PHAR 6766: Biotechnology-Derived Drugs

PHAR 6766: Biotechnology-Derived Drugs Course Syllabus Fall 1.0 Credits This course adheres to the College of Pharmacy Central Syllabus. Please see the following link for this information: https://docs.google.com/a/umn.edu/document/d/1artq5e1rbzxe8letwo7be8k8snzaegmmz_qcw8yj-ii/edit?pli=1 Course Web Site: http://moodle.umn.edu Term: Fall PD Dates: August 25 to October 9, Day Time Duluth Room Twin Cities Room Tuesday 10:10 11:00 Lib 410 WDH 7-15 Thursday 10:10 11:00 LSci 16 MoosT 1-451 Friday 10:10 11:00 Lib 410 WDH 7-15 Course Instructional Team (in order of appearance): Name Office Location Phone Email Preferred contact Office hours Tom Shier (TC) 8-168 WDH 612-624-9465 shier001@umn.edu either Open door Erin Sheets (D) 121 LSci 218-726-6046 edsheets@d.umn.edu e-mail By appoint ment Pamala Jacobson Steve Schondelmeyer (TC) 7-151 WDH (TC) 7-159 WDH 612-624-6118 jacob117@umn.edu either By appoint ment 612-624-991 schon001@umn.edu e-mail By appoint ment Tim Stratton (D) 209 LSci 218-726-6018 tstratto@d.umn.edu e-mail By appoint ment Lowell Anderson (TC) 7-172 WDH 612-626-5158 ander245@umn.edu email By appoint ment Teaching Assistants: G.T.A. (Duluth): Grady Nelson, nels518@d.umn.edu 1

G.T.A. (Twin Cities): William (Bill) McCue, mccu020@umn.edu Overview of the course Course content: In 201, seven of the eight top drugs by sales were recombinant DNA-derived drugs. Sales numbers are not as important to pharmacies as number of scripts filled, but they do matter, because that is where the pharmaceutical industry is going to make its investments going forward. The pipeline for biotechnology drugs isn t empty, so we can expect more of these agents will be brought to market in the future. Pre-filled syringe formulations are bringing more and more of these drugs into community pharmacies. Biotechnology-derived drugs are key participants in several important clinical areas, such as arthritis, kidney diseases and oncology, and more penetration into other fields can be expected. Biotechnology-derived drugs are where the future is, and pharmacy students need to understand how they are made, how they act and what special considerations are involved. This course will provide the foundational knowledge necessary to understand, recommend and counsel patients on current biotechnology-derived drugs and provide the basis for self-education needed to appreciate the biotechnology-derived drugs of the future. This course will also prepare pharmacists to assist patients with self-administered protein drug medications (e.g., insulin) and in the use and interpretation of home diagnostic monoclonal antibody kits (e.g. pregnancy and ovulation test kits). The material covered in this course will provide valuable background information about drugs used in strategically aligned modules/courses, including the diabetes clinical module; dermatology; genetics; immunology; cardiovascular; neurology (multiple sclerosis); oncology; infectious diseases; and inflammatory diseases (arthritis). Course format Class will meet for 50-minute sessions, three days per week, for the first half of the semester. Class time will be used for lectures and various types of in-class learning activities (discussion, problem-solving, small group, etc.). In the clinical topic sessions, class sessions will include clinical case study activities and may include student response system (clicker) participation, and Team-Based (TBL) activities. Students should plan to spend 2 hours outside of class for every 1 hour in class for this course. Prerequisites Successful completion of Biochemical Sciences, Medicinal Chemistry, Pharmacology, Immune System and Infectious Disease, Cellular Metabolism and Nutrition, and Endocrinology. Course Materials There is no required textbook at this time. If a suitable, focused text in the subject appears, it will be considered for adoption. Computer/Technology Requirements Moodle: This course will use Moodle to distribute learning materials. See an introduction to Moodle at http://uttc.umn.edu/training/tutorials/moodle/orientation/moodle-introduction/index.htm E-Textbooks: There are no E-Texts at this time. You will access these through the course Moodle site, if they become available. E-Mail: Course instructors may communicate through email about course administrative issues. You should check your U of M email daily. 2

