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International Partnership for International Partnership for MicrobicidesMicrobicides
International Partnership for International Partnership for MicrobicidesMicrobicides
Vaginal Rings and MicrobicidesMark Mitchnick, MD.
October 30, 2007
Microbicide Delivery System Microbicide Delivery System GoalsGoalsMicrobicide Delivery System Microbicide Delivery System GoalsGoals
Safe Effective Coitally Independent
Daily Monthly
Affordable Ease of manufacture Broadly stable Long shelf life
Acceptable Versatile
Forgiving PK Multiple actives
Microbicide Delivery: Choice will be Key to Microbicide Delivery: Choice will be Key to Widespread Adoption of MicrobicidesWidespread Adoption of Microbicides
Microbicide 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 Physical barriers
Other?
Most developers are focusing on ARV’s HIV specific Highly active Affordable Can be formulated to be Coitally
independent Safe, lots of experience with most
classes Stable in relevant climatic zones
Antiretroviral (ARV) MicrobicidesAntiretroviral (ARV) MicrobicidesAntiretroviral (ARV) MicrobicidesAntiretroviral (ARV) Microbicides
Microbicides in Product Microbicides in Product DevelopmentDevelopment
Microbicides in Product Microbicides in Product DevelopmentDevelopment
Free virusLactin-VInvisible Condom
AttachmentFusion
Replication(RT)
Protein synthesis and assembly
Budding
Maturation
Locus small molecules
CarraguardPRO2000SPL7013 (VivaGel)Monoclonal antibodiesDS003 (BMS)DS001 (Merck)DS006 (Maraviroc)
S-DABODapivirine (TMC120)UC781Tenofovir (PMPA)PC815 (MIV150 + Carraguard)
Pyrimidinediones (Samjin)
BufferGel
Integration
IPM Drug Product Grid: IPM Drug Product Grid: Medium TermMedium Term
IPM Drug Product Grid: IPM Drug Product Grid: Medium TermMedium Term
API• NNRTI
• Dapivirine• NRTI
• PMPA• R5 Blocker
• Merck 167• Maraviroc
(pending)• GP 120 binding
• BMS 793
Delivery Formats• Semisolids
• Gels• Emulsions• Gel caps
• Vaginal Rings• Matrix• Reservoir
• Films• Dissolving Tablets
DapivirineDapivirineDapivirineDapivirine
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, very cheap Stable drug substance IP clarity Multiple dosage forms
Sustained Release: Vaginal RingsSustained Release: Vaginal RingsSustained Release: Vaginal RingsSustained Release: 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
Regulatory path in multiple countries
Feasibility of multi-drug combinations
Environmental impact
Addressing the UnknownsAddressing the UnknownsAddressing the UnknownsAddressing the Unknowns
Acceptability in relevant populations Acceptability studies ongoing
Scale up manufacture Survey of methods with scale-up of each investigated Redundant capacity being installed
Regulatory path in multiple countries Priority Engaging regulators
Feasibility of multi-drug combinations Multiple groups engaged to tackle Several novel approaches
Environmental impact Being quantified, primary concern is control over HIV Additional matrix materials being investigated
Types of Vaginal rings: Reservoir & Matrix Types of Vaginal rings: Reservoir & Matrix Types of Vaginal rings: Reservoir & Matrix Types of Vaginal rings: Reservoir & Matrix
Courtesy or Karl Malcolm, QUB Matrix-type
Core-type
Cross-sectional profiles
DapivirineRaman maps
Drug
-Sink conditions: Release medium is 50% IPA. Daily vaginal gel dose= 500 g (red line)
In-Vitro Daily Release of Dapivirine From a In-Vitro Daily Release of Dapivirine From a Silicone Elastomer Matrix Vaginal RingSilicone Elastomer Matrix Vaginal Ring
In-Vitro Daily Release of Dapivirine From a In-Vitro Daily Release of Dapivirine From a Silicone Elastomer Matrix Vaginal RingSilicone Elastomer Matrix Vaginal Ring
0
100
200
300
400
500
600
700
800
900
1000
0 5 10 15 20 25 30
25 mg
20 mg
15 mg
10 mg
g D
apiv
irin
e
Days
Human Experience with Vaginal Human Experience with Vaginal Rings To DateRings To DateHuman Experience with Vaginal Human Experience with Vaginal Rings To DateRings To Date
Several marketed products Hormone releasing FemRing
Vagianl menapuse symptoms Silicone reservoir
NuvaRing Birth control EVA reservoir
Microbicide containing rings In development Several Phase I studies
PK looking very promising No safety issues to date
Dapivirine Levels in Clinical SamplesDapivirine Levels in Clinical SamplesDapivirine Levels in Clinical SamplesDapivirine Levels in Clinical Samples
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
1.E+06
introitus(T)
cervix(T)
ring (T) introitus(S)
cervix(S)
ring (S) plasma
4 hours
24 hours
7 days
<50 pg/mL
Dap
ivir
ine
ng
/mL
EC50= 0.33 ng/mL
Next StepsNext StepsNext StepsNext Steps
Complete manufacturing development Install manufacturing capacity Larger safety studies in 2008 Phase III study with Dapivirine ring in
2010 Part of larger multi-arm study
Strong efforts in additional development Multiple actives in single ring Additional Matrix materials