From Discovery to Development of new Drugs. and pitfalls along the way. by Kim Dekermendjian, PhD in Medicine BD & Key Account manager

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1 From Discovery to Development of new Drugs. and pitfalls along the way by Kim Dekermendjian, PhD in Medicine BD & Key Account manager

2 The roots of Drug Discovery Before 20 th 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 years and cost > $.

3 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

4 The modern Drug Discovery Cycle

5 Major steps in the Drug Discovery process Can be in an academic lab Often Pharma industry Require GLP lab Require mg of compound that could be of mixed quality Require >100g of compound of GMP quality

6 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)

7 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.

8 From Discovery to Development

9 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.

10 Pre-clinical studies According to guideline ICH M3 (R2) Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals 100 MABEL therapeutic range unacceptable toxicity 80 NOAEL 60 Effect NOEL? Dose or Exposure -Determine safety window in relation to NOAEL= no observed adverse effect level. -MABEL= minimal anticipated biological effect level. -MED= minimum effective dose. MED

11 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

12 Selecting your animal model, mice are not men Regulatory requirement for pharmaceutical product: One rodent and one non-rodent species.

13 Bio availability, Human vs animal

14 How to ensure Bio availability pre-clinical studies Considerations for formulation Considerations for formulation in pre-clinical studies

15 Bridging further from discovery to development SAFETY EFFICACY RISK QUALITY BENEFITS Quality in a regulatory environment: 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 GLP - GOOD LABORATORY PRACTICE GMP - GOOD MANUFACTURING PRACTICE GCP - GOOD CLINICAL PRACTICE GDP GOOD DISTRIBUTION PRACTICE

16 The long hard clime to a clinical candidate drug Development candidate Pharmacokinetic problems Solubility issues.. Lead series 1 Metabolic issues.. Lead series 3 Lead series 2