Download Antiretroviral Drug Development: progress and

Antiretroviral Drug Development:
Progress and Challenges
Charles Knirsch, MD, MPH
VP, New York Site Head,
Clinical Research and Development
Pfizer, Inc
R&D Perspective on ART’s
• Progress and Future ART Research and
Development
• Developing World Considerations
– Access and Distribution
– Regulatory
– Pediatrics
• Planning
Antiviral Agents for HIV
Entry
Inhibitors
RNA
Nucleus
Protease
Reverse
transcriptase
Reverse transcriptase
inhibitors
DNA
Protease inhibitors
ART approvals: 1987 through 2005
Year
NRTI
1987
zidovudine
1991-2
didanosine
zalcitabine
1995
stavudine
1996
lamivudine
1997
abacavir
nevaripine
(delavirdine)
1998
tenofovir
efavirenz
1999
emtricitabine
2000
NNRTI
PI
EI
saquinavir
ritonavir
indinavir
nelfinavir
amprenavir
lopinavir
2001
2003
atazanavir
fosamprenavir
2005
tipranavir
enfuvirtide
ARV Development
• AZT 1987
Easier Regimens, Longer Lives
• ddI 1993
Deaths
Cases
• Protease Inhibitor 12/95
•HAART era begins 1996
•Good drugs made easier 1998- present
ADULT AIDS IN THE US
End of year figures
Early Steps
1987-mid-90’s
The first of anti-H.I.V. drugs was AZT.
It and drugs like it were found to have
some impact on the virus but were
often defeated as the virus developed
resistance through mutations.
FINDING THE RIGHT
TREATMENT
The ‘Cocktail’
1996-present
Dr. David Ho introduced protease
inhibitors, which block a protein
necessary for HIV to reproduce. Used
in combination with drugs like AZT,
they proved more effective but required
a complex and often unsustainable
drug regimen.
1998-present: Good.
Drugs Made Easier
CHANGING REGIMENS
HIV Drug Development 1981-1999
Sources: Centers for Disease Control and Prevention: Gay Men’s Health Crisis
adapted from New York Times, June 25, 2000
Jim McManus for the NY Times
Survival in Africa with ART
• HIV+ cohort followed since 1995
• ART available since 2003
• ART impact on mortality and causes of death assessed
1995-2000
2003-2006
Pt-years of follow-up
658
1819
Median CD4 cells at enrollment
75
93
Deaths (%)
74%
6%
Mortality/1000 pt-yrs
577
34
Survival Probability after 1 year
55%
95%
Survival Probability after 2 years
28%
94%
Munden P, et al. XVI IAC Toronto, Canada Aug 13-18, 2006 Abst THLB0208
Class-Specific Toxicities
NRTI
Mitochondrial DNA toxicity
NtRTI
Proximal renal tubular dysfunction
NNRTI
Hypersensitivity, Rash
PI
Metabolic disorders
Drug-Specific Toxicities
ABC
Hypersensitivity reaction (3-6%)
APV
Rash, GI Intolerance
ATZ
Hyperbilirubinemia, 1st degree AVB
AZT
Anemia, leukopenia, pigmentation, GI intolerance
ddC
Oral ulceration
ddl
GI intolerance (formulation), pancreatitis, neuropathy
d4T
neuropathy, pancreatitis, lipoatrophy, lactic acidosis
EFV
CNS toxicity (first 3 weeks), avoid pregnancy, rash
IDV
Renal stones, hyperbilirubinemia
NVF
Diarrhea
NVP
Hepatotoxicity, Stevens-Johnson syndrome
RTV
GI intolerance, perioral paresthesias
Implications of Toxicities
• Poor adherence/compliance
• Loss of antiretroviral control of resistance
• Long-term morbidity
–
–
–
–
AZT myopathy
NRTI peripheral neuropathy
IDV renal stones and renal dysfunction
PI metabolic disorders and IHD
• Mortality (low but reported)
–
–
–
–
Thymidine analog NRTIs hepatic steatosis/lactic acidosis
ddI pancreatitis
ABC hypersensitivity
NNRTI Stevens-Johnson syndrome
• Long-term trade-off between toxicity and efficacy
unclear.
Risk Management Is Core
Activity Across Product Lifecycle
FIM
Ph I
Ph II
Ph III
Ph IV
Product
Life Cycle
Approval
Drug
Discovery/Preclinical
Capabilities
Provided
 Estimate potential
benefit
 Predict potential
candidates
 Disease Mechanism
of Action Studies
Clinical Development
 Studies to better
understand population,
risks, etc
 Promote better
approval analysis
 Achieve appropriate
label
Post Marketing
Pharmacovigilance
 Execution of defined
risk management plan
 Address any
new emerging
safety issues
 Epidemiological studies
 Signal detection using
correct scientific
standards
DRUG RESISTANCE*
Method: multicenter, 10 cities, U.S.
