Microbicide Products Microbicide Products in the Pipelinein the Pipeline

Regional Meeting on Regulatory Issues in Regional Meeting on Regulatory Issues in Microbicide ResearchMicrobicide Research

Dr. Zeda F. Rosenberg Dr. Zeda F. Rosenberg International Partnership for MicrobicidesInternational Partnership for Microbicides

29 October 200729 October 2007New Delhi, IndiaNew Delhi, India

Microbicides in Product DevelopmentMicrobicides in Product DevelopmentMicrobicides in Product DevelopmentMicrobicides in Product Development

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

Vaginal applicator Vaginal ring

Ideally long acting, safe, effective, low cost and user-friendly

Potential for combinations of drugs to increase effectiveness

Microbicide OptionsMicrobicide OptionsMicrobicide OptionsMicrobicide Options

– gel

– intravaginal ring

– film

– tablet

– sponge

Multiple delivery types:

Rationale for Vaginal DosingRationale for Vaginal DosingRationale for Vaginal DosingRationale for Vaginal Dosing

Local drug levels can be high and systemic exposure low

Maximum drug:virus levelLower chance for systemic related side effectsPrecedent in contraception

No one prevention option will satisfy all; multiple approaches available to address acceptability preferences

Women-initiated

Early-Generation MicrobicidesEarly-Generation MicrobicidesEarly-Generation MicrobicidesEarly-Generation Microbicides

Non-specifically block HIV from interacting with target cells

Polyanions recently or currently in HIV efficacy trials (Carraguard, CS, PRO 2000, Buffergel)

Some polyanions are also acid-buffering agents

Partial, low or no effectiveness

Early Generation MicrobicidesEarly Generation MicrobicidesEarly Generation MicrobicidesEarly Generation Microbicides

Advantages inexpensive broad activity lack of systemic absorption some are contraceptive

Disadvantages reduced or no activity against R5 viruses coitally dependent may not be at the right place at the right time activity reduced in seminal plasma

Next-Generation Anti-retroviral Next-Generation Anti-retroviral (ARV) Microbicides(ARV) MicrobicidesNext-Generation Anti-retroviral Next-Generation Anti-retroviral (ARV) Microbicides(ARV) Microbicides

AdvantagesHighly potent and HIV-specificDocumented safety and efficacy as

therapeuticsCan be formulated for sustained

protection• Once a day or less frequent• Gels, intravaginal rings, others

DisadvantagesPotential for resistanceLack of activity against other STDs

Topical TenofovirTopical TenofovirTopical TenofovirTopical Tenofovir

Nucleotide reverse transcriptase inhibitor Viread marketed as a therapeutic Preclinical development began in late

1990s HPTN 050 Phase I Safety Study completed

in US (NIH) Well tolerated Low serum levels in 56% of subjects

HPTN 059 Phase II Safety Study ongoing in US and India (NIH)

CONRAD PK study of 1% Tenofovir gel to determine systemic and local tissue levels – ongoing (IPM)

Topical Tenofovir (cont.)Topical Tenofovir (cont.)Topical Tenofovir (cont.)Topical Tenofovir (cont.)

CAPRISA 004 Phase IIb study began in May 2007 (USAID)

– Dosing regimen: coitally +/- 12 hours MTN 001 Comparison of once daily

tenofovir oral and gel pK, adherence and acceptability in 120 women

– Planned in Uganda, SA, and US MTN 003 Phase IIb Vaginal Tenofovir and

Oral Tenofovir and Truvada in 4200 women– Dosing regimen: once per day– Planned in SA, Malawi, Uganda, Zambia and

Zimbabwe

TMC120 (Dapivirine): BackgroundTMC120 (Dapivirine): BackgroundTMC120 (Dapivirine): BackgroundTMC120 (Dapivirine): Background

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, cheap Stable drug substance IP clarity Multiple dosage forms N

CH3

CH3H3C

H

N

N

N

H

CN

Dapivirine gel/ring: Clinical studiesDapivirine gel/ring: Clinical studiesDapivirine gel/ring: Clinical studiesDapivirine gel/ring: Clinical studiesStudy Study Name Location Volunteers Status

