This document discusses innovation and pre-clinical development in Brazil. It outlines characteristics of innovative countries, recent advances in science and technology in Brazil, and the growth of post-graduate programs. It then discusses the importance of pre-clinical studies like toxicology, pharmacokinetics, safety pharmacology, and local tolerance to support clinical trials. Finally, it introduces the Centre of Innovation and Pre-Clinical Studies, which aims to conduct pre-clinical research, support pharmaceutical development, and contribute to generating national competence in drug innovation.

1. Desenvolvimento Pré-Clínico e Inovação
João B. Calixto
Centro de Inovação e Ensaios Pré- Clínicos (CIEnP)
São Paulo, 18 de Agosto de 2014

2. Inovação tecnológica:
"introdução de novidade no ambiente produtivo, seja ela produto ou processo, que traga melhoria significativa ou crie algo novo".

3. A inovação é o nosso lema. O único problema é que não a praticamos. Anônimo

4. ALGUMAS CARATERÍSTICAS IMPORTANTES DOS PAÍSES INOVADORES.
Confiança nas instituições e nas pessoas.
Cooperação com reciprocidade baseada em meritocracia.
Mercados regulados e controlados com transparência (The role of law). Baixos níveis de corrupção.
Respeito ao direito a propriedade e patentes. Pirataria é crime.
Ética no trabalho e esforço pessoal. Promoção por mérito.
Estímulo ao trabalho em equipe.
Lideranças pragmáticas (pouca ideologia).
Competição livre. Experimentar sempre e aprender com os próprios erros.
Inovação nasce em função do ambiente existente.
Países NÂOinovadores, apostam no curto prazo, tendem a se apegarem ao certo, evitam o risco e odeiam o incerto.

5. Avanços Recentes Nas Áreas de C,T&I No Brasil
•12.000 Doutores e 41.000 Mestres em 2010
•37.895 artigos publicados em revistas indexadas ISI em 2013
•~ 2,7% da produção científica mundial
•13 lugar no ranking mundial de publicações científicas
•Maior produtor de grãos do mundo: papel da EMBRAPA
•Domínio de exploração de petróleo de águas profundas: Petrobrás
•Produção de aviões: EMBRAER
•Sétima economia mundial
•~1% das exportações mundiais baseada em commodities

6. NÚMERO DE CURSOS DE PÓS-GRADUAÇÃO NO BRASIL
Ano
Nível
Doutorado
Mestrado Profissional
Mestrado
Total geral
1976
181
0
518
699
1980
260
0
680
940
1985
332
0
784
1.116
1990
469
0
993
1.462
1992
537
0
1.083
1.620
1995
682
0
1.289
1.971
2000
903
98
1.620
2.621
2005
1.099
202
1.923
3.224
2010
1.602
334
2.706
4.642
2011
1.738
417
2.925
5.080
Fonte: CAPES, dados atualizados em 08/05/2012.

7. Trabalhos Publicados Por Cientistas Brasileiros em Revistas Indexadas
1.923
2.329
2.521
3.597
4.461
5.482
7.550
10.839
12.773
16.950
18.743
18.998
27.482
29.125
31.444
33.783
36722
37895
0
5.000
10.000
15.000
20.000
25.000
30.000
35.000
40.000
1981
1984
1986
1990
1993
1995
1997
2000
2002
2005
2006
2007
2008
2009
2010
2011
2012
2013
Fonte: Web ofScience.

9. Patentes no USPTO
Ano
2010
2009
2008
2007
2006
Brasil
111
71
63
61
77
Rússia
82
52
45
41
39
Rússia/Brasil
0,74
0,73
0,71
0,67
0,5
Índia
363
254
267
266
257
Índia/Brasil
3,2
3,58
4,23
4,36
3,33
China
2.351
1.415
1.170
800
506
China/Brasil
21,18
19,93
18,57
13,11
6,57

10. Fonte: Folha de S. Paulo, 20/04/2014.

11. Importação de Fármacos
Em US$ milhões
Fonte: FarmaBrasil com base em dados da Funcex
Importação de Medicamentos
Em US$ milhões

12. Close Window
•Using Images
•Image Index
Paul Erlich(1854-1915)
“Corpora Non Agunt Nisi Fixate’”
“A Substance will not work unless it is bound”or
“A drug is efficacious only so long as it is bound to, and modulating the action of, its physiological target”
Source: Lancet 182: 445-451, 1913
1906, composto 606, Arsfenamina (Salvarsan).

13. Desenvolvimento de Novo Medicamento
•Praticamente todas os novos medicamentos (novas entidades químicas), originaram de pesquisa básica inovadoras na academia e nos institutos de pesquisas.
•O custo de desenvolvimento médio (incluindo todos os riscos) de um medicamento inovador (NCE), pode ultrapassar 1 bilhão de dólares. Ignorando as falhas, esse custo ficaria em torno de 200-300 milhões de dólares.
•Isso significa que a taxa de sucesso para o desenvolvimento de um novo medicamento (NCE) está em torno de 0.6%, e de 6% para um medicamento cujo alvo já conhecido.
•Doenças importantes como: câncer, psicoses, depressão, ansiedade, hipertensão, diabetes, dislipidemias, osteoporose, artrite, infecções, transplantes etc, são atualmente tratadas com sucesso, graça a essas descobertas.

