Drug Discovery Process Explained

• Explains the drug discovery process, focusing on the discovery phase with Dr. Jason Gill as the presenter.

Drug Substance

• Drugs are articles intended for diagnosis, cure, mitigation, treatment, or prevention of disease.
• Drug substances or APIs exert pharmacological action.
• Excipients and other ingredients are used to formulate medicinal products.
• A drug product has one or more APIs.
• Excipients are components other than the API and enhance stability or control the release of API.
• Excipients also assist in product identification or improve other product characteristics.

Drug Discovery Process Overview

• Preclinical studies involve forming a research team, synthesizing novel chemicals, and testing for efficacy and safety in test tubes and animals.
• Formulation, stability, and chronic safety studies are performed in animals to choose a drug candidate.
• A company files an Investigational New Drug (IND) application with the FDA after preclinical studies.
• Clinical studies involve Phase I studies in healthy humans for toleration.
• Phase II studies in patients assess efficacy.
• Phase III studies include large clinical trials in many patients.
• The company then files a New Drug Application (NDA).
• The FDA reviews the NDA and, if approved, the drug can be marketed.

Discovery Phase

• Start by identifying the disease issue and gather as much information as possible about the disease.
• Identify a molecule in the body for the drug to target, and confirm its role in the disease.
• Then design and synthesize compounds/therapeutics, screen against the target, to identify 'hit' compounds
• Conduct stability studies, preliminary pharmacokinetics, initial solubility, and formulation studies.
• This includes altering physicochemical properties, formulation, delivery route, scale-up, and cost.

Development Phase

• Pre-clinical testing involves in vitro and in vivo testing of drug toxicity and safety to identify a safe starting dose for human trials.
• Phase 1 clinical trials are initial human trials with healthy volunteers.
• Drug safety and dose escalation are determined here
• Phase 2 clinical trials test a small group of patients to evaluate efficacy.
• Phase 3 clinical trials involve a larger group of patients for comparison to standard treatments.
• Apply to the appropriate authorities for marketing authorization.
• Manufacturing involves full-scale production.
• On-going studies and Phase 4 trials involve continuing monitoring and clinical success evaluations.

Drug Actions

• High failure rates of drugs can be credited to a primitive understanding of the molecular actions of drugs.
• A deeper comprehension of molecular action reduces failures.

Target-Oriented Drug Discovery

• Process that includes target identification, target validation, and lead compound identification.
• Involves lead optimization and preclinical profiling/clinical trials.
• Employs both chemical biology (high-throughput screening) and structural biology (3D protein modelling).

Drug Target Characteristics

• A Drug Target is a bio-molecule that is either present in diseased tissue, has elevated expression, and/or is overactive.
• Drug targets have a contributing function to the disease or an involvement/role in the disease process.

Drug Target Mechanisms:

• Enzymes are targeted with reversible and irreversible inhibitors.
• Receptors are targeted with agonists and antagonists.
• Viral Surface Proteins are targeted to block entry into the cell.
• Ion channels are blocked or opened.
• Transporters are targeted to block or promote transport.
• Nucleic Acids are used to inhibit function and prevent gene expression.

Target Validation

• Requires extensive evidence to show the central role in disease and clinical relevance.
• A good target will produce a safe and efficacious response when targeted.
• Demonstrated disease functionality in vitro and in vivo.
• The mechanism for how the drug works must be understandable with molecular methods.
• Target modulation should be monitored in the clinic.

Hit Identification

• Once a validated target is available, synthesize compounds and identify those that have an affinity for it.
• Little information about 'druggability' will be established.
• Identify recombinant proteins, isolated enzyme assays, and/or biochemical assays.
• Involves high-throughput screening or targeted screening.

In Vitro Pharmacology Assays

• Utilizes isolated tissues, cells, or enzymes for testing.
• Enzyme inhibitors, receptor agonists/antagonists, cytotoxicity, and cellular response can be tested.

Intellectual Property

• Securing intellectual property is vital in the drug discovery process

Hit to Lead Pharmacology Studies

• Preclinical proof-of-principle involves screening development, high-throughput screening, and target identification.
• Moves through primary HTS, parallel medicinal chemistry, optimal potency/selectivity, and identification of efficacy
• Includes discovery pathology modeling and toxicity screens.

