PHA2022 Drug Development Introduction PDF

PHA2022 DRUG DEVELOPMENT Introduction Tracey Gaspari I wish to acknowledge the people of the Kulin Nations, on whose land we are gathered today. I pay my respects to their Elders, past and present. Unless otherwise indicated, the follo...

PHA2022 DRUG DEVELOPMENT Introduction Tracey Gaspari I wish to acknowledge the people of the Kulin Nations, on whose land we are gathered today. I pay my respects to their Elders, past and present. Unless otherwise indicated, the following notice may apply to content within this lecture: COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been reproduced and communicated to you by or on behalf of Monash University pursuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice.  Lecture outline ⇒ learning objectives The Pharmaceutical Industry – World wide – Australia The main steps in drug discovery & development – describe the time and financial costs involved in developing new drugs – identify the steps involved in taking a drug from discovery to the market place – discuss how therapeutic targets are decided on – define terms associated with the drug development process including: hit; lead; generic; bioequivalence; biosimilar  Further information …. Rang et al (2019) RANG & DALE’S PHARMACOLOGY Chapter 60 Hill & Rang (2013) DRUG DISCOVERY AND DEVELOPMENT Medicines Australia www.medicinesaustralia.com.au  Pharmaceutical Industry - world-wide > 6000 different drugs available global drug sales $US1.48 trillion/year (2022) USA = largest single market other major markets incl: Japan > China > Germany Blockbuster drug sales: >$1 billion per year 2021 global R&D >US $238 billion https://www.statista.com/statistics/263102/pharmaceutical-market-worldwide-revenue-since-2001/  Pharmaceutical Industry - Australia - ≈ 1% world market Medicines Australia Facts Book 2021 Fifth Edition  Pharmaceutical Industry - Australia - ≈ 1% world market ~12,000 directly employed ~80% with Bachelor degree of higher Economic-Contribution-Innovative-Pharma-industry-Australia.pdf (Medicines Australia Feb 2020)  Pharmaceutical Industry - Australia - Companies ? – overseas vs local owned – research-based vs non-research-based Sources: http://medicinesaustralia.com.au/files/2011/03/20100603-pub-MedicinesAustralia-winds-of-Change.pdf http://www.industry.gov.au/industry/PharmaceuticalsandHealthTechnologies/Pharmaceuticals/Pages/PharmaceuticalsIndustryDataCard.aspx  Top pharmaceutical companies in Australia (2019-2020) by PBS sales (in $) by PBS sales (volume) 1. Novartis ($910 million) 1. Alphapharm (54.2 million) 2. Janssen ($709 million) 2. Apotex (53.3 million) 3. AbbVie ($576 million 3. Sandoz (31.3 million) 4. Bayer ($545 million) 4. Arrow (23.3 million) 5. Pfizer ($396 million) 5. Pfizer (13.1 million) 6. Gilead ($387 million) 6. AstraZeneca (12.7 million) 7. AstraZeneca ($351 million) 7. Sanofi (11.9 million) 8. Alphapharm ($339 million) 8. Aspen (11 million) 9. Boehringer ($297 million) 9. Boehringer (9.4 million) 10. Apotex ($277 million) 10. GSK (7.2 million)  Top pharmaceutical companies in Australia (2019-2020) by PBS sales (in $) 1. Novartis (Switzerland) 2. Janssen (USA) The World’s Largest 3. AbbVie (USA) Pharmaceutical Companies 2023 4. Bayer (Germany) 5. Pfizer (USA) 6. Gilead (USA) 7. AstraZeneca (USA) 8. Alphapharm (RSA) 9. Boehringer (Germany) 10. Apotex (Canada) https://www.proclinical.com/blogs/2023-7/the-top-10-pharmaceutical-companies-in-the-world-2023  Pharmaceutical Industry - Australia - Companies – overseas vs local owned – research-based vs non-research-based  Originator vs generic A generic … copy shown to be the same as the brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use  Pharmaceutical Industry - Australia - Companies – overseas vs local owned – research-based vs non-research-based – commercial products vs not “Big Pharma” vs “Biotech”  Small molecule drug vs biologic Small molecule drug Biologicals manufactured through manufactured in a living chemical synthesis system (eg microorganism, plant or animal cell) well defined chemical usually large complex or structures mixtures of molecules can be analysed to determine difficult/impossible to all components characterize; some components maybe unknown can change the manufacturing “the product is the process” process and get same product ⇒ generics ⇒ biosimilars  Leading biotech companies in Australia (2022) Statista 2022  Medicines in Australia ~209 million PBS prescriptions* (2019-2020) – (estimated that ~55% doctor visits ⇒ prescription) Government expenditure on PBS >$12.5 billion (=~89% total cost)* (2019-2020) + OTCs; herbals…… Australia’s Top 10 subsidised drugs by prescription counts (July 2020 – June 2021) Aust Prescr 2021;44:205 Australia’s Top 10 subsidised drugs by cost to government (July 2020– June 2021) Aust Prescr 2021;44:205 Do we need more drugs? From the bench to the shelf….  