Os Ensaios Clínicos na era da

Medicina de Precisão

Clinical Trials in Medicine Precision era

Health Cluster Portugal, CCAB, Braga , 20 de Abril, 2016

Manuel Sobrinho Simões

Ipatimup/i3S, Faculdade de Medicina e CHSJoão, Porto, Portugal

Ensaios clínicos em Portugal (2012)

• Uma das mais baixas taxas por milhão de habitantes na Europa

Ocidental

• Investimento de 36 milhões de euros com 3,5 milhões de poupanças na

despesa pública em medicamentos e meios complementares de

diagnóstico

• VAB global de 72 milhões de euros com retorno de 2€ por cada 1€

investido

CEIC & CNPD Faltam: Ensaios clínicos de

fase 1 e Ensaios clínicos de

iniciativa dos investigadores

There is lack of

understanding in general

Curing vs Understanding

DOENÇAS CIVILIZACIONAIS &

EMERGENTES

OBESIDADE

DIABETES

S.I.D.A.

TUBERCULOSE

CANCRO

DEPRESSÃO

D.NEURODEGENERATIVAS

PAT GERIÁTRICA

....................................

MEDICAMENTOS

DISPOSITIVOS

PROCESSOS

…………………

ENVELHECIMENTO

Future of Health Sciences Research

Basic research

Clinical trials and

Translational research

Clinical

practice

Plagues Tuberculosis Cardiovascular

diseases Cancer Neurodegenerative

diseases

Middle Age

XXI Century

Genomics

Postgenomics

Metagenomics

Modern medicine

Microbes maketh man

People are not just people. They are an awful lot of

microbes, too

Aug 18th 2012 | from the print edition

METAGENOMICS

WHO ARE WE? Highly dynamic multicellular “super-

organisms” with huge turnover rates at

intracellular components (e.g. proteins), and

at the regeneration level (e.g. bone marrow,

oral mucosa, digestive tract, skin,…).

The human genome has been deciphered

Hail to Personalized Medicine

The biggest mistake of the century!

Personalized medicine: temper expectations.

Nebert DW, Zhang G. Science 337(6097):910, 2012

(De)Personalized Medicine

Ralph I. Horwitz, Mark R. Cullen, Jill Abell, Jennifer B. Christian

Science Vol. 339 no. 6124 pp. 1155-1156, 2013

Evidence based medicine

Personalized medicine

Precision medicine

NIH opens precision medicine study to nation

Panel's plan would allow anyone living in the United States to join million-strong effort.

Kaiser J. Science, 2015

The “brave new world” of clinical

trials

One-person clinical trials

Adaptive clinical trials

The New York Review of Books, March 2016

IMPRECISION

MEDICINE !

The flexible approach at the NCI, modifying a treatment in real

time, is anathema to many clinical researchers.

Constantly shifting variables, like dose and timing of drugs,

makes it difficult to accurately assess either benefits or side

effects.

It also requires great trust in the probity of the clinicians

conducting the trial—trust that they are able to make the right

decisions as they alter the protocols as they go along.

Adaptive Clinical Trials

Review of The Death of Cancer by DeVita Jr. and DeVita-Raeburn

The New York Review of Books, March 2916

Traditionally, the FDA has rejected such an approach,

requiring that a set protocol be carried through to its

prescribed end. (Recently, the FDA has stated it is open to

considering adaptive trials in approving new drugs.)

In addition to adaptive clinical trials, DeVita believes in

individual innovation; he writes that an oncologist should be

free to draw on preliminary data and employ an agent not yet FDA-approved for a specific cancer.

Review of The Death of Cancer by DeVita Jr. and DeVita-Raeburn

The New York Review of Books, March 2916

Adaptive Clinical Trials

Most promising strategies to control

advanced cancer particularly

appropriated for one-person clinical trials

• To turn the immunological system able to

recognize and to “kill” the cancer cells

• To induce cancer cells apoptosis

• To block cancer cells increased motility and

invasibility

Manuel Sobrinho-Simões, 2015

OPPORTUNITIES & RISKS IMMUNOTHERAPY, LIQUID BIOPSIES, OVERDIAGNOSIS & OVERTREATMENT,...

Jocelyn Kaiser, Science 18 March, 2016

Liquid biopsies Tests of blood-borne DNA pinpoint tissue damage

Assays spot cell

death from

diabetes, cancer,

and more….

Era já possivel analisar a

presença no sangue de

células neoplásicas e de

moléculas de DNA e RNA

livres

Os exossomas potenciaram

este tipo de análises

Sonia Melo et al Cancer Cell, 2014 Dr Andrejs Liepins/Science Photo Library

Biopsias líquidas

RISKS: Overdiagnosis & Overtreatment

Herton Escobar, Science, 1 April 2016

RISKS Brazil president signs law legalizing renegade cancer pill

The congress voted to legalize the production and distribution of

synthetic phosphoethanolamine, even though the putative cancer

drug has not been clinically tested or registered with the Brazilian

Health Surveillance Agency.

