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CHM496: Federal Regulatory Affairs: From Discovery to Approval Student Project Choice 3. Pamela Rizos 16-Nov-2004. PR Pharma Restricted Confidential. L-001234567 PR-Virase for Treatment of Early Exposures to HIV and Post Inhalation of Anthrax General Development and Approval Strategy.

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CHM496: Federal Regulatory Affairs: From Discovery to Approval Student Project Choice 3

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    1. CHM496: Federal Regulatory Affairs: From Discovery to ApprovalStudent Project Choice 3 Pamela Rizos 16-Nov-2004

    2. PR Pharma Restricted Confidential L-001234567 PR-Virasefor Treatment of Early Exposures to HIV and Post Inhalation of AnthraxGeneralDevelopment andApproval Strategy Pamela Rizos November 16, 2004

    3. PR Pharma Restricted Confidential Overview • Background / Commercial Value • Probability of Success • Regulatory Strategy: Areas of Serious, Unmet Medical Need • Showing Safety And Efficacy to Gain FDA Approval • Target Timeline • Budget and Resource Requirements • Conclusion and Recommendation

    4. PR Pharma Restricted Confidential Background / Commercial Value • HIV (Human Immunodeficiency Virus) • In the US, the estimated number of -adults and children living with HIV/AIDS, end of 2003:950,000 -deaths, 2003 : 14,000 -total deaths of persons with AIDS: 501,669 (496,354 adults and adolescents and 5,315 children under age 15) • Globally -the number of people living with HIV grew from 35 million in 2001 to 38 million in 2003. -In 2003 alone, 3 million were killed by AIDS • High Market Value for HIV

    5. Background / Commercial Value • Anthrax (Acute Infectious disease caused by Bacillus anthracis) • B. anthracis predominantly a cause of livestock disease • NIAID: 236 cases reported between 1955 and 1999 (~ 5 per year) • Anthrax is a top choice for use as a biological warfare agent • spores remain dangerous for decades • spores can be processed to become easily airborne • can be produced in large quantities with basic technology • Anthrax was used as a biological weapon in the US (AVIP) • Delivering anthrax was a simple as putting it in an envelope and dropping it in the mail • 7 confirmed and 4 possible cases of cutaneous anthrax, all survived • 11 people contracted inhalational anthrax, 5 died • Emergency Preparedness and Response: Strategic National Stockpile • 1999: DHHS & CDC established the National Pharmaceutical Stockpile, which will supply large quantities of medical material to states during an emergency within 12 hours of the federal decision to deploy • 2003:NPS became SNS managed jointly by DHS and HHS • Material stock is rotated and kept within potency shelf life limits • There is also a market for anthrax

    6. PR Pharma Restricted Confidential Probability of Success (Scientific Feasibility): • Promising Compound for both Anthrax and HIV • Low toxicity • Contains functional groups that are known to be highly anti-resistant to HIV isolates that show resistance to currently approved drugs • Based on the structure of the anthrax toxin, the candidate has high potential for the desired interference with active sites • Emerging Data that Earlier Treatment of HIV infection Is More Beneficial • Past: Believed that ART should start at >200 CD4+ cells/uL • Drug Toxicities were of special concern because long-term clinical consequences were unknown • Fear of Exhaustion of therapeutic options if start too early • Today: Emerging data that ART should start at >350 CD4+ cells/uL • Risk of new opportunistic infection or death is lower when start ART earlier • There are newer and safer drugs that are less toxic • Difficult to exhaust therapeutic options as there are a lot more approved drugs • Reduction of sexual transmission

    7. PR Pharma Restricted Confidential Regulatory Strategy • PRIORITY: Primary Indication: HIV, Secondary Indication: Anthrax • Fast Track Drug Development for Both indications • Designation based on: serious and unmet medical need • Serious: HIV and anthrax both serious , drug intended to affect serious aspects of each (HIV- prevention of opportunistic infection or death, Anthrax-Survival) • Unmet: Other drugs are available for both indications, L-001234567 has possible improved benefits (lower toxicity, higher viral anti-resistance) Will demonstrate drug’s potential through pharmacologic and animal model data • 1-Accelerated approval: Approval based on surrogate endpoints • HIV: HIV-1 RNA and CD4+ levels • Anthrax: Bacterial levels in the rhesus monkey • 2-Priority review: Products regulated by CDER are eligible if they provide a significant improvement compared to marketed products in the treatment of disease • L-001234567, PR-Virase is less toxic and highly anti-resistant to HIV-1 mutants • 3-Rolling Submission: Portions of the marketing application are accepted for review prior to the complete application • Meetings with the FDA: Earlier and More Frequent (pre-IND, EOP1, EOP2, pre-NDA, Labeling)

