Principles of Drug Discovery & Development

• Principles of Drug Discovery & Drug Development

Objectives of the Study

• Identify the six approaches to discovering new drugs/leads.
• Identify the common methods (compound-based vs. target-based) for selecting compounds.
• Recognize the six stages of new drug development and their timelines.
• Identify the FDA's role in the drug approval process.

Approaches to New Drugs/Lead Discovery

• Screening for biologic activity can lead to unforeseen drug discovery.
• Chemical modification of a known molecule to improve efficacy, reduce side effects, or alter pharmacokinetic properties.
• Rational drug design is based on understanding molecular mechanisms and designing drugs to modulate specific targets.
• Biotechnology and recombinant DNA techniques allow for the development of biologic drugs like proteins and antibodies.
• Development of new drug targets includes understanding the underlying disease mechanisms and identifying new targets.
• Combinations of known drugs aim to obtain additive or synergistic effects, or to repurpose existing drugs for new therapeutic uses.

Methods for Developing Chosen Leads

• Compound-based approach involves using naturally occurring products, purely synthetic drugs, or drug metabolites.
• Naturally occurring products, such as digitoxin from Digitalis purpurea, can be leads to drug development.
• Purely synthetic drugs, like Hycamptin from Camptothecin, are developed in the lab through chemical synthesis.
• Drug metabolites, for example, Fexofenadine (a metabolite of terfenadine), can be developed into drugs.

Hycamptin (Topotecan) Success Story

• 1958: Dr. Monroe E. Wall (USDA) and Dr. Jonathan Hartwell (NCI) discovered Camptotheca's anticancer properties.
• 1966: Dr. Wall and Dr. Mansukh Wani (Research Triangle Institute) isolated camptothecin from the bark, supported by NCI.
• 1970s: Dr. Wall produced the sodium salt of camptothecin, which improved solubility and allowed Phase I clinical trials.
• The improvement of topotecan was insufficient and compound did not progress to Phase II trails due to poor solubility and toxicity.
• Camptothecin remained active by discovering DNA replication enzyme topoisomerase I.
• 1980s: NCI provided camptothecin to the University of Florida where Dr. Warren Ross developed topotecan, supported by SmithKline Beecham, who further supported phase I clinical trials and formulations as a semisynthetic, water-soluble analog.
• The analog of camptothecin was confirmed as inhibition of topoisomerase I by Dr. Leroy Liu of Johns Hopkins University.
• 1990s: NCI supported phase II clinical trials of topotecan, gaining FDA approval in 1996 for ovarian and small-cell lung cancer treatment.
• Topotecan is one of four NCDDG-developed agents approved by the FDA under the NCDDG program.
• DTP's RAID program helped develop a liposomal form of camptothecin (DB67).
• In cell cultures, DB67 was twofold more cytotoxic and 25 times more lipophilic than camptothecin, as well as more stable in human blood.
• RAID I supported formulation, GMP synthesis, preliminary toxicology, and pharmacology studies.
• The principal investigator applied under RAID IV for support by providing additional bulk substance and IND-directed toxicology with correlative pharmacology and histopathology.
• RAID IV was closed out upon licensure of the agent to Novartis.

Allegra's Origin

• Woosley, pharmacology chairman at Georgetown University Medical Center, was called-in to investigate Seldane (terfenadine).

• Seldane was introduced in 1985 and the first "non-drowsy" allergy medicine.

• Woosley found overlooked reports of arrhythmias/deaths suggesting interactions between Seldane and common drugs could cause serious heart rhythm disorders, resulting in death.

• Woosley discovered terfenadine suppresses allergy symptoms with limited side-effects.

• Woosley patented fexofenadine as a non-toxic allergy drug with Georgetown University's Office of Technology Commercialization.

• After FDA approval in 1996, the drug was commercialized as Allegra by Sanofi-Aventi.

• Subsequently, terfenadine was withdrawn by the FDA because of risks.

• In 2011, the FDA cleared over-the-counter (OTC) sales of Allegra, earning $221.6 million in 2016.

• The FDA and regulatory agencies published guidelines for testing drug induced potential heart arrhythmias per Woosley's studies for terfenadine.

Target-Based Approach

• This approach uses a systematic way to identify molecular targets by understanding disease and pathogen processes.
• Hypothesis related to the target include, developing protease inhibitors for HIV, using β-adrenergic antagonists for hypertension, and β-adrenergic agonists for asthma.

Screening Methods

• Combines a library generation of compounds and receptors for selections to bind the best candidates.

• High Throughput Screening uses robotics, data processing control software, and sensitive detectors.

• High-throughput screening allows researchers to conduct millions of tests.

• High Throughput Screening allows for quickly recognizing active compounds, antibodies, or genes in order to modulate a particular biomolecular pathway.

• Results from high-throughput screening experiments provide crucial starting points for drug design.

• Microplates with reaction wells in multiples of 96 are the labware for HTS.

• Wells contain test chemicals, cells, and enzyme, and are available as stock plates.

• Measurements give a readout; Automation permits "high-throughput” analysis, replicates, and repetition from this data.

• Aided by computer design for identifying targets.

• Ligands use structure and information for virtual screening.

• In 2003, Eli Lilly discovered a lead with traditional HTS in vitro experiments.

• Biogen Idec discovered identical lead using a CADD approach with virtual HTS.

Screening Activity of Chosen Leads

• In vitro studies use cell membranes and can involve more complicated cell-based systems with high potential selectivity, and for false +/- results.
• In vivo studies require the drug to have activity at a molecular level, tested in the whole animal.

Characteristics of Effective Therapeutic Agents

• Effectiveness (Efficacy)
• Selectivity (Affinity)
• Action site delivery
• Good Pharmacokinetics (ADME)
• No side effects in all patients (race/genetic polymorphisms)
• Good physicochemical properties making it easy to formulate and administer.
• Benefit to risks ratio

Stages of New Drug Development:

• Pre-clinical In vitro studies: large scale synthesis and physicochemical properties includes stability, shelf-life, ADME,degradation products, formulations, toxicity studies with a new FDA rule in 2022 no longer needs to require animal tests.
• Investigational New Drug (IND):
  • Applications evaluated by FDA's Center for Drug Evaluation (CDER) within a 30-day window.

Clinical Trials include Phases 1 through 3, which can take 1 year to 4 years.

• Phase 1: Determines SAFETY in 20 -100 healthy volunteers (18-65 yrs), and evaluates maximum tolerated dose and pharmacokinetics (ADME). Takes 1 year.

• Phase 2: Determines efficacy (testing in patients), effects in 100-200 patients with a disease, any side effects, and is single-blinded (patients) to help the FDA decide whether to continue with trials. Takes up to 2 years.

• Phase 3: Confirms efficacy, optimizes dosing. Performed in 1000 - 6000 patients with disease at multiple clinical sites using double-blinded study results, side effects, and PK. It helps the FDA decide whether to continue with the trials. Takes up to 4 years.

• New Drug Application(NDA): Including manufacturing specifics, stability and bioavailability data, analysis methods for each dosage form, packaging and labeling for physicians/consumers, and new toxicology data since IND.

• Phase 4 - Post-marketing Surveillance: Includes safety-first initiative by the FDA to determine any previously unrecognized adverse effects and may require more clinical studies to clarify aspects of any drug effects.

• The drug discovery process includes multiple steps consisting of 5,000-10,000 compounds.

• Pre-clinical steps require only 250 compounds.

• Clinical Trials only need 5 compounds.

• All this research and testing nets 1 new drug.

• This process uses Target identification for validation and assays in the development of lead generations for in vitro and in vivo toxicity with ADMET and PK/PD.

FDA Drug Review Categories

• Fast Track: Designed to expedite review of drugs for serious conditions and unmet medical needs

• Breakthrough Therapy: Speeds up the development of drugs for conditions that that may demonstrate substantial improvement

• Accelerated Approval: Approves drugs for serious conditions filling an unmet need based on a surrogate endpoint.

• Priority Review: Sets FDA's goal to take action on an application within 6 months using overall attention and resources for any safety or effectiveness for standard applications.

• Fast Track expedites the development of drugs for serious conditions and unmet needs by providing more frequent meetings and communications, which applies eligibility for Accelerated Approval and Priority Review that occurs as a rolling review.

• Breakthrough Therapy enhances drug development of preliminary clinical evidence with intensive guidance beginning in Phase 1 plus organizational commitment for senior managers.

• Accelerated Approval implemented approval regulations used a surrogate endpoint that relies on conducting studies in order to confirm real clinical benefit

• All drugs marketed in the United States must go through a detailed FDA review process where, in 1992, under the Prescription Drug User Fee Act (PDUFA), this created Standard Review and Priority Review.

• Designating a drug as "Priority" will not alter the scientific and medical standard nor increase the clinical trial period.

• Supporting new treatments for rare diseases is key priority for the FDA who can grant orphan drug designation to develop a biological product to diagnose, prevent or treat a condition that qualifies sponsors for incentives and tax credits for qualified clinical trials, exemption from user fees, and seven years market exclusivity along strict scientific review.

• On January 4, 2023 the orphan drug act had its 40th anniversary of the legislation of incentivizing drug companies regarding research, development, and distribution for rare diseases.

• FDA ensures good quality affordable generic drugs via the Office of Generic Drugs (OGD) within the Center for Drug Evaluation and Research and approves rigorous review includes a regulatory process with research/educational scientific data and reports.

• Generic drugs contain the same active ingredients with the same strength and use the same route on administration and dosage.

• In the USA, almost all prescriptions (9/10) filled are for generic drugs.

• The Abbreviated New Drug Application (ANDA) for generics is so named because applicants scientificly demonstrate the same generic product for the bloodstream in healthy volunteers.

• Bioequivalence is the rate on absorption, bioavailability, and the amount of active ingredients for approval.

Review:

• Drug discovery involves six approaches.
• Developing leads includes two major methods: Compound-based and Target-based.
• Drug development stages include: Pre-clinical (in vitro and in vivo), Clinical (Phases 1-3), and Post-marketing (Phase 4).
• Drug review includes the categories, approvals, and role of the FDA.