The Business of Science: From Molecules to Medicines

1. Rutgers - GSBS PATH N5209 The Business of Science From Molecules to Medicines Fall 2016 Course Organizers: Nick Ponzio Steve Ritland Shanon Hunt Holly Hilton

2. Today’s Agenda • Welcome and Introduction (Nick) • A whirlwind tour of drug discovery and development (Shanon) • Business meets Science: The Drug Innovation Industry (Steve) • Course structure and deliverables(Shanon) • Project team: Introduction to your target • Course Website: http://njms.rutgers.edu/gsbs/olc/fmtm/

3. Introduction This course is about how new drugs get created This course will provide… • An introduction to the Big Picture of How Things Are Actually Done in Biotech/Pharma • Insight into the day-to-day activities of scientists / clinicians working in industry • Practical experience in how molecules move through the drug development cycle (semester project) • Examples of areas where industry and academia collaborate to solve healthcare problems • Examples of career possibilities related to stages of the drug development cycle for graduates with advanced degrees in biomedical sciences Whether you pursue a career in industry or academics, it’s an advantage to understand how the biotech/pharma industry works

4. Course Directors

5. Will work for Diet Coke!

6. Expectations and Evaluation Expectations: • Courtesy to our guest speakers and team members • Active participation in group work and Project Teams • Critical Thinking – applying concepts from lectures to the team project that you will develop Evaluation: • No Exams ! (are you kidding me?) • Several oral team presentations • Project Portfolio • Class assignments and participation (by course directors) • Peer feedback on team participation

7. If you think what you are doing in school is only to please your teacher or get a grade, you are missing a chance to not only learn, but also practice what you will be doing in the “real world” after you graduate. So: Be on time Be prepared Speak up and contribute without fear Collaborate on your projects Make professional presentations

8. M2M Biotechnology M BIO M2M Biotechnology specializes in the full drug discovery and development lifecycle through first US Registration. M 2 As M2MBio employees, you will work on one of 3 teams involved in developing new drugs

9. Field Trips!

10. Faculty and Student Introductions Nick Your name Your major (or your job) Your prior experience (if any) with Pharma/Biotech Your favorite way to celebrate after your (successful) project presentations!

11. Course Structure and Organization Shanon

12. Course Overview When and where you need to be • Session Dates • Wednesday evenings • Sept 7 - Dec 21 (see syllabus) • Session Times • 6:00 PM - 9:00 PM (with one break, if you’re really, really lucky) • Classroom Location • GSBS Newark Campus • Medical Sciences Building (MSB) in the Department of Pathology • Room C-555 (main lecture); breakout rooms for team activities • Critical Due Dates • Date of your assigned Debate Session • MC Presentation #1: October 19 • MC Presentation #2: November 16 • Final Project Portfolios: December 21th (last day of class)

13. Course Overview 6 pm ~ 7:00 15 mins 7:15 ~ 9 pm Lecture Break Activities How you’ll spend your class time Lecture (first ~1hour of each class) • Each session will begin with a high level Introduction of the topic and its context for your semester project Activities Section (~2 hours for each class) • Activities will apply concepts from that day’s lecture • The activities conducted in class will be part of your Project Portfolio, due at the end of the course.

14. Game Rules Lectures • Our guest speakers are industry professionals who volunteer their time to teach this class. • Please come to class on time. • Please do not do emails, texts, Amazon shopping, etc. during lectures. Computers or notepads are fine for taking notes, and they will be very useful during project time (the second half of class), so please bring them. • Please feel free to ask questions/interact with lecturers. This is a good opportunity for you to get to know experts in their fields who do drug development every day.

15. What you will deliver over the semester The good... Textbook: There is no expensive text book needed. We will provide articles as pre-read. Exams: There are no exams in this course! Project portfolio:You will build you final project portfolio one step at a time as we proceed through the individual class sessions Debates: are more fun than work, honest. The bad... Teams:Your team members, therapeutic area, and target/compound are assigned (welcome to our world) Team grading:You will be graded as a team on your project portfolio including a component of peer feedback The ugly... Presentations:Holly has been known to bring students to tears...but Steve will make it up to you with a beer afterward. • Semester Project: The Project Portfolio • Two Class Presentations • One Topic Debate

16. Semester Project Project Portfolios Course Overview • The Project Portfolio (PP) is a collection of deliverables that you will prepare over the course of the semester • Each group will be required to submit a project portfolio at the end of the semester • PPs will count for 30% of your semester grade • Due Date: December 21 Project Portfolios include the following: Executive Summary Overview of Disease Pathogenesis, Epidemiology, and Current Treatment Target Rationale Investigator’s Brochure (Non-clinical Section) Phase 1 Protocol Synopsis Summary Investigator’s Brochure (Clinical Section) Target Product Profile (Start of Phase 3) Gantt Chart Lifecycle Strategic Plan