    8. PR Pharma Restricted Confidential Showing Safety and Efficacy for HIV • Pre-Clinical: • In-Vitro Activity and Resistance Studies • Animal Studies • Single and repeat dose toxicity studies in rats, mice, dogs • Pre-carcinogenicity and reproductive toxicity studies • Phase I : Healthy Subjects: Safety and Pharmacokinetic Studies • Single Dose and Multiple Dose • Phase II: Dose- Finding/ Efficacy Studies: (In Order to Accelerate: Limited Ph II program- 3 studies) • Two Studies in Therapy- Naïve patients:~250-500 subjects of > 350 CD4+ cells/ uL will be randomized to receive either PR-virase 200 mg, 400 mg, 600mg once daily and/or another currently approved drug. This study will also provide initial data on drug-drug interaction and evaluate monotherapy and combination therapy. • A smaller Ph II study may be conducted in treatment-experienced subjects. • These studies will support dose selection for Ph III • A rollover study may be conducted to collect long term safety data

    9. PR Pharma Restricted Confidential Showing Safety and Efficacy for HIV • Phase III: • Several (3-5) Ph III studies will be conducted and will consist of 100-1,000 patients (Two of the studies will be relatively small: 100-300). • Data will be collected for 24-48 weeks (24 week FDA guidance) and safety and Efficacy Will be Based On Surrogate markers • These studies will be randomized, multinationalized, open-label or double blind, active controlled. • Several drug-drug interaction studies • Phase IV (Post marketing): TBD

    10. PR Pharma Restricted Confidential Showing Safety and Efficacy for Anthrax • Pre-clinical Toxicology data required (animal toxicity in at least two species) • These studies will be already completed (for the HIV indication) • In Vitro Microbiology data • Several strains and multiple isolates will be tested • Testing will be done in 2-3 labs  reproducibility • Cipro, doxycycline and penicillin-G will be used as control drugs • Clinical studies of inhalational anthrax cannot be performed in humans as one cannot ethically intentionally expose patients to B. anthracis: The rhesus monkey model: Applicable to the human disease • The study of the human disease that resulted from the 1979 outbreak in Sverdlovsk has provided an understanding of anthrax that demonstrates that the rhesus monkey model is a relevant animal model of this disease. • End Points include survival, bacterial levels at different time intervals and microbial burden in infected organs and tissues collected at the time of necropsy. • ~50-70 moneys in 5-7 groups • After exposure, animals observed for ~3 months • FDA: Priority given to those products already approved and have had extensive use

    11. PR Pharma Restricted Confidential Target Timeline

    12. PR Pharma Restricted Confidential Estimated Budget and Resource Requirements

    13. PR Pharma Restricted Confidential Conclusions and Recommendations • Program should be pushed forward through the developmental and regulatory fast track for both indications with higher priority (in terms of efforts and resources) given to the HIV indication • If data does not look promising for the HIV indication, the anthrax indication should still be pursued • Orphan Drug Status • Tax incentives • 7 year exclusivity • Meanwhile: R&D investigation of other possible indications

    14. References • Application Number 19-537/ S038 (CIPRO) : approval letter, medical review • Application Number 2-567 (REYATAZ) : approval letter ,medical review, microbiology review, administrative documents, approved labeling • Buckheit, R, Specialized Anti-HIV Testing: Expediting Pre-Clinical Drug Development, Drug Information Journal, 1997:31:13 • Chuang-Stein, C, DeMasi R, Surrogate Endpoints in Aids Drug Development: Current Status. Drug Information Journal, 1998:32:439 • Cocchetto, D, The Evolving Paradigm for Clinical Development and Regulatory Approval of the Antiretroviral Drugs In the United States. Drug Information Journal, 1999:33:357 • Code of Federal Regulations: 21CFR312, 314 • FDA Guidance for Industry: Inhalational Anthrax (Post- Exposure)- Developing Antimicrobial Drugs • FDA Guidance for Industry: Fast Track Drug Development Programs- Designation, Development, and Application Review • Hammer S, Use of Surrogate Versus Clinical Markers in Trials for HIV Infection. Drug Information Journal, 1999: 33:374 • Holmberg, S, Pallela, F, Lichtenstein, K, Havlir, D, The Case for Earlier Treatment of HIV Infection. Clinical Infectious Diseases, 2004:39:1699 • Meadows, Michelle. The FDA and the Fight Against terrorism. FDA Consumer magazine, 2004: Jan-Feb. • Meyerfoff, A, Albrecht R, Meyer J, Dionne, P, Higgins, K, Murphy D, US Food and Drug Administration Approval of Ciprofloxacin Hydrochloride for Management of Postexposure Inhalational Anthrax. Clinical infectious Diseases, 2004:39:303 • Milne, CP, Bergman, E, Fast Track Product Designation Under the Food and Drug Administration Modernization Act: The Industry Experience. Drug Information Journal, 2001: 35:71 • National Institute of Allergy and Infectious Disease Factsheet on Anthrax ( • Physician’s Desk Reference • UNAIDS/WHO Epidemiological Fact Sheet Update : United States of America, 2004 • • • •

    15. Thank you for your attention! ?Questions?