International Partnership for International Partnership for MicrobicidesMicrobicides

International Partnership for International Partnership for MicrobicidesMicrobicides

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

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

Diversity of delivery systems Semisolids/Solids

Gels Emulsions Films Tablets

Devices Vaginal rings Sponges Diaphragm

Oral

Vaginal RingsVaginal RingsVaginal RingsVaginal 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

Reservoir vs. Matrix Type Vaginal RingsReservoir vs. Matrix Type Vaginal RingsReservoir vs. Matrix Type Vaginal RingsReservoir vs. Matrix Type Vaginal Rings

Courtesy or Karl Malcolm, QUB Matrix-type

Core-type

Cross-sectional profiles

TMC120Raman maps

TMC120 (Dapivirine): Background/StatusTMC120 (Dapivirine): Background/StatusTMC120 (Dapivirine): Background/StatusTMC120 (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

N

CH3

CH3H3C

H

N

N

N

H

CN

Daily Release of Dapivirine from a Silicone Daily Release of Dapivirine from a Silicone Elastomer Reservoir RingElastomer Reservoir RingDaily Release of Dapivirine from a Silicone Daily Release of Dapivirine from a Silicone Elastomer Reservoir RingElastomer Reservoir Ring

0

50

100

150

200

250

300

350

0 5 10 15 20 25 30

Days

Mic

rogr

ams

(ug)

10 mg

25 mg

50 mg

100 mg

0

500

1000

1500

2000

2500

0 5 10 15 20 25 30

Days

Mic

rog

ram

s (u

g)

10 mg

25 mg

50 mg

100 mg

Cumulative Release of Dapivirine from a Cumulative Release of Dapivirine from a Silicone Elastomer Reservoir RingSilicone Elastomer Reservoir RingCumulative Release of Dapivirine from a Cumulative Release of Dapivirine from a Silicone Elastomer Reservoir RingSilicone Elastomer Reservoir Ring

Dapivirine Formulation: PharmacokineticsDapivirine Formulation: PharmacokineticsDapivirine Formulation: PharmacokineticsDapivirine 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

C131/IPM008: Trial SummaryC131/IPM008: Trial SummaryC131/IPM008: Trial SummaryC131/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

C131/IPM008: Safety SummaryC131/IPM008: Safety SummaryC131/IPM008: Safety SummaryC131/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

C131/IPM 008 Trial: AE SummaryC131/IPM 008 Trial: AE SummaryC131/IPM 008 Trial: AE SummaryC131/IPM 008 Trial: AE Summary

ARM N= per arm n= With Any AE

% with any AE

Placebo 3 2 66

25 mg TMC120

10 8 80

Total 13 10 77

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

Drug Release: Specimen Type/ScheduleDrug Release: Specimen Type/ScheduleDrug Release: Specimen Type/ScheduleDrug 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

C131/IPM005: Specimen AnalysisC131/IPM005: Specimen AnalysisC131/IPM005: Specimen AnalysisC131/IPM005: Specimen Analysis

4 Hours 24 hours 7 days

Geo. Ratio Geo. Ratio Geo. Ratio

Dapivirine Group (N=10) Mean to EC501 Mean to EC50

1 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.

Dapivirine Levels in Clinical SamplesDapivirine Levels in Clinical SamplesDapivirine Levels in Clinical SamplesDapivirine Levels in Clinical Samples

TMC120 Concentrations

1.00

10.00

100.00

1,000.00

10,000.00

100,000.00

1,000,000.00

introitus(T)

cervix(T)

ring (T) introitus(S)

cervix(S)

ring (S) plasma

ng

/mL

(L

og

)

4 hours

24 hours

7 days

<50 pg/mL

EC50= 0.33 ng/mL

Dapivirine concentrations in vaginal fluids Dapivirine concentrations in vaginal fluids (Sno-Strip samples)(Sno-Strip samples)Dapivirine concentrations in vaginal fluids Dapivirine concentrations in vaginal fluids (Sno-Strip samples)(Sno-Strip samples)

EC50= 0.33 ng/mL

Sno-Strip Concentrations

10

100

1,000

10,000

100,000

4 hour 24 hour 2 days 3 days 5 days 7 days

ng/m

L (L

og)

introitus

cervix

ring

C131/IPM008: Conclusions & Next StepsC131/IPM008: Conclusions & Next StepsC131/IPM008: Conclusions & Next StepsC131/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

AcknowledgementsAcknowledgementsAcknowledgementsAcknowledgements

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