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