BREAKTHROUGH THERAPIES: MARKET DYNAMICS AND INVESTMENT OPPORTUNITIES

BREAKTHROUGH THERAPIES: MARKET DYNAMICS AND INVESTMENT OPPORTUNITIES PHM176A January 2017 Dr. Cheryl Lee Barton Project Analyst ISBN: 1-62296-431-4...
Author: Beryl Jacobs
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BREAKTHROUGH THERAPIES: MARKET DYNAMICS AND INVESTMENT OPPORTUNITIES

PHM176A January 2017

Dr. Cheryl Lee Barton Project Analyst

ISBN: 1-62296-431-4

BCC Research 49 Walnut Park, Building 2 Wellesley, MA 02481 USA 866-285-7215 (toll-free within the USA), or (+1) 781-489-7301 www.bccresearch.com [email protected]

PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TABLE OF CONTENTS TOPIC

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CHAPTER 1 INTRODUCTION STUDY GOALS AND OBJECTIVES REASONS FOR DOING THE REPORT SCOPE OF REPORT INTENDED AUDIENCE METHODOLOGY AND INFORMATION SOURCES ANALYSTS' CREDENTIALS RELATED BCC RESEARCH REPORTS BCC RESEARCH WEBSITE DISCLAIMER

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CHAPTER 2 SUMMARY SUMMARY TABLE GLOBAL MARKET FOR BREAKTHROUGH THERAPY DESIGNATION DRUGS, BY THERAPY, THROUGH 2022 ($ MILLIONS) SUMMARY FIGURE GLOBAL MARKET FOR BREAKTHROUGH THERAPY DESIGNATION DRUGS, BY THERAPY, 2015-2022 ($ MILLIONS)

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CHAPTER 3 OVERVIEW DEFINING BREAKTHROUGH THERAPY DESIGNATION QUALIFYING CRITERIA FOR BREAKTHROUGH THERAPY DESIGNATION Serious Condition Existing (or Available) Therapies Preliminary Clinical Evidence May Demonstrate Substantial Improvement on Clinically Significant Endpoint(s) THE BENEFITS OF BREAKTHROUGH THERAPY DESIGNATION FDA'S APPROACHES TO EXPEDITED DRUG DEVELOPMENT DRUGS GRANTED BREAKTHROUGH THERAPY DESIGNATION TABLE 1 CDER BREAKTHROUGH THERAPY DESIGNATION REQUESTS RECEIVED BY FISCAL YEAR COHORT: JULY 9, 2012*-SEPTEMBER 30, 2015 TABLE 2 CBER BREAKTHROUGH THERAPY REQUESTS FOR FINAL YEAR, OCTOBER 1, 2014–SEPTEMBER 30, 2015 FIGURE 1 BREAKTHROUGH THERAPY REQUESTS GRANTED BY DIVISION, 2015* (%) PRIME (PRIORITY MEDICINE) SCHEME FIGURE 2 PRIME SCHEME APPLICATIONS AND ELIGIBILITY FIGURE 3 PRIME DRUG BY TYPE OF APPLICATION AND THERAPEUTIC AREA FIGURE 4 PRIME DRUG APPLICATIONS, THERAPEUTIC AREA TABLE 3 DRUGS GRANTED PRIME DESIGNATIONS, MARCH 7, 2016-AUGUST 24, 2016

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CHAPTER 4 COMMERCIAL APPLICATION OF BREAKTHROUGH THERAPY DESIGNATION INTRODUCTION FIGURE 5 FDA APPROVALS, BREAKTHROUGH THERAPY DESIGNATION AND DESIGNATION RESCINDED, BY STATUS, 2012-2016 (NUMBER) FIGURE 6 FDA APPROVALS, BREAKTHROUGH DESIGNATION AND DESIGNATION RESCINDED, BY THERAPY AREA, 2012-2016 (NUMBER) CARDIOVASCULAR

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PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TOPIC FIGURE 7 CARDIOVASCULAR BREAKTHROUGH THERAPY DESIGNATION DRUGS, BY STAGE (NUMBER) TABLE 4 GLOBAL MARKET FOR CV BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) CV - BTD DRUGS APPROVED TABLE 5 FDA APPROVED CV BREAKTHROUGH THERAPY DESIGNATION DRUGS Promacta/Revolade (Eltrombopag Olamine: Novartis/GlaxoSmithKline) BTD: February 6, 2014 Drug Class: Thrombopoietin Receptor Agonist (Small Molecule) Indication: Severe Aplastic Anemia (SAA; CV) Clinical Stage: Approved Forecast TABLE 6 GLOBAL MARKET FOR PROMACTA, THROUGH 2022 ($ MILLIONS/%) Praxbind (Idarucizumab; Boehringer Ingelheim) BTD: June 30, 2014 Drug Class: Humanized Antibody Fragment (Biologic) Indication: Reversal of Bleeding and Clotting Associated with Pradaxa (CV) Clinical Stage: Approved Forecast TABLE 7 GLOBAL MARKET FOR PRAXBIND, THROUGH 2022 ($ MILLIONS/%) CV - BTD IN DEVELOPMENT TABLE 8 UNDER DEVELOPMENT CV BREAKTHROUGH THERAPY DESIGNATION DRUGS Reasanz (Serelaxin; Novartis) BTD: June 21, 2013 Drug Class: Human Relaxin 2 Hormone (Biologic) Indication: Acute Heart Failure (AHF; CV) Clinical Stage Forecast TABLE 9 GLOBAL MARKET FOR REASANZ, THROUGH 2022 ($ MILLIONS/%) Actemra/RoActemra (Tocilizumab; Roche) BTD: June 10, 2015, and August 5, 2016 Drug Class: Humanized Anti Interleukin L-6 Receptor mAb (Biologic) Indication: Systemic Sclerosis and Giant Cell Arteritis (CNS/Rare Disease) Clinical Stage: Approved/Phase 3 BTD SSC Trial CGA Trials Forecast TABLE 10 GLOBAL MARKET FOR ACTEMRA/ROACTEMRA, THROUGH 2022 ($ MILLIONS/%) CENTRAL NERVOUS SYSTEM AND NEUROLOGICAL DISORDERS FIGURE 8 CNS BREAKTHROUGH THERAPY DESIGNATION DRUGS, BY STAGE, 2016 (NUMBER) TABLE 11 GLOBAL MARKET FOR CNS BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) CNS - BTD DRUGS APPROVED

