Antiretroviral Drug Development: Progress and Challenges

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Antiretroviral Drug Development Progress and
Challenges

• Charles Knirsch, MD, MPH
• VP, New York Site Head,
• Clinical Research and Development
• Pfizer, Inc

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RD Perspective on ARTs

• Progress and Future ART Research and Development
• Developing World Considerations
• Access and Distribution
• Regulatory
• Pediatrics
• Planning

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Antiviral Agents for HIV
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ART approvals 1987 through 2005
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• ARV Development
• AZT 1987
• ddI 1993
• Protease Inhibitor 12/95
• HAART era begins 1996
• Good drugs made easier 1998- present

Easier Regimens, Longer Lives
Cases
Deaths
ADULT AIDS IN THE US End of year
figures
Early Steps
1987-mid-90s
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.
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
FINDING THE RIGHT TREATMENT
CHANGING REGIMENS
HIV Drug Development 1981-1999
Sources Centers for Disease Control and
Prevention Gay Mens Health Crisis
adapted from New York Times, June 25, 2000
Jim McManus for the NY Times
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Survival in Africa with ART

• HIV cohort followed since 1995
• ART available since 2003
• ART impact on mortality and causes of death
  assessed

Munden P, et al. XVI IAC Toronto, Canada Aug
13-18, 2006 Abst THLB0208
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Class-Specific Toxicities

• NRTI Mitochondrial DNA toxicity
• NtRTI Proximal renal tubular dysfunction
• NNRTI Hypersensitivity, Rash
• PI Metabolic disorders

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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

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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.

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Risk Management Is Core Activity Across Product
Lifecycle
Ph IV
FIM
Ph I
Ph II
Ph III
Product Life Cycle
Approval
Clinical Development
Drug Discovery/Preclinical
Post Marketing Pharmacovigilance

• Estimate potentialbenefit
• Predict potentialcandidates
• Disease Mechanism of Action Studies

• Studies to better understand population, risks,
  etc
• Promote betterapproval analysis
• Achieve appropriate label

• Execution of defined risk management plan
• Address anynew emergingsafety issues
• Epidemiological studies
• Signal detection using correct scientific
  standards

CapabilitiesProvided
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DRUG RESISTANCE
Method multicenter, 10 cities, U.S. Acute
HIV, 1995-2000
Little S. NEJM 2002347385
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New Agents to Treat HIV Infection
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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?

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Drug development costs in relation to therapeutic
areas
..The most striking change was in the cost of
anti-infectives, 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)
doi10.1038/nrd1436Therapeutic area influences
drug development costs
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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

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Collaborations Between Regulator, Industry
Public Sector
BasicResearch
Biology
Chemistry
Development Pre-Clinical/Clinical
Post MarketingStudies
Ongoing efforts focused on improving RD
productivity/safety
NIH Roadmap FDA Critical Path Pharmaceutical
Innovation Steering Committee (PISC) EFPIA
Innovative Medicines Initiative

• Improving efficiency of late-stage clinical
  research
• SAE data-mining validation
• Best regulatory practices and sponsor/regulator
  communication
• Predictive models for safety and efficacy

• Biomarkers Consortium
• Novel adaptive trial design
• Accelerating proof of concept
• Enriched patient population trial designs
• Rolling dose studies
• Exploratory IND

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Industry Support of Healthcare System

• Industry can play a role in strengthening
  healthcare systems in LDCs
• Support of pharmacovigilence in the regions
• Registration and effectiveness studies to
  further define value of therapies in the region
  (HIV clade variations)
• Potential for industry support of wrap around
  services as members of Public-Private Partnerships

• Research Infrastructure Partnerships
• Technical Collaborations
• Infrastructure required for diagnostic testing
• Optimization of healthcare support for ARTs in
  LDCs
• Infectious Diseases Institute

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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

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Access REGISTRATIONBroad, Efficient
Registration Expected by Stakeholders

• 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 LDCs? How does
  one prioritize registration efforts to match
  needs of the country?

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Summary

• Current ARTs 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 PPPs to address challenges