Student-response systems: s may use TurningPoint software. You may need a TurningPoint clicker or app. Course Goals & Concepts/Goals/ Domains Scientific Foundations Concept 1: Biotech-derived drugs are different from other drugs. Course goal 1: Explain ways in which biotech-derived drugs differ from other drugs. Objective (LO) 1a: Compare and contrast properties of biotechnology-derived drugs and properties of small-molecule drugs; and describe how the differing properties affect drug storage, preparation, and administration methods. LO 1b: Explain site-directed mutagenesis and directed evolution, and how these techniques can be used to produce second generation biotechnology-derived drugs. LO 1c: Describe how a mouse monoclonal antibody can be reengineered to minimize its immunogenicity by making it look human. LO 1d: Explain how receptors are made to look and act like antibodies (pseudoantibodies), and the limitations of this method for making other drugs. LO 1e: Detail the mechanisms of action for some important biotechnology-derived drugs. LO 1f: Explain how the pharmacokinetics of biotechnology-derived drugs can be improved to make second generation drugs by the following: (i) pegylation; (ii) altering glycosylation; (iii) altering the molecular weight and (iv) altering solubility LO 1g: Describe the legal and economic considerations for the production of generic biotechnology-derived drugs (biosimilars). Concept 2: Biotechnology drugs are important to pharmacy. 6.1, 6..1, 6.4.1, 6..1, 6.4.1, 6..1, 6.4.1, 6..1, 6.4.1, 6..1, 6.4.1, 6..1, 6.4.1, 1.8, 6..1, 6.4.1,, 6.4.6 1.5.1-5,..4,..5, 4.1.1, 4.1.7 1.5.1-5, 4.1.7, 4.2.1-4 1.4.1-4, 4.1.7 1.4.1-4, 4.1.7 1.5.1-5, 4.1.1, 4.1.7 1.5.1-5,.2, 4.1.7 4.1.7, 5.1.2, 5.2.1, 5.2.2 Course goal 2: Explain how and why biotechnology drugs are important to pharmacy. LO 2a: Describe the basic tools used by scientists to clone genes and transform them into biotechnology-derived drugs. 6.2, 6..1, 6.4.1 1.5.1, 1.5.4, 1.5.5, 1.6.1-6, 4.1.7, 4.2.1, 4.2.

