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The HIV Prevention Pipeline: A Future of Possibilities

The HIV Prevention Pipeline: A Future of Possibilities . IRMA Webinar August 23, 2012. Jim A. Turpin, Ph. D. Branch Chief Preclinical Microbicide and Prevention Research Branch Prevention Science Program Division of AIDS, NIAID , NIH. DHHS/NIH Required Disclaimer.

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The HIV Prevention Pipeline: A Future of Possibilities

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  1. The HIV Prevention Pipeline:A Future of Possibilities IRMA Webinar August 23, 2012 Jim A. Turpin, Ph. D. Branch Chief Preclinical Microbicide and Prevention Research Branch Prevention Science Program Division of AIDS, NIAID, NIH

  2. DHHS/NIH Required Disclaimer The views expressed are those of the presenter and do not necessarily reflect the official policies of the Department of Health and Human Services (HHS), nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government If your particular candidate, delivery system or prevention strategy is not presented--I apologize in advance

  3. Today I Will Address the Question: Do we currently have what it takes to create a sustainable prevention pipeline? DAIDS/PSP/PMPRB

  4. To Answer the Question I Need to Change Your Perception of What the HIV Prevention Pipeline Is Pipeline Library of Compounds >100,000 to 1,000,000 Combinations 1000 Integrase CCR5 100 Truvada 10 Lead(s) TFV TMC120 Toxicology Pharmacology UC78 Preclinical Formulation Carraguard PRO2000 Manufacturing CS Phase I Savvy Phase II Clinical BG Phase III Phase IV Product N9 DAIDS/PSP/PMPRB

  5. Start by looking back! DAIDS/PSP/PMPRB

  6. Prevention Clinical Trials: The Good, the Bad, and the Ugly DAIDS/PSP/PMPRB

  7. HIV Prevention in the Summer of 2012 2012 June, 2010 July, 2011 Chinese Proverb/Curse: May You Live in Interesting Times! DAIDS/PSP/PMPRB

  8. Evolution Charles Darwin  “It is not the strongest of the species that survives, nor the most intelligent that survives. It is the one that is the most adaptable to change.” Charles Sanders Peirce (Father of Pragmatism) “All the evolution we know of proceeds from the vague to the definite.” The objective of the prevention pipeline must be to evolve a candidate to the safest, most effective and acceptable prevention strategy DAIDS/PSP/PMPRB

  9. Evolution of the Prevention Pipeline • For pipelines the forces of evolution are also controlled by the realities of the down-selection process inherent in identifying and advancing lead candidates: • Dollars versus doability--What can be accomplished with budgets and makes sense to undertake • Complex preclinical, clinical and regulatory requirements • Need for Sustainability—continually deliver new and improved prevention strategies DAIDS/PSP/PMPRB

  10. Dollars versus Doability: Opposing Forces 1 or 2 100 To 1,000,000 Number of Compounds I II III Preclinical Studies (Critical Path) Preclinical Virology Implementation Clinical Studies Discovery $.01 to $1.00 Cost of Development Per Compound $ millions DAIDS/PSP/PMPRB

  11. Complex Requirements R&D Supply Marketing Distribution In vitro Validation Virology Pharmacology Toxicology Clinical Testing Clinical Testing Phase IV Studies OTC Product Consumer In Vivo Validation Preclinical Studies SAFETY EFFICACY Pre formulation + formulation Implementation Chemistry, Manufacturing and Controls (CMC) Determined by the properties of the inhibitor and delivery system Federal, State and Local regulations may apply to specific activities State, Federal and Local Regulations Consumer preferences and needs • Code of Federal regulation (CFR) for GLP and GMP are primary determinates • FDA requirements • Virology • Toxicology • CMC Drug Developer Concerns • Meet a desired outcome • Potential for advancement • Cost of product • Ease of synthesis • Marketing outlook • Long term safety • Profit and loss • Next generation products DAIDS/PSP/PMPRB

  12. Sustainability Initial Pipeline Lead Expansion Targeted Expansion New Target Time Library of Compounds >100,000 to 1,000,000 Library of Compounds >100,000 to 1,000,000 Successful Failure Discovery Iterative Screen 1000 1000 100 100 New Limited Synthesis 10 10 Lead(s) Lead(s) Toxicology Toxicology 100 Lead(s) Pharmacology Preclinical Pharmacology 10 Formulation Toxicology 10 Formulation Pharmacology Lead(s) Manufacturing Lead(s) Manufacturing Formulation Toxicology Phase I Toxicology Phase I Pharmacology Manufacturing Phase II Clinical Pharmacology Phase II Formulation Phase III Phase I Phase III X Phase IV Manufacturing Phase II Phase IV Phase III Product Phase I Product Phase IV Phase II Phase III Product Phase IV Product DAIDS/PSP/PMPRB

