Microbicide Delivery: Choice will be Key to Widespread Adoption of Microbicides

1. Characterization of In Vitro Release and In Vivo Delivery of TMC120 with an Intravaginal Ring: Implications for Microbicide Delivery Joseph Romano, Ph.D. August 16, 2006

2. Microbicide Delivery: Choice will be Key to Widespread Adoption of Microbicides • Diversity of delivery systems • Semisolids/Solids • Gels • Emulsions • Films • Tablets • Devices • Vaginal rings • Sponges • Diaphragm • Oral

3. Vaginal Rings • Attractive technology: • 30+ days of drug delivery • Potentially reduces compliance burden • Easy to use • “Low” cost • Unknowns: • Acceptability in relevant populations • Scale up manufacture • Feasibility of multi-drug combinations • Environmental impact

4. Reservoir vs. Matrix Type Vaginal Rings TMC120 Raman maps Cross-sectional profiles Core-type Matrix-type Courtesy or Karl Malcolm, QUB

5. TMC120 (Dapivirine): Background/Status • NNRTI developed by Tibotec/J&J, licensed to IPM (2004) • Developed originally as therapeutic, 11 clinical studies conducted via oral administration • Highly potent ARV • Low cytotoxicity, non-mutagenic, non-teratogenic • Easily manufactured • Stable drug substance • Very economical • IP clarity • Gel formulation development H C C H C N 3 3 N N N N C H H H 3

6. Daily Release of Dapivirine from a Silicone Elastomer Reservoir Ring

7. Cumulative Release of Dapivirine from a Silicone Elastomer Reservoir Ring

8. Dapivirine Formulation: Pharmacokinetics • Gel in rabbits and macaques • Tissue associated levels all much greater than EC50 even 24 hours post application • Good distribution of drug throughout vagina • Very low plasma levels • Human PK study (IPM004): Completed in Q1, 2006 • Vaginal ring in humans (IPM008) • Good distribution of drug throughout vagina • Very low plasma levels

9. C131/IPM008: Trial Summary • Trial period: Start: 27 June 2005; End: 04 August 2005 • Primary objective: Evaluate the feasibility of using a silicone elastomer reservoir type vaginal ring to deliver the candidate microbicide TMC120. • Specific objectives: • Assess the safety and tolerability of 7-day use of a vaginal ring containing TMC120. • Assess TMC120 concentrations in vaginal fluids, vaginal and cervical epithelial tissue, and plasma during and after 7-day use. • Methodology: Randomized, double blind, placebo control design • 10 women with the dapivirine ring (25 mg) • 3 women with placebo ring

10. C131/IPM008: Safety Summary • No consistent or clinically relevant changes in lab parameters were observed • One treatment emergent grade 1 lab abnormality • No clinically relevant changes in urinalysis or vital sign parameters • No mean changes in vaginal ecology pH • Nugent scores unchanged between screen and Day 14 in 9/10 women in drug arm (1 improved); no change in 2/3 in placebo arm (1 worsened) • One clinically relevant abnormality on pelvic exam (cervical uterine ulcer on day 14) • Doubtful as drug related

11. C131/IPM 008 Trial: AE Summary • Majority of AE’s were grade 1 (mild); 3 subjects with grade 2 (moderate) which were doubtful as related to drug • Four subjects with AE’s possibly related to drug; none were considered probable or very likely related to drug • No deaths, SAE’s, or AE’s leading to premature discontinuation were recorded

12. Drug Release: Specimen Type/Schedule • Plasma • Blood draw: 4 hrs, 24 hrs, 7 days (pre) • Vaginal fluid • Sno-strips: 4 hrs, 24 hrs, 7 days (pre) • Subgroups at 2, 3, and 5 days • Tissue • Biopsies: 7 days (post) • Introitus • Vaginal wall • Endocervix

13. C131/IPM005: Specimen Analysis 4 Hours 24 hours 7 days Geo. Ratio Geo. Ratio Geo. Ratio Dapivirine Group (N=10) Mean to EC501 Mean to EC501 Mean to EC501 Cervicovaginal epithelium (ng/gm)2 Vaginal ring area ND - ND - 121,208 367,296 Vaginal introitus ND - ND - 54,947 166,505 Cervix3 ND - ND - 42,338 128,297 Vaginal Fluids (ng/mL)4 Vaginal ring area 6,378 19,326 9,087 27,536 8,266 25,047 Vaginal introitus area 819 2,481 1,804 5,466 2,191 6,638 Cervix 1,480 4,485 3,195 9,683 915 2,772 Plasma (ng/mL) 0.03 0.09 0.03 0.09 0.04 0.11 1 EC50 is 0.33 ng/mL; 2 Tissues were collected as 3 mm punch biopsies, with 1 gm tissue assumed to be equivalent to 1 mL; 3 4 samples were not available for analysis, therefore N=6 for this group; 4 Values were converted from the 8 L samples (i.e. x125) collected per Sno-stripTM. ND= not done.

14. Dapivirine Levels in Clinical Samples <50 pg/mL EC50= 0.33 ng/mL

15. Dapivirine concentrations in vaginal fluids (Sno-Strip samples) EC50= 0.33 ng/mL

16. C131/IPM008: Conclusions & Next Steps Conclusions: • TMC 120 was delivered via a vaginal ring at high multiples of EC50 • TMC120 was detectable, but near LLOQ (5 pg/mL) in plasma samples from TMC120 treatment group. • Both active and placebo rings were safe and well tolerated. Next Steps: • IPM to conduct a ring acceptability study in Africa in 2006 • Expanded safety studies with TMC120 in ring • Alternative ring designs • Development of manufacturing capability

17. Acknowledgements • University of Ghent • Steven Weyers • Luc van Bortel • Marleen Temmerman • Queen’s University, Belfast • Karl Malcolm • David Woolfson • Warner Chilcott • Claire Gilligan • Robert Patrick • Tibotec • Jens van Roey • IPM • Paul Coplan • Karen Douville • Richard Erwin • Mark Mitchnick • Zeda Rosenberg • Joe Romano