Novel therapies From research hypothesis to clinical routine

Drug development process

Target

Right molecule Candidate drug

Preclinical documentation

Clinical documentation

Drug Discovery 5-7 years

Drug Development 7 years

Drug Discovery and Development

CD(Candidate Drug) NDA(New Drug Application) Launch Drug Discovery PhI

Drug Development

Registration

Preclinical

PhII PhIII Clinical

PhIV

Compound production Manufacturing

FDA/EMEA review 0.5-2 years

QA and regulatory
IND Investigational New Drug (first time in man) Drug Discovery Preclinical Preclinical Drug Development PhI PhII PhIII Registration NDA New Drug Application

GLP (Good Laboratory Practice) GCP (Good Clinical Practice) GMP(Good Manufacturing Practice)

Intellectual Property, IP (Patents)

Drug Discovery Preclinical Drug Development PhI PhII PhIII Registration

Patents: Structure class Compound specific Synthesis Indication Formulation ....

Patent time: 20 years from the filing date Drug development 10-14 years

Trends in Pharma Industry

Benchmarking Small molecules Biologics Blockbusters Orphan drugs Inhouse Outsourcing (CRO)

How to identify relevant targets? (Per-Gran)

How to find the right molecule? (Ingrid)

Attrition Rate

How to find the right molecule?

What is the right molecule?

Where is the target?
Peripheral or local?

Disease and treatment duration?

Life threatning disease? Acute or chronic treatment?

Compound profile (1)

Potent on the target Selective Site of target

Example: Design for local action in the gut

Entocort
Local action in terminal ileum &colon High first pass metabolism in the liver Low systemic exposure 10-20%

Compound profile (2)

Safe: Large therapeutic window

Therapeutic Window

Low risk of interaction with other drugs

Compound profile (3)

Dose
Acceptable dose regimen oral once daily dosing

Manufacturing
Acceptable synthesis route and production costs

How to find the right molecule?

Target based drug design Knowledge based drug design Me too (improve present drugs)

Knowledge/ Mechanism based drug design

Some examples
Sulfasalazine Omeprazol

Sulfasalazine
(Nanna Svartz) Inflammatory Bowel Disease

+
Sulfapyridine Anti-bacterial 5-aminosalicylic acid Anti-inflammatory

Sulfasalazine (Prodrug)
Azoreductase (Bacterial)
Sulphapyridine Anti-bacterial

5-aminosalicylic acid Anti-inflammatory

The Omeprazole (Losec) story

Antisecretory Severe acute toxicity Lead compound No acute toxicity Covered in a patent Lit. search Tioureas with no toxicity Potent in human. In vitro assay available

Metabolite Not in patent More potent Thyroid toxicity in long-term tox studies

Losec
Knowledge of proton pump mechanism Accumulatioan of bases in parietal cells: increase pKa

Nexium
Enantiomer More potent

Nature 2003

Nexium
Me too
Improve existing compounds

Way to success
Build on knowledge creative ideas Scilled medicinal chemists Dedicated project team Serendipity and luck - prepared mind

Chemistry
Toxicology
Pharmacology Metabolism PK

Target based drug design

High through put screen, HTS
Screen of chemical libraries

Virtual screen
Ligand based Structure based

HTS: High Throughput Screen

Known target
In vitro assay

Compounds:
Chemical libraries Natural products

HTS Issues
Drugability
Lipinskys rule of five
Mw<500 Log P <5 H-donor<5 H-acceptors<10

Relevant in vitro assay

Membrane bond proteins (GPCRs)

Lead generation
Hit to lead (lead generation) Lead optimisation Candidate drug
Activity Selectivity Drug-like properties

Virtual screen ( in silico)

Ligand based
Knowledge of other molecules that bind to the target Build on known pharmacophore

Structure based
Knowledge of three dimensional structure of the target (X-ray or NMR) Docking

Lead Optimisation
Potency Efficacy DESIGN AND SYNTHESIS Pharmacokinetics Metabolism

Selectivity

Phys.chem

CD Candidate Drug

NK antagonists for IBS

NKr involved in IBS related biological effects
Visceral sensitivity /pain Gut dysmotility

Secretion
Neuroinflammation Stress

Neurokinin (NK) Receptors and Tachykinin Ligands

GPCR NK1 NK2 NK3
Preferred Receptor
Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met His-Lys-Thr-Asp-Phe-Phe-Val-Gly-Leu-Met

Ligand

Substance P NKA

NK1 NK2

NKB

Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met

NK3

NK project Challenges in the lead optimisation

Potency on two receptors In vivo effect CYP inhibition Safety Transporters Receptor selectivity Ion channels (hERG) Permeability Metabolism CNS
Balancing many properties Do right things at right time Prediction to human

> 1000 compounds

Potency
In vitro
Functional cell-based assays (FLIPR)
Intracellular calcium mobilization (GCRP)

In vivo Species differences!

