Transcript Document

Microbicide Products
in the Pipeline
Regional Meeting on Regulatory Issues in
Microbicide Research
Dr. Zeda F. Rosenberg
International Partnership for Microbicides
29 October 2007
New Delhi, India
Microbicides in Product Development
Lactin-V
Invisible Condom
Free virus
BufferGel
Attachment
Locus small molecules
S-DABO
Dapivirine (TMC120)
UC781
Tenofovir (PMPA)
PC815 (MIV150 + Carraguard)
Fusion
Carraguard
PRO2000
SPL7013 (VivaGel)
Monoclonal antibodies
DS003 (BMS)
DS001 (Merck)
DS006 (Maraviroc)
Pyrimidinediones (Samjin)
Replication
(RT)
Integration
Protein synthesis
and assembly
Budding
Maturation
Microbicide Options
 Multiple delivery types:
– gel
– intravaginal ring
– film
– tablet
– sponge
Vaginal applicator
Vaginal ring
 Ideally long acting, safe, effective, low
cost and user-friendly
 Potential for combinations of drugs to
increase effectiveness
Rationale for Vaginal Dosing
 Local drug levels can be high and systemic
exposure low
 Maximum drug:virus level
 Lower chance for systemic related side effects
 Precedent in contraception
 No one prevention option will satisfy all;
multiple approaches available to address
acceptability preferences
 Women-initiated
Early-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 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
(ARV) Microbicides
 Advantages
 Highly potent and HIV-specific
 Documented safety and efficacy as
therapeutics
 Can be formulated for sustained
protection
• Once a day or less frequent
• Gels, intravaginal rings, others
 Disadvantages
 Potential for resistance
 Lack of activity against other STDs
Topical 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.)
 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): 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
HC
CH
CN
 IP clarity
N
 Multiple dosage forms
N
N
N
3
3
CH3
H
H
Dapivirine gel/ring: Clinical studies
Study
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 Background
Carboxanilide type of NNRTI
H
N
O
CH3 S
O
Cl
Potent anti-HIV-1 activity (nM range)
Tight binding to HIV-1 RT
Active against cell-free and cell-associated virus
Little to no cytotoxicity (>M)
Active against RT inhibitor resistant strains
Reduced likelihood for resistance selection
Exhibits so-called “Memory Effect”
Phase I safety study in 48 women completed
UC-781 Ongoing Studies
SAFETY
STUDIES
CDC/Emory
ENROLLMENT
GEL TYPE
DURATION
ENDPOINTS
Twice-daily for
14 days
Systemic/local toxicity,
absorption, flora, acceptability
36 sexually
active women
18 abstinent
HIV positive
women
0.1, 0.25,
placebo
University of
Pittsburgh/NIH
60 abstinent
women
0.1% or
placebo at 0,
2, 4, and 8
hrs duration
Single dose
Safety, persistence of UC781, 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
0.25 (12♀)
UP (6♀)
MIV-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 Entry
HIV
HIV
gp120
Coreceptor
Binding
gp120 CD4
Binding
HIV
gp41
gp120
CD4
CCR5
CXCR4
CD4
gp120
gp41
CCR5
CXCR4
gp120
Gp41 Mediated
Fusion
Host Cell
gp41
HIV-Specific Entry/Fusion Inhibitors
 Act on virus: gp120 or gp41 blockers
 DS003 (BMS793), cyanovirin, FI peptides
 Disadvantages
- current gp41 blockers are peptides
 Act on target cell: CCR5 blockers
 DS001 (M167), Maraviroc, PSC-Rantes
 Disadvantages
- lack of activity against X4 virus
Next-Generation Product Development
Tenofovir Gel
Dapivirine Gel & Ring
UC781 Gel
MIV150 + Carraguard Gel
Monoclonal antibodies
DS001 (M167)
DS001 (M167) + Dapivirine
Dapivirine Tablet & Film
S-DABO
Pyrimidinediones
DS003 (BMS793)
Maraviroc
Early Preclinical
1-2 years
Preclinical
1-2 years
Phase I/II
2+ years
Phase III
3 years
Filing Approval
1 year
Future 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 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:
Pre-Clinical
 Compounds assessed to identify best candidates for clinic
MECHANISMS
OF ACTION
LABORATORY
STUDIES
 Earlier in life cycle is better
 Toxicity / Potency
 New mechanism of action
 Pre-formulation
 Comparison with other
 Stability
candidates with same
mechanism of action
BUSINESS CASE
IP access to compound
 Cost
 Drug synthesis process
 Ease of manufacture
Criteria for Moving Forward:
Early Clinical Trials
 Candidates assessed in small numbers of volunteers
PHARMACOKINETICS
ACCEPTABILITY
SAFETY
 Where drug goes in body,
 Placebo formulations
 Drug, formulation, delivery
concentration, duration
assessed in diverse
populations
assessed for prolonged use
 Preferred dosage:
 Wide distribution
in genital tract
 Long duration
 Sufficient concentration
 Product safety evaluated in
 Acceptability measured in
diverse populations
all clinical trials
 Early clinical trials cannot
fully predict risk of enhancing
HIV transmission
Criteria for Moving Forward:
Efficacy Trials
 Top candidates move into efficacy trials
BEST-IN-CLASS
Essential criteria:
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


Potency
Safety
PK
Acceptable formulation
Secondary criteria:
 Mechanism of action
 Cost
 Ease of manufacture
 Access / IP
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
and Review Process
250 compounds
10,000
compounds
6.5 years
Stage 3
Clinical trials
Phase I
Phase II
5 compounds
7 years
Phase III
Marketing application submitted
Stage 2
Pre-clinical
First clinical trial application submitted
Stage 1
Drug discovery
Stage 4
Regulatory
review
1
approved
drug
1.5 years
Adapted from: Pharmaceutical Research and Manufacturers of America, 2006
Lessons Learned from HIV/AIDS
Treatment
1981
1997
1987
1983
First AIDS
case reported
in the US
1995
AZT
mono-therapy
approved for
use
HIV virus
identified
2003
2002
Three-drug
therapy: HAART
Brazil offers free
universal access
to treatment
Two-drug therapy
becomes
available
2006
Drug combinations/
reducing pill burden
“3 by 5” Initiative &
PEPFAR launched
Global Fund
established
26 FDA-approved
drugs and research
continues