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PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TOPIC TABLE 12 FDA APPROVED CNS BREAKTHROUGH THERAPY DESIGNATION DRUGS Nuplazid (Primavanserin: Acadia Pharmaceuticals) BTD: February 9, 2014 Drug Class: Selective Serotonin Inverse Agonist (Small Molecule) Indication: Major Depressive Disorder Clinical Stage: Approved Forecast TABLE 13 GLOBAL MARKET FOR NUPLAZID, THROUGH 2022 ($ MILLIONS/%) CNS - BTD IN DEVELOPMENT TABLE 14 UNDER DEVELOPMENT CNS BREAKTHROUGH THERAPY DESIGNATION DRUGS Deutetrabenazine ER (Teva Pharmaceuticals) BTD: November 9, 2015 Drug Class: Vesicular Monoamine 2 Transporter Inhibitor (Small Molecule) Indication: Tardive Dyskinesia (CNS) Clinical Stage: Phase 2/3 Forecast TABLE 15 GLOBAL MARKET FOR DEUTETRABENAZINE ER, THROUGH 2022 ($ MILLIONS/%) Ingrezza (Valbenazine; Neuroscience Biosceinces) BTD: October 30, 2014 Drug Class: Vesicular Monoamine 2 Transporter Inhibitor (Small Molecule) Indication: Tardive Dyskinesia (CNS) Clinical Stage: Phase 3 Kinect 2 - Phase 2b Kinect 3 - Phase 3 Forecast TABLE 16 GLOBAL MARKET FOR INGREZZA, THROUGH 2022 ($ MILLIONS/%) Arzerra (Ofatumumab; Novartis/Genmab) BTD: October 11, 2013 Drug Class: Human Monoclonal Antibody Targeting CD20-Positive B Cells (Biologic) Indication: Relapse Remitting Multiple Sclerosis (CNS/Autoimmune) Clinical Stage: Phase 3 Forecast TABLE 17 GLOBAL MARKET FOR OF OFATUMUMAB, THROUGH 2022 ($ MILLIONS/%) Oliceridine (TRV130; Trevena) BTD: February 22, 2016 Drug Class: M Opioid Receptor Agonist (Small Molecule) Indication Clinical Stage: Phase 3 Forecast TABLE 18 GLOBAL MARKET FOR OLICERIDINE, THROUGH 2022 ($ MILLIONS/%) Rapastinel (GLYX-13; Allergan) BTD: January 31, 2016 Drug Class: NMDA Partial Receptor Antagonist (Small Molecule)

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PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TOPIC Indication: Major Depressive Disorder (CNS) Clinical Stage: Phase 2 Forecast TABLE 19 GLOBAL MARKET FOR RAPASTINEL, THROUGH 2022 ($ MILLIONS/%) Sepranolone (UC1010; Asarina Pharma) TD: February 22, 2016 Drug Class: GABA-A Modulating Steroid Antagonist (Small Molecule) Indication: Premenstrual Dysphoric Disorder (PMDD) Clinical Stage: Phase 2 Forecast TABLE 20 GLOBAL MARKET FOR SEPRANOLONE, THROUGH 2022 ($ MILLIONS/%) NaBen (SND-13; SyneuRx International Corporation) BTD: December 10, 2014 Drug class: D-Amino Acid Oxidase (DAAO) Inhibitor (Small Molecule) Indication: Schizophrenia (CNS) Clinical Stage: Phase 2/3 Forecast TABLE 21 GLOBAL MARKET FOR SND-13, THROUGH 2022 ($ MILLIONS/%) AVXS-101 (AveXis) BTD: July 20, 2016 Drug Class: Gene Therapy (Biologic) Indication: Spinal Muscular Atrophy (SMA; Rare Disease) Clinical Stage: Phase 1 Forecast TABLE 22 GLOBAL MARKET FOR AVXS-101, THROUGH 2022 ($ MILLIONS/%) Esketamine (Johnson & Johnson) BTD: November 2013 and August 16, 2016 Drug Class: N-methyl-D-aspartate (NMDA) Receptor Antagonist (Small Molecule) Indication: Major Depressive Disorder (MDD) Clinical Stage: Phase 3 Forecast TABLE 23 GLOBAL MARKET FOR ESKETAMINE, THROUGH 2022 ($ MILLIONS/%) RBP-8000 (Indivior) BTD: November 18, 2014 Drug Class: Cocaine Esterase Rescue Blocker (Small Molecule) Indication: Cocaine Abuse Clinical Stage: Phase 2 Forecast TABLE 24 GLOBAL MARKET FOR RBP-8000, THROUGH 2022 ($ MILLIONS/%) INFECTIOUS DISEASES FIGURE 9 INFECTIOUS DISEASE BREAKTHROUGH THERAPY DESIGNATION DRUGS, BY STAGE, 2016 (NUMBER) TABLE 25 GLOBAL MARKET FOR INFECTIOUS DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) INFECTIOUS DISEASES - BTD APPROVED

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PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TOPIC TABLE 26 FDA APPROVED INFECTIOUS DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS, 2016 Sovaldi (Gilead Sciences) BTD: December 6, 2013 Drug Class: Nucleotide Analog Inhibitor (Small Molecule) Indication: Hepatitis C Virus (Infectious Diseases) Clinical Stage: Approved Forecast TABLE 27 GLOBAL MARKET FOR SOLVADI, THROUGH 2022 ($ MILLIONS/%) Epclusa (Gilead Sciences) BTD: April 22, 2014 Drug Class: Nucleotide Analog Inhibitor + Pan-Genotypic NS5A Inhibitor (Small Molecule) Indication: Hepatitis C Virus (Infectious Disease) Clinical Stage: Approved Forecast TABLE 28 GLOBAL MARKET FOR EPCLUSA, THROUGH 2022 ($ MILLIONS/%) Technivie/Viekirax (AbbVie) BTD: June 30, 2014 Drug Class: Fixed Dose Triple Antiviral (Small Molecule) Indication: Hepatitis C Virus (Infectious Disease) Clinical Stage: Phase 3 Forecast TABLE 29 GLOBAL MARKET FOR VIEKERA/TECHNIVIE, THROUGH 2022 ($ MILLIONS/%) Zepatier (Elbasvir/Grazoprevir; Merck) BTD: October 1, 2013 Drug Class: NS5A Inhibitor, NS3/4A Protease Inhibitor (Small Molecule) Indication: Hepatitis C Virus (Infectious Disease) Clinical Stage: Approved Forecast TABLE 30 GLOBAL MARKET FOR ZEPATIER, THROUGH 2022 ($ MILLIONS/%) Harvoni (Gilead Sciences) BTD: October 10, 2014 Drug Class: NS5A Inhibitor NS5B Inhibitor (Small Molecule) Indication: Hepatitis C Virus (Infectious Disease) Clinical Stage: Approved Forecast TABLE 31 GLOBAL MARKET FOR HARVONI, THROUGH 2022 ($ MILLIONS/%) INFECTIOUS DISEASES - BTD IN DEVELOPMENT TABLE 32 UNDER DEVELOPMENT INFECTIOUS DISEASE BREAKTHROUGH THERAPY DESIGNATION DRUGS, 2016 Arikayce (Amikacin Sulfate: Insmed) BTD: June 20, 2014 Drug Class: Aminoglycoside Antibiotic. (Small Molecule) Indication: Nontuberculous Mycobacterial (NTM; Infectious Disease) Clinical Stage: Phase 3