IPM003 Gel 002 Safety SA, Tanzania, Rwanda

112 completed

IPM004 Gel 002 PK South Africa 18 completed

IPM005B Gel 002 Expanded Safety

Belgium 36 completed

IPM001 PC Ring Feasibility Belgium 12 completed

IPM008 WC Ring Feasibility Belgium 13 completed

IPM011 WC Placebo Ring Safety /Acceptability

South Africa, Kenya, Tanzania

200 ongoing

IPM012 Gel 4750 and 4789 pK and Safety

Belgium 36 November 2007

start

IPM018 Dapivirine Matrix and Reservoir Ring pK

Belgium 24 completed

UC-781 BackgroundUC-781 BackgroundUC-781 BackgroundUC-781 Background

Carboxanilide type of NNRTI

Potent anti-HIV-1 activity (nM range)Tight binding to HIV-1 RTActive against cell-free and cell-associated virus

Little to no cytotoxicity (>M)Active against RT inhibitor resistant strains

Reduced likelihood for resistance selectionExhibits so-called “Memory Effect”Phase I safety study in 48 women completed

O

Cl

N

S

O

CH3

H

UC-781 Ongoing StudiesUC-781 Ongoing StudiesUC-781 Ongoing StudiesUC-781 Ongoing Studies

SAFETY STUDIES

ENROLLMENT GEL TYPE DURATION ENDPOINTS

CDC/Emory 36 sexually active women18 abstinent HIV positive women

0.1, 0.25, placebo

0.25 (12♀) UP (6♀)

Twice-daily for 14 days

Systemic/local toxicity, absorption, flora, acceptability

University of Pittsburgh/NIH

60 abstinent women

0.1% or placebo at 0, 2, 4, and 8 hrs duration

Single dose Safety, persistence of UC-781, systemic absorption , anti-HIV-1 activity, vaginal flora, acceptability

CDC/Thailand 45 sexually active women

0.1, 0.25, placebo

Twice-daily for 14 days

Systemic/local toxicity, absorption, flora, acceptability, anti-HIV activity

CONRAD/CFHC

36 abstinent men

0.25 %, placebo

Once-daily for 7 days

Systemic/local toxicity, absorption

UCLA/NIH 36 women and men

0.1, 0.25, placebo

2 phases:Single dose; Once-daily for 1 week

Systemic/local toxicity, rectal mucosal damage, PK subset

MIV-150 BackgroundMIV-150 BackgroundMIV-150 BackgroundMIV-150 Background

PC-815, Carraguard plus MIV-150 (NNRTI) Phase 1 crossover study (Dominican Republic,

Profamilia) PC-815 and Carraguard – 20 women, 1 week single dose/day followed by 1 week

twice dosing/day– Safety and pharmacokinetic for systemic absorption of

MIV-150– Planned start Nov 2007

Phase I male tolerance, (South Africa, Setshaba Research Center)

– Safety and pharmacokinetic for systemic absorption of MIV-150

– 10 circumcised and 10 uncircumised males– IRB approved;– Planned start following Phase I in women

HIV EntryHIV EntryHIV EntryHIV Entry

HIV

gp120Coreceptor

Binding

Host Cell

gp120 CD4Binding

gp41

gp120

CCR5CXCR4

CD4

Gp41 MediatedFusion

CCR5CXCR4

gp41

gp120 CD4

HIV

HIV

gp120

gp41

HIV-Specific Entry/Fusion InhibitorsHIV-Specific Entry/Fusion InhibitorsHIV-Specific Entry/Fusion InhibitorsHIV-Specific Entry/Fusion Inhibitors

Act on virus: gp120 or gp41 blockersDS003 (BMS793), cyanovirin, FI peptidesDisadvantages

- current gp41 blockers are peptides

Act on target cell: CCR5 blockersDS001 (M167), Maraviroc, PSC-RantesDisadvantages

- lack of activity against X4 virus

Next-Generation Product DevelopmentNext-Generation Product DevelopmentNext-Generation Product DevelopmentNext-Generation Product Development

Early Preclinical Preclinical Phase I/II Phase III Filing Approval

1-2 years 1-2 years 2+ years 3 years 1 year

Dapivirine Gel & Ring

UC781 Gel

MIV150 + Carraguard Gel

Dapivirine Tablet & Film

DS001 (M167) + Dapivirine

DS003 (BMS793)

Maraviroc

S-DABO

Pyrimidinediones

Monoclonal antibodies

DS001 (M167)

Tenofovir Gel

Future PipelineFuture PipelineFuture PipelineFuture Pipeline

New mechanisms of action Integrase inhibitors Small molecule fusion inhibitors ??

