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The Modern Drug Development - from Bench to Market

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The Modern Drug Development - from Bench to Market How are new drugs discovered and developed ? Discovery • Target identification, selection and validation • Target to Hit, Hit to Lead • Lead to Candidate (Lead Optimization) Development • Preclinical (safety, toxicology) • Clinical (Phase I, II, III) • Post-approval (Phase IV, post-market surveillance) 1 What is a drug ? Article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals; and articles (other than food) intended to affect the structure or any function of the body of humans or other animals. (FDA definition) Food and Drug Administration (FDA): a federal agency responsible for monitoring trading and safety standards in the food and drug industries. European Medicines Agency (EMA, EMEA): a European Union agency for the evaluation of medicinal products. Agenzia Italiana del Farmaco (AIFA). Once upon a time … Paul Ehrlich (1854–1915) 1890 German immunologist Paul Ehrlich (1854-1915) developed a chemical theory to explain the body’s immune response and did important work in chemotherapy, coining the term magic bullet. Ehrlich received the Nobel Prize in 1908. http://tibbs.unc.edu/magic-bullet-or-shot-in-the-dark/ The Side-chain theory and the magic bullet 3 From Immunology to The Magic Bullet Zauberkugel-Theorie’ A chemical substance can selectively affect physiological processes in the body. “A ‘magic bullet’ is a substance that can seek out and kill the disease causing agents only”. 4 The Movie 1940 5 Salvarsan (Hoechst) the first chemotherapy Arsphenamine (Salvarsan or compound 606) is a drug introduced at the beginning of the 1910s as the first effective treatment for syphilis, and was also used to treat trypanosomiasis. This organoarsenic compound was the first modern chemotherapeutic agent. Arsphenamine was first synthesized in 1907 in Paul Ehrlich's lab by Alfred Bertheim. The antisyphilitic activity of this compound was discovered by Sahachiro Hata in 1909, during a survey of hundreds of newly synthesized organic arsenical compounds 6 Salvarsan, Neosalvarsan and Penicillin Salvarsan supplanted inorganic mercury compounds that had been used previously. Main side effects were rashes, liver damage, and risks of life and limb. This caused Ehrlich, who worked assiduously to standardize practices, to observe, "the step from the laboratory to the patient's bedside ... is extraordinarily arduous and fraught with danger." Then, Ehrlich's laboratory developed a more soluble (but slightly less effective) arsenical compound, Neosalvarsan (neoarsphenamine) (1912). These arsenical compounds were supplanted as treatments for syphilis in the 1940s by penicillin. 7 Salvarsan, Neosalvarsan and the Lesson Learned Patient care Basic Research Toxicity Reverse Translational medicine Translational medicine Tolerability Side effect Drug profile improvement 8 The Modern Drug Development - From Bench to Market GENERAL PROPERTIES FOR DRUG ELIGIBILITY • Medical need / Patients • SAFETY • Efficacy • Personalized • Bioavailability (solubility, lipophilicity, PPB, ADME profile) • Specificity of the effect (mechanism of action) • Potency, duration of action • Chemical manufacture/price • Multi-target drugs (MTDs), sometimes termed “magic shotgun” • Other (marketing, IP, competition, pharmacovigilance…) 9 Drug Development, a perfect mix of: Financial Technology Resources Expertise & know-how Time & Patience Strategy Luck 10 From Bench to Market Takes 8 to 15 years Costs about $ 1.8 billion Success is quite limited High risk indeed! The drug discovery and development process is designed to ensure that only those pharmaceutical products that are > 90% of FAILURE both safe and effective are brought to market. 11 Biopharmaceutical Drug Development: Attrition 30K 5 12 How are new drugs discovered and developed ? Discovery • Target identification, selection and validation • Target to Hit, Hit to Lead • Lead to Candidate (Lead Optimization) Development • Preclinical (safety, toxicology) • Clinical (Phase I, II, III) • Post-approval (Phase IV, post-market surveillance) 13 The Therapeutic Target Modern drug discovery is primarily based on the search and subsequent testing of drug candidates acting on a pre-selected therapeutic target. Therapeutic target: typically, the “target” is a naturally existing cellular or molecular structure involved in the pathology of interest that the drug-in-development is meant to act on The Target could be a protein, nucleic acid, sugar or other biological structure whose activity can be modified by an external stimulus to obtain clinical