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PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TOPIC Forecast TABLE 33 GLOBAL MARKET FOR ARIKAYCE, THROUGH 2022 ($ MILLIONS/%) Fostemsavir (ViiV Healthcare) BTD: July 22, 2015 Drug Class: Fusion Inhibitor (Small Molecule) Indication: Human Immunodeficiency Virus (HIV) Clinical Stage: Phase 3 Forecast TABLE 34 GLOBAL MARKET FOR FOSTEMSAVIR, THROUGH 2022 ($ MILLIONS/%) Glecaprevir/Pibrentasvir (ABT-493/ABT-530; AbbVie/Enanta Pharmaceuticals) BTD: September 30, 2016 Drug Class: NS3 Protein Inhibitor (Small Molecule) Indication: Hepatitis C Virus (HCV; Infectious Disease) Clinical Stage: Phase 2 Forecast TABLE 35 GLOBAL MARKET FOR GLECAPREVIR/PIBRENTASVIR, THROUGH 2022 ($ MILLIONS/%) Ibalizumab (TaiMed Biologics/Theratechnologies) BTD: February 2015 Drug Class: CD4 mAb (Biologic) Indication: Human Immunodeficiency Virus (HIV) Clinical Stage: Phase 3 Forecast TABLE 36 GLOBAL MARKET FOR IBALIZUMAB, THROUGH 2022 ($ MILLIONS/%) Tafenoquine (GlaxoSmithKline/MMV) BTD: 20 December, 2013 Drug Class: 8-Aminoquinoline Derivative (Small Molecule) Indication: Hepatitis C Virus (HCV; Infectious Disease) Clinical Stage: Phase 2 Forecast TABLE 37 GLOBAL MARKET FOR TAFENOQUINE, THROUGH 2022 ($ MILLIONS/%) V920 (Merck & Co./NewLink Genetics Corporation) BTD: 25, July 2016 Drug Class: Ebola Vaccine (Biologic) Indication: Ebola Zane (Infectious Disease) Clinical Stage: Phase 3 Forecast TABLE 38 GLOBAL MARKET FOR V920, THROUGH 2022 ($ MILLIONS/%) ONCOLOGY FIGURE 10 CANCER DRUGS WITH BREAKTHROUGH THERAPY DESIGNATION, BY CANCER TYPE, 2016 (NUMBER OF APPROVED BTD DRUGS) FIGURE 11 CANCER BREAKTHROUGH THERAPY DESIGNATION, BY COMPANY, 2016 (NO. OF BTD IN ONCOLOGY) TABLE 39 GLOBAL MARKET FOR ONCOLOGY BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) ONCOLOGY - BTD DRUGS APPROVED TABLE 40 FDA APPROVED ONCOLOGY BREAKTHROUGH THERAPY DESIGNATION DRUGS, 2013-2015

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PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TOPIC Alecensa (Alectinib: Genentech/Roche) BTD: June 2013 and October 2016 Drug Class: Oral Inhibitor of Anaplastic Lymphoma Kinase (ALK) Inhibitor (Small Molecule) Indication: ALK+ NSCLC (Oncology) Clinical Stage: Approved Second Line Therapy - NP28761 (Study 1) Second Line Therapy - NP28673 (Study 2) First Line Therapy - J-ALEX Study Forecast TABLE 41 GLOBAL MARKET FOR ALENCENSA, THROUGH 2022 ($ MILLIONS/%) Arzerra (Ofatumumab; GlaxoSmithKline/Genmab) BTD: September 13, 2013 Drug Class: mAb Target CD20 (Biologic) Indication: CLL Clinical Stage: Approved Forecast TABLE 42 GLOBAL MARKET FOR ARZERRA, THROUGH 2022 ($ MILLIONS/%) Blincyto (Blinatumomab; Amgen) BTD: December 3, 2014 Drug Class: CD3/CD19 BiTE Antibody (Biologic) Indication: B-Cell ALL (Oncology) FIGURE 12 TREATMENT ALGORITHM FOR ALL PATIENTS Clinical Stage: Approved Forecast TABLE 43 GLOBAL MARKET FOR BLINCYTO, THROUGH 2022 ($ MILLIONS/%) Darzalex (Daratumumab; Genmab/Johnson & Johnson) BTD: May 1, 2013, May 27, 2013, and July 2016 Drug Class: mAb CD38 (Biologic) Indication: Multiple Myeloma (Oncology) Clinical Stage: Phase 3 CASTOR Trial-Second Line POLLUX Trial - Second Line Forecast TABLE 44 GLOBAL MARKET FOR DARZALEX, THROUGH 2022 ($ MILLIONS/%) Gazyva/Gazyvaro (Obinutuzumab; Genentech/Roche) BTD: May 2013 Drug Class: mAb TargetingCD20 (Biologic) Indication: CLL Clinical Stage: Approved Forecast TABLE 45 GLOBAL MARKET FOR GAZYVA, THROUGH 2022 ($ MILLIONS/%) Ibrance (Palbociclib; Pfizer) BTD: February 3, 2015 Indication: Her2 Metastatic Breast Cancer (Oncology) Drug Class: CDK4/6 Inhibitor (Small Molecule) Clinical Stage: Phase 3 PALOMA-2 Trial - Combination Therapy First-Line

