Corporate Preclinical Development THECULPRIT THEVECTOR

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Corporate Preclinical Development Page 11 Corporate Preclinical Development Page 12 Combinations!!!Combinations!!! BetterBetter use use of of the the availableavailable weapons weapons FixedFixed DoseCombinations!!!! DoseCombinations!!!! PRODUCT COMPANY FIRSTAPPROVAL Artemisinin-basedArtemisinin-based Combination Combination Therapies Therapies Coartem® Novartis Switzerland Artemisinins Quinine Artemether &Lumefantrine Pyrimethamine Piperaquine 1980/1970 Mefloquine Coarsucam® Sanofi Morocco Artesunate &Amodiaquine 1980/1946

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TraditionalChineseMedicineTraditionalChineseMedicine OnlyOnly 541Scientists 541Scientists Were Were Exempt Exempt FromFrom theReeducation theReeducation Process Process Qng Ho ArtemisiaAnnua Beijing: Project523HeadOffice Biophysics CASInst. 1971-1974 Traditional Chinese MateriaMedicaInst. Jinan: MateriaMedicaInst. QUINGHAOSU Parasitic Diseases Inst. Artemisinin 哴 㣡 㫯 Shanghai: MateriaMedicaCASInst. Organic Chemistry Inst. H Chongqing: SichuanMateriaMedicaInst. O O 1977 Jiansu Province: Gaoyou Country Health Dept. O H Guangzhou: Univ.of Chinese Traditional Medicine O Kunming: Yunnan MateriaMedicaInst. O Guilin: Guiling Pharmaceutical Factory

Corporate Preclinical Development Page 15 Corporate Preclinical Development Page 16 THEFIRSTTODISCOVERANDSHARETHEFIRSTTODISCOVERANDSHARE

Milutin Stefanovic

Corporate Preclinical Development Page 17 Corporate Preclinical Development Page 18

EURARTESIM® ArtemisininArtemisinin derivatives derivatives EURARTESIM® O O

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Corporate Preclinical Development 2-6 July 2012 Page 23 Corporate Preclinical Development Page 24 EURARTESIMLOGISTICSEURARTESIMLOGISTICS ArtemisiaannuaArtemisiaannuaFIELDSFIELDS

China Vietnam Collaboration with the Kenya InternationalPharmacopoeia Artemisinin

Collaboration with theInternational GMP Pharmacopoeia andtheUSP Supplier 1 Suppliers 2 DHA PQP

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ArtemisininArtemisinin WW THEKEYPHARMACOPHORICTHEKEYPHARMACOPHORIC ArtemisininArtemisinin WW 1972.Artemisinin isolation.Milutin Stefanovic 1979.Artemisinin identification.Chinese Research Group Pharmacophoric mojety 2007. Identification and isolation of all the impurities by

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Corporate Preclinical Development Page27 27 Corporate Preclinical Development Page 28 DHAThe Process DHAThe Process Molecules 2010,15, 13091323 Review Stereodynamic InvestigationofLabileStereogenic Centres inDihydroartemisinin

IlariaD’Acquarica 1,*,FrancescoGasparrini 1,*,Dorina Kotoni 1,MarcoPierini 1, NaBH 4 ClaudioVillani1,WalterCabri2,MichelaDiMattia2andFabrizioGiorgi2 1DipartimentodiChimicaeTecnologiedelFarmaco,SapienzaUniversità diRoma,P.leAldoMoro5 methanol 00185Roma,Italy 2Analytical Development,R&D Department,sigmatauS.p.A.,ViaPontinakm30,400,00040 Pomezia,Italy Artemisinin DHA crude

crystallization

DHA pure

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JOC 2011,76, 1751–1758 JOC 2011,76, 4831–4840

Corporate Preclinical Development 2-6 July 2012 Page 31 Corporate Preclinical Development 2-6 July 2012 Page 32 PQPTHEPROCESSPQPTHEPROCESS

H+ H+

Ref lux 7-Chloro-4-[4- (3-piperazin-1-yl- propyl)-piperazin- 1-yl]-quinoline 1-Br-3-Cl-propane MW 157.44 7-Cl-4-[4-(3-Cl-propyl)- Piperaquine tetraphosphate tetrahydrate 4,7-DI Chloro-quinolin piperazine Piperaquine tetraphosphate tetrahydrate 4-piperazinyl 7-Cl-quinoline piperazin-1-yl]-quinoline MW =198.05 MW 86.14 MW 247.73

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4,4'-(propane-1,3-diylpiperazine-4,1-diyl)bis(7-chloroquinoline) tetrakis (phosphate) tetrahydrate PQP MW 999.56 4 X H2O

Corporate Preclinical Development Page 33 Corporate Preclinical Development Page 34

Cl Cl N N WeWe Achieved Achieved : : N N N N Cl N N N N Complete control of the processes, the logistic. N N N Cl Cl Identification and control of all decomposition pathways. N N All impurities have been qualified from a toxicological N Cl O point of view. Genotoxic evaluation was generated Piperaquine HPLCmethod N according to the more recent ICH, EMA and FDA Cl N N OH guidelines. N N Our suppliers have established a complete N Cl N Environmental, Health and Safety control. Cl N Satisfactory 2y stability data at 30㼻 Cl N Cl Cl

N N N N 0 5 10 15 20 25 30 Eurartesim®Eurartesim® is is free free from from genotoxic genotoxic impurities impurities minutes

Corporate Preclinical Development Page 35 Corporate Preclinical Development Page 36 PhaseIIItrialinAfrica:5countriesPhaseIIItrialinAfrica:5countries Manhiça,MozambicoManhiça,Mozambico

278patientsi

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304patients 447 patients

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DoseRegimensDoseRegimens for for children children EurartesimisequivalenttoCoartem28dEurartesimisequivalenttoCoartem28d

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Corporate Preclinical Development Page 39 Corporate Preclinical Development Page 40 EurartesimprotectthepatientbetterthenCoartemfromEurartesimprotectthepatientbetterthenCoartemfrom 1882Italy&Malaria1882Italy&Malaria newinfectionsnewinfections

Malaria map (1882) by sen. Luigi Torelli

The map was developed to 24.0 verify the health and hygienic Coartem conditions along the railway % lines.

13.6% Eurartesim About 8331 kilometers of railways, 3762 were well in malarial areas.

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AnalyticalDevelopment Chemical&PharmaceuticalDevelopment FabrizioGiorgi SilviaArmaroli MichelaDiMattia GiulioCarzana CristinaDiGiovanni MarcoTorri SilvanaLalli StefanoBanfi GiuseppeMarazzi RobertoCastagnani ElenaBadaloni AndreaQuattrociocchi MichelaForte FabrizioPiccirilli Technical Support RobertoDeias EmanuelaTassoni (MedChem) LucillaMastrofrancesco LiaDell’uomo(Scientific staff) GianfrancoD’amore Mosè Santaniello(Developability) LuciaCritelli MariaGraziaCima(Developability) MarcoQuaglia MassimilianoRicci Metabolism SilviaPace Toxicology CarloTallarico RitaLucreziotti FrancescoManera GiancarloGramiccioli DomenicoIntorre General Pharmacology DanielaPesce FrancoBorsini RosangelaFerretti GiovanniMattera MariaAntoniettaStasi ProfessorFrancescoGasparrini &ProfessorGuy Mazue Corporate Preclinical Development Page 43 Corporate Preclinical Development Page 44