  13. However, we must not get lost in the complexity of the task Drugs: ARV/Non-ARV Small Molecule Peptide Protein Natural Products Nucleic Acid Other Strategies Systemic Topical Dosage Form: Pills Injectable Implantable Sustain. Release Gels/films/tablet Dosing: Peri-Coital Daily Monthly Quarterly Longer? Courtesy of Joe Romano DAIDS/PSP/PMPRB

  14. Our Question: Do we currently have what it takes to create a sustainable prevention pipeline? • To answer we must examine 2 critical elements of the prevention pipeline: • Delivery systems • Candidates DAIDS/PSP/PMPRB

  15. We will look at: • Delivery systems • Currently in clinical trials • Next generation- in development • The future • Candidates • Now • To 2015 • 2015 to 2020 • Emerging Candidates DAIDS/PSP/PMPRB

  16. Delivery Systems Systems Currently in Clinical Trials (Phase I to III) Vaginal gels Tenofovir FACTS 001 Rectal Gels Tenofovir CHARM, MTN 013 Silicon Rings Oral Injectable Dapivirine Aspire Maraviroc + Dapivirine MTN 013/IPM 026 Truvada, Maraviroc, Maraviroc + FTC HPTN 069 TMC278 LA BMGF DAIDS/PSP/PMPRB

  17. Next of Generation Delivery Systems In Development Vaginal Films Pod Rings Injectables Segmented Rings Devices +/- Gels Other gels pH transition Subliming Solid matrix Rings with other polymers Quick Dissolve Tablets DAIDS/PSP/PMPRB

  18. Some Thoughts on Rings Polymer Options Where ? Types of Rings Reservoir Matrix Silicon Ethyl Vinyl Acetate (EVA) Polyurethanes • Barnhart et al. Contraception, 2005 72:196 DAIDS/PSP/PMPRB

  19. Further Thoughts on Rings Segmented • Advantages • Release chemically incompatible drugs • Control drug release • Segmented-size of segment • Pod-# of pods, size of pore Pod (Versaring™) Pore Pod Johnson, et al. Eur. J. Pharm. Sci. 2010 39:203 Baum et al. J. Pharm Sci 2012 101:2833 DAIDS/PSP/PMPRB

  20. Some Thoughts on Vaginal Films Water-soluble polymers designed to dissolve in the vagina and release its active ingredient • Films Under Development: • PMPA • Dapivirine • Maraviroc • IQP0528 • RC101 ADVANTAGES • Precise and Reproducible dosage form • Minimal leakage • No applicator • Scalable manufacturing process • (Listerine Pocket Paks >200,000 million units sold/yr.) • Low unit dose cost (fractions of a penny/dose) • Can be used to deliver multiple active agents Courtesy of Lisa Rohan DAIDS/PSP/PMPRB

  21. Thoughts on Injectables Very Exciting Development, But------- • Very Limited pipeline • TMC278LA: (Janssen/BMGF) • NNRTI • S-GSK1265744: (744 LA, Viiv) • Integrase inhibitor • Major strength of the injectible approach • Long half-life---weeks to months DAIDS/PSP/PMPRB

  22. Lots of Delivery Options, But Will Women and Men Use Them! Optimizing for delivery device acceptability/adherence • Formulation • Scientist • Rheological parameters • Compatibility with drug • Viscosity • Osmolarity • Shearing • Stickiness • Mixing /miscibility • Color • Spreading • Coating • Adhesion to surfaces • Behavioral • Scientist • Perceptions • Leakage • Wetness • Sexual pleasure • Sexual comfort • Removal & disposal • Long residence • Application Link Rheological with Women’s perception Identify specific formulation characteristics that yield specific women responses • Kate Morrow , Brown Univ. • David Katz, UNC • John Hayes, Penn. State. Univ. • Greg Ziegler, Penn. State Univ. Use Decisions Handling Intercourse DAIDS/PSP/PMPRB

  23. The Future! Nanotechnology DAIDS/PSP/PMPRB

  24. Nanotechnology for Prevention Increasing Delivery Options Drug in Nanoparticles Drug-containing Nanoparticles in: Drug • Vaginal Film or Drug in Nanoparticles • Vaginal Ring Normal Tissue Drug alone Vaginal Lumen Ham, et al. Pharm. Res. 2009 26:502 DAIDS/PSP/PMPRB Pictures courtesy of Lisa Rohan

  25. A Novel Approach for Delivery ElectrospunNanofibers • A new delivery platform • Multiple types of drugs • Combinations • Time release • Biodegradable • Potentially cost effective • MPT compatible Courtesy of Kim Woodrow, Univ. of Washington DAIDS/PSP/PMPRB

  26. Our Question: Do we currently have what it takes to create a sustainable prevention pipeline? • We have delivery systems • Do we have the candidates? DAIDS/PSP/PMPRB