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PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TOPIC PALOMA-3 - Combination Therapy Forecast TABLE 46 GLOBAL MARKET FOR IBRANCE, THROUGH 2022 ($ MILLIONS/%) Imbruvica (Ibrutinib; Johnson & Johnson/ Pharmacyclic) BTD: January 2013 Drug Class: BTK Inhibitor (Small Molecule) Indication: CLL (Oncology) Clinical Phase: Approved Forecast TABLE 47 GLOBAL MARKET FOR IMBRUVICA, THROUGH 2022 ($ MILLIONS/%) Keytruda (Pembrolizumab; Merck) BTD: October 27, 2014, November 2, 2015, April 18, 2016 Drug Class: Anti-PD-1 Monoclonal Antibody (Biologic) Indication: Solid Tumors (Oncology) Clinical Stage: Approved Melanoma KEYNOTE-001: Phase 1b KEYNOTE-002: Phase 2 KEYNOTE-028 Study: Phase 1b KEYNOTE-006 Study: Phase 3 NSCLC - First-Line KEYNOTE-010 Phase 2/3 Classical Hodgkin Lymphoma Colorectal Cancer Forecast TABLE 48 GLOBAL MARKET FOR KEYTRUDA, THROUGH 2022 ($ MILLIONS/%) Lartruvo (Olaratumab; Eli Lilly) BTD: August 6, 2015 Drug Class: Platelet Derived Growth Factor Receptor Alpha Antagonist (Small Molecule) Indication: Soft Tissue Sarcoma Clinical Stage: Approved Forecast TABLE 49 GLOBAL MARKET FOR LARTRUVO, THROUGH 2022 ($ MILLIONS/%) Lenvima/Kisplyx (Lenvatinib; Eisai) BTD: August 6, 2015 Drug Class: Tyrosine Kinase Inhibitor (Small Molecule) Indication: Thyroid Cancer (Oncology) Clinical Stage: Phase 3 Forecast TABLE 50 GLOBAL MARKET FOR LENVIMA/KISPLYX, THROUGH 2022 ($ MILLIONS/%) Lynparza (Olaparib; AstraZeneca) BTD: January 27, 2016 Drug Class: Poly ADP-Ribose Polymerase Inhibitor (PARP Oncology) Indication: Metastatic Castration-Resistant Prostate Cancer (mCRPC; Oncology) Clinical Stage: Phase 2 Forecast

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PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TOPIC TABLE 51 GLOBAL MARKET FOR LYNPARZA, THROUGH 2022 ($ MILLIONS/%) Midostaurin (PKC412; Novartis) BTD: February 19, 2016 Drug Class: Oral, Multi-Targeted Kinase Inhibitor (Small Molecule) Indication: Acute Myeloid Leukemia (AML; Oncology) Clinical Stage: Phase 3 Forecast TABLE 52 GLOBAL MARKET FOR MIDOSTAURIN, THROUGH 2022 ($ MILLIONS/%) Opdivo (Nivolumab; BMS) BTD: April 25, 2016, and June 27, 2016 Drug Class: PD-1 Inhibitor (Small Molecule) Indication: Solid Tumors (Oncology) Clinical Stage: Advanced Melanoma Checkmate 067: Phase 3 Checkmate 069: Phase 2 Bladder Cancer CheckMate-032: Advanced Squamous Non-Small Cell Lung Cancer: CheckMate -017: Phase 3 CheckMate -063: Phase 2 Second-Line Treatment of Metastatic Non-Squamous NSCLC Metastatic Renal Cell Carcinoma CheckMate 025 Trial: Phase 3 CheckMate-057: Phase 3 Forecast TABLE 53 GLOBAL MARKET FOR OPDIVO, THROUGH 2022 ($ MILLIONS/%) Tagrisso (Osimertinib; AstraZeneca) BTD Date; April 24, 2104 Drug Class: EGFR- Tyrosine Kinase Inhibitor (Small Molecule) Indication: Non-Small-Cell Lung Cancer (Oncology) Clinical Stage: Approved Forecast TABLE 54 GLOBAL MARKET FOR TAGRISSO, SALES FORECASTS, THROUGH 2022 ($ MILLIONS/%) Tafinlar/Mekinist (Dabrafenib/Trametinib; GlaxoSmithKline) BTD: January 2014 (Monotherapy) and July 23, 2015 (Combination Therapy) Drug Class: BRAF Inhibitor plus MEK Inhibitor (Biologic) Indication: NSCLC (Oncology). Clinical Stage: Approved Monotherapy Trial Combination Therapy Trial Forecast TABLE 55 GLOBAL MARKET FOR TAFINLAR/MEKINIST, THROUGH 2022 ($ MILLIONS/%) Tecentriq (Atezolizumab; Genentech/Roche) BTD: January 23, 2014 Drug Class: Programmed Cell Death–1 Ligand 1 Monoclonal Antibody (Biologic) Indication: Metastatic Urothelial Carcinoma (Oncology) Clinical Stage: Approved

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TOPIC Forecast TABLE 56 GLOBAL MARKET FOR TECENTRIQ, THROUGH 2022 ($ MILLIONS/%) Venclexta (Venetoclax; AbbVie/Roche/Genentech) BTD: April 2015 and January 2016 Drug Class: Oral B-cell Lymphoma-2 Inhibitor (Small Molecule) Indication: CLL (Oncology) Clinical Stage: Approved Forecast TABLE 57 GLOBAL MARKET FOR VENCLEXTA, THROUGH 2022 ($ MILLIONS/%) Xalkori (Crizotinib; Pfizer) BTD: August 26, 2011 Drug Class: Anaplastic Lymphoma Kinase (ALK) Tyrosine Kinase Receptor Inhibitor (Small Molecule) Indication: ALK+ NSCLC (Oncology) Clinical Stage: Approved First-Line Therapy - Study 1 Second-Line Therapy - Study 2 Forecast TABLE 58 GLOBAL MARKET FOR XALKORI, THROUGH 2022 ($ MILLIONS/%) Zydelig (Idelalisib, Gilead Sciences) BTD: November 18, 2013 Drug Class: Oral Phosphoinositide 3-Kinase (PI3K) Delta Inhibitor (Small Molecule) Indication: CLL Clinical Stage: Approved Forecast TABLE 59 GLOBAL MARKET FOR ZYDELIG, THROUGH 2022 ($ MILLIONS/%) Zykadia (Ceritinib; Novartis) BTD: March 15, 2013 Drug Class: Anaplastic Lymphoma Kinase (ALK) Tyrosine Kinase Receptor Inhibitor (Small Molecule) Indication: ALK+ NSCLC (Oncology) Clinical Stage: Approved Forecast TABLE 60 GLOBAL MARKET FOR ZYKADIA, THROUGH 2022 ($ MILLIONS/%) ONCOLOGY - BTD IN DEVELOPMENT TABLE 61 UNDER DEVELOPMENT ONCOLOGY BREAKTHROUGH THERAPY DESIGNATION DRUGS Abemaciclib (Eli Lilly) BTD: August 8, 2015 Indication: Her2 Metastatic Breast Cancer (Oncology) Drug Class: CDK4-6 Inhibitor (Small Molecule) Clinical Stage: Phase 3 Forecast TABLE 62 GLOBAL MARKET FOR ABEMACICLIB, THROUGH 2022 ($ MILLIONS/%) Avelumab (Merck KGaA/PFizer) BTD: November 18, 2015