Need to add back-up drugs to hedge against drop-out

Need to add better options In late stage development or marketed

therapeutic

Combination MicrobicidesCombination MicrobicidesCombination MicrobicidesCombination Microbicides

Advantages potential increased efficacy against resistant

virus coverage of multiple transmission pathways potential synergy and need for less drug

Disadvantages unclear regulatory pathway possible difficulties in co-formulation possible increased cost increased potential for toxicity cross company/institutional agreements

Criteria for Moving Forward: Criteria for Moving Forward: Pre-ClinicalPre-Clinical

Criteria for Moving Forward: Criteria for Moving Forward: Pre-ClinicalPre-Clinical

Compounds assessed to identify best candidates for clinic

LABORATORY STUDIES

Toxicity / Potency

Pre-formulation

Stability

MECHANISMS OF ACTION

Earlier in life cycle is better

New mechanism of action

Comparison with other candidates with same mechanism of action

BUSINESS CASE

IP access to compound

Cost

Drug synthesis process

Ease of manufacture

Criteria for Moving Forward: Criteria for Moving Forward: Early Clinical TrialsEarly Clinical Trials

Criteria for Moving Forward: Criteria for Moving Forward: Early Clinical TrialsEarly Clinical Trials

Candidates assessed in small numbers of volunteers

SAFETY

Drug, formulation, delivery assessed for prolonged use

Product safety evaluated in diverse populations

Early clinical trials cannot fully predict risk of enhancing HIV transmission

ACCEPTABILITY

Placebo formulations assessed in diverse populations

Acceptability measured in all clinical trials

PHARMACOKINETICS

Where drug goes in body, concentration, duration

Preferred dosage: Wide distribution in genital tract Long duration Sufficient concentration

Criteria for Moving Forward: Criteria for Moving Forward: Efficacy Trials Efficacy Trials

Criteria for Moving Forward: Criteria for Moving Forward: Efficacy Trials Efficacy Trials

Top candidates move into efficacy trials

BEST-IN-CLASS

Essential criteria: Potency Safety PK Acceptable formulation

Secondary criteria: Mechanism of action Cost Ease of manufacture Access / IP

Will Microbicides Work?Will Microbicides Work?Will Microbicides Work?Will Microbicides Work?

Predicated on getting the RIGHT drug at the RIGHT levels in the RIGHT place at the RIGHT time

Right Drugs and Right Levels Highly potent ARVs acting early in HIV lifecycle

Right Place and Right Time Formulations to keep drug(s) in vaginal lumen

and/or in tissue depending on drug’s MOA Long acting sustained release

Drug Discovery, Development Drug Discovery, Development and Review Processand Review Process

Drug Discovery, Development Drug Discovery, Development and Review Processand Review Process

Adapted from: Pharmaceutical Research and Manufacturers of America, 2006

Phase I Phase IIIPhase II

Stage 1Drug discovery

Stage 2Pre-clinical

Stage 3Clinical trials

Stage 4Regulatory review

7 years7 years6.5 years 1.5 years

5 compounds250 compounds

1approved

drug

10,000compounds

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Lessons Learned from HIV/AIDS Lessons Learned from HIV/AIDS TreatmentTreatment

Lessons Learned from HIV/AIDS Lessons Learned from HIV/AIDS TreatmentTreatment

19811981

19831983

19871987

19951995

19971997

First AIDS First AIDS case reported case reported

in the USin the US

HIV virus HIV virus identifiedidentified

AZT AZT mono-therapy mono-therapy approved for approved for

useuse

Two-drug Two-drug therapy becomes therapy becomes

availableavailable

Three-drug Three-drug therapy: HAARTtherapy: HAART

Brazil offers free Brazil offers free universal access universal access

to treatment to treatment

26 FDA-approved 26 FDA-approved drugs and research drugs and research

continuescontinues

20022002

Global Fund Global Fund establishedestablished

20032003

Drug combinations/ Drug combinations/ reducing pill burdenreducing pill burden

““3 by 5” Initiative &3 by 5” Initiative &PEPFAR launchedPEPFAR launched

20062006