15. Industry-funded academic inventions boost innovation
BrianD.Wrightandcolleaguespresentdatachallengingtheassumptionthatcorporate- fundedacademicresearchislessaccessibleandusefultoothers.
•Individualuniversitiesmaytrackpatentsandlicense'sattheirwoninstitutions,butthesedatasetsaregenerallysmallandconfidential;
•Corporate-sponsoredresearchisvaluableforfurtherinnovation;
•DatafromUniversityofCalifornia(15years)showthatcorporate-sponsoredinventionsarelicensedandcitedmoreoftenthanfederallysponsoredones(12.8versus5.6);
•OfalldatainventiongeneratedattheuniversityofCalifornia,20%arelinkedtoatleastonelicense,andnear25%werepatented;
•Corporate-sponsoredinventionsresultedinlicenses(29%)andpatents(35%)morefrequentlythanfederalsponsoredones(22%and26%,respectively);
•Althoughacademicsmayactconservativelytogainacceptanceofpeers,papersandgrantproposals,he(she)writes,industrypartnershipdrawhigh-statusacademicsawayfromconfirmingestablishedtheoriesandtowardsspeculation.
Nature,2014.

18. What testing is needed?
•Usepreclinicaldatatoincreasetheoverallstrategicsuccessin
–Pickingtherightcompound
–Pickingtherightformulation
–Pickingtherightdeliverymethod
•Avoidcompoundslikelytocauseproblemsinclinicaltrials.
•Useparalleloptimization:IntegrationofanalysisofbindingqualitiesandADME/Toxproperties.
20

19. Good Lead Candidate for Drug Development
•Adequate bioactivity;
•Appropriate physical-chemical property to enable formulation development;
•The ability to cross crucial membranes;
•Reasonable metabolite stability;
•Appropriate safety and efficacy (pre-clinical studies);
•Efficacy in human (clinical studies).

20. Preclinical Study Design (Toxicology)
•Essential for safety/start dose decision.
•Toxicology studies should mimic the schedule, duration, formulation, and route as that proposed for the clinical trial.
•Conform to standard toxicology protocols.
•Conduct according to GLP.

21. Preclinical StudiesAcute Toxicity
•Objective:To determine the Maximum Tolerated Dose (MTD) and No Observable Effect Level (NOEL)
•Duration:Typically 14 days after single dose
•Animals Required:2 species (rodent and non- rodent)
•Parameters:
•MortalityClinical pathologyGross necropsy
Weight changeClinical observations
•Points to consider:
•Dose selection for repeat dose studies
•Choice of the appropriated animal species

22. Preclinical StudiesSub Acute Toxicity
•Objective:To determine toxicity after repeated administration of the test material
•Duration:14 –28 days
•Animals Required:2 species (rodent and non-rodent)
•Parameters:
•MortalityClinical pathologyUrinalysis
HistologyWeight changeClinical observation
•Points to consider:
•Dosing regimen –similar to clinical use
•Recovery period when indicated
•Drug Toxicokinetics(TK)
•Immunotoxicityin case biological products

23. Absorption, Distribution, Metabolism and Elimination (ADME)
Advantages performing ADME testing early in the process, before a molecule gets into development:
•Improvement of Pharmacokinetic (PK) properties.
•Saves time and costs associated with progressing an unsuitable drug candidate through the pipeline.
The ADME properties that are routinely measured are:
•Solubility
•Permeability
•Plasma protein binding
•Movement across transporters
•Metabolism by liver enzymes

24. Local Tolerance
•Dermal (skin) Irritation/Sensitization
•Eye Irritation
•Phototoxicity
–The potential for sunlight (or other light frequencies) to transform a drug or a metabolite is:
–a useful tool for activating some drugs and
–A cause for a significant adverse effects for others (Quinolone antibiotics).

25. Genotoxicity
•Minimum of 2 in vitro Assays:
–Bacterial mutation Assay
–Ames test (point mutations)
–Chromosomal Aberration
•Mammalian cells in vitro or in vivo
•Dominant Lethal Tests in Rodents
OR
–Mouse Lymphoma Assay
•If either of them positive or for Phase II
–Micronucleus Assay (In vivo Assay).
–Others Assays: Unscheduled DNA Synthesis
•Not needed for Biologics

26. Carcinogenicity
•Objective:To evaluate the potential tumorigenic effect in animals and risk to humans for continuous use of drug candidate in humans for 6 months or more.
•Duration:12 to 24 months
•Species:Mouse or Rat
•Parameters:
•Tumor developmentClinical pathology
•Clinical observations and assessment
•Points to consider:
•Pharmacology, Pharmacokinetic or Toxicology (mechanistic in vitroand in vivo) data,
•Structure-activity relationships,
•Compound accumulation over long-term use,

27. Pharmacological Assessment of the Underlying Mechanism of Action
•Molecular Level
–Receptor binding, enzyme activity, molecular studies etc,
–Cellular/Tissue Level
–Cell function (tissue culture), isolated tissues.
•Organ/System Level
–Identify primary and secondary targets.