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PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TOPIC Drug Class: Fully Human Monoclonal Antibody Targeting Programmed Death Ligand-1 (Biologic) Indication: Metastatic Merkel Cell Carcinoma (Oncology) Clinical Stage: Phase 3 NSCL/ Phase 2 MCC/ Phase 1 Solid Tumors Forecast TABLE 63 GLOBAL MARKET FOR AVELUMAB, THROUGH 2022 ($ MILLIONS/%) Brigatinib (AP26113; ARIAD Pharmaceuticals) BTD: October 1, 2014 Drug Class: Oral Inhibitor of Anaplastic Lymphoma Kinase (ALK) Inhibitor (Small Molecule) Indication: ALK+ NSCLC (Oncology) Clinical Stage: Filed Forecast TABLE 64 GLOBAL MARKET FOR BRIGATINIB, THROUGH 2022 ($ MILLIONS/%) CTL019 (Novartis) BTD: July 2014 Drug Class: Autologous Chimeric Antigen Receptor (CAR)- T Tell Therapy targeting CD19 (Biologic) Indication: CLL Clinical Stage: Phase 2 Forecast TABLE 65 GLOBAL MARKET FOR CTL019, THROUGH 2022 ($ MILLIONS/%) CRS-207 and GVAX (Aduro Biotech) BTD: 17 February, 2016 Drug Class: Tumor-Associated Antigen Mesothelin (Biologic) Indication: Metastatic Pancreatic Cancer (Oncology) Clinical Stage: Phase 2b Forecast TABLE 66 GLOBAL MARKET FOR CRS-207 AND GVAX PANCREAS, THROUGH 2022 ($ MILLIONS/%) Durvalumab (MEDI4736; AstraZeneca-MedImmune) BTD: February 17, 2016 Drug Class: Humanized Monoclonal Antibody Targeting Programmed Death Ligand-1 (Biologic) Indication: Metastatic Urothelial Bladder (Oncology) Clinical Stage: Phase 3 Forecast TABLE 67 GLOBAL MARKET FOR DURVALUMAB, THROUGH 2022 ($ MILLIONS/%) EBV-CTL (Atara and MSKCC) BTD: February 3, 2015 Drug Class: Allogeneic Hematopoietic Cell Transplant (Biologic) Indication: EBV-Associated Lymphoproliferative Disease (Oncology) Clinical Stage: Phase 3 Forecast TABLE 68 GLOBAL MARKET FOR EBV-CTL, THROUGH 2022 ($ MILLIONS/%) Entinostat (Syndax Pharmaceuticals) BTD: September 11, 2013

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PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TOPIC Drug Class: Antibody Histone Deacetylase Inhibitor (Small Molecule) FIGURE 13 ENTINOSTAT MECHANISM OF ACTION Indication: Advanced HER2 Breast Cancer Clinical Stage: Phase 3 Forecast TABLE 69 GLOBAL MARKET FOR ENTINOSTAT, THROUGH 2022 ($ MILLIONS/%) Inotuzumab Ozogamicin (Pfizer, Celltech) BTD: October 19, 2015 Drug Class: Antibody Drug Conjugate (ADC) mAb Targeting CD22 plusC Agent Inotuzumab (Biologic) Indication: B-cell ALL Clinical Stage: Phase 3 Forecast TABLE 70 GLOBAL MARKET FOR INOTUZUMAB OZOGAMICIN, THROUGH 2022 ($ MILLIONS/%) JCAR015 (Juno Therapeutics) BTD: November 24, 2014 Drug Class: Autologous Chimeric Antigen Receptor (CAR) - T Cell Therapy Targeting CD19 (Biologic) Indication: Relapse-Refractory B-Cell ALL Clinical Stage: Phase 1-2 Forecast TABLE 71 GLOBAL MARKET FOR JCAR015, THROUGH 2022 ($ MILLIONS/%) KTE-C19 (Kite Pharma) BTD: December 7, 2015 Drug Class: Allogenic Chimeric Antigen Receptor (CAR) - T Cell Therapy Targeting CD19 (Biologic) Indication: Refractory, Diffuse Large B-Bell Lymphoma (DLBCL; Oncology) Clinical Stage: Phase 2 Forecast TABLE 72 GLOBAL MARKET FOR KTE-C19, THROUGH 2022 ($ MILLIONS/%) LOXO-101 (Loxo Oncology, Inc) BTD: July 13, 2016 Drug Class: Pan Tropomyosin Receptor Kinase Inhibitor (Small Molecules) Indication: Solid Tumors (Oncology) Clinical Stage: Phase 2 Forecast TABLE 73 GLOBAL MARKET FOR LOXO-101, THROUGH 2022 ($ MILLIONS/%) Nicord (Elbit Imaging/Gamida Cell) BTD: October 11, 2016 Drug Class: Allogeneic Hematopoietic Cell Transplant (Biologic) Indication: haematological malignancies (Oncology) Clinical Stage: Phases 1 and 2 Forecast TABLE 74 GLOBAL MARKET FOR NICORD, THROUGH 2022 ($ MILLIONS/%) Olmutinib (Boehringer Ingelheim)

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TOPIC BTD: December 21, 2015 Drug Class: Fully Human Monoclonal Antibody Targeting Programmed Death Ligand-1 (Biologic) Indication: T790M Mutation NSCLC (Oncology) Clinical Stage: Phases 1 and 2 (Approved in South Korea) Forecast TABLE 75 GLOBAL MARKET FOR OLMUTINIB, THROUGH 2022 ($ MILLIONS/%) NY-ESO Peptide (Affinity Enhanced T-Cell Therapy; Adaptimmune) BTD: February 9, 2016 Drug class: T-cell Therapy (TCR; Biologic) Indication: Synovial Sarcoma (Oncology) Clinical Stage: Phases 1 and 2 Forecast TABLE 76 GLOBAL MARKET FOR NY-ESO, THROUGH 2022 ($ MILLIONS/%) Pexidartinib (Daiichi Sankyo/Plexxikon) BTD: October 30, 2015 Drug Class: Multitargeted Receptor Tyrosine Kinase (RTK) Inhibitor (Small Molecule) Indication: Tenosynovial Giant Cell Tumor (TGCT; Oncology) Clinical Stage: Phase 1 Forecast TABLE 77 GLOBAL MARKET FOR PEXIDARTINIB, THROUGH 2022 ($ MILLIONS/%) Pracinostat (MEI Pharma) BTD: August 1, 2016 Drug Class: HDAC Inhibitor (Small Molecule) Indication: AML (Oncology) Clinical Stage: Phase 2 Forecast TABLE 78 GLOBAL MARKET FOR PRACINOSTAT, THROUGH 2022 ($ MILLIONS/%) PVS-RIPO (Duke Medicine) BTD: May 16, 2016 Drug Class: Genetically Modified Poliovirus (Biologic) Indication: Glioblastoma (Oncology) Clinical Stage: Phase 1 Forecast TABLE 79 GLOBAL MARKET FOR PVS-RIPO, THROUGH 2022 ($ MILLIONS/%) Ribociclib (LEE011; Novartis) BTD: August 3, 2016 Indication: Her2 Metastatic Breast Cancer (Oncology) Drug Class: CDK4-6 Inhibitor (Small Molecule) Clinical Stage: Phase 3 Forecast TABLE 80 GLOBAL MARKET FOR RIBOCICLIB, THROUGH 2022 ($ MILLIONS/%) Rintega (Celldex) BTD: February 23, 2015 Indication: Glioblastoma (Oncology) Drug class: Cancer Vaccine (Biologic) Clinical Stage: Discontinued