17. Course Overview Group Presentations Management Committee Requests for Decision • Each group will develop and deliver two Management Committee Presentations (20 min. each) • This is a “decision point” presentation, with a request to management • Teams must select 2-3 presenters for each of the presentations (all team members must present at least once) • Week 7: MC Presentation #1 – Entry into Development Portfolio • Therapeutic Area • Target, MoA, Scientific Rationale • Pharmacology • 20% of your final grade • Week 11: MC Presentation #2 – Proof of Concept, Entry into Phase 3 • Opportunity assessment, market potential • CMC strategy to FMI • Clinical Proof of Concept (Ph1 & 2 data, efficacy & safety) • 20% of your final grade

18. Course Overview Class Debates; Assignments and Participation • Debates: • 4 – 6 people will be assigned to each debate, assignments to follow • Students will need to prepare for their role ahead of class • More details on the debates will be provided as we get closer • Debates will count for 10% of your final grade Week 8 (Oct 26) Ethics of Ph1 studies: How much risk? Week 12 (Nov 30) Expedited Approvals: Success or Failure? Week 14 (Dec 14) Drug Pricing and Access: What is fair? Class Assignments and Participation: • These count for 10% of your final grade

19. Course Overview Peer Evaluation - Teams Feedback from your teammates will determine 10% of your final grade

20. Session Evaluation Your feedback helps lecturers and course design Course Overview After EACH lecture... Shared with organizers and lectureres

21. Course Website Resources for Students Course Overview http://njms.rutgers.edu/gsbs/olc/fmtm/ Course Syllabus Schedule of Classes and Topics Course logistics Project information Background Reading Course Files Organized by session date Reference articles/pre-read material Lecture presentations Examples and templates for exercises Relevant websites Faculty contact info

22. M2M Biotechnology M BIO M2M Biotechnology specializes in the full drug discovery and development lifecycle through first US Registration. M2M’s expertise covers oncology, inflammation and autoimmune diseases. The current M2M pipeline includes: • CDK4/6 in solid tumors • FGFR in solid tumors • PDE4 in chronic inflammation • JNK in fibrosis M 2

23. Project Team and Debate Assignments

24. Assignment for Tonight Team Introductions • Collect your group into a breakout room • Introduce yourselves and your background Research and discuss your target for the semester project • Start with the articles we provided • Understand the target, the pathway, and potential therapeutic applications • What other companies are developing agents with this target, and what diseases are they in?

25. Q&A

26. A Whirlwind Overview of DD (Shanon)

27. Overview of Drug Discovery and Development The fairy-tale version 2-6 years Target identification, lead identification, lead optimization, clinical candidate selection Discovery Starts after a lead molecule (clinical candidate) is found Lab testing, animal studies for safety (tox studies) and efficacy Phase 0 IND 20-80 Healthy Volunteers Purpose: determine safety and dosage Phase 1 Health Authority End of Ph 1 Meeting 100-300 Patients Purpose: demonstrate efficacy Phase 2 Health Authority End of Ph 2 Meeting Phase 3 1000-5000 Patients Purpose: monitor adverse reactions to long term use NDA Launch! 16 0 2 4 6 8 10 12 14 18 Years

28. Q: Is it really this simple? A: No way. • It is not a stepwise linear process. • The compound could be sent backward to further explore a safety issue or even skip phases • Some phases might be duplicated (e.g, combinations) • There is considerable overlap of activities between Phases. • Toxicology animal studies continue to the NDA • Phase 1 or Phase 2 clinical trials can be running concurrently with Phase 3 trials • Phase 1/2 studies...Phase 2/3 studies.... • There are other aspects of drug development beyond the Clinical Plan • Health Authorities beyond the FDA, like MHRA (UK), Health Canada, Ministry of Health (China), PMDA (Japan) • Parallel development processes: drug manufacturing (CMC), companion diagnostics • New competitor activities or changes in market demand could change the development strategy (Business teams)

