of new drugs…

byKim Dekermendjian, PhD in Medicine

BD & Key Account manager

From Discovery to Development

of new Drugs….and pitfalls along the way

The roots of Drug Discovery

• Before 20th century the term didn't exists, in those days it was simply Pharmacology or Medicine.

• Drug Discovery as its own discipline came from the interdisciplinary collaboration (with an industrial base) between the more specific scientific disciplines of Pharmacology, Medicine and Chemistry after the 1 world war.

• The process of R&D for novel drugs from start to market typically take 12-14 years and cost > 1.000.000.000 $.

The goal of Drug Discovery

Identify a drug candidate with unique profile to treat unmet needs of a

disease

The drug candidate:

-Defined pharmacology to address unmet needs

-Balanced drug-like properties to produce a therapeutic effect with an

acceptable dosage regiment

-Adequate therapeutic window to side-effects

-Limited PK and therapeutic effect variations in defined patient segments

-Patentable

- First-in-class or competitive with other drug candidates in development

The modern Drug Discovery Cycle

Major steps in the Drug Discovery process

Require mg of compound that could be of mixed quality Require >100g of compound of

GMP quality

Can be in an academic lab Often Pharma industry Require GLP lab

Evaluation of new small molecule drugs

Primary biological testing

- Affinity for primary target

- Efficacy & selectivity

Physical/Chemical properties testing

- Solubility

Initial Pharmacokinetic testing

- Microsomal stability, oral bio availability in rodent

- Membrane passage and transport

Early Toxicology testing

- Searching in databases for “problem structures”

- Rapid initial tox screening, (not much compound needed)

Initial toxicology

Rapid Toxicological screening

- easy and high throughput

In silico Gene tox. Cytotox. Organ/tissue

models

- but doesn’t predict low frequency tox issues or other mechanisms, full in-vivo toxicology studies needed to minimize risk.

From Discovery to Development

From Discovery to Development cont…

As a project mature the knowledge of the compound

expands and so does the requirements.

Key aspects to consider:

•IP strategy

-When and what to patent?

•In-vivo models to bridge to clinical studies.

•Toxicology testing to match clinical studies.

•When to initiate GMP production, quality requirements.

Pre-clinical studies

According to guideline ICH M3 (R2) Non-clinical safety studies for the

conduct of human clinical trials for pharmaceuticals

-Determine safety window in relation to NOAEL= no observed adverse effect level.

-MABEL= minimal anticipated biological effect level.

-MED= minimum effective dose.

Dose or Exposure

10 100 1000 10000

Effect

0

20

40

60

80

100

therapeutic

rangeunacceptable

toxicityMABEL

MED

NOAEL

NOEL ?

Dose or Exposure

10 100 1000 10000

Effect

0

20

40

60

80

100

therapeutic

rangeunacceptable

toxicityMABEL

MED

NOAEL

NOEL ?

The guideline ICH M3 (R2)

Guideline objectives

-Recommend international standards for non-clinical safety studies to

support clinical trials

-Facilitate timely conduct of non-clinical studies

-Reduce use of experimental animals (RRR)

-Promote ethical development of safe pharmaceuticals

Scope of guideline

-Safety pharmacology studies

-Single and Repeat dose toxicology studies

-Toxicokinetics / pharmacokinetics

-Reproductive toxicology studies

-Genotoxicity studies

-Carcinogenicity studies

-Phototoxicity, immunotoxicity, juvenile toxicity, abuse studies

-Other studies

Selecting your animal model, mice are not men…

Regulatory requirement for pharmaceutical product:

One rodent and one non-rodent species.

Bio availability, Human vs animal

Considerations for formulation in pre-clinical studiesConsiderations for formulation

How to ensure Bio availability pre-clinical studies

QUALITY

EFFICACYSAFETY

RISK BENEFITS

Bridging further from discovery to development

Quality in a regulatory environment:

GLP - GOOD LABORATORY PRACTICE

GMP - GOOD MANUFACTURING PRACTICE

GCP - GOOD CLINICAL PRACTICE

GDP – GOOD DISTRIBUTION PRACTICE

Like all other aspects of

R&D (and life in general)

there is no guarantee for

success, but use your

best judgment and keep a

balanced approach…

The long hard clime to a clinical candidate drug

Development

candidate

Pharmacokinetic problems

Lead

series 3

Lead

series 1

Lead

series 2

Metabolic

issues..

Solubility

issues..