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PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TOPIC Forecast TABLE 81 GLOBAL MARKET FOR RINTEGA, THROUGH 2022 ($ MILLIONS/%) Rociletinib (Clovis Oncology) BTD: August 3, 2016 Indication: Her2 Metastatic Breast Cancer (Oncology) Drug Class: Epidermal Growth Factor Receptor Inhibitor (Small Molecule) Indication: Non-small Cell Lung Cancer (Oncology) Clinical Stage: Discontinued Forecast TABLE 82 GLOBAL MARKET FOR ROCILETINIB, THROUGH 2022 ($ MILLIONS/%) Rucaparib (Clovis Pharmaceuticals) BTD: April 2015 Drug Class: Oral PARP Inhibitor (PARP; Small Molecule) Indication: Ovarian Cancer (Oncology) Clinical Stage: Phase 2 Forecast TABLE 83 GLOBAL MARKET FOR RUCAPARIB, THROUGH 2022 ($ MILLIONS/%) Sacituzumab Govitecan (IMMU-132; Immunomedics) BTD: February 8, 2016 Drug Class: Antibody-Drug Conjugate (ADC; Biologic) Indication: Triple-Negative Breast Cancer (TNBC; Oncology) Clinical Stage: Phase 2 Forecast TABLE 84 GLOBAL MARKET FOR SACITUZUMAB GOVITECAN, THROUGH 2022 ($ Millions/%) Volasertib (Boehringer Ingelheim) BTD: September 17, 2013 Drug Class: Polo-Like Kinase (Plk) Inhibitor (Biologic) Indication: Acute Myeloid Leukemia (AML) Clinical Stage: Phase 3 Forecast TABLE 85 GLOBAL MARKET FOR VOLASERTIB, THROUGH 2022 ($ MILLIONS/%) Vyxeos (Cpx-351; Celator Pharmaceuticals-Jazz Pharmaceuticals) BTD: May 19, 2016 Drug Class: Nano-Scale Liposomal Formulation of Cytarabine: Daunorubicin (Small Molecule) Indication: AML Clinical Stage: Phase 3 Forecast TABLE 86 GLOBAL MARKET FOR VYXEOS, THROUGH 2022 ($ MILLIONS/%) RARE DISEASES FIGURE 14 RARE DISEASE BREAKTHROUGH THERAPY DESIGNATION DRUGS, BY STAGE, 2016 RARE DISEASES - BTD APPROVED TABLE 87 FDA APPROVED RARE DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS, 2015-2016 TABLE 88 GLOBAL MARKET FOR RARE DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%)

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PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TOPIC Ilaris (Canak Inumab, Novartis) BTD: April 27, 2016 Drug Class: Human Monoclonal Antibody Targeting Interleukin-1 Beta (Biologic) Indication: PFS, TRAPS and FMF (Rare Disease) Clinical Stage: Approved Forecast TABLE 89 GLOBAL MARKET FOR ILARIS, THROUGH 2022 ($ MILLIONS/%) Kanuma (Sebelipase Alfa; Alexion Pharmaceuticals) BTD May 20, 2013 Drug Class: Enzyme Replacement Therapy (Biologic) Indication: Lysosomal Acid Lipase Deficiency (Rare Disease) Clinical Stage: Approved Forecast TABLE 90 GLOBAL MARKET FOR KANUMA, THROUGH 2022 ($ MILLIONS/%) Strensiq (Asfotase Alfa; Alexion Pharmaceuticals) BTD: May 28, 2013 Drug Class: Enzyme Replacement Therapy (Biologic) Indication: Hypophosphatasia (Rare Disease) Clinical Stage: Approved Forecast TABLE 91 GLOBAL MARKET FOR STRENSIQ, THROUGH 2022 ($ MILLIONS/%) RARE DISEASES - BTD IN DEVELOPMENT TABLE 92 UNDER DEVELOPMENT RARE DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS, 2013-2016 ALXN1101 (Alexion Pharmaceuticals) BTD: October 24, 2013 Drug Class: Enzyme Co-Factor Replacement Therapy (Biologic) Indication: Molybdenum Cofactor Deficiency (MoCD; Rare Diseases) Clinical Stage: Phase 2 and Phase 3 Forecast TABLE 93 GLOBAL MARKET FOR ALXN-1101, THROUGH 2022 ($ MILLIONS/%) Firdapse (Amifampridine; Catalyst Pharmaceuticals) BTD: February 22, 2016 Drug Class: Potassium channel blocker (Small Molecule) Indication: Lambert-Eaton Myasthenic Syndrome (LEMS; Rare Disease) Clinical Stage: Phase 3 Forecast TABLE 94 GLOBAL MARKET FOR FIRDAPSE, THROUGH 2022 ($ MILLIONS/%) Olipudase Alfa (Sanofi Genzyme) BTD: June 4, 2014 Drug Class: Enzyme Replacement Therapy (Biologic) Indication: Acid Sphingomyelinase Deficiency-Niemann-Pick Disease Type B Clinical Stage: Phase 2 and Phase 3 Forecast