28. Safety Pharmacology
•Objective:To investigate undesirable pharmacological effects of the test material;
•Duration:Usually single dose;
•Animals Required:2 species (rodent and non-rodent);
•Core battery:Cardiovascular, Respiratory, CNS, Renal, Blood, Immunological etc.;
•Telemetry ;

29. Preclinical Support for Phase I Clinical Trials
•Acute/Sub-acute some time chronic Toxicity Studies;
•Genotoxicity;
•Pharmacokinetic/TK;
•Studies about the mechanism of action of the compound;
•Safety pharmacology (CNS; CV; Respiratory, Renal etc);
•Local tolerance;

30. ToxicologyStudyDuractions
Durations needded to support Phase I, II and III trials
DuractionofClinical
Trial
MinimumDurationofRepeat
Dose ToxicityStudies
RodentsNon-Rodents
Single dose
2-4 Weeks
2 Weeks
Up to2 Weeks
2-4 Weeks
2 Weeks
Up to1 Month
1 Month
1 Month
Up to3 Months
3 Months
3 Months
Up to6 Months
6 Months
6 Months
> 6 Months
6 Months
9 Months
Source: charles River

32. CENTRE OF INNOVATION AND
PRE-CLINICAL STUDIES

33. Funding:Ministry of Health, Ministry of Science and Technology, FINEP and State Government of Santa Catarina
Support: UFSC –Federal University of Santa Catarinaand CERTI Foundation
Buildings: Scheduled for completion of infrastructure in December of 2012
Executive and Scientific Director:Dr. João B. Calixto
Built area:5.300 m2
TheCenterInnovationandpre-clinicalstudiesistheresultofBraziliangovernmentinitiativefordevelopingpreclinicalstudiesindifferentareasofknowledgetomeetthedemandofpharmaceuticalindustries.

34. Infrastructure
MainBuilding
5.300m2ofconstructedarea,dividedinto:
•Basement:parkingandsupportarea
•Rodentfacility:600m2forthecreation/maintenanceofrodentsstandardSPFwithinternationalcertification
•ResearchLabs:About20laboratorieswithhighlevelequipmenttoperformpreclinicalresearch
•OfficeandAdministration
•Auditorium:tohostsmallerevents~120people
•Businessincubator:1,000m2fordevelopmentofnewideasandcompanies
•Staffofabout60-80people,including15-20PhDs
Non-rodentanimalfacility
Secondarybuildingwithabout2,000m2onlyformaintenanceofnonrodentanimals(nonhumanprimates,dogs,rabbit,guineapig,pigsamongothers).

35. Objetives
-Conductpreclinicalstudies:pharmacodynamics,safetypharmacology,pharmacokineticsandtoxicology(rodentsandnon-rodents),actinginaccordancewiththeguidelinesofgoodlaboratorypractices;
-Supporttheresearch,developmentandinnovationtothepharmaceuticalcompanies,supportingdrugdevelopment;
-Integratethenationalnetworkofdrugdevelopment, cooperatingwithcompanies,institutionsandtechnologicalmechanisms/agentstopromoteinnovation;
-ContributetotheestablishmentofnationalcompetenceandthegenerationofpatentsinBrazilandabroad.

36. Location

37. Drug Discovery
Desenvolvimento Pré-clínico
Clínico
Cadeia do desenvolvimento de medicamentos: atuação do CIEnP
LNBio
LassBio
FIOCRUZ
NPDM
Universidades
LAFEX
Inst. Royal
BioAgri
Ciallyx
Universidades
Rede de pesquisa
NPDM
Universidades
Nacionais
Internacionais
Nacionais
Internacionais
CIEnP
Drug Discovery
Clínica
AGENCIAS DE FOMENTO
GOVERNO/ EMPRESAS
EMPRESAS
FUNDOS DE INVESTIMENTOS
Parcerias Estratégicas
Parcerias Estratégicas
Inc. Empresas
Escalonamento
Inc. Empresas
CIEnP
Inovação Radical
Inovação Incremental
Centro de Inovação em Medicamentos

38. Oportunidades em P&D
Formação RH
Indústria
Patentes
Publicações
OPORTUNIDADES

39. “Se você não erra, provavelmentenão está trabalhando em problemas suficientemente desafiadores. E isto sim é um grande erro” Frank Wilczek, Prêmio Nobel de Física (1951-).

40. A Ignorância Gera Confiança Com Mais Frequência Que o Conhecimento. Albert Einstein (1879-1955)

41. www.cienp.org.br
Contato: joão.calixto@cienp.org.br

42. FinanciamentoeApoio
Centro de Inovação e Ensaios Pré-clínicos