Drug Discovery & Development Commercialization MARKETING from product to therapeutic application to sales Discovery Development RESEARCH DEVELOPMENT from therapeutic concept to molecule from molecule to registered product Target Target Lead Lead Preclinical Clinical Regulatory Validation Development Development PRODUCT Selection Discovery Optimization Approval Regulation GOVERNMENT AGENCIES - TGA; FDA ensure safety, efficacy & quality Adapted from Hill & Rang (2013) Drug Discovery & Development  Drug Discovery & Development Drug Discovery (4-8 years) Basic exploratory research to identify targets etc Pre-clinical (1 year) Toxicity & safety studies of selected compounds Clinical trials (6.5 years) Phases 1, 2 & 3 – tests for safety, efficacy etc Registration (1-2 years) Registration dossiers submitted to regulatory authority for review & approval ⇒ approved for marketing ⇒ $$$$$  Drug Discovery & Development Drug Discovery (4-8 years) 5,000 to 10,000 Basic exploratory research to identify targets etc screened Pre-clinical (1 year) 250 enter preclinical Takes Toxicity & safety studies of selected compounds testing 12-15years Clinical trials (6.5 years) 5 enter Costs clinical >$2billion Phases 1, 2 & 3 – tests for safety, efficacy etc testing Registration (1-2 years) Registration dossiers submitted to regulatory 1 approved authority for review & approval for marketing  Drug Discovery & Development From a company’s perspective….. income from marketed drugs is needed to fund development ‘pipeline’ estimates are that only 3 in 10 bring in enough revenue to cover cost of development!! few are “blockbusters” – generate annual sales of > $1billion “…a blockbuster drug is one that achieves acceptance by prescribing physicians as a therapeutic standard for, most commonly, a highly prevalent chronic (rather than acute) condition. Patients often take the medicines for long periods.“ Finkelstein & Temin 2008  2013 - Pharma’s Blockbusters Brand Peak year Peak year sales Primary indication(s) Product type name (to 2013) ($m) Lipitor Dyslipidemia 2006 atorvastatin 13696 Small molecule Plavix Atherosclerosis 2011 clopidogrel 9318 Small molecule Humira Autoimmune diseases 2012 adalimumab 9265 Biologic Seretide Asthma/COPD 2011 fluticasone/salmeterol 8148 Small molecule Enbrel Autoimmune diseases 2011 etanercept 7830 Biologic Abilify Schizophrenia 2011 ariprazole 7363 Small molecule Crestor Dyslipidemia 2011 rosuvastatin 7021 Small molecule Rituxan Autoimmune diseases 2011 rituximab 6798 Biologic Remicade Autoimmune diseases 2011 atinfliximab 6782 Biologic Losec Dyslipidemia 2000 omeprazole 6260 Small molecule Avastin Colon, lung, renal cancer 2010 bevacizumab 6216 Biologic Seroquel Schizophrenia 2011 quetiapine 6177 Small molecule Diovan Hypertension 2010 valsartan 6053 Small molecule Herceptin HER-2 + breast cancer 2011 trastuzumab 5947 Biologic Singulair Asthma 2011 montelukast 5479 Small molecule Lantus Diabetes 2011 insulin glargine 5452 Biologic Zocor Dyslipidemia 2002 simvastatin 5445 Small molecule Nexium Gastroesophageal reflux 2007 esomeprazole 5216 Small molecule Zyprexa Schizophrenia 2010 olanzapine 5026 Small molecule Taken from: http://www.forbes.com/sites/simonking/2013/01/28/the-best-selling-drugs-of-all-time-humira-joins-the-elite/  Top sellers! 1. Lipitor….(Pfizer) lifetime sales US$150 billion Patent expired 2011 2. Humira ….