Issues and Challenges in Issues and Challenges in Drug Discovery and Drug Discovery and DevelopmentDevelopment

Discovering and Developing MedicinesDiscovering and Developing Medicines

Mike SumnerMike Sumner

ProductsProductsDrugsDrugsTargets & LeadsTargets & Leads

Target selection

Target to Lead

Lead to candidate

Candidate selection to

FTIH

FTIH to PoC

PoC to Commit to Phase III

Phase III File &

LaunchLifecycle

mgt

The Drug Discovery and Development process is a progression from

Targets and Leads… to Drugs...to Products

9 - 16 y

12-24m 12-24m 30-33m 8-12m 12-44m 0-30m 18-66m 10-13m

Costs ~ $1 billion per successful product

Drug Discovery Process

chemical diversity

(compound library)

test safety&efficacyin animals and

humans

gene screen and identify lead

Lead

optimisationprotein target

DrugsDrugsTargets & LeadsTargets & Leads

Target Validation & Selection Target to Lead(compounds)

Lead to candidate Drugs

Candidate progress to FTIH and PoC in patients

Part 1:Target Selection & Compound Screening

Topics

Target selection & Validation

Compound Screening

Hit optimisation

Genome Disease

Potential Drug Target

Select protein of interest Pathology

Link with disease or disease process

Selection of Biological Target

Genetics

Target SelectionApproaches to Finding

a Drug Target

Target Validation - Linking Targetsto Diseases and Treatments

Target validation is a series of activities, which aim to build confidence that a drug which acts by modifying the function of the target will deliver the efficacy and safety required

Degree of target validation varies, depending upon the nature of the disease, type of target etc.

A target is never fully validated until a drug acting on it works in patients!

Screening to Generate Hits

Types of screens– Functional assay

– Binding assay

Cell response

Compound binds to cell surface receptor - this can be measured

in a “binding assay”

This can evoke a cellularresponse - which can bemeasured in a “functionalassay”

Screening to Generate Hits - where do the hits come from?

High throughput screening (millions of compounds)

– Multi-well plates (384, 1536)

– Automated - advanced robotics

Knowledge-based rational design– Computer modelling

– Structural knowledge, eg X-ray crystallography

– Cheminformatics

Hit Optimisation

Hits from initial screening are rarely adequate for further progression as they stand, so they are further optimised

How is this done?

– Through an iterative cycle of Chemistry (automated arrays) Biological testing in-vitro

Key lead criteria:- Potency (“strength” of interaction with target protein)- Selectivity for target (panel of selectivity tests)- Enablers (facilitate further progression of leads)

What is meant by “Enablers”?

Properties which are desirable but not essential at this stage, e.g.

– Confirmed mode of action (e.g., competitive inhibitor)– Demonstrable structure-activity-relationships (SAR)– Physicochemical properties (solubility, lipophilicity, stability,

purity, chemical complexity)– No difficulties with species differences– Acceptable intellectual property situation (no major concerns

about patents related to leads)– No obvious anticipated safety liabilities (Predictive

Toxicology)

Summary

The starting point for Drug discovery is picking the right target and the right compound(s)

– “Picking the winners”

– It may be 12-16 years and cost >£500M before you find out if you were right !

To reach this point will have taken 3-4 years and cost £1-2M per successful lead!

Part 2:Selecting a Drug Candidate

Topics

Lead optimisation – addition of extra properties (ADME)

Safety testing

Molecules into Medicines

Testing in Humans

Objective of this Phase

This is a major challenge!!!!!Aiming to combine all desired properties into

one molecule – like “winning the lottery”Back-up Program(s)Follow-up Program(s)

To optimise lead molecules to identify a single compound with potential to reach the clinic with: - right properties – potency, selectivity, PK etc. - low probability of failure in development

Optimizing Lead Compounds is an Iterative Process

MedicinalChemistry

Biology

Lead compounds from Screening

Candidate selected for testing in man

Developability

DMPK

Hypothesise, design molecules and synthesise

Analyse/rationaliseresults

Test hypothesis

AbsorptionDistributionMetabolismElimination

Drug Metabolism and Pharmacokinetics (DMPK)

Understanding the fate of drug candidates in animals and man

Animals to Humans

Characteristics of the drug candidate……….

DMPK studies aim to answer some key questions:

What is the relationship between exposure and dose?

Is it readily excreted or retained with potential to

accumulate?

How is the drug metabolised?

Are the toxicology species adequate models to make a

human safety assessment?

What are the safety margins for clinical trials?

Challenges to support First Time in Humans?DMPK

Assays may need very low limits of quantification (<1ng/mL) especially for inhaled drugs and for the human assay to support FTIH

Compounds selected to have low metabolism in vitro so in vitro metabolism studies often generate very small quantities of metabolites

Low levels of radioactivity in plasma samples often makes metabolite profiling difficult

SENSITIVITYSENSITIVITY

The Bridge Between Animals and Humans

Are the toxicology species good models for humans in terms of…

Systemic exposure to the drug?