Preclinical Studies: Basic Goals

• Identify pharmacological properties, mode of action (PD), and metabolism (PK).
• Conduct comparative physiology to extrapolate data to humans.
• Understand the toxicological profile, establish a safe initial dose, and identify parameters for monitoring.
• Evaluate special toxicities: genotoxicity, carcinogenicity, and reproduction toxicity.

Preclinical Assessment Details

• Establishes mechanistic hypotheses for toxicology/safety and applies risk-benefit considerations.
• Uses in vitro methods, alongside in vivo animal experiments.
• Normal package includes one rodent and one non-rodent species, with relevance to humans depending on tissue.
• Trans-species toxicology findings indicate higher significance for humans.

ICH (International Council for Harmonisation) Guidelines

• Guidelines are harmonized for better health, covering quality, safety, efficacy, and multidisciplinary aspects.

Preclinical Safety Assessment

• Aims to ensure that developed products do not cause harm to humans within reasonable limits.
• Establishes dose-response and exposure-response relationships and allows informed risk assessment.
• Identifies the initial safe starting dose for humans, stopping doses, and affected organ systems.

Safety Pharmacology Objectives

• Provide a perspective on the potential risks to humans from exposure to a new therapeutic agent.
• Investigate the mechanism of adverse pharmacodynamic effects.
• Evaluate adverse effects observed in preclinical toxicology and/or clinical trials.
• Determine the temporal relationship between pharmacodynamic responses and drug blood levels.

Hierarchy of Organ Systems

• The Cardiovascular, Respiratory, and Central Nervous Systems carry Life-supporting functions.
• Secondary systems include the Renal, Gastrointestinal, and Immune System, plus others.
• Immune system of immune-compromised patients is an example of a clinical factor.

Drug Discovery and Its Side Effects

• Many non-anti-arrhythmic drugs had acquired long QT syndrome and were withdrawn from the market.
• Inhibition of lKr = decreased K+ efflux = Long QT

ICH Guidelines S7B

• Focus on non-clinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation).
• Provides a nonclinical testing strategy to assess the potential of a test substance for delaying ventricular repolarization.
• QT prolongation can lead to arrhythmias and/or Torsades de pointes.
• Includes nonclinical assays and integrated risk assessment.

hERG Channel and Cardiac Repolarization

• hERG is the 'human ether-a-go-go related gene'
• hERG encodes for K₁11.1 Potassium channel and causes prolongation of electrical impulses, and can lead to fatal arrhythmias.
• Drugs can induce a block of the hERG channel which leads to cardiac issues.

QT Prolongation Risks

• Prolongation can cause drug effects on cardiac electrophysiology.
• Leads to Ventricular, Tachycardia, and/or Torsades de pointes potentially leading to sudden death.

CiPA (Comprehensive In VitroProarrhythmia Assay)

• Assesses the proarrhythmic risk, and integrates multiple cardiac ion channels.
• In Vitro assessment of drug effects on multiple ionic currents.
• In Silico computer modeling predicts clinical risk.
• Uses In Vivo ECG biomarker models during Phase 1 trials to assess efficacy.

Secondary Pharmacology

• Secondary Pharmacology Brennan, et al examines safety screens Best practices include additional safety-associated targets and interpret and reports off-target activities.

Candidate Selection Considerations

• Identify potency (duration of activity), selectivity (differential potency), and bioavailability (metabolic stability).
• Focus on half-life, clearance route, drug-drug interactions, mutagenic/cytotoxic properties, and safety.
• Check for scalable potential and pharmaceutical stability.

Phases of Clinical Trials

• Phase 1 focuses on safety, tolerability, and bioavailability in a small number of healthy volunteers.
• Phase 2 assesses efficacy in a larger number of patients suffering from the condition.
• Phase 3 is larger versions of previous trials to answer specific efficacy questions.
• Phase 4 includes post-marketing studies to show long-term effects and use indications.

Summary of Phases

• The entire process includes target selection, lead discovery, medicinal chemistry, in vitro studies, and in vivo studies.
• Efficacy and drug safety are equally important.