Phenotypic Drug Discovery

Striving towards the highest level of

biological relevance

John Comley, Drug Discovery World Winter 2015/16

Currently there is a resurgence in interest in PDD, driven by

many factors, not least the limited success of target-based drug

discovery.

It should always include an attempt to understand

Conselho Nacional dos Centros Académicos Clínicos

Centros de

Saúde de

última geração

Faculdade de Medicina

Hospitais afiliados

Hospital Universitário

Instituto de Investigação

Futura(?) Agência de Investigação Clínica e Inovação Biomédica

Resoluções do C.Ministros, 24 de Março, 2016

Estratégias mais promissoras para

conseguir controlar cancros avançados

• Induzir o suicídio das célula cancerosas

• Bloquear a sua motilidade e invasibilidade

• Adestrar o sistema imunitário no sentido de o

tornar capaz de reconhecer e destruir as células

cancerosas (Imunoterapia)

Manuel Sobrinho-Simões, 2015

Successful therapies using L-asparaginase-

induced asparagine deprivation have been

developed for acute lymphoblastic leukaemia

Richards and Kilberg, Annu Rev Biochem 75:629, 2006

Certain types of cancer cells depend on leucine,

glycine, suine and glatamine metabolism to proliferate

and/or survive (block apoptosis)

Sheen JH et al, Cancer Cell 19:613, 2011

Jain M et al, Science 336:1040, 2012

Maddocks OD et a,l Nature 493:542, 2013

Son J et al, Nature 496:101, 2013

Developmental biologist Kathy Niakan has received permission from U.K. authorities to

modify human embryos using CRISPR/Cas9 gene-editing technology.

A U.K. researcher has gotten a green light to modify

human embryos (pictured, 4 days after fertilization).

Scientist can

edit human

embryos

Science, 5 February 2016

Healthy aging: The ultimate preventative medicine

Matt Kaeberlein, Peter S. Rabinovitch, George M. Martin

Age is the greatest risk factor for nearly every

major cause of mortality in developed nations.

“It is clear that directly targeting aging is theoretically superior to

treating individual chronic diseases, but until recently, translational

approaches to achieve this goal have been just that – purely

theoretical”

Science, 4 December 2015 – Vol 350

Blackburn EH, Epel ES, Lin J , Science, Dec 4, 2015.

Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection

The biggest problem

The GENOME has been deciphered

Hail to PRECISION MEDICINE!

Two main paradigms for understanding human

diseases including cancer

1. Core biological processes associated with a disease are driven

by responses to changes in a small number of genes

2. Disease states are considered as emergent properties of

molecular networks originating from a very complex interplay

between constellations of changes in DNA and a broad range of

factors such as diet, age, gender and exposure to environmental

toxins.

Chen et al Nature 452:429, 2008

Schadt EE, Nature, September 10, 2009

Cancer cells can ‘infect’ normal neighbours Editorial Science, 23 October 2014 Heidi Ledford Tiny RNAs shed by tumours can transform healthy cells into cancerous ones. Sonia Melo et al Cancer Cell, 2014

A cancer cell (yellow) sheds membrane vesicles. When a cancer cell throws out its trash, it can turn healthy neighbours into fellow tumour cells, researchers have found. Dr Andrejs Liepins/Science Photo Library

A cancer legacy

Once viewed as tragic anomalies, many childhood cancers

may have their roots in inherited mutations

Jennifer Couzin-Frankel, Science 29 Jan 2016

Surgery, Pathology and Oncology

in the Precision Medicine Era

• Huge amount of new informations

• Pressure to predict

• Very complex decision-making procedure

Manuel Sobrinho-Simões, 2010

Need to integrate the molecular data into the

clinical and anatomopathologic context.

Please read: need to understand and to

focus in single patients

GENE – ENVIRONMENT INTERACTION

Genotype Environment

Height Longevity

Diseases

Phenotype

lincRNAs

siRNAs

miRNAs

TRANSPOSONS

PSEUDO-GENES

DNA RNA PROTEIN 20,000 genes 100,000 mRNAs 2,000,000 proteins

EPIGENETICS

GENETICS

POSTGENOMICS

MUDANÇA DO PARADIGMA

Medicina baseada Medicina

na evidência personalizada/estratificada

para a população-alvo

Genomics

The future of health care: Making informed

decisions in the age of genomic medicine Henry T. Greely. Science, 2015