LO 2b: Explain how biotechnology-derived drugs can be made more effective by structure modification. LO 2c: List clinically important drugs that have been discovered because of the availability of site-directed mutagenesis. LO 2d: Describe the localization techniques used to diagnose disease with monoclonal antibody-based imaging diagnostics. LO 2e: Outline DNA sequencing from research tool to genome sequencing for individualized patient care. LO 2f: Describe how DNA-based aptamers work, why they are of interest, how they are made, and how they compare in effectiveness with protein-based antibodies. Concept : Biotechnology-specific clinical skills are needed for practice. 6.2, 6..1, 6.4.1, 6.4.5 6..1, 6.4.1, 6.4.5 1.1, 6..1, 6..2, 6.4.1 1.1, 6..1, 6..2, 6.4.1 6..1, 6..2, 6.4.1, 6.4.4, 6.4.5 1.5.1, 1.5.4, 1.5.5, 1.6.1-6, 4.1.7, 4.2.1, 4.2. 1.5.1, 1.5.4, 1.5.5, 1.6.1-6, 4.1.7, 4.2.1, 4.2. 2.2.1, 2.2.2, 6.1.14, 6.4.7 1.5.1, 1.5.4, 1.5.5, 1.6.1-6, 4.1.7, 4.2.1-4 1.5.1, 1.5.4, 1.5.5, 1.6.1-6, 4.1.7, 4.2.1-4 Course goal : Apply knowledge of biotech-derived drugs to patient care. LO a: Explain who, how and why erythropoietin, growth hormone and sometimes insulin are abused. 1.6,.6, 6..2, 6.4.1, 6.4.2, 6.4.6 4..2, 5.1.7 LO b: Explain how home diagnostic kits work. 1.1, 6..1, 6..2, 6.4.5 2.2.1, 2.2.2, 6.1.1 LO c: Outline the potential and limitations of gene and cell-based experimental therapies and what limits their use. LO d: Explain the high cost of biotechnology-derived drugs, and how that cost affects reimbursement, inventory practice and counterfeiting. LO d: Describe the qualities of a biosimilar drug, approval process and cost implications 1.8, 6.0, 6.1, 6.2, 6..1, 6..2, 6.4.5, 6.4.6 1.8,.0,.1,.6, 6.4.6 1.8,.0,.1,.6, 6.4.6 4.1.7, 5.7.5, 6.8.6 5.1., 5.2.2, 5..5, 5.7.2, 5.7.5 LO f: Analyze the ethical issues around the use of biotechnology drugs 1.8,.0,.1,.6, 6.4.6 Competency Domains Domain 1: Patient-Centered Care As a provider of care, the pharmacist is ethical, benevolent, empathetic, competent, open-minded, prudent in making judgments, and devoted to serving others. The pharmacist applies knowledge, experience, and skills to protect the welfare of humanity. The pharmacist 4

willingly and respectfully cares for patients to assure optimal therapeutic outcomes Domain 2: Population Health & Vulnerable Communities As a promoter of public health, the pharmacist uses his/her expertise to partner with others to improve care for vulnerable communities or at risk populations. The pharmacist recognizes the differences between populations of individuals and seeks to alleviate disparities that exist. Domain : Health Systems Management As a manager of health system resources, the pharmacist examines critical issues, assumptions, and limitations to produce and validate ways to deliver medications safely, effectively, and in a timely manner. The pharmacist demonstrates imagination, inventiveness, and courage by undertaking new endeavors to produce improved quality, productivity, efficiency, effectiveness, and innovation. Domain 4: Leadership & Engagement In leading, the pharmacist demonstrates integrity and is habitually resolute, focused on excellence, knowledgeable about the big picture, strategic, focused, persuasive, open to feedback, decisive, visionary, empowering, and service-oriented. Domain 5: Professional & Interprofessional Development When collaborating, the pharmacist demonstrates critical thinking, excellent communication and leadership, and is goal-oriented, cooperative, assertive, respectful, enthusiastic, and reliable. The pharmacist consistently and consciously demonstrates high ethical and moral standards by considering how and when to act, acting in a manner that is clearly consistent with those standards and exercising accountability for those actions. Domain 6: Knowledge, Scientific Inquiry, and Scholarly Thinking In making use of scientific knowledge, the pharmacist explains with thoroughly researched, evidence based accounts of facts and data, and provides interpretations based on analysis of the importance, meaning, and significance. The pharmacist applies knowledge fluently, flexibly, and efficiently in diverse contexts. * refer to College of Pharmacy Competency Domains for Section descriptions. Attendance Policy Students are expected to attend every class for which they are registered. Students are expected to attend classes on the campus where they are enrolled. Although instructors may choose to take attendance, it is recognized that sometimes students will need to attend to other obligations, and on those occasions they will listen to the recorded version of the lecture on their computer. Expectations You are expected to participate actively in your own education while in the College of Pharmacy. This will prepare you to be a lifelong learner. Assessments and Grading The following graded assessments will count toward your final grade for this course in the following amounts: # Date Title Brief description Assessment Goal (required to link to domain) Points % of final grade 1 Week 4 Exam 1 (Lectures 1-7) Objective 1-2 85 42.5% 2 Week 8 Exam 2 (Lectures 8 - end) Objective 1-9 46.5% Weeks 6 and 7 Active learning activities Objective 20 10% 5