(AbbVie) Lifetime sales US$109.2 billion Patent expired 2018 3. Advair…(GSK) Lifetime sales US$95.7 billion Patent expired 2010…  Patent expired https://customwritings.co/blockbuster-drugs-in-the-pharmaceutical-industry/  2020 - Pharma’s Blockbusters Rank Brand Drug Company Therapy Area/Drug class Year Annual Launch Sale US $ billion 1 Humira Adalimumab Abbvie Rheumatic diseases/ 2003 20.4 TNFα inhibitors 2 Keytruda Pembrolizumab Merck & Cancer chemotherapy/ 2015 14.4 Co. Anti-PD-1 monoclonal antibodies 3 Revlimid Lenalidomide BMS Cancer chemotherapy/ 2005 12.2 Antineoplastic Agent 4 Eliquis Apixaban BMS/ Anticoagulant 2013 9.2 Pfizer for Heart Arrhythmias/ Factor Xa inhibitors 5 Imbruvica Ibrutinib Abbvie / Leukemia and Lymphoma / BTK 2013 8.4 J&J inhibitors 6 Eylea Aflibercept Regeneron Wet Macular Degeneration / Anti- 2011 8.4 / Bayer angiogenic ophthalmic agents 7 Stelara Ustekinumab Janssen Immunosuppressant/ 2009 7.9 Interleukin inhibitors 8 Opdivo Nivolumab BMS Cancer Chemotherapy/ 2015 7.9 Anti-PD-1 monoclonal antibodies https://www.pharmadigicoach.com/top-selling-drugs-by-2020-sales/ The Pharmaceutical Industry is a Business Business Needs Return on Investment Shareholders demand a better return than in a bank – Pharmaceutical development takes a long time and is risky – Profits from launched drugs needed for R & D pipeline – Many drug projects fail to deliver Risk management is the key  Feasibility of a Project What is the medical need? Are they novel research ideas? What is the feasibility of success? What is the competitive situation? What are the current capabilities - portfolio? What is the commercial attractiveness? – orphan drugs………  Orphan drugs Drugs use in the treatment of rare (low prevalence < 5/10,000) diseases – includes cystic fibrosis; multiple myeloma  Commercial attractiveness.. Disease mongering? e.g. male-pattern baldness; erectile dysfunction? motivational deficiency disorder? Time is an important consideration  Patents “owner has exclusive rights to commercially exploit the invention for the life of the patent” http://www.ipaustralia.gov.au/patents/what_index.shtml standard patent = 20 years from date of filing + extension of 5 years for pharmaceuticals  Effective patent life = 10-13 yrs Time to market Standard 20-year + extension patent term (max 5 yrs) 0 12-15 20 25 yrs  Patents “owner has exclusive rights to commercially exploit the invention for the life of the patent” http://www.ipaustralia.gov.au/patents/what_index.shtml standard patent = 20 years from date of filing + extension of 5 years for pharmaceuticals company must provide full description of product ⇒ this information becomes public & can provide basis for further research of others  Originator vs Generics Drug Discovery(4-8 years) Basic exploratory research to identify targets etc Pre-clinical (1 year) Toxicity & safety studies of selected compounds Clinical trials (6.5 years) Phases 1, 2 & 3 – tests for safety, efficacy etc Registration (1-2 years) Registration dossiers submitted to regulatory authority for review & approval  Originator vs Generics…… original...goes through full R&D process generics...bypass discovery, preclinical testing & some clinical testing – MUST demonstrate therapeutic equivalence (= bioequivalence)  Generics vs biosimilars Bioequivalence comparable to a “brand” drug product in dosage form, strength, quality, pharmacokinetics, performance characteristics and intended use. vs Biosimilars “highly similar to an … approved biological product and has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.” (http://www.fda.gov/) What can happen once our drug is marketed? PRECLINICAL DEVELOPMENT DISCOVERY Novel chemicals Medical need synthesized / chemical biological identified developed characterisation characterisation CLINICAL DEVELOPMENT Drug marketed Phase III Phase II Phase 1..but development doesn’t stop there…  Marketing approval ARTG given for a specific indication RESOLUTION 9425 1. The ACPM recommends approval of the submission from Servier Laboratories Australia Pty Ltd to register a new chemical entity, agomelatine (VALDOXAN) film coated tablets 25 mg, for the indication: Treatment of major depression in adults including prevention of relapse  Lecture objectives From this lecture you should be able to: describe the time and financial costs involved in developing new drugs identify the steps involved in taking a drug from discovery to the market place discuss how therapeutic targets are decided on define terms associated with the drug development process including: generic; bioequivalence; biosimilar