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TOPIC TABLE 95 GLOBAL MARKET FOR OLIPUDASE ALFA, THROUGH 2022 ($ MILLIONS/%) Zorblisa (SD-101; -Amicus Therapeutics /Scioderm BTD: April 23, 2013 Drug Class: Topical Cream (Small Molecule) Indication: Epidermolysis Bullosa (Rare Disease) Clinical Stage: Phase 2 Forecast TABLE 96 GLOBAL MARKET FOR ZORBLISA, THROUGH 2022 ($ MILLIONS/%) Setmelanotide (RM-493; Rhythm Pharmaceuticals) BTD: January 7, 2016 Drug Class: Melanocortin-4 Receptor (MC4R) Agonist (Small Molecule) Indication: Pro-Opiomelanocortin (POMC) Deficiency Obesity (Rare Diseases) Clinical Stage: Phase 2 Forecast TABLE 97 GLOBAL MARKET FOR SETMELANOTIDE, THROUGH 2022 ($ MILLIONS) VTS-270 (Vtesse Pharmaceuticals) BTD: January 6, 2016 Drug Class: 2-Hydroxypropyl-B-Cyclodextrin (Small Molecule) Indication: Niemann-Pick Type C1 (NPC) Disease (Rare Disease) Clinical Stage: Phase 2 and Phase 3 Forecast TABLE 98 GLOBAL MARKET FOR VTS-270, THROUGH 2022 ($ MILLIONS/%) OTHER DISEASES FIGURE 15 OTHER DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS, BY STAGE, 2016 (NUMBER) OTHER - BTD APPROVED TABLE 99 FDA APPROVED OTHER BREAKTHROUGH THERAPY DESIGNATION DRUGS, 2015 TABLE 100 GLOBAL MARKET FOR OTHER DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) Rapamune (Sirolimus, Pfizer) BTD Date: May 28, 2015 Drug Class: Macrolide Lactam Immunosuppressant (Small Molecule) Indication: Lymphangioleiomyomatosis (LAM) Clinical Stage: Approved Forecast TABLE 101 GLOBAL MARKET FOR RAPAMUNE BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) Lucentis (Ranibizumab Genentech-Roche) BTD Date: December 15, 2014 Drug Class: (EGF Inhibitor (Biologic) Indication Diabetic Retinopathy (DR) Clinical Stage: Approved Forecast TABLE 102 GLOBAL MARKET FOR LUCENTIS BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%)

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TOPIC Eylea (Aflibercept; Bayer) BTD Date: September 16, 2014 Drug Class: VEGF Fusion Protein (Biologic) Indication Diabetic Retinopathy (DR) Clinical Stage: Approved Forecast TABLE 103 GLOBAL MARKET FOR EYLEA BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) OTHER DISEASES - BTD IN DEVELOPMENT TABLE 104 OTHER DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS AWAITING APPROVAL, 2015-2022 Dupilumab (Sanofi-Regeneron) BTD Date: November 20, 2014 Drug Class: IL-4 mAb (Biologic) Indication: Severe Atopic Dermatitis Clinical Stage: Filed Forecast TABLE 105 GLOBAL MARKET FOR DUPILUMAB BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) AR101 (Aimmune Therapeutics) BTD Date: June 18, 2015 Indication: Peanut Allergen (Small Molecule) Clinical Stage: Phase 3 Forecast TABLE 106 GLOBAL MARKET FOR AR101 BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) Ocaliva (Obeticholic acid; Intercept Pharmaceuticals) BTD Date: January 1, 2015 Drug Class: Farnesoid X Receptor Agonist (Small Molecule) Indication: Nonalcoholic Steatohepatitis (NASH) with Liver Fibrosis (Rare Disease) Clinical Stage: Phase 3 Forecast TABLE 107 GLOBAL MARKET FOR OCALIVA BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) Viaskin Peanut (DBV Technologies) BTD: April 9, 2015 Drug Class: Peanut Allergen (Small Molecule) Indication: Peanut Allergen (Small Molecule) Clinical Stage: Phase 2 Forecast TABLE 108 GLOBAL MARKET FOR VIASKIN PEANUT BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) CHAPTER 5 IMPLICATIONS OF BREAKTHROUGH THERAPY DESIGNATION ON BUSINESS STRATEGY INTRODUCTION FIGURE 16 COMPARISON OF APPROVAL TIMES STANDARD VERSUS BREAKTHROUGH DESIGNATION (MONTHS)

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187 187 187

PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TOPIC IMPLICATIONS FOR CLINICAL DEVELOPMENT STRATEGIES FOR EXPEDITING CLINICAL DEVELOPMENT Process and Formulation Development Process Validation Analytical Development Availability of Stability Data IMPLICATIONS FOR MANUFACTURING Companion Diagnostics STRATEGIES FOR EXPEDITING MANUFACTURING CAPABILITIES MANAGING TECHNICAL RISKS VERSUS PATIENT BENEFIT LOOKING AHEAD CHAPTER 6 REGULATORY IMPLICATIONS AND BREAKTHROUGH THERAPY DESIGNATION EXPEDITED PROGRAMS TABLE 109 AN OVERVIEW OF THE KEY FEATURES OF THE FDA'S EXPEDITED PROGRAMS REGULATORY PATHWAYS TABLE 110 AN OVERVIEW OF THE FDA'S EXPEDITED DEVELOPMENT AND REVIEW PROGRAMS FAST TRACK DESIGNATION Qualifying Criteria Serious Condition Demonstrates the Potential to Address Unmet Medical Need Key Features of Fast Track Designation BREAKTHROUGH THERAPY DESIGNATION Qualifying Criteria Key Features Intensive Guidance on an Efficient Drug Development Program, Beginning as early as Phase 1 TABLE 111 BREAKTHROUGH THERAPIES CONSIDERATIONS: DRUG DEVELOPMENT Organizational Commitment Involving Senior Managers Submission of Portions of an Application (Rolling Review) TABLE 112 BREAKTHROUGH THERAPY CONSIDERATIONS: MARKETING APPLICATION REVIEW Other Actions to Expedite Review When to Make a BTD Request Submission The BTD Review Process FIGURE 17 COMPARISON OF STANDARD AND BREAKTHROUGH THERAPY APPROVAL TIMES (MONTHS) Rescinding BTD Status ACCELERATED APPROVAL Qualifying Criteria ACCELERATED APPROVAL ENDPOINTS Conditions of Accelerated Approval PRIORITY REVIEW DESIGNATION Qualifying Criteria Key Features DRUGS GRANTED BREAKTHROUGH THERAPY DESIGNATION