4 Last Week Complete a course evaluation 2 1% You will complete two in-class exams (50 minutes), worth 85 and 9 points. The dates of these exams are announced in the course schedule. All exam answers must be written in ink. Five points will be deducted from exams not written in ink. REGRADE POLICY All exams submitted for regrade must have a written explanation attached detailing the need for the exam to be regraded. The request must be submitted to the instructor within one week of receiving the graded exam. No changes will be made in the final grade without the consent of the course faculty. Regrading exams may also result in point deductions, if overlooked grading errors are found. MAKE-UP EXAM POLICY Under no circumstances will make-up exams or in-class discussion sessions be scheduled for unexcused absences. Excused absences include 1) illness verified by a physician's letter, 2) serious family emergency, and ) a University-sponsored event, verified by a note from the leader of the sponsoring institution. Notification of the course director must occur in advance of the regularly scheduled exam. HONOR CODE Each student is bound by the following specific provisions as part of the Code: Academic misconduct is any unauthorized act which may give a student an unfair advantage over other students, including but not limited to: falsification, plagiarism, misuse of test materials, receiving unauthorized assistance and giving unauthorized assistance. Each student will be asked to sign a cover sheet on tests and written assignments that reaffirms the honor code as it applies to this course. Specifically, each student will be required to do their own work on all tests and written assignments. For written assignments, students are allowed to discuss the assignment with other students, but all written material must be their own work and not the result of group discussions. GRADING POLICY Grades will be assigned at the end of the term and will be based on the total number of points out of a maximum of 200 points. See the grades table below. To pass the course you must obtain 60% of the total points. Incomplete grades will be given only by prior arrangement approved by the course director. EXAM POLICIES All in class written exams will be given during scheduled class time. Exams will not be graded on a curve. The use of electronic devices such as cell phones, tablets, PDAs, pocket computers, programmable calculators, and other devices with electronic data bases is not permitted during written exams unless specified by course director. Exams will be comprehensive and will build on previous content. Standard analyses of composite class responses for all exam questions will be conducted by the authors of those exams prior to releasing the scores. An opportunity to request an exam regrade is provided for all exams. Grades will not be given out over the telephone or by email. Course Letter Grades Grade Percentage 6

A 9.0-100 A- 90.0-92.99 B+ 87.0-89.99 B 8.0-86.99 B- 80.0-82.99 C+ 77.0-79.99 C 7.0-76.99 C- 70.0-72.99 D 60.0-69.99 F 0-59.99 Detailed Course Outline & Schedule* * Subject to change at course director's discretion. Class Sessions Agenda/Topics Competency Objective Activities / Assignments/ Assessments Courses Total EST HRS Week 1: August 25, Lecture 1 Introduction to biotechnology drugs Importance of Biotech drugs; sales in 201; special challenges with biotech drugs: Stability ( slides, covered by Panyam); handling and storage; IV administration, pre-filled pens (DX: Pegasys, Humalog); adverse effects; immunogenicity; financial issues; lack of generics (biosimilars coming)(dx: Growth Hormone); counterfeit drugs (DX: bevacizumab; filgrastim); large synthetic peptides (DX: Byetta; Angiomax, Forteo; Fuzeon); drugs of abuse (DX: Erythropoetin; Growth Hormone). 1a, 1g, Endocrinology (growth hormone); Oncology drugs (bevacizumab, romiplastim, rituximab, trastuzumab); Diabetes (Byetta, Humalog), Week 1: August 27, Lecture 2 Recombinant DNA toolkit I Refresher on DNA, gene structure; enzyme tools: restriction endonucleases, polymerases, ligase, reverse transcriptase; DNA probes; PAGE, blots 1b, 2a, 2b, Endocrinology ; Cellular Physiology Genetics Week 1: Recombinant DNA toolkit II 7