Potency in vivo?
Agonist induced models ( NK1 and NK2)

Effective in IBS?
Disease related models

AZD5329

Potent on NK1 and NK2 in vivo

NK1 peripheral Cromodacryorrhoea
NK1 central Gerbil Foot Tap NK2 peripheral Fecal Pellet Output

Agonist icv Agonist ip Agonist iv

IBS related animal models Gut dysmotility

Gut dysmotility in IBS
Exaggerated motility response to stresshormone CRH in IBS patients

Role of NK in gut dysmotility

AZD5329 attenuate stress-induced fecal pellet output in gerbil

15

# of pellets

10

** **
5

0
ss um ol /k g 3 um ol /k g 10 um ol /k g 20 um ol /k g 1 Ba sa l St re

IBS related animal models Visceral hypersensitivity

Visceral sensitivity in IBS
Lower threshold of pain in IBS patients in colorectal distension

Role of NK in visceral sensitivity

AZD5329 normalise the response to colorectal distension in gerbils

(( ))
0.15

Response to CRD

vehicle AR-H077597

0.10

0.05

** * ** ***

** *********

0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13

pulses 12x80mmHg

Bioavailable

Permeability

Metabolism

Permeability
Caco-2 cells
Papp Efflux

Apical Basolateral

Metabolism in vitro
Hepatic clearance Unwanted metabolites
Liver slices

Hepatocytes

Microsomes

Bioavailability in vivo
Oral dosing
Cp (umol/l)
0.7000 0.6000 0.5000 0.4000 0.3000 0.2000 0.1000 0.0000 0 2 4 6 8 10 12 14 16 18 20 22 24

Iv dosing
Cp (umol/l)
8.0000 6.0000 4.0000 2.0000 0.0000 0 2 4 6 8 10 12 14 16 18 20 22 24

Time (h)

Time (h)

Bioavailability = AUC (iv) / AUC (po) correction for dose diff.

CNS permeability
Blood brain barrier Efflux (Pgp)

Risk of drug drug interaction? CYP inhibition

CYP2D6 30%

CYP3A4 50%

CYP2C19 3% CYP2C9 5% CYP1A2 7%

Drug drug interaction CYP inhibition

Tolbutamide + sulfaphenazole

Tolbutamid

I.Phlman / 061012

Risk of drug drug interaction? Transporters

Nature Reviews, 2010

Acceptable dose regimen!

Dose size: Dose interval: < 300 mg once daily

Predicted human dose

Ceff x CL x Dose interval Dose =

Bioavailability

Dose prediction
In vitro potency, IC50 In vivo effect, EC50 Plasma protein binding Scaling from animal to man

24 h (once daily) 12 h (b.i.d)

Ceff x CL x Dose interval Dose = Bioavailability

Animal in vivo data Human in vitro data

Dose interval: t1/2, therapeutic range

I.Phlman / 061012

Allometric scaling of clearance

Human (predicted=3.7 mL/min/kg)
3 2.5 log(CL) = 0.58(log W) + 1.35 R2 = 0.9894

log CL

Rat

1.5 1 0.5

Cyno

Dog

-1.00

-0.50

0 0.00

0.50

1.00

1.50

2.00

log(bodyweight)

Dose regimen
NOAEL Therapeutic window
Compound=-63

1.5

Max Ceff
1.0

Min Ceff
0.5 0.0 0 20 40 60 80 100 120

Time (h)

CD nomination!
Next steps before going into man
Safety studies Synthesis of clinical batch GMP Formulation: solution, capsules.. Application for clinical study - IND

Preclinical documentation (Ingrid)

Preclinical documentation
Phase I Phase II Phase IIII Registration

Non-clinical risk and benefit assessment for

estimation of an initital safe starting dose in human to support the clinical program

Studies
Pharmacodynamics Pharmacokinetics Toxicology

Regulatory guidelines Quality requirements

Good Laboratory Practice GLP

Acceptable facilities Good laboratory routines
State-of-the-art, validated methods Well controlled instruments

Documentation back-track Dates and signatures Audited study reports Inspections by the authorities

Pharmacodynamics
Primary pharmacodynamics
Efficacy in appropriate animal models

Secondary pharmacodynamics
Selectivity over other receptors

Safety pharmacology
Study package according to guidelines Required before first clinical study

Safety Pharmacology
Definition:
Studies that investigate the potential undesireable pharmacodynamic effects of a compound on physiological functions in relation to exposure in the therapeutic range and above

Studies:
Cardiovascular System Central Nervous System Respiratory System Renal/Urinary System Gastrointestinal System

Pharmacokinetics
Important for interpretation of pharmacological and toxicological studies and for prediction of human dose and safety
Absorption Distribution Metabolism Excretion Drug interactions Toxicokinetics
Dose proportionality Time dependency Sex differences

Toxicology
Aim
Increase the dose to find toxicity
Top dose 2000 mg/kg (correspond to 120 g dose to 60 kg man!)

Establish highest tolerable dose in animal studies (No Adverse Effect Level, NOAEL) Identify toxicity findings/target organs Dose dependency and reversibility Establish exposure in tox animals: Cmax and AUC Calculate safety margins vs therapeutic doses (AUC)
Cmax

AUC

Toxicity studies are related to the clinical program

Phase I Phase II Phase IIII

IND (IMPD)

NDA

Single and repeated dose studies

At least two species ( rodent and non-rodent)
Duration of clinical study Single dose Up to 2 weeks Up to 1month Up to 3months Up to 6 months >6 months Minimum duration of rodent study 2 weeks 2 weeks 1 month 3 months 6 months 6 months Minimum duration of nonrodent study 2 weeks 2 weeks 1 month 3 months 6 monhts 9/12 months

Other toxicity studies

Genotoxicity studies
Mutagenicity (bacteria) Chromosomal damage (in vitro) In vivo genotoxicity (micronucleus)

Reprotoxicity ( relevant species for human)

Fertility Early embryonic development Maternal function Embryofetal development

Carcinogenicity studies
Rat and mouse 2 years dosing Expensive Critical timeline
Phase I Phase II Phase IIII

ICH Guidelines
M3 Nonclinical Safety Studies for Conduct of Human Clinical Trials for Pharmaceuticals