Characterization of In Vitro Release and In Vivo Delivery of TMC120 with an Intravaginal Ring: Impli

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
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TMC120 (Dapivirine) Background/Status

• NNRTI developed by Tibotec/JJ, 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

C
H
H
C
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
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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

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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

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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

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C131/IPM 008 Trial AE Summary

• Majority of AEs were grade 1 (mild) 3 subjects
  with grade 2 (moderate) which were doubtful as
  related to drug
• Four subjects with AEs possibly related to drug
  none were considered probable or very likely
  related to drug
• No deaths, SAEs, or AEs leading to premature
  discontinuation were recorded

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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

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C131/IPM005 Specimen Analysis


4 Hours 24
hours 7 days

Geo. Ratio Geo. Ratio
Geo. Ratio Dapivirine Group
(N10) 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 N6 for this
group 4 Values were converted from the 8 ?L
samples (i.e. x125) collected per Sno-stripTM.
ND not done.
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Dapivirine Levels in Clinical Samples
lt50 pg/mL
EC50 0.33 ng/mL
15
Dapivirine concentrations in vaginal fluids
(Sno-Strip samples)
EC50 0.33 ng/mL
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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

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Acknowledgements

• University of Ghent
• Steven Weyers
• Luc van Bortel
• Marleen Temmerman
• Queens 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