August 28, Lecture PCR; qpcr; DNA sequencing; automation of DNA sequencing; Next-Gen DNA sequencing; human genome project. 1b, 2a, Cellular Physiology Genetics Week 2: 1, Lecture 4 DNA: from gene cloning to drugs DNA cloning (DX: Growth Hormone; Erythropoetin); PCR cloning; expression vectors; expression of bacterial proteins, mammalian proteins; industrial production; drug formulation; gene pharming (DX: ATryn). 1 b, 2a, Endocrinology (growth hormone); Kidney drugs (Erythropoetin); Cellular Physiology Genetics Week 2:, Lecture 5 Site-directed mutagenesis; directed evolution Site-directed mutagenesis (DX: Inferogen); directed evolution/phage display (DX: Humira); protein engineering 1b, 2a, 2b, Biochemical Sciences (sitedirected mutagenesis); Cellular Physiology Genetics Week 2: 4, Lecture 6 Monoclonal antibody production Antibody refresher; mono vs polyclonal antibodies; Kohler and Milstein production; MoAbs from phage display (DX: Humira); commercial scale up production 1c, 1d, 2a, 2b, Arthritis drugs (infliximab; adalimimab); Oncology drugs (bevacizumab, romiplastim, rituximab, trastuzumab); immunology Week : 8, Lecture 7 Diagnostics: monoclonal antibodies and DNA-based Early pregnancy test kits and how they work; other types of kits; mouse monoclonals in diagnosis (DX: Tositumomab); DNA probe assays and PCR; FISH; companion diagnostics (DX: Trastuzumab). 1c, 1d, 2a, 2d, b Pharmaceutical Care Skills Lab I (OTC test kits); Cellular Physiology Genetics, immunology Week : 10, Lecture 8 Humanized monoclonal antibodies IgG refresher; engineered MoAb types (DX: infliximab; adalimimab); pseudoantibodies (DX: etanercept; aflibercept; alefacept; abatacept; rilonacept; belatacept); peptibody drugs (DX: 1d, 2a, 2b, 2c, 2d Peds (pavilizumab); Arthritis drugs ( infliximab; adalimimab, etanercept); 8

romiplastim); phage display (DX: adalimimab) Cellular Physiology Genetics, immunology Week : 11, Lecture 9 Novel therapies, including gene and cellbased therapies Antisense and sirna drugs (DX: Fomivirsen sodium); gene therapy; aptamers (DX: Pegaptanib sodium; ranibizumab; bevacizumab; aflibercept); cell therapy (DX: Sipuleucel-T); immunotherapy with targeted T-cells; stem cell therapy. 2a, 2b, 2e, 2f, Geriatrics (Pegaptanib sodium; ranibizumab; bevacizumab), Week 4: 15, Exam 1: Lectures 1-7 written exam Week 4: 17, Lecture 10 Recombinant and DNA Vaccines Structural issues with HBV (DX: Recombivax HB; Engerix-B, Twinrix, Pediarix ); HPV (DX: Gardasil; Cervarix ); influenza (DX: FluBlok); emerging viruses; DNA vaccines; canarypox veterinary vaccines (DX: Recombitek ); targeted virus therapies; 2a, 2c, 2e Applied PharmCare (vaccines); Endocrinology; immunology Week 4: 18, Lecture 11 Pharmacology of recombinant DNA-derived drugs Transmembrane signaling mechanisms; receptor binding (DX: insulin; PDGF; EGF; erythropoietin; peginesatide); signal transduction mechanisms through the membrane; JAK-STAT pathway; Srckinase pathway; nuclear response element activation; anti-vegf mechanism (DX: bevacizumab, romiplastim); interferon mechanisms (DX: Intron A, Betaseron Avonex, Rebif, Actimmune ); anti-tnfα mechanisms (DX: infliximab; adalimimab, etanercept); antibody-mediated cell killing mechanisms (DX: rituximab); apoptosis triggering mechanisms (DX: rituximab, trastuzumab) 1e, 2a, 2b, 2c, Endocrinology; Kidney Diseases (epoetin alfa, darbepoetin, peginesatide); Oncology ( bevacizumab, romiplastim, rituximab, trastuzumab), Arthritis drugs: natalizumab, adalimumab, infliximab, Etanercept Week 4: 22, Lecture 12 Second generation biotechnology drugs: pegylation et al. Second generation drugs; eliminating unnecessary molecule parts (DX: Alteplase, Reteplase, Tenecteplase); improving 2a, 2b, 2c, 2e, 1f, Pharmacokinetics, Diabetes (Humulin, Insulin Lispro, Insulin aspart, Insulin glargine Insulin glulisine, 9

