Lecture 1 and 2.pdf

Lecture 1 and 2– Drug discovery and development pipeline 1. Recall the stages of the drug discovery and development pipeline and describe the purpose of each stage. 2. Differentiate between clinical trial phases and describe typical primary and secondary outcome measures. 1. Recall the stages of th...

Lecture 1 and 2– Drug discovery and development pipeline 1. Recall the stages of the drug discovery and development pipeline and describe the purpose of each stage. 2. Differentiate between clinical trial phases and describe typical primary and secondary outcome measures. 1. Recall the stages of the drug discovery and development pipeline and describe the purpose of each stage. Drug discovery – the process to get to a candidate drug, starting with therapeutic concept. Drug development – developing a candidate drug into a final drug that goes on the market. ◼ Therapeutic Concept: What’s the working hypothesis? ◼ Target Selection: What’s the molecular target? and… ◼ Target Validation: Is it likely to be effective? ◼ Lead Finding: Can a (chemical) starting point be identified? ◼ Lead Optimisation: Can the drug-like properties be optimised? ◼ Preclinical Development: Will it be appropriate for testing in humans? ◼ Clinical Development: Is it safe & therapeutically useful in humans? ◼ Regulatory Approval: Does this drug have value to society? ◼ Product: Is the drug commercially attractive? Pneumonic to remember: teacher tanya told logical lucy playing chess requires patience. Drug discovery pipeline is ‘leaky’ The discovery success rate is 0.2% and the development success rate is 11.8%. It is very expensive - $1.4 billion per compound. It is very slow – 10-15 years from concept to product. Therapeutic concept: the working hypothesis of what the drug does, combining a research, development and commercial view. Considerations to be made when developing a therapeutic concept: Research = can it be done? Is the technology available? Development = can it be tested? Are there the correct assays or animal models that can determine if the drug is safe and effective? Commercial = can it be sold?  Is the drug going to make any money, is it innovative and are there new molecular targets or pharmacokinetics? Target selection Approaches tend to be based on early target validation. 3 possible approaches: Analysis of disease pathophysiology o Which receptors are involved? o Which enzymes are up or down regulated? Mechanism of action of existing drugs o E.g. antipsychotics developed from antihistamines - they targeted dopamine receptors so this was utilised. E.g. chlorpromazine. Information from gene expression or genomic studies. o E.g. cells with genetic fault e.g. CFTR channels in exocrine cells in cystic fibrosis. Effective target validation relies on understanding how systems work together. GPCRs are the most common drug target. Target selection is enhanced by increasing structural information – you can use structural databases to optimise drug structure (bioinformatic drug development). Rational drug design: target comes first by understanding pathophysiology. Examples: Disease Target Identified Drugs developed AIDS Reverse transcriptase HIV protease Zidovudine, saquinavir Cancer Dihidrofolatereductase Methotrexate Alzheimer’s Acetylcholinesterase Donepezil Depression 5HT transporter Fluoxetine Alternatively, you can identify drug targets by analysis of existing drugs’ effects. You can register drugs without knowing exactly how they work. Targets identified by analysis of existing drugs: Target validation Target validation can occur across several stages of clinical trials, but real target validation happens in phase 2 clinical trials. Preclinical validation can give confidence e.g. does the drug bind the receptor, is there a clinical effect in animal models etc. Preclinical validation approaches: Pharmacological Non-selective compounds from literature. Early stage project compounds. Different classes of compounds with the same effect (e.g. antibodies). Genetic Antisense oligonucleotides – if you switch off the gene does the disease stop? RNAi Transgenic animals – deletion/overexpression Helps you confirm if a certain gene/gene product is the appropriate target or not. Examples for how current drugs have been developed: Ranitidine: Once a day H2 receptor antagonist, used to treat peptic ulcers. How has it followed the Therapeutic Concept considerations? o Research: strong chemistry and Drug Metabolism and Pharmacokinetics (DMPK) expertise o Development: clinical trial end points & regulatory strategy established o Commercial: once a day H2 antagonist therapy would improve compliance How were target selection and validation done? o Mechanism of action of existing drug – cimetidine (taken twice a day) ·  o Ranitidine – designed to improve compliance as it is a once a day drug. o Analysis of disease pathophysiology - role of histamine acting on H2 receptor in gastric acid hypersecretion. Ticagrelor: Oral P2Y12 receptor antagonist (anti-platelet drug). How has it followed the Therapeutic Concept considerations? o Research: Strong chemistry and purinoceptor expertise o Development: Clinical trial end points & regulatory strategy established o Commercial: Product placement focused on differentiation from cangrelor (administered intravenously ) and in turn clopidogrel (which is a pro-drug requiring activation by hepatic metabolism). How were target selection and validation done? o Analysis of disease pathophysiology - known role of platelet in CV disease o Mechanism of action of endogenous