Acute HIV, 1995-2000
Results:
1995-98
1999-2000
n=264
n=113
Any drug
3.4%
12.4%
NRTI
2.3%
6.2%
NNRTI
1.9%
7.1%
PIs
0.4%
8.0%
*Little S. NEJM 2002;347:385
New Agents to Treat HIV Infection
Protease
Inhibitors
Entry
Inhibitors
Phase
Reverse
Transcriptase
Inhibitors
Integrase/
Maturation
Inhibitors;
Immunologics
2/3
Etravirine (TMC 125)
Darunavir
Maraviroc
Vicriviroc
MK-0518
2
BILR 355 BS
TNX-355
GS-9137
1/2
Amdoxovir
Apricitabine
Rilpivirine (TMC 278)
Brecanavir
AMD 070
PRO 542
Bevirimat
CTLA4-mAb
1
Fosalvudine
PPL-100
PRO 140
TAK 652
Preclinical
22
7
21
11
Combination Therapies
• Goal: improve compliance by combining drugs into
single pill
• Examples
– 3 drugs:
• tenofovir + emtricitabine (FTC) + efavirenz [ = Atripla]
• AZT + 3TC + abacavir [ = Trizivir]
• AZT + 3TC + tenofovir
– 2 drugs:
• AZT + 3TC [ = Combivir]
• tenofovir + emtricitibine [ = Truvada]
• abacavir + lamivudine [ = Epzicom]
• Next Combinations?
Drug development
costs in relation to
therapeutic areas
‘..The most striking change
was in the cost of antiinfectives, which has risen
from 25% below average to
6% above average [between
1970-82 and 1997]. "This
increase in costs has been
driven largely, but not
exclusively, by HIV
treatments, which weren't
being developed in the
previous analysis," says
DiMasi….’
Nature Reviews Drug Discovery 3; 466(2004); doi:10.1038/nrd1436
Therapeutic area influences drug development costs
Innovation Across Research and
Development
• Efficient lead identification
•
•
•
•
•
•
•
Novel biological targets
Formulation innovation
Clinical science innovation
Clinical trial design innovation
Risk management
Power of collaboration
Emerging opportunities
Collaborations Between Regulator,
Industry & Public Sector
Basic
Research
Biology
Chemistry
Development
Pre-Clinical/
Clinical
Post
Marketing
Studies
Ongoing efforts focused on improving R&D productivity/safety:
NIH Roadmap
FDA Critical Path
Pharmaceutical Innovation Steering Committee (PISC)
EFPIA Innovative Medicines Initiative
 Biomarkers Consortium
 Novel adaptive trial design
 Accelerating proof of concept
 Enriched patient population
trial designs
 Rolling dose studies
 Exploratory IND
 Improving efficiency of late-stage
clinical research
 SAE data-mining validation
 Best regulatory practices and
sponsor/regulator communication
 Predictive models for safety
and efficacy
Industry Support of Healthcare System
Industry can play a role in
strengthening healthcare
systems in LDC’s…
• Research Infrastructure
Partnerships
• Technical Collaborations
• Support of pharmacovigilence
in the regions
• Registration and ‘effectiveness’
studies to further define value
of therapies in the region (HIV
clade variations)
• Infrastructure required for
diagnostic testing
• Optimization of healthcare
support for ART’s in LDC’s
• Potential for industry support of
wrap around services as
members of Public-Private
Partnerships
• Infectious Diseases Institute
Access: Distribution and Scale Up
• Forecasting of demand
– Matching availability of drug with healthcare
infrastructure to manage the supply
– Estimating the regulatory timelines
• Identification of manufacturing facilities
– Sometimes within the region
– Considerations: workforce; government policies towards
private investment; logistical practicalities
• Distribution mechanisms within the region
Access: REGISTRATION
Broad, Efficient Registration Expected by Stakeholders
ARV-originator
Viramune - BI
Combivir - GSK
Kaletra - Abbott
29
39
41
-
-
9
22
14
2
# African
countries(1)
where
registered
where registration pending
# not registered &
lowest pricing tier
Registered
Pending reg.
Not registered
•What is the best registration strategy for developing countries?
•For novel mechanisms, is Africa ready to accept a emerging
risk/benefit profile?
•Side effects to monitor? Opportunistic infection exposure?
•Are all drugs of equal value in LDC’s? How does one prioritize
registration efforts to match needs of the country?
Summary
• Current ART’s effective but further innovation of
dose, safety and efficacy desirable
• Drug development costs in HIV rising
• Developing world concentration of epidemic
presents unique challenges
–
–
–
–
Clinical Trial Conduct
Regulatory
Distribution and Access
Pharmacovigilance
• Learning from PPP’s to address challenges