How Targets Are Chosen. Chris Wayman 12 th April 2012

Transcription

1 How Targets Are Chosen Chris Wayman 12 th April 2012

2 A few questions How many ideas does it take to make a medicine?

3 A few questions How long does it take to bring a product from bench to bedside? 0 5 years 5 10 years years

4 A few questions How much does it cost to produce a new medicine? $ M $250M 1B $1-2.5B

5 A Few Facts About Drug Discovery 1 in 64 ideas become a medicine 1 in 10 clinical compounds achieves approval It takes $1-2.5B to go idea-medicine, and takes circa 12 years R&D = High Risk and High Cost

6 The long road to a new medicine Full Development Studies in Patients (Phase II) Studies in Healthy Volunteers (Phase I) Exploratory Development Clinical Data Analysis Large Amounts of Candidate Medicine Synthesized NDA/MMA Candidate Medicine Tested in 3-10,000 Patients (Phase III) Formulations Developed Registration Extensive Safety Studies Candidate Project Team and Plans Synthesis of Compounds Screening Early Safety Studies Research

7 15 Years From Idea-Approval First synthesis (May 1989) FIM (5 July 1991) Filing (Sept 1997) US launch (27 March 1998) Research Development Years Candidate Nomination Idea Tox Ph1 PK & Safety Ph2 Pilot Efficacy Ph3 Full Development Comparative Agents Filing Approval Process Preclinical Clinical Registration

8 The Hurdles We Face Regulatory Approval Process 4 th Hurdle Prescription Safety Efficacy Quality Value for Physicians money

9 The R&D problem...

10 Why potential medicines fail

11 R&D has to adapt to challenge Design molecules that survive Be Faster Than The Competition Be right about targets Select the right patients

12 R&D Mission New medicines must address unmet medical need and deliver benefit to the patient. To do this it is essential that scientists:- Understand the disease and it s pathophysiology. Identify the targets that will modify the disease, providing symptom relief in patients and, very importantly, be safe upon pharmacological intervention.

13 There is no shortage of targets The key is how do we identify targets we believe in, ie the right target, rather than the next target?

14 Successful identification of a promising drug target Access to models & technologies Drug target Disease understanding Understanding of basic molecular mechanism

15 Just how easy is target identification? Hypertension Atherosclerosis Parkinson s Disease Diabetes Cancer? Heart failure? Alzheimer's Disease?

16 Types of Targets / Associated Risk 1. Precedented - clinical benefit has already been shown following pharmacological intervention, agents may already be approved. Low risk of negative POC. 2. Unprecedented - a novel target where the outcome of pharmacological intervention is unclear from the perspective of efficacy and toleration. High risk of negative POC.

17 So Where Do Targets Come From? Building an understanding of the disease pathophysiology. Performing basic scientific studies using techniques such as Gene expression/molecular profiling. Proteomics. Isolated tissue preparations. In vivo studies using a pathophysiological model. Systematically producing gene deleted/knockout mice to identify novel phenotypes.

18 So Where Do Targets Come From? Mapping out the precedented pathways, ie the ones we know if influenced result in clinical benefit, with an aim of identifying alternative target points. Reverse pharmacology - Side effects of existing drugs. Cleaning up the pharmacology of poorly tolerated non-selective drugs. Using clinical research to increase our disease and symptom understanding. Perform human experiments with approved medicines ie clinical trial validation studies

19 So Where Do Targets Come From? Scientific literature including abstracts/meeting reports from scientific meetings, peer reviewed journals and competitive information. One needs to be aware of the quality of publications as often they have been generated with sub-standard pharmacological tools. Serendipity, where a target for a disease can about by accident, often during clinical testing for another indication.

20 Choosing the right target Localisation - Target organ/tissue. Other tissues - indicative of potential safety issues. Is the target altered in the disease state in human tissues/fluids or is there genetic linkage between target and disease? Is the target drugable? What modality are we going to use eg small molecule, antibody, peptide, vaccine, etc? Chemical Doability.

21 Target classes and their modulation Drug Covered target classes Mode of action Small molecular weight chemical compounds Enzymes Receptors Transcription factors Ion channels Transport proteins Protein-protein interface Nucleic acids Inhibitors, activators Agonists, antagonists, modulators, allosteric activators, sensitizers Inhibitors, activators Inhibitors, openers Inhibitors Biologics (Extracellular) proteins Antibodies Trans-membrane receptors, extracellular proteins Cell surface receptors Substrates and metabolites Inhibitors of protein-protein interactions Alkylation, complexation, intercalation Recombinant proteins Anitbody-drug conjugates Enzymatic cleavage Nucleic acids RNA RNA interference

22 Choosing the right target Is there a preclinical disease model or can the pathophysiology be mimicked in animal / isolated tissue to provide a disease assay? Validation? Are there tools available to test the hypothesis in vivo / in vitro. If not, then it may be necessary to run a high throughput screen (HTS), or profile peptide/antibody/sirna libraries so a tool/lead can be found? Does pharmacologically effecting the target have the desired efficacy outcome to answer your hypothesis preclinically? Do we understand the relationship between plasma exposure and pharmacokinetic effect?

23 Choosing the right target Is pharmacologically influencing the target safe? Can we define a therapeutic index for example from efficacy to cardiovascular and/or CNS effects. Intellectual property (IP) Does the use of this target in treating the disease represent an IP opportunity? If not, does the target have freedom to operated (FTO), and if not seek a licence from the patent holder.

24 Target Choice Balancing A Number Of Factors

25 Beyond Target Validation Can we screen for / identify a candidate to test the mechanism in humans? Development of screen sequence capable of identifying / derisking compounds. Can we screen in a cost ($$ & FTE) efficient way? Chemical doability and series IP protection. How are we going to predict dose for clinical studies, and be confident in the pharmacological translation? Early investment and validation of novel and rapid POM design eg in healthy volunteers rather than patients? Will the drug modality be marketable? Are we timely with respect to the competition and is a therapy still needed?

26 Target Knowledge Management Is Key Pathways Genomics Chemical tools Synteny Expression Molecular Interactions druggability Protein Structure and Function mutagenesis Sequence Variation Splice Variants Target Antisense sirna Knockouts and Phenotypes SNPs and Pharmacogenomics Reagents, Antibodies Phylogeny Homologues and Orthologues Screen data Binding cavity predictions Differences in model species

27 Disease with high unmet medical need Identification of a molecular drug target Target assessment Molecular target assessment (experimental) Characterisation of the molecular mechanisms addressed by the target Modification of disease by target modulation in a relevant in vivo model? Drugability assessment (theoretical) SMOL binding domain existing? Extracellular domain (for BIOL) existing? Crystal structure available? High-throughput assay feasible? Ideas on target-related/stratification biomarkers Ensure early proof-of-concept Adverse events evaluation Tissue selectivity of expression Phenotype data Clinical data (if existing) Drug class related adverse events IP/Competitors Freedom to operate (FTO) analysis Options for commercialization Common mechanism potential of target Options for IP generation

28 Pharma R&D Has To Be Innovative & Adapt To Challenge Be right about targets Design molecules that survive Be Faster Than The Competition Select the right patients