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The TB Drugs Pipeline: From Drugs to Regimens (CPTR and NC-001) Dr. Ann Ginsberg

The TB Drugs Pipeline: From Drugs to Regimens (CPTR and NC-001) Dr. Ann Ginsberg Chief Medical Officer, TB Alliance November 12, 2010 Berlin, Germany. The Threat of TB.

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The TB Drugs Pipeline: From Drugs to Regimens (CPTR and NC-001) Dr. Ann Ginsberg

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  1. The TB Drugs Pipeline: From Drugs to Regimens (CPTR and NC-001) Dr. Ann Ginsberg Chief Medical Officer, TB Alliance November 12, 2010 Berlin, Germany

  2. The Threat of TB • TB remains one of the world’s deadliest infectious diseases – second only to HIV/AIDS – killing one person every 20 seconds • Each year, TB kills more than 1.8 million people, and there are 9.4 million new cases, primarily in developing countries • TB’s complex and deadly interaction with HIV/AIDS has even further exacerbated the global TB epidemic • There is an urgent unmet need for better treatments.

  3. Current TB Therapy and Unmet Needs • All treatments for active TB must be multidrug regimens • Significant improvements in therapy are needed for all patient populations

  4. 1960 Standard Therapy 2 months: R, H, Z, E + 4 months: R, H Rx shortened to 6 months TB Treatment Evolution 1950 1970 1980 2005 1946 Strepto-mycin 1st used for TB • 1952 • 1st regimen: • Streptomycin • PAS • Isoniazid 1974 BMRC Trials add R & Z 1998 Rifapentine approved 1963Rifampin (R) discovered 1970 BMRC Trials add R 1961Ethambutol (E) discovered 1954 Pyrazinamide (Z) discovered – but liver toxicity Standard Regimen by 1960s based on 1952 drugs Rx shortened to 9 months Rx lasts from 12-24 months

  5. Product Development Partnerships (PDPs) • Non-profit enterprises to accelerate the R&D and adoption of new, affordable global health products • Create and manage partnerships and resources across public, private and philanthropic sectors • Utilize a portfolio management approach to maximize efficiency and prioritize resources to the most promising candidates • Act as a catalyst to advance the field of new “tools” for all participants  PDPs are a proven model to fill critical scientific gaps and accelerate the development and delivery of new health technologies

  6. TB Alliance Founded in 2000 Not-for-profit Product Development Partnership (PDP) headquartered in New York, with offices in Brussels and Pretoria Entrepreneurial, virtual drug development approach Largest portfolio of TB drug candidates in history GOVERNMENTS PHARMA BIOTECH TB Alliance ACADEMIA INSTITUTES FOUNDATIONS

  7. TB Alliance Mission Develop new, better treatments for TB that are: faster-acting and less complex compatible with anti-retrovirals for HIV/AIDS coinfection active against drug sensitive and drug resistant strains Ensure that new regimens are affordable, adopted for use, and made widely available Coordinate and act as catalyst for global TB drug development activities

  8. Commitment to “AAA” Affordable • Regimens must be sufficiently low cost to be procured in developing countries • Ensured through negotiation of agreements, cost-of-goods considerations in development process Adoptable • Public programs and private sector must accept and implement new regimens • Ensured through acceptability studies, engagement with local communities, and direct negotiations with country programs, WHO, and other stakeholders to bring about guideline change Available • New regimens must be made available to patients in countries that adopt them • Ensured by developing a robust manufacturing and distribution plan with pharmaceutical partners, generics, countries, donors, and other actors

  9. FDCs TB Alliance Vision 10 days 2 – 4 months Success will require novel multi-drug combinations 6 – >24 months

  10. TB Alliance Portfolio Discovery Clinical Development Preclinical Development Lead identification Lead Optimization RNA Polymerase Inhibitors AZ/Rutgers MalateSynthase Inhibitors GSK/TAMU Phenotypic Hit to Lead Program U. Ill Chicago Protease Inhibitors IDRI Energy Metabolism Inhibitors AZ/U. Penn Folate Biosynthesis Inhibitors AZ Menaquinone Biosynthesis Inhibitors CSU Target Or Cell-Based Screening Clinical Phase I Clinical Phase II Clinical Phase III NitroimidazolesU. of Auckland/ U. Ill Chicago Natural Products IMCAS Whole-Cell Hit to Lead Program GSK MycobacterialGyrase Inhibitors GSK PA-824 Novartis Moxifloxacin (+ H, R, Z) Bayer InhA Inhibitors GSK Preclinical TB Regimen Development JHU/U. Ill Chicago TMC207 Tibotec Moxifloxacin (+ R, Z, E) Bayer Diarylquinolines Tibotec/U. of Auckland TB Drug Discovery Portfolio NITD PA-824/Pyrazinamide Topoisomerase I Inhibitors AZ/NYMC TMC207/Pyrazinamide Riminophenazines IMM/BTTTRI PA-824/Moxifloxacin/Pyrazinamide Pyrazinamide Analogs Yonsei Gyrase B Inhibitors AZ Whole-Cell Hit to Lead Program AZ Novel TB regimen development November 2010