Routes of metabolism?

Systemic exposure to metabolites?

DMPK provides vital data to assess ‘developability’

Safety Assessment

Animals to Man

Conduct initial non-clinical safety studies to assess

developability and potential risks for first administration to

humans

Conduct additional studies to build confidence that longer term clinical trials can be conducted safely, and the medicine can be approved for use

To complete safety evaluation and assist in dose selection for first clinical trials, Safety Assessment has to:

Genetic damage? Carcinogenicity?

Aspects of a Safety Assessment

One dose Lifetime use

Acute Responses Chronic Effects

Reproduction

Development

Toxicology - What Do We Examine?EXPERIMENTS

Safety Pharmacology(in vitro, rodent, non-rodent)

General Toxicology(rodent & non-rodent)

Genetic Toxicology(in vitro, in vivo)

Carcinogenicity(rodents)

Reproductive & Developmental Toxicology(rodent & non-rodent)

ENDPOINTS

Behaviour, function, physiology

Behaviour, function,

physiology, clinical

biochemistry, pathology

Mutation, chromosomal changes

Non-genotoxic carcinogens

Fertility, pregnancy,

Fetal and peri/post-natal development

Toxicology Tests More Than the Active Drug Substance

Active drug substance

Related substances

Solvents

Degradation products

Excipients

Other active materials

Extractives

All medicines contain more than the active drug!

Assessments of Margins of SafetyExposure in Animal and Human Data

Major considerations

Dose administered

Extent and duration of systemic exposure

Daily systemic exposure

Some other factors...

Exposure & identity of metabolites between species

Exposure in target organs (accumulation?)

Preclinical safety studies will … Explore the response at up to maximum achievable doses

Primarily designed to detect potential hazards

Generate data to enable a risk assessment to be made

Assist in dose-selection for initial clinical studies

Suggest ‘markers’ to monitor safety in humans

Provide a foundation for targeted specialist investigations

Preclinical safety studies cannot necessarily… Guarantee safety in humans

Predict the human response

Define a mechanism for the changes

Summary

Chemical Development (CD), in

collaboration with Pharmaceutical

Development (PD), is charged with

delivering a cost effective, efficacious

medicine...

Drug Substance (DS)Drug Substance (DS) Drug Product (DP)Drug Product (DP)

Molecules to Medicines

Drug Substance synthesis: Scale - up

10-100g

10-100kgLab scale

Factory scale

Testing in Humans - Key Messages

Entry into man is a major milestone– Major ethical and safety reviews before approval

There are no absolutes in designing a clinical plan - but subject safety is always paramount

Initial studies are usually undertaken with healthy male volunteers and at very low doses, with intensive monitoring

Verified surrogate or early clinical markers make all the difference – is the drug getting to the right target at the required levels

Initial goal is to establish safety & tolerability in man Only then will the drug move into patients and “proof of

concept”

Part 3:Product development

Topics

Proof of Concept in Patients

Large scale clinical studies

Registration & Approval

Launch & Life cycle managment

Why Have Proof of Concept?Why Have Proof of Concept?

Comprehensive statement describing clinical outcomes necessary to achieve market forecast

ProductProfile

Proof ofConcept

Clinical evidence giving confidence that the Drug works and is likely to meet the required Product Profile

Proof of Concept is achieved when significant risk of further

development has been reduced, such as demonstrating safety and

potential for efficacy in the patient population

Phase IIb and III

Spend big $$$$$

Objectives of PoC to Commit to Phase III

Demonstrate clinical activity & acceptable safety profile in target patient population

Establish appropriate dose & regimen for Phase III clinical trials

Consult with Regulatory Authorities

FDA:US Food and

Drug Administration

EMEA:European Medicines

Evaluation Agency

MHLW:Japan Ministry

of Health Labour

& Welfare

Agencies providehelpful insight into

study design and doses

Reduce risk of conducting long,

expensive studies that don’t lead

to approval

May change Phase III clinicalplan based on

feedback

Objectives of Phase III

Gather primary safety & efficacy information to:Evaluate overall risk-benefit Provide basis for labeling

Generate data to support positioning & differentiation

Prepare commercial supply sites to pass regulatory inspection

Pivotal Phase III StudiesWhy

Determine safety & efficacy in target indication to provide data for regulatory approval

WhatTwo adequate, well-controlled, double-blind clinical trials

Compare with gold standard, placebo or supportive care

How600 - 3,000 patients1.5 years to 5 years£4 to 50 million per trialMultiple sites & countries

Regulatory Authorities

Food and Drug Administration

European Medicines Agency

Ministry of Health Labour and Welfare

Therapeutic Goods Administration

Health Canada

International Conference on Harmonisation

Over 120 ‘International’ markets

Life Cycle Management

What do Product Line Extensions give?

New indications expand claims

New target patient populations expand patient base

New administration routes

New formulations

Combination therapies

expand patient base, improve compliance

improve access/ease of use

simplify therapy, improve compliance