of new drugs…
TRANSCRIPT
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..