  11. TB Alliance – 3 Clinical Stage Compounds • Moxifloxacin • Phase of Development: 3 • Partner: Bayer • Potential use against DS- and MDR-TB; currently being tested in DS-TB • PA-824 • Phase of Development: 2 • Partner: In-licensed from Chiron, which was subsequently acquired by Novartis • New mechanism of action • Potential use against DS-, MDR- and XDR-TB • TMC-207 • Phase of Development: 2 • Partner Tibotec/Johnson & Johnson • New mechanism of action • Potential use against DS-, MDR- and XDR-TB, currently being tested in both DS and MDR patients

  12. Historic Opportunity For the first time in history, the opportunity exists to develop truly novel regimens, containing multiple new chemical entities with novel mechanisms of action TB treatment of 2-4 months

  13. Paradigm Change in TB Drug Development • Current TB drug development approach replaces one drug at a time, requiring decades to introduce a new regimen that consists of multiple novel agents • New paradigm needed for rational selection and development of new combinations

  14. New Development Paradigm: Combination testing of novel regimens • Under the new paradigm, the regimen, not an individual drug, is the unit of development • New drugs are tested in combinations in clinical trials simultaneously, rather than successively Combination approach reduces time to market to as little as 1/4th

  15. How We Are Shifting the Paradigm …From Drugs to Regimens: CPTR and NC-001

  16. Launch of Critical Path to TB Drug Regimens (CPTR)- BMGF, Critical Path Institute and TB Alliance US FDA Commissioner, Dr. Margaret Hamburg 18 March 2010 Please visit: CPTRinitiative.org for more information

  17. Critical Path to TB Drug Regimens (CPTR) • Accelerates the development of new regimens by testing promising new drugs together, rather than by sequential testing of individual drugs • Overcomes intellectual property barriers to private sector collaboration • Commitment to access puts patients before profits • Collaboration maximizes synergy, reduces cost, increases efficiency • Engages regulatory authorities to develop new pathways and guidances for combination testing and approval • Endorsed by donors, governments, multilaterals, corporations, civil society, and non-profits • A model for other therapeutic areas that require combinations, such as cancer and hepatitis

  18. The New Opportunity: trial NC-001 For the first time, there is an opportunity to treat both drug-sensitive (DS-TB) and multidrug-resistant TB (MDR-TB) with the same regimen, and alter the course of the TB pandemic by shortening and simplifying treatment worldwide 3-drug regimen in NC-001 = Moxifloxacin(TB Alliance, Bayer) + PA-824(TB Alliance) + Pyrazinamide(existing antibiotic)

  19. Significance of NC-001 Trial Potential to: • treat DS-TB and MDR-TB with the same regimen: would simplify treatment and delivery • shorten treatment for drug-sensitive and MDR-TB to less than 6 months • simplify treatment for people with TB/HIV (should not have significant interactions with antiretrovirals – no rifampicin) • enable scale-up of MDR-TB treatment - shorter, simpler (no injectables), more affordable treatment for MDR-TB • Sets stage for new era in TB drug development: new drugs tested in combination, enabling delivery of new treatments in years vs. decades

  20. Current TB Therapy and Unmet Needs This trial addresses at least three major unmet needs in TB therapy • Significant improvements in therapy are needed for all patient populations

  21. Thank You

  22. The Drug Development Process Phase II DISCOVERY: Identify lead structural series; optimize activity in vitro, efficacy in animals, and other pharmacological properties. Perform preclinical safety studies allowing filing of a new drug application. Use combination testing to identify the best potential new regimens for clinical development. PHASE I: Test drug candidates and regimens in small numbers of healthy volunteers for safety, tolerability, and pharmacokinetic properties. PHASE II: Evaluate single drug candidates (Phase IIa) and multidrug regimens (Phase IIb) in TB patients for potential efficacy and further assessment of safety. PHASE III: Test multidrug regimens in large numbers of TB patients for efficacy and safety. REGULATORY APPROVAL: Regulatory authorities license the drug/regimen after reviewing all preclinical and clinical results (also called registration) ADOPTION/ AVAILABILITY: National TB control programs adopt the new drug/regimen.

  23. Need for a Stronger Global TB Drug Pipeline Discovery Preclinical Clinical ONE approved drug 50 31 19 12 7 4 2 Number of Projects • Global TB Drug Pipeline • (10) (7) (7) (2) (6) (2) 5 Years 1.5 Years 6 Years (Data based on: Brown, D.; Superti-Furga, G. Drug Discovery Today 2003, 8, 1067-1077)

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