mediator – ADP o Proof of concept with cangrelor Adalimumab: Humanised anti-TNFα antibody for the treatment of rheumatoid arthritis How has it followed the Therapeutic Concept considerations? o Research: Unique phage display based antibody generation technology o Development: Clinical trial end points & regulatory strategy established o Commercial: Company placement based on value of anti-TNF market How were target selection and validation done? o Analysis of disease pathophysiology - known role of TNFα in RA o Mechanism of action of existing drug – etanercept (fusion protein that mimics TNFα receptor and binds soluble TNF-α) Imatinib: AbI-kinase inhibitor for the treatment of chronic myeloid leukaemia. How has it followed the Therapeutic Concept considerations? o Research: Strong chemistry, kinase inhibitor background o Development: No “prior-art”. Novel, accelerated clinical trials programme established. o Commercial: Commercial potential limited but no direct competition; kinase inhibitors toxic & non-specific. How were target selection and validation done? o Information from gene expression studies - oncogene product Bcr-Abl constitutively active o Analysis of disease pathophysiology - mutated tyrosine kinase led to malignancy o Clear association of oncogene, Abl kinase and CML Lead Finding Lead compounds can be identified by analysis of pathophysiology or by the analysis of drug effects in a bioassay. Lead finding through analysis of pathophysiology: MOLECULAR TARGET KNOWN AT PROJECT INCEPTION Project is driven by finding & refining novel chemicals with affinity for the molecular target- Increase affinity to pathophysiological target. As project matures, improved compounds can be used to validate the molecular target. Lead finding strategies: o Virtual Screening’ based on computer model of target o High Throughput Screening; chemical libraries o Natural Product Screening; extract libraries o Fragment Screening; binding efficiency o Privileged Structure screens o ‘Family-based’ compound libraries; kinase inhibitors, GPCRs o Natural ligands; catecholamines, purines, tryptamines, histamine o Known drugs with overlapping activity Leads identified by analysis of drug effects in a bioassay REGULATORY AUTHORITIES DO NOT REQUIRE THAT THE MOLECULAR TARGET OF A DRUG IS IDENTIFIED prior to authorisation, although some intelligent guesswork, or a working hypothesis is useful. Project is driven by refining the desirable drug effect Target may not be known at project inception As project matures, improved compounds can be used to identify molecular target Example; levetiracetam o Anti-epileptic discovered & developed using complex models of epilepsy in vivo o Approved in the USA for myoclonic seizures in 2000 o Putative molecular target (SV2A; synaptic vesicle protein) published in 2004 Lead Optimisation The physicochemical and PK/PD properties of a drug will determine if it is likely to be safe, effective and get to its site of action. Physical properties Molecular weight (Mr) For orally active drugs, the molecular weight should not exceed 500. Log P (lipophilicity) P = partition coefficient, describes lipid solubility of the drug. Comparison of solubility in octanol vs water. P = [drug]octanol/[drug]water Log P = Log {[drug]octanol/[drug]water} High P = lipophilic, low P = hydrophilic Log scale, therefore logP of 3 = 1000 times more soluble in water. Log P>5 – likely to be too lipid soluble and won’t leave lipids. Log D (distribution coefficient) P assumes the drug is in a non ionised form Many drugs are ionisable. Log D measures the relative concentration of all forms of the drug (ionised and non- ionised) in octanol vs an aqueous phase of stated pH (typically pH 7.4). {[ionised drug] + [non-ionised drug]}octanol Log D = Log {[ionised drug] + [non-ionised drug]}aqueous pKA (ionisation properties) Aqueous solubility PPB (plasma protein binding) “In the discovery setting ‘the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight is greater than 500 and the calculated Log P is greater than 5”. Pharmacokinetic properties Pharmacokinetic properties Multiple doses Steady Toxicity level Safety State Cmax window Single doseCmax Single dose [Plasma] Therapeutic window Steady State Cmin Minimum effective conc. Time of action tmax Time Area Under the Curve Onset time (AUC) Cmax = maximum concentration a drug achieves after the drug has been administered. Cmin = minimum concentration drug reaches between doses. Toxicity level – dose at which toxic effects occur. Minimum effective concentration – the concentration needed in the plasma to produce a therapeutic effect. Therapeutic window – the range of doses where a drug is effective without producing significant adverse effects. Metabolism Phase 1: oxidation – makes drug more polar so it is more readily excreted. Phase 2: conjugation – makes drug larger and more hydrophilic Metabolism should always be considered as you will have active and inactive metabolites. Pharmacodynamic properties We need to know: Mechanism of Action: is the drug an enzyme inhibitor, receptor antagonist or receptor agonist? Affinity: over what concentration range will the drug have its effect? Efficacy: What is the drug’s maximum effect? Kinetics: does the drug bind reversibly or irreversibly to its target receptor (is it ↳wI competitive)? Specificity: what effects will the drug have on other targets, and over what concentration range? Does it have off target affects? Parallel screening cascade: Parallel assessment of affinity, physical properties and metabolism assessed at the same time to speed up development. Preclinical development The focus shifts to: Physical properties -> Scaling up pharmaceutics for production Pharmacodynamic properties -> Safety pharmacology and toxicology. Pharmacokinetic properties -> metabolite identification, dose linerarity (is concentration and effect linear, therefore will metabolic processes become saturated?), toxicokinetics. Formal safety testing prior to first in human studies happens at this point. This can establish the safety window. See core battery tests in clincal trials lecture. 