IP/CP for Topical Microbicides