  27. Candidates structural formula: structural formula: Next-Generation–to 2015 In Clinical Testing Single • Truvada Ring (pod) • TFVRing, Film, Tablet • Maraviroc Gel, Film • Dapivirine gel Film, Ring • IQP 0528 (NNRTI/Entry) Gel, Ring • TDF Ring (pod) • Maraviroc + TFV Ring, Gel • Dapivirine + TFV Ring, Film • MIV-150 (NNRTI) + Zn Gel (Carrageenan) • IQP0528+ TFVRing • Injectable • TMC278LA Nano-Liquid • S-GSK1265744 (744 LA) Liquid Tenofovir (TFV) NRTI, Gel Dapavirine (TMC120) NNRTI, Ring Combinations + Truvada Emtricitabine + Tenofovir DisoproxilFumarate (TDF) Oral Maraviroc CCR5, Oral, Ring DAIDS/PSP/PMPRB

  28. In Development 2015-2020 (Select small molecule inhibitors) DAIDS/PSP/PMPRB

  29. The Protein Microbicides –An Emerging Class DAIDS/PSP/PMPRB

  30. ON THE HORIZON OR AT THE FAR EDGE OF KNOWN SPACE • Bioengineered microbicides • Endogenous (vaginal, GI tract) bacteria expressing protein microbicides • Immunomodulation as a prevention strategy • TLR and other pattern recognition receptor inhibitors and antagonists • AbasicPhosphorothiolate 2’ Deoxyribose 14-mer (PDB) • Antiviral and Anti-inflammatory (Peter Katsikis, Drexel Univ.) • Genetic microbicides • siRNAs (multiple investigators) • Adenovirus vector delivered microbicides • (Wayne Marasco, Harvard Medical School) DAIDS/PSP/PMPRB

  31. Live Bacteria Delivery Systems Recent advances in Lactobacillus delivered microbicides Lagenaur et al. Mucosal Immunol. 2011 4:648 Lactobacillus bioengineered to express the HIV entry inhibitor Cyanovirin-N (CV-N) protect 4 of 12 monkeys and reduce viral load in infected Li et al. J. Acquir. Immune Defic. Syndr. 2011 58:379 Bioactive CV-N was detected in rectal secretions after feeding monkeys with bioengineered Lactobacilli in yogurt • RemainingIssues • Immunotoxicity: Unknown in Humans if there will be immune responses to prevention protein in the bioengineered bacteria and/or loss of tolerance to endogenous bacteria • Colonization: Will bioengineered bacteria stably colonize without some environmental advantage, e.g. antibiotic pre-treatment • Regulatory Requirements: Genetically Modified Organism (GMO) • Human Trials: Unique trial designs will be needed to assure environment control and removal of GMO and restoration of normal microbiomein subjects DAIDS/PSP/PMPRB

  32. Our Question: Do we currently have what it takes to create a sustainable prevention pipeline? • We have delivery systems • We have the candidates DAIDS/PSP/PMPRB

  33. The Answer Do we currently have what it takes to create a sustainable prevention pipeline? • YES—we have the necessary depth and numbers of delivery systems and prevention drug candidates to create a sustainable prevention pipeline DAIDS/PSP/PMPRB

  34. But a Sustainable Pipeline is Not a Slam Dunk Some Additional Challenges • What criteria(s) must the delivery system and candidate meet (down-selection) to advance to clinical testing? • Delivery formats (Gel, Film, Ring, Tablet, Injectable, Oral ) • Candidates • Do any of our options hold the key to global acceptability/adherence or will we need a range of delivery systems to satisfy needs and how will we manage this? • With devices now allowing combinations of biophysically diverse compounds, how do we manage the potential proliferation of combination strategies? • Roll-out and beyond challenges—How do we • Maintainsupplies of drugand vehicles? • Manage the ecological and biological impact of non-biodegradable delivery devices that may contain residual drug ? DAIDS/PSP/PMPRB

  35. Final Thoughts and Take Home Messages One of our greatest prevention challenges in the next decade will not be that we lack options, but prioritizing to advance the best prevention options The prevention field is positioned to not only optimally deliver prevention strategies, but to also provide a range of delivery choices to men and women The prevention pipeline is not static and limited to only “here and now candidates”, the door is open and the infrastructure is there for continued evolution of HIV prevention strategies. DAIDS/PSP/PMPRB

  36. Acknowledgements Jim Pickett and IRMA For slides and discussions: Chelsea Polis Joe Romano Lisa Rohan Tom Smith Chuck Wira Kim Woodrow The many investigators who are making the HIV Prevention Pipeline a reality PMPRB James Cummins Anabel Lowry Leslie Marshall Cherlynn Mathias Hans Spiegel PSP Fulvia Veronese Lyric by Timbuk 3 –The future is so bright I gotta wear shades! DAIDS/PSP/PMPRB

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