7-28 day toxicity studies in 2 species define the maximum tolerated dose and no observable adverse effect level. Clinical development Purpose of clinical trials: To gain market authorisation e.g. from FDA, MHRA, EMEA and local healthcare recommendations e.g. get drugs into the NICE guidelines.  To assess the clinical benefit of the drug e.g. the efficacy, does it improve standard of care or quality of life. To assess risk – e.g. adverse effects, on target and off target adverse effects. Likelihood and power of adverse effects Likelihood of detecting an event depends on exposure x frequency Exposure = Number of patients observed & Duration of study Frequency = Likelihood of an event & Threshold for event For Adverse Drug Reactions (ADRs) o Very Common ~ 1/10 o Common ~ 1/100 o Uncommon ~ 1/1000 o Rare ~ 1/10,000 o Very rare < 1/10,000 Power 95% likelihood of observing an ADR with 1/n frequency requires ~3n patients, therefore to detect an effect in 1/10 people, you would need to test 30 people. 2. Differentiate between clinical trial phases and describe typical primary and secondary outcome measures. Phases of clinical trials in drug development: Phase 1 First in human  Drug will already have been tested in 2 species, 1 non rodent to identify chronic toxicity therefore it is likely to be safe in humans. Has the following primary endpoints: o Safety – does it have any dangerous side effects? o Tolerability – does it have any unpleasant side effects that could affect compliance. Tested in 40-60 healthy volunteers exposed to single ascending dose and multiple ascending doses. Placebo controlled randomised, double-blind. May have a selected subject group. Can include other readouts e.g. pharmacokinetics, proof of mechanism Phase 2 and 3 Trial Design and Clinical Outcomes Patients/people with the disease divided into treatment groups (arms). There will be inclusion and an exclusion criteria. RANDOMIZATION is essential, but may be stratified where patients in each group are matched for age, sex, disease severity, ethnicity One arm is CONTROL group (receive existing treatment or PLACEBO or nothing at all). Other arm is TREATMENT group Trial usually carried out DOUBLE BLIND to avoid investigator bias (objective data) and participant expectations. Not always possible though e.g. if drug makes you nauseous. Crossover trials may be performed where patients receive both treatments in a randomised order. Trials may also incorporate a period of independent, interim analysis. Outcomes are established in the design phase and must be relevant to the purpose of the trial. Measures often include clinical efficacy or improved side effect profile. Definitive endpoints e.g. survival rate are not always practical therefore surrogate measures may be used e.g. reduction in tumour size. Other measures include quality of life measurements like QALY – quality- adjusted life years. You can measure cost per qaly which can allow prioritisation of health service spending. Phase 2 specifics Studies efficacy, proof of concept and safety. Small number of patients exposed to limited dosing regime in specialised facility. Placebo controlled, randomised, double blind where possible. Phase IIa – exploratory o 50-200 patients o 1 year o Dose and treatment based on phase 1 results Phase IIb – confirmatory  o Confirms if efficacy is statistically significant o Confirms dose and treatment regime for larger trial o 200-500 patients o 2 years o Compared to placebo or current treatment Phase 3 specifics Full scale evaluation of how effective and safe a drug is compared to current standard treatment/placebo 2000-10,000 patients in multi centres and with different groups Lasts several years, especially with chronic diseases like arthritis. Provides data to support registration for a specific condition. Phase 4 Post market surveillance (pharmacovigilance) Doctors and patients report side effects through yellow card scheme. Monitors consequences of increasing exposure Large patient group allows you to see rare or very rare long term adverse effects. Regulatory approval Regulatory approval is a contract between the health authority e.g. MHRA and the pharmaceutical company. Health authority protects interests of society and public health and ensures the drug has a clear benefit for patients. The pharmaceutical company has permission to market the drug product for a specific indication. They own the documentation used for assessment and compile and evaluate safety and quality data. Regulatory documentation must describe, often in a standardised format: ̈Quality: Chemistry & Pharmaceutics Pharmacology Pharmacokinetics, ADME Toxicology Efficacy assessment (studies in humans) Regulatory body provides approvable letter with indication, labelling, monitoring and product information in the relevant territory. Reasons for drug failure: Safety – often comes out in phase 1 or 2 trials. Efficacy – phase 2 and above. Economics – low return on investment, crowded market, too short period of market exclusivity.