29. | LEE011 | LEE F2F 2013 | S Hunt | LEE at 40K | Confidential LEE011 Clinical Development Overview 2015 2016 2013 2014 LEE011X2101 FIH single agent FPFV May LEE011X2102 Ph1 s.a. Pediatric MRT/NB FPFV June LEE011X1101 Japan s.a. solid tumors LEE011 s/a in teratoma FPFV June PHASE 1/2 MELANOMA STUDIES MEK162X2114 Ph1b/2 combo LEE + MEK162 N-RAS melanoma FPFV June LEE011X2105 Ph1b/2 combo LEE + LGX818 BRAF melanoma FPFV Sept LGX818X2102 Phase 2 rational combo study BRAF melanoma FPFV Sept MEK162X2110 Phase 2 triple combo LGX+MEK+LEE BRAF melanoma PHASE 1/2 BC STUDIES LEE011X2106 Ph1b/2 combo LEE + RAD011 and exemestane in BC LEE011X2107 Ph1b/2 combo LEE + Let ± BYL in ER+ BC LEE011X2108 Ph1b/2 combo LEE + Fulv + BYL/BKM in ER+ BC MONALEESA-1 Ph2 pre-surgical PD dose opt MONALEESA-3 Ph2 Neoadjuvant ER+ HER2- Premenopausal Women Phase 1/2, HER2+mBC, Trastuzumab-Resistant Patients MONALEESA-5 PHASE 3 STUDIES MONALEESA-2 Phase 3: ER+ HER2- untreated mBC MONALEESA-4 Ph3: ER+ HER2- mBC after NSAI Phase 3 HR+ HER2+ Untreated mBC MONALEESA-6 NSCLC LEE011 + LDK378 in pts with NSCLC

30. TRD Development Plan CD&MA SDP DDP/FDP ML-4, ER+ HER2- mBC after NSAI Decision Point: if BE +, decide between tablet and DiC if BE -, continue both development streams BE study DiC vs FCT CPIC DS (March) PC1-500kg LC1-750kg CHAD PAC3-300kg Resupply 2 - 750kg LC2-500kg PAC4-350kg Resupply 1 - 750kg DS reg stabs program CPIC DP (March) DiC PHAD / PharmOps New equipment order, delivery, installation, qualification QbD3.1–verification 1 QbD3.2–verification 2 ML-2, ER+ HER2- untreated mBC PDC WS2 PDC WS3 DiC resupply PDC WS4 QbD2 -FMI pilot DiC DP reg stab program FCT-RC PDC WS2 Targeting 50-200-300 mg tablet strengths. Details tbd at PDC WS2 QbD3.2–verification 2 QbD3.1–verification 1 Transfer to PharmOps/WST Scale-up (405) QbD2 -FMI lab/pilot PDC WS3 PED oral liquid PDC WS4 QbD3.2–verification 2 QbD3.1–verification 1 PDC WS2 Transfer to PharmOps Scale-up (Siegfried) QbD1&2 -FMI lab/pilot PDC WS3 PDC WS4 | LEE011 EPT Feb 14, 2014 | TRD Update | Business Use Only

31. Overview of Drug Discovery and Development The fairy-tale version 2-6 years Target identification, lead identification, lead optimization, clinical candidate selection Discovery Starts after a lead molecule (clinical candidate) is found Lab testing, animal studies for safety (tox studies) and efficacy Phase 0 IND 20-80 Healthy Volunteers Purpose: determine safety and dosage Phase 1 Health Authority End of Ph 1 Meeting 100-300 Patients Purpose: demonstrate efficacy Phase 2 Health Authority End of Ph 2 Meeting Phase 3 1000-5000 Patients Purpose: monitor adverse reactions to long term use NDA Launch! 16 0 2 4 6 8 10 12 14 18 Years

32. All said and done, Drug Development can rival the US Immigration Process

33. Drug Development ...is typically organized into three groups

34. Overview of Drug Discovery and Development Discovery Lead Series Identified (LSI) Clinical Lead(s) Selected (CLS) Clinical Candidate(s) Selected (CCS) Target Assessment (TA) Entry Into Human (EIH) Target Identification and Validation Lead Identification Lead Optimization Preclinical or Nonclinical Testing Identify a biological pathway and molecular structure of interest Identify one or more leads (biological or chemical compounds) that interact with the target to get the desired therapeutic effect. Optimize the physicochemical characteristics of the compound to make it more druggable. Demonstrate safety in animals prior to human trials, show therapeutic advantages Genomics Proteomics GLP Tox High Throughput Screening Literature/research IND Package In silico modeling

35. Overview of Drug Discovery and Development Exploratory Development Start of Phase 3 Entry Into Human (EIH) or FIH FIM Start of Phase 2 Phase 2 PoC Phase 1 Evaluate safety in healthy human volunteers Establish PK and PD profile for better characterized drugs. Evaluate efficacy and side effects in patients Establish PK and PD profile for better characterized drugs. Dosage Biomarkers Treatment Duration Modeling and Simulation

36. Overview of Drug Discovery and Development Confirmatory Development Filing Decision Post Marketing Phase 3 NDA Approval and Launch Evaluate use of the drug in different patient groups Identify new therapeutic opportunities Develop new formulations Demonstrate/confirm the compound is as effective as existing drugs, if not more so Refine safety profile (long-term toxicity, undesirable side effects) across a large number of patients Post Approval Commitments Market Preparation Brand Management