pharmacokinetics by pseudoantibody or peptibody formation (DX: ); improving pharmacokinetics by pegylation (DX: pegvisomant, pegfilgrastim, pegaptanib sodium, peginterferon alfa 2a & 2b); improving pharmacokinetics by increased glycosylation for increased half-life (DX: erythropoietin and darbepoetin); random structure variation and evaluation of properties (DX: Humulin, Insulin Lispro, Insulin aspart, Insulin glargine Insulin glulisine, Insulin detemir); consensus sequences; lysosome-targeting of glycoproteins (DX: ); immunotoxin drugs (DX: ado-trastuzumab emtansine); fusion toxins (DX: denileukin diftitox). Insulin detemir), Oncology pegfilgrastim, adotrastuzumab emtansine) Infectious diseases (peginterferon alfa 2a & 2b) Cardiovascular (Alteplase, Reteplase, Tenecteplase), Kidney disease ( erythropoietin and darbepoetin) Week 5: 24, Lecture 1 Types of biotechnology drugs A brief summary of the structure/activity properties of the most important biotechnologyderived drugs. Pharmacology Week 5: 25, Lecture 14 (Jacobson) Biosimilars Biosimilars are biological products that are demonstrated to be biosimilar to or interchangeable with an FDA-licensed biological product; difference between generic drugs and biosimilars. Zarxio (filgrastim-sndz)... 2b, 2c, 2e GI/Derm/Genit/ Arthritis/Gout Week 6: 29, Lecture 15 (Schondelm eyer) Costs of biotechnology drugs Reasons for high cost agents, specialty pharmacies, prior approvals ex: multiple sclerosis, cancer, RA drugs. 1g, c, d Pharmacology Week 6: October 1, Lecture 16 (Jacobson) Biotechnology drug case discussions Ex: Filgrastim, insulins, anticancer, conversion between biosimular products, examples of biotech drug use, insurance coverage and considerations for inclusion on formularies 1g, d, e, Case studies, active learning Pharmacology Week 6: October 2, Biotechnology drug case discussions Ex: Filgrastim, insulins, anticancer, conversion between biosimular products, examples of 1g, d, e Case studies, active learning Pharmacology 10

Lecture 17 (Jacobson) biotech drug use, insurance coverage and considerations for inclusion on formularies Week 7: October 6, Lecture 18 (Jacobson/ Stratton) Case discussions on ethics around the use of biotechnology agents Case discussion on the use of high cost agents, impact on society, the healthcare system and payors, allocation of resources 1g, d, e Case studies, SAPh content; active learning Ethics Week 7: October 8, Lecture 19 (Jacobson/ Anderson) Case discussions on ethics around the use of biotechnology agents Rare diseases, health disparities, etc 1g, d, e Case studies, SAPh content; active learning Ethics Week 7: October 9, Exam 2: Lectures 9-19 written exam Additional Policy Sources: University of Minnesota and College of Pharmacy Policy Reference (Centralized Syllabus) [This page includes all required UMN and CoP policies, e.g., Academic Freedom; Copyright; Course Evaluations; Disability Accommodations; FERPA, etc.] 11