Semi-synthetic Artemisinin: A New Source of Artemisinin to Reduce Barriers to ACT Access

Transcription

1 Semi-synthetic Artemisinin: A New Source of Artemisinin to Reduce Barriers to ACT Access Artemisia/Artemisinin Production and Marketing Conference November 24-26, 2008 Guilin, China Presented By Tue. Nguyen PhD

2 iw Mission The Institute for neworld ealth Develops Safe, Effective, and Affordable New Medicines for People with Infectious Diseases in the Developing World 1

3 The Partnership 2

4 The Artemesinin Enterprise The Artemisinin Enterprise consists of complementary scientific projects funded by BMGF to improve artemisinin production technologies which should: Diversify the sources of high quality artemisinin (iw) Lower the cost of artemisinin production (MMV, York) Stabilize supplies, preventing cyclical fluctuations in artemisinin prices (iw, York) Provide new antimalarial combinations (MMV) Make high-quality ACTs less expensive and therefore more accessible (iw, York, MMV) Improve extraction techniques (MMV) The semi-synthetic artemisinin project is one of several initiatives to ensure global demand for ACTs can be met 3

5 Project Vision: Semi-synthetic Artemisinin Global ealth Challenges (Artemisinin Supply) Synthetic Biology (Biotechnology) Increase Access to ACT Cures 4

6 Semi-Synthetic Artemisinin Project Goals Create a complementary source of non-seasonal, highquality and affordable artemisinin to supplement the current plant-derived supply Contribute to stabilizing the price of artemisinin to benefit all stakeholders Ensure semi-synthetic artemisinin is available to all eligible manufacturers who comply with W/GF harmonized quality criteria Enable millions of people infected with malaria to gain consistent access to affordable, high-quality, life-saving ACTs 5

7 A Second Source Supplements & Stabilizes the Artemisinin Supply Chain Cultivation Extraction Artemisinin ACT Therapy Yeast + Sugar Months Fermentation Artemisinic Acid Chemistry DERIVATIVES Artemisinin Days Controlled Process 6

8 Simple Sugar Acetyl-CoA Acetoacetyl-CoA MG-CoA Mevalonate ERG10 ERG13 tmgr X2 Synthetic Biology ADS Amorphadiene AM/CPR Chemical Conversions xidation and Ring-Closure Microbially Derived Artemisinin ERG12 Mevalonate-P ERG8 Mevalonate-PP AM/CPR Dihydroartemisinic Acid Ester ydroperoxide ERG19 IDI1 IPP DMAPP Non-Enzymatic Peroxidation ERG20 GPP ERG20 FPP AM/CPR Artemisinic acid Dihydroartemisinic Acid Ester Met erg9::p MET3 -ERG9 Esterification Squalene ERG1,7,11,24,25,6,2,3,5,4 Ergosterol Purification Artemisinic acid Reduction Dihydroartemisinic Acid 7

9 Achievements & Next Steps Achievements Completed strain engineering to reach productivity targets at bench scale fermenter level Transferred technology (fermentation, purification, and chemistry) to manufacturing partner Reproduced laboratory data at pilot scale Next steps Demonstrate chemical comparability between semisynthetic and plant derived artemisinin No need for bioequivalence studies Process optimization and development of industrial processes suitable for 100,000L scale 8

10 Artemisinin As A Starting Material Dihydroartemisinin Artesunate Artemisinic acid Raw material Defined specifications Artemisinin Starting material Defined specifications GMP manufacturing Artemether Artelinate Arteether API Compendial specifications 9

11 Artemisinin: A Starting Material In the production of an antimalarial active pharmaceutical ingredient (API), artemisinin is a starting material Derivatives manufactured from artemisinin are the API in ACTs The W monograph, which currently classifies artemisinin as an API, applies for monotherapy formulations where artemisinin is used as active ingredient. The semi-synthetic process will consist of a well documented microbial fermentation to produce artemisinic acid (AA) followed by synthetic chemical steps to reach artemisinin. The plan is to pursue chemical comparability as a regulatory approach for semi-synthetic artemisinin 10

12 Semi-synthetic Artemisinin Timeline Pre-Development Process Development and Scale up Industrialization Commercial Production 1000L 10,000L 100,000L 2 nd Source of artemisinin for antimalarial API 11

13 Market Impact Supplement botanical supply to support projected increased demand for ACTs Semi-synthetic artemisinin cost is anticipated to be comparable to the current cost of high quality field production Semi-synthetic artemisinin will be made broadly available for use in ACT 12

14 Updates since the last meeting sanofi-aventis has joined the Artemisinin Project Excellent fermentation and chemical process development experience First- class manufacturing facilities and capabilities Already working in the malaria field Cost analysis is a dynamic exercise Initial cost target, developed in timeframe, was theoretical and aspirational Technical and manufacturing reality will influence actual cost Cost analysis will be done regularly as technical milestones are achieved. It will be pro-actively communicated 13

15 UC Berkeley professor Jay Keasling, the originator of the technology, initially identified the genetic pathway and developed a microbial system that produces artemisinin via fermentation. Amyris provides strain engineering and bench scale fermentation expertise using the novel tools of synthetic biology to achieve more productive titers and yields of artemisinic acid: Jack Newman, Chris Paddon, Doug Pitera, Patrick Westfall, Mike Leavell, Derek McPhee, Glenn Dorin, Karl Fisher, Rika Regentin,Kirsten, Benjamin, Chris Ring, Tammy Tompkins, Ann Guiney neworld ealth manages the research and development collaboration with Amyris, UCB and sanofi: Nina Grove, Julie Cheng, James ickman, Louise Johnson, Rachel Boller, Nyla Plouche-Gonzales, Kay Monroe The Bill & Melinda Gates Foundation provides funding for the project: Thomas Brewer, eidi ansen, Mannny McBride, Zoey Diaz Sanofi-aventis provides fermentation and chemistry process development expertise to the project, it will commercialize the semisynthetic artemisinin: Philippe Farabolini, Philippe Charreau, ans Feess, Paul Baduel, enri Farrret, Pierre- enri Maguet, Philippe Mackiewicz, Corinne Lehman, Ronan Gueval, Marc Feron, Vincent Colombe, Nicolas Salavin, Alexandre Willocquet, Denis Thibault 14

16 Thank You 15