Antiretroviral Drug Development: Progress and Challenges

Charles Knirsch, MD, MPHVP, New York Site Head,

Clinical Research and DevelopmentPfizer, 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 HIVAntiviral Agents for HIV

RNA

Reversetranscriptase

ProteaseDNA

Nucleus

Protease inhibitorsReverse transcriptase

inhibitors

EntryInhibitors

ART approvals: 1987 through 2005Year NRTI NNRTI PI EI

1987 zidovudine

1991-2 didanosine

zalcitabine

1995 stavudine

1996 lamivudine saquinavir

1997 abacavir nevaripine

(delavirdine)

ritonavir

indinavir

nelfinavir

1998 tenofovir efavirenz

1999 emtricitabine amprenavir

2000 lopinavir

2001

2003 atazanavir

fosamprenavir

enfuvirtide

2005 tipranavir

Easier Regimens, Longer Lives

ARV Development

• AZT 1987

• ddI 1993

• Protease Inhibitor 12/95

•HAART era begins 1996

•Good drugs made easier 1998- present

FINDING THE RIGHT TREATMENT

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.

CasesDeaths

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

ADULT AIDS IN THE US End of year figures

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

CHANGING REGIMENS

HIV Drug Development 1981-1999

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

NRTI Mitochondrial DNA toxicity

NtRTI Proximal renal tubular dysfunction

NNRTI Hypersensitivity, Rash

PI Metabolic disorders

Class-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

Drug-Specific 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.

Implications of Toxicities

Clinical DevelopmentClinical DevelopmentDrug Drug Discovery/PreclinicalDiscovery/Preclinical

Post Marketing Post Marketing PharmacovigilancePharmacovigilance

Product Life Cycle

FIM Ph I Ph II Ph III Ph IV

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

Risk Management Is Core

Activity Across Product Lifecycle

Approval

CapabilitiesProvided

DRUG RESISTANCE*

Results: 1995-98n=264

1999-2000n=113

Any drugNRTINNRTIPIs

3.4%2.3%1.9%0.4%

12.4%6.2%7.1%8.0%

*Little S. NEJM 2002;347:385

Method: multicenter, 10 cities, U.S. Acute HIV, 1995-2000

New Agents to Treat HIV Infection

Phase

Reverse Transcriptase

Inhibitors

Protease

Inhibitors

Entry

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

Pre-clinical

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?

‘..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….’

Drug development costs in relation to therapeutic areas

Nature Reviews Drug Discovery 3; 466(2004); doi:10.1038/nrd1436Therapeutic 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

NIH Roadmap

FDA Critical Path

Pharmaceutical Innovation Steering Committee (PISC)

EFPIA Innovative Medicines Initiative

BasicBasicResearchResearch

BasicBasicResearchResearch BiologyBiologyBiologyBiology ChemistryChemistryChemistryChemistry

Ongoing efforts focused on improving R&D productivity/safety:

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

DevelopmentDevelopmentPre-Clinical/Pre-Clinical/

ClinicalClinical

DevelopmentDevelopmentPre-Clinical/Pre-Clinical/

ClinicalClinical

Post Post MarketingMarketing

StudiesStudies

Post Post MarketingMarketing

StudiesStudies

Industry Support of Healthcare System

Industry can play a role in strengthening healthcare systems in LDC’s…

• 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 ART’s in LDC’s

• Infectious Diseases Institute

23

Programs Spanning R&D to AccessPrograms Spanning R&D to Access

HIV/AIDS

Malaria

“Truly” Neglected Diseases

Anti-Infectives

Anti-Fungals

Research and Development Research and Development Research and Development

Infectious Diseases Inst.

Global Health Fellows

Southern HIV/AIDS Prevention Initiative

Border Health Initiative

Sustainable Solutions: Capacity-Building

Sustainable Solutions: Sustainable Solutions: CapacityCapacity--BuildingBuilding

Diflucan Partnership Program

Int’l Trachoma Initiative

Patient Assistance Programs

Immediate Need: Medicine DeliveryImmediate Need: Medicine DeliveryImmediate Need: Medicine Delivery

Millennium Development Goals

Tsunami Relief/Katrina

Special InitiativesSpecial InitiativesSpecial Initiatives

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: REGISTRATIONBroad, Efficient Registration Expected by Stakeholders

where registra-tion pending

# not registered & lowest pricing tier

Registered Not registeredPending reg.

29 41

- 9

39

-

1422 2

Viramune - BI Kaletra - AbbottCombivir - GSKARV-originator

# African countries(1)

whereregistered

•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