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PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TOPIC TABLE 113 CDER BREAKTHROUGH THERAPY DESIGNATION REQUESTS RECEIVED BY FISCAL YEAR COHORT: JULY 9, 2012*-SEPTEMBER 30, 2015 TABLE 114 CDER BREAKTHROUGH THERAPY DESIGNATION REQUESTS RECEIVED BY FISCAL YEAR COHORT: OCTOBER 1, 2015-SEPTEMBER 30, 2016 TABLE 115 CDER BREAKTHROUGH THERAPY DESIGNATION APPROVALS DATA AS OF DECEMBER 31, 2015 TABLE 116 CUMULATIVE CBER BREAKTHROUGH THERAPY DESIGNATION REQUESTS RECEIVED BY FISCAL YEAR COHORT: JULY 9, 2012*-DECEMBER 31, 2015 TABLE 117 CBER BREAKTHROUGH THERAPY DESIGNATION REQUESTS RECEIVED BY FISCAL YEAR COHORT: OCTOBER 1, 2015-SEPTEMBER 30, 2016 TABLE 118 CUMULATIVE CBER BREAKTHROUGH THERAPY APPROVAL DATA AS OF SEPTEMBER 30, 2016 TABLE 119 MOST RECENTLY ANNOUNCED BREAKTHROUGH THERAPY DESIGNATIONS DATA AS OF FEBRUARY 29, 2016 SIGNIFICANCE OF BTD FOR THE PHARMACEUTICAL AND BIOTECHNOLOGY INDUSTRIES CHAPTER 7 COMPANY PROFILES ABBVIE INC. ACADIA PHARMACEUTICALS INC. ADAPTIMMUNE THERAPEUTICS PLC ADURO BIOTECH INC. AIMMUNE THERAPEUTICS INC. ALEXION PHARMACEUTICALS INC. ALLERGAN PLC AMGEN INC. ANATARA LIFESCIENCES LIMITED ARIAD PHARMACEUTICALS INC. ASTRAZENECA PLC AVEXIS INC. BOEHRINGER INGELHEIM GMBH CELLDEX THERAPEUTICS INC. CLOVIS ONCOLOGY INC. DAIICHI SANKYO COMPANY, LIMITED DBV TECHNOLOGIES EISAI CO. LTD. ELI LILLY AND COMPANY EXELIXIS INC. F. HOFFMANN-LA ROCHE LTD. GILEAD SCIENCES INC. GLAXOSMITHKLINE PLC IMMUNOMEDICS INC. INDIVIDOR PLC JAZZ PHARMACEUTICALS JOHNSON & JOHNSON JUNO THERAPEUTICS INC. KITE PHARMA INC. MERCK & CO. INC.

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PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

TOPIC MERCK KGAA NOVARTIS AG PFIZER INC. PHARMACYCLICS INC. PROGENICS PHARMACEUTICALS INC. REGENERON PHARMACEUTICALS INC. RHYTHM PHARMACEUTICALS INC. SYNDAX PHARMACEUTICALS INC. SYNEURX INTERNATIONAL CORPORATION TEVA PHARMACEUTICALS INC. TREVENA INC. VERTEX PHARMACEUTICALS INC. VTESSE INC. WELLSTAT THERAPEUTICS CORPORATION

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CHAPTER 8 REFERENCES CHAPTER 3 CHAPTER 4 CHAPTER 5 CHAPTER 6

248 248 249 249 250

CHAPTER 9 ACRONYMS

255

CHAPTER 10 ENDNOTES

258

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PHM176A - Breakthrough Therapies: Market Dynamics and Investment Opportunities

LIST OF TABLES TABLE HEADING SUMMARY TABLE GLOBAL MARKET FOR BREAKTHROUGH THERAPY DESIGNATION DRUGS, BY THERAPY, THROUGH 2022 ($ MILLIONS) TABLE 1 CDER BREAKTHROUGH THERAPY DESIGNATION REQUESTS RECEIVED BY FISCAL YEAR COHORT: JULY 9, 2012*-SEPTEMBER 30, 2015 TABLE 2 CBER BREAKTHROUGH THERAPY REQUESTS FOR FINAL YEAR, OCTOBER 1, 2014–SEPTEMBER 30, 2015 TABLE 3 DRUGS GRANTED PRIME DESIGNATIONS, MARCH 7, 2016-AUGUST 24, 2016 TABLE 4 GLOBAL MARKET FOR CV BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) TABLE 5 FDA APPROVED CV BREAKTHROUGH THERAPY DESIGNATION DRUGS TABLE 6 GLOBAL MARKET FOR PROMACTA, THROUGH 2022 ($ MILLIONS/%) TABLE 7 GLOBAL MARKET FOR PRAXBIND, THROUGH 2022 ($ MILLIONS/%) TABLE 8 UNDER DEVELOPMENT CV BREAKTHROUGH THERAPY DESIGNATION DRUGS TABLE 9 GLOBAL MARKET FOR REASANZ, THROUGH 2022 ($ MILLIONS/%) TABLE 10 GLOBAL MARKET FOR ACTEMRA/ROACTEMRA, THROUGH 2022 ($ MILLIONS/%) TABLE 11 GLOBAL MARKET FOR CNS BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) TABLE 12 FDA APPROVED CNS BREAKTHROUGH THERAPY DESIGNATION DRUGS TABLE 13 GLOBAL MARKET FOR NUPLAZID, THROUGH 2022 ($ MILLIONS/%) TABLE 14 UNDER DEVELOPMENT CNS BREAKTHROUGH THERAPY DESIGNATION DRUGS TABLE 15 GLOBAL MARKET FOR DEUTETRABENAZINE ER, THROUGH 2022 ($ MILLIONS/%) TABLE 16 GLOBAL MARKET FOR INGREZZA, THROUGH 2022 ($ MILLIONS/%) TABLE 17 GLOBAL MARKET FOR OF OFATUMUMAB, THROUGH 2022 ($ MILLIONS/%) TABLE 18 GLOBAL MARKET FOR OLICERIDINE, THROUGH 2022 ($ MILLIONS/%) TABLE 19 GLOBAL MARKET FOR RAPASTINEL, THROUGH 2022 ($ MILLIONS/%) TABLE 20 GLOBAL MARKET FOR SEPRANOLONE, THROUGH 2022 ($ MILLIONS/%) TABLE 21 GLOBAL MARKET FOR SND-13, THROUGH 2022 ($ MILLIONS/%) TABLE 22 GLOBAL MARKET FOR AVXS-101, THROUGH 2022 ($ MILLIONS/%) TABLE 23 GLOBAL MARKET FOR ESKETAMINE, THROUGH 2022 ($ MILLIONS/%) TABLE 24 GLOBAL MARKET FOR RBP-8000, THROUGH 2022 ($ MILLIONS/%) TABLE 25 GLOBAL MARKET FOR INFECTIOUS DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) TABLE 26 FDA APPROVED INFECTIOUS DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS, 2016 TABLE 27 GLOBAL MARKET FOR SOLVADI, THROUGH 2022 ($ MILLIONS/%) TABLE 28 GLOBAL MARKET FOR EPCLUSA, THROUGH 2022 ($ MILLIONS/%) TABLE 29 GLOBAL MARKET FOR VIEKERA/TECHNIVIE, THROUGH 2022 ($ MILLIONS/%) TABLE 30 GLOBAL MARKET FOR ZEPATIER, THROUGH 2022 ($ MILLIONS/%) TABLE 31 GLOBAL MARKET FOR HARVONI, THROUGH 2022 ($ MILLIONS/%) TABLE 32 UNDER DEVELOPMENT INFECTIOUS DISEASE BREAKTHROUGH THERAPY DESIGNATION DRUGS, 2016 TABLE 33 GLOBAL MARKET FOR ARIKAYCE, THROUGH 2022 ($ MILLIONