translational medicine: challenges from...

Drug Information Association www.diahome.org 1

TRANSLATIONAL MEDICINE: CHALLENGES

FROM PRECLINICAL TO CLINICAL

João B. Calixto

Center of Innovation and Preclinical Studies, Florianópolis, SC, Brazil.

DIA Meeting, São Paulo, October 20-22nd, 2013.


DEVELOPMENT OF A NEW DRUG

• Virtually all new drugs (new chemical entities - NCE) are originatedfrom university and research institutes’ innovative basic research.

• The average cost of development (including all risks) of an innovatordrug (NCE), may exceed US$ 1 billion. Ignoring the flaws, this costwould be around 200-300 million dollars.

• It means that the success rate for the development of a new drug(NCE) is around 0.6% and 6% for a target drug already known.

• Major diseases such as cancer, psychosis, depression, anxiety,hypertension, diabetes, dyslipidemia, osteoporosis, arthritis,infections, transplants, etc., are now successfully treated, gracethese findings.


Development of New Chemical Entities (NCE)1950-2008

• From 1950 to 2008, the FDA approved 1,222 new drugs (newmolecular entities (NMEs) or new biologics), of which 1,103 aresmall molecules and 119 are biologics.

• At present, there are more than 4,300 companies that areengaged in drug innovation, yet only 261 organizations (6%) haveregistered at least one NME since 1950. Of these, only 32 (12%)have been in existence for the entire 59-year period.

• NME costs have been growing exponentially at an annual rate of13.4% since the 1950s. The average cost of a NCE is between 0.4and 1 billion dollars.


TRANSLATIONAL MEDICINE


The role of academic labs


M.S. Brown, J. L. Goldstein, Multivalent feedback regulation ofHMG CoA reductase, a control mechanism coordinatingisoprenoid synthesis and cell growth. J. Lipid Res. 21, 505-517(1980).

MERCK turned basic science into medicines.

Lovastatin (Mevacor)

Simvastatin (Zocor)

These and other HMC-CoA reductase inhibitors haverevolutionized the treatment of dyslipidemia and atherosclerosis.

Clinical studies of these drugs were almost stopped because wereobserved tumor formation in rodents.

In 2009, this drug class sold 30 billion dollars worldwide.

TRANSLATIONAL MEDICINE – case I


David JuliusDepartment of Physiology,University of California, San

FranciscoPapers: 206Citations: 28,008Citation average : 136H-index: 56Published article in Cell, Nature,Science: 37

The Company's key flavor programs focus on thediscovery and development of savory, sweet andsalt flavor ingredients that are intended to allowfor the reduction of MSG, sugar and salt in foodand beverage products. In addition, Senomyxhas a bitter blocker program to reduce or blockbitter tastes and thereby improve the tastecharacteristics of foods, beverages andpharmaceutical products. Senomyx also has acool flavor program for the discovery of novelflavor ingredients intended to provide a coolingtaste effect for confectioneries, foods andbeverages, as well as oral care and OTChealthcare products.

TRANSLATIONAL MEDICINE – case II


TRANSLATIONAL MEDICINE - case


WHY THE INTEREST IN RED WINE?

“French Paradox”

Loaded with natural health aids

Cholesterol Detoxifier

Anticoagulant

Artery Relaxant

Lowest rate of cardiac disease mortality

Fairly high intake of saturated fatty acids


TRANSLATIONAL MEDICINE – case III

Sirtuins in aging and disease: calorierestriction; mitochondria; cancer; diabetesStudy sirtuin pathways, their role inmultiple diseases and their lifespanextension capabilities

April 24, 2008, BioWorld Today, “GSK Grabbing Sirtuin Platform with $720MSirtris Acquisition

David Sinclair, PhD

Professor, Department of

PathologyHarvard Medical

School

SRT2104, a new chemical entity (NCE) that activates SIRT1 – structurally unrelated to and up to 1,000 times morepotent than resveratrol. Currently under way with multiple Phase IIa trials in patients with metabolic disease (Type 2Diabetes), inflammation and cardiovascular diseaseSRT2379, a potent NCE that activates SIRT1 – structurally distinct from resveratrol and SRT2104. Currently beingevaluated for safety, tolerability and pharmacoknetics in a Phase I clinical trialSRT501, a formulation of resveratrol with roughly five times higher bioavailability than the natural product.Completed Phase IIa trial in Type 2 Diabetes (Elliott et al. Drugs Future 2009, 34, 291-295.). Currently being evaluatedin a Phase II trial in oncology; new patient enrollment has been suspended as of April 22, 2010 (see ClinicalTrials.govfor updates)

http://www.clinicaltrials.gov/


TRANSLATIONAL MEDICINE – case IV

Charles N. SerhanPapers: 510Citations: 28,577h-index: 97

Average citations: 56

Director of the Center for Experimental Therapeutics and Reperfusion Injury (CET&RI)

at Brigham and Women’s Hospital (BWH);

Full Professor of Anaesthesia, Perioperative and Pain Medicine, Harvard Medical

School and BWH Endowed Distinguished Scientist;

The overall mission at his laboratory is "To identify novel pathways and cellular targets

critical in regulating neutrophil-mediated inflammation and to establish the templates

for physiologic small molecule-based interventions."

Drug Information Association

• Xu Z-Z, Zhang L, Liu T, Park J-Y, Berta T, Yang R, Serhan CN, Ji R-R.

Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and

peripheral actions. Nat Med. 2010; Epub April 11;

doi:10.1038/nm.2123.

• Spite M, Norling LV, Summers L, Yang R, Cooper D, Petasis NA,

Flower RJ, Perretti M, Serhan CN. Resolvin D2 is a potent regulator of

leukocytes and controls microbial sepsis. Nature 2009; 461:1287-91.

• Schwab JM, Chiang N, Arita M, Serhan CN. Resolvin E1 and protectin

D1 activate inflammation-resolution programmes. Nature 2007;

447:869-74.

• Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual

anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol.

2008; 8:249-61 (issue cover). A concise review.

• Serhan CN, Yang R, Martinod K, Kasuga K, Pillai PS, Porter TF, Oh

SF, Spite M. Maresins: novel macrophage mediators with potent anti-

inflammatory and pro-resolving actions. J Exp Med. 2009; 206:15-23.

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A Core Set of Reporting Standards For Rigorous Preclinical Study Design (Part I)

Randomization• Animals should be designed randomly to the various experimental groups and the

method of randomization reported;• Data should be collected and processed randomly or appropriately blocked;

Blinding• Allocation concealment: the investigator should be unaware of the group to

which the next animal taken from a cage will be allocated;• Blinding conduct of the experiment: animal caretakers and investigators

conducting the experiments should be blinded to the allocation sequence;• Blinding assessment of outcome: investigators assessing measuring or quantifying

experimental outcomes should be blinded to the invention;Sample-size estimation

• An appropriate sample size should be computed when the study is being designed and the statistical method of computation reported;

• Statistical methods that take into account multiple evaluations of the data should be used when an interim evaluation is carried out;

NATURE REVIEWS | DRUG DISCOVERY VOLUME 11 | OCTOBER 2012 | 733


A Core Set of Reporting Standards For Rigorous Preclinical Study Design (Part II)

Data handling • Rules for stopping data collection should be defined in advance;• Criteria for inclusion and exclusion of data should be established

prospectively;• How outliers will be defined and handled should be decided when the

experiment is being designed, and any data removed before analysis shouldbe reported;

• The primary end point should be prospectively selected. If multiple endpoints are to be assessed then appropriate statistical corrections should beapplied;

• Investigators should report on data missing because of attrition or exclusion;• Pseudo replicate issues need to be considered during study design and

analysis;• Investigators should report how often a particular experiment was performed

and whether results were substantiated by repetition under range ofconditions;

NATURE REVIEWS | DRUG DISCOVERY VOLUME 11 | OCTOBER 2012 | 733


Main Problems Associated With Decision-Making at the Crucial Point Where Drug Proceeds to Human Dosing

Preclinical profile could not be affected by lack ofoptimal formulation or low bioavailability;

Validated animal models might not exist;

Metabolism in Preclinical profile could not be affected bylack of optimal formulation or low bioavailability;

Validated animal models might not exist;

Metabolism in an could differ from animal specie used;

Choice of indication might be uncertain and this canaffect risk or benefit assessment.

Source:Shllingford & Vose, TDT 6: 941, 2001.


Reasons for Failure in Clinical Development

Reason for failure Percentage

• Pharmacokinetics 39

• Lack of efficacy 30

• Toxicology 11

• Adverse effects in man 10

• Commercial considerations 5

• Others 5

Note: Of the 198 compounds that failed in development, 77 were anti-infective drugs; if these are excluded, lack of clinicalefficacy was the main cause of failure (49%), and pharmacokinetic failures were less common (7%).

Source: Drug Discovery and Development - Technology in transition, H.P.Rang; 141, 2006.


Percentage Concordance Between Animal and Human Toxicities (grouped by organ)

0 20 40 60 80 100

Other

Urinary

Neurological

Hepatic

Haemopoietic

Gastrointestinal

Endocrine

Cardiovascular

Skin

Source: Nature Drug Disc 3: 232, 2004.

Percentage of human toxicities found in animals

Toxi

city


DOSE-BY-FACTOR APPROACH: FASE I

• Calculating the NOAEL (no observed adverse effect onanimal toxicology) is done using allometric scaling

• Based on body surface area the human equivalentdose (HED) is obtained

• The FDA issued a conversion table to calculate theHED from the NOAEL, multiplying by a correction factor


TRANSLATION OF ANIMAL DOSE TO HUMAN

HED= Human equivalent dose BSA= Body surface area


SAFETY FACTOR FOR PHASE I TRIALS

• It is used to ensure that the first dose in humans will not

cause toxic effects, since man can be more sensitive to the toxic

effects of a therapeutic agent than the animals and inter-

species differences in pharmacokinetics of the drug could exist

• Generally, the safety factor is 10

• The MRSD (maximum recommended starting dose) is

obtained by dividing the HED by 10.


PRECLINICAL SUPPORT FOR PHASE- I CLINICAL TRIALS

• Acute/Sub-acute some time chronic ToxicityStudies

• Genotoxicity

• Pharmacokinetic/TK

• Studies about the mechanism of action ofthe compound

• Safety pharmacology (CNS; CV; Respiratory,Renal etc)

• Local tolerance


Nature Biotechnology, 2013

Drug Development Phase and Price of Project


PHARMACEUTICAL INNOVATION: 2000-2009

Nature Review Drug Discovery, 2010


“If you don't make mistakes, you're not working on hard enough

problems. And that's a mistake.”

Frank Wilczek, Nobel Winer, 2004.


“If you want to succeed, double

your failure rate”

Thomas Watson - IBM

João Batista Calixto,

PhD.

Managing Director CIEnP

[email protected]

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