Vaginal Rings and Microbicides
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Vaginal Rings and Microbicides Mark Mitchnick, MD. October 30, 2007. Microbicide Delivery System Goals. Safe Effective Coitally Independent Daily Monthly Affordable Ease of manufacture Broadly stable Long shelf life Acceptable Versatile Forgiving PK Multiple actives.

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Vaginal Rings and Microbicides

Mark Mitchnick, MD.

October 30, 2007


Microbicide delivery system goals
Microbicide Delivery System Goals

  • 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 widespread adoption of microbicides
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

      • Physical barriers

    • Other?


Antiretroviral arv microbicides
Antiretroviral (ARV) Adoption of MicrobicidesMicrobicides

  • 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


Microbicides in product development
Microbicides Adoption of Microbicides in Product Development

Lactin-V

Invisible Condom

Free virus

BufferGel

Carraguard

PRO2000

SPL7013 (VivaGel)

Monoclonal antibodies

DS003 (BMS)

DS001 (Merck)

DS006 (Maraviroc)

Attachment

Locus small molecules

Fusion

S-DABO

Dapivirine (TMC120)

UC781

Tenofovir (PMPA)

PC815 (MIV150 + Carraguard)

Pyrimidinediones (Samjin)

Replication

(RT)

Integration

Protein synthesis and assembly

Budding

Maturation


Ipm drug product grid medium term
IPM Drug Product Grid: Adoption of MicrobicidesMedium Term

  • Delivery Formats

    • Semisolids

      • Gels

      • Emulsions

      • Gel caps

    • Vaginal Rings

      • Matrix

      • Reservoir

    • Films

    • Dissolving Tablets

  • API

    • NNRTI

      • Dapivirine

    • NRTI

      • PMPA

    • R5 Blocker

      • Merck 167

      • Maraviroc (pending)

    • GP 120 binding

      • BMS 793


Dapivirine
Dapivirine Adoption of Microbicides

  • 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 rings
Sustained Release: Vaginal Rings Adoption of Microbicides

  • 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 unknowns
Addressing the Unknowns Adoption of Microbicides

  • 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 Adoption of Microbicides

Dapivirine

Raman maps

Cross-sectional

profiles

Drug

Core-type

Matrix-type

Courtesy or Karl Malcolm, QUB


In vitro daily release of dapivirine from a silicone elastomer matrix vaginal ring
In-Vitro Daily Release of Adoption of MicrobicidesDapivirine From a Silicone Elastomer Matrix Vaginal Ring

g Dapivirine

Days

-Sink conditions: Release medium is 50% IPA. Daily vaginal gel dose= 500 g (red line)


Human experience with vaginal rings to date
Human Experience with Vaginal Rings To Date Adoption of Microbicides

  • Several marketed products

    • Hormone releasing

    • FemRing

      • Vagianlmenapuse 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 samples
Dapivirine Levels in Clinical Samples Adoption of Microbicides

EC50= 0.33 ng/mL

Dapivirine ng/mL

<50 pg/mL


Next steps
Next Steps Adoption of Microbicides

  • 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


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