benefits 14 Target Identification & Validation: Definition Understand the molecular mechanism of the disease Identify and select a potential therapeutic target in that pathways (e.g gene, key enzyme, receptor, ion-channel, nuclear receptor) Demonstrate that target is relevant to disease mechanism using genetics, animal models, lead compounds, antibodies, RNAi, etc. 15 Target Validation as Critical Step for Drug Discovery Choosing the right biological target is the critical primary decision for the development of new drugs. An appropriate target validation increases success in drug discovery 16 The Mission 30000 17 Strategic Role Target Identification and Validation Activities have to indicate the most promising paths for drug development Drug Development How ? Which Target 18 Target ID and validation is a multifunctional process Br J Pharmacol. 2011 Mar; 162(6): 1239–1249. 19 Pre-Discovery - RESEARCH Understand the disease (genes, expression, function, p-p interaction, biomarkers) Network Generation - Researchers from government, academia and industry all contribute to this knowledge base. Data base, PubMed, publications, congresses… Contact with KOLs and patients organizations / associations However, even with new tools and insights, this research takes many years of work and, too often, leads to frustrating dead ends. And even if the research is successful, it will take many more years of work to turn this basic understanding of what causes a disease into a new treatment. 20 Therapeutic target identification and selection strategies • Transcriptomics • Proteomics • Metabolomics / Lipidomics … • Phenotypic • Genomics / Genome Association Studies (GWAS) 21 Phenotypic and target-based strategies Nat Rev Drug Discov. 2007 Nov;6(11):891-903. 22 Target Knowledge • Structural • Functional • Efficacy / Side effect 23 Target Validation Tests are conducted to confirm that interactions with the drug target are associated with a desired change in the diseased behavior Research scientists can then identify compounds that have an effect on the target selected Natural compounds Newly synthesized molecules Commercial tools The target should be validated in in vitro assays and in in vivo disease model 24 Therapeutic target validation strategies • In vitro (knock-in / knock-out) • In vivo (knock-in / knock-out) • Antisense (DNA/RNA), siRNA, dsRNA, RNA interference) • Antibodies 25 Hit Identification – Hit to Lead (H2L) Armed with their understanding of the disease, scientists are ready to begin looking for a drug. Laboratory scientists can compare known substances with new compounds to determine their likelihood of success. A high number of compounds are synthetized and screened. High 30000 Throughput Screening (HTS) is one of the most used techniches 26 High-Throughput Screening 27 Lead Optimization Find compounds with the greatest potential to be developed into safe and effective medicines Lead compounds that survive the initial screening are then “optimized,” or chemically altered to make them more effective and safer. Studies are conducted in living organisms (in vivo) and in cells in the test tube (in vitro) to compare various lead compounds and how they are metabolized and affect the body. Hundreds of different variations or “analogues” of the initial leads are made and tested. SAR The resulting compounds (2-4) move to the preclinical stage 28 ADME and Early Safety Tests Absorption, Distribution, Metabolism, Excretion and Toxicological (ADME/Tox) properties, or “pharmacokinetics,” of each lead. Demonstrate the drugs are: Absorbed: into the bloodstream (if oral) / into the lung and retained (if inhaled), Distributed: to the proper site of action in the body, Metabolized: efficiently and effectively, Excreted from the body and Not toxic (Ames test, genotoxicity, mutagenicity) Not active on undesired targets (e.g. hERG) These studies help researchers prioritize lead compounds early in the discovery process. ADME/Tox studies are performed in living cells, in animals and via computational models. 29 Preclinical Pharmacology and Toxicology (Formal Preclinical Phase) Is the drug safe enough for human testing ? Extensive characterization of optimized compounds Scale up for clinical trials (techniques for making a drug in the lab on a small scale do not translate easily to larger production) EMEA and FDA requires extremely thorough testing the candidate in animals before drug can be studied in humans (acute and chronic toxicity and in vivo safety pharmacology, dose prediction). At the end of several years of intensive work, the discovery phase concludes. The DRUG CANDIDATE MOVES INTO THE CLINICAL DEVELOPMENT 30 .
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