Engage with us on Twitter: #Molecule2Miracle

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2 Engage with us on Twitter: #Molecule2Miracle

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4 Kassy Perry President & CEO Perry Communications Group PhRMA Alliance Development

5 Emily Burke, Ph.D. Director of Curriculum BioTech Primer

6 Drug Discovery & Development Overview

7 Research & Development: Where New Drugs Come From

8 Biologic vs. Small Molecule Drugs Small molecule Chemically synthesized in the lab Straightforward to manufacture following established laboratory protocols Typically stable at room temperature Simple structure Exact chemical structure determined using standard analytic techniques Biologic Protein produced by a living cell Manufacture requires growing large quantities of living cells Growth conditions of cells vary depending on cell type and quantity Require tight temperature control/storage to maintain stability Complex structure Requires multiple analytic tools to characterize and cannot be completely defined

9 How Drugs Work Drug Target is a cellular structure or molecule in the body whose activity is modified by a drug, resulting in a desirable therapeutic effect Druggability is suitability of protein to be targeted by a drug or biologic in a way that this interaction will alter the protein s function and correct disease causing behavior Intended drug target Cell surface receptors Biologics Small molecule drug

10 Targeting Chronic Inflammation: Monoclonal Antibody Capturing inflammatory cytokine TNF-α TNF-α Receptor TNF-α Antibody White blood cell such as T-cell or macrophage

11 Antibodies As Cancer Therapeutics: Mechanisms Of Action (MOA) Trigger the immune system to destroy a target cell Breast cancer, lymphoma Bind a receptor to block a signaling molecule Colorectal cancer), melanoma Capture a signaling molecule Colon, renal, and lung cancer Receptor Signal molecule

12 Step 1: Target Identification Drug Target: Physiologic molecule that can be modified to change disease pathology Compare normal tissue/cells to diseased tissue/cells to look for differences in: Genetic sequence Are specific genes mutated in the diseased tissue? Whole genome sequencing increasingly used Protein expression Are specific proteins present at a higher or lower level in the disease samples compared to healthy samples? Normal sequence ATGACTGCATGTTACGGT ATGACTGCACGTTACGGT Cancer Cell Cancer sequence

13 Potential Target EGFR Epidermal growth factor receptor Signals cell proliferation Extracellular Intracellular Proliferation

14 Step 2: Target Validation Does the target play a key role in the disease process? Is the target druggable? Druggable Target: Cellular structure or molecule against which researchers can develop a drug? Is targeting it likely to be effective and safe? In vitro: cell models sirna Cancer cells stop growing or die? Normal cells survive? In vivo: animal models Are EGFR knock-out mice less susceptible to cancer? Still healthy?

15 Therapeutic Choices: Small Molecule vs. Large Molecule Small Molecule (Drug) Large Molecule (Biologic) Can enter cells Medium to high specificity Relatively short half-life Chemists make them Some cross blood-brain barrier Cannot enter cells Extremely high specificity Often very long half-life Cells make them Usually do not cross blood-brain barrier Biologic blocks signal Drug blocks signal NO SIGNAL NO SIGNAL

16 Step 3: Assay Development Measure Fluorescence

17 Step 3: Assay Development

18 Step 4: High Throughput Screening Hit = Automated and scaled up to screen thousands of compounds from libraries Hit =

19 Step 5: In Vitro Safety & Efficacy Testing Is it specific? X but not: A Y Disease B Health Is it effective? Die Stop Dividing Is it safe?

20 The Drug Development Process Stage Phase Regulatory Drug Discovery Drug Testing Early discovery (in vitro) Preclinical (animal studies) Approval for clinical trials Clinical trials Approval for marketing Further testing GLP Guidelines FDA Regulation GCP Guidelines Drug Production Formulation Manufacture cgmp Guidelines

21 Preclinical Trials Discovery Phase 2-12 yrs Preclinical Testing: Safety Testing Using Animal Studies Short Term IND Application: Animal study results Manufacturing information Clinical protocols Long Term Investigational New Drug (IND) Review FDA Time

22 Phase I Clinical Studies Healthy volunteers receive escalating doses until side effects seen - Establishes maximum tolerated dose (MTD) For oncology studies, phase I studies are often conducted in patients Two strategies to determine MTD Single ascending dose (SAD) Small groups of subjects given single dose of drug If no adverse effects, new group of subjects given higher dose Multiple ascending dose (MAD) Small groups of subjects given multiple low doses of the drug Dose is subsequently escalated for further groups, based on safety data

23 Phase II Clinical Studies Larger number of participants all patients Determine safety and efficacy in targeted disease group Drug efficacy is tested Against standard of care (active control) or placebo (sugar pill) Endpoints defined (mortality, tumor size, mobility) Determine effective dose and dosing regimen Route, frequency and duration

24 Extensions Of Phase II Different regimens based on results of Phase II Phase IIA: Specifically designed to assess dosing requirements How much drug should be given? Phase IIB: Specifically designed to study efficacy How well the drug works at anticipated optimal doses?

25 Phase III Clinical Trials Confirms efficacy of drug in large defined patient group Conducted at several geographically distinct locations Standard study design Double-blind studies: no one knows who gets drug or placebo Randomized: patients randomly assigned to treatment or control group Results determine dosage, treatment frequency, duration, target patient groups

26 Phase IV: Post Marketing Surveillance Monitors drug efficacy and safety in uncontrolled, real life situations Cost to sponsor is comparatively small Surveillance continues for life of drug

27 New Drug Application (NDA)/ Biologic License Application (BLA) Submitted following completion of all 3 phases of clinical trials if data demonstrates safety and efficacy Contains all relevant scientific information gathered by company Typically run 100,000 pages or more Average review time is ~ 1 year

28 Success Metrics Test Population Purpose Years Success Rate Small Molecule Discovery/ Preclinical Testing Phase I Phase II Phase III FDA Phase IV Laboratory & animal studies Assess safety, biological activity & formulations compounds evaluated File IND at FDA 20 to 100 healthy volunteers Determine safety & dosage 100 to 500 patient volunteers Evaluate effectiveness; Look for side effects drugs enter trials 1,000 to 5,000 patient volunteers Confirm effectiveness. Monitor adverse reactions from long-term use File NDA/BLA at FDA Review process/ approval approved Additional postmarketing testing required by FDA Years Success Rate Large Molecule 250 biologics evaluated 7 therapeutic biologics enter trials 1 approved Industry average cost of development 2.6 Billion* *Source: Tufts Center for the Study of Drug Development

29 Patents Preclinical Many years Patent office Clinical 6-10 years Patent Protection 20 years Exclusivity period 5 years for new molecular entity Additional 6 months for pediatric drug 7 years for orphan drug 12 years for biologics FDA Exclusivity 5-12 years Patent and exclusivity may or may not expire at same time Product Erythropoietin G-CSF TNF-alphaR Anti-CD20 Anti-HER2 Anti-VEGF Brand Epogen Neupogen Enbrel Rituxan Herceptin Avastin Company Amgen Amgen Amgen BI/Genentech Genentech Genentech Patent Expiry* EU Expired Expired Expired Expired Expired 2018 US Expired Expired Expired *Source: Nature Reviews Drug Discovery 11, (June 2012)

30 Continue Learning With Us! Blog: the.biotechprimer.com Twitter: biotechprimer Additional Live Classes Drug Development Molecular Diagnostics BioSafety In-house classes can be customized to fit your team s needs franklin@biotechprimer.com

31 Steve Gibson Chief Mission Strategy and Public Policy Officer ALS

32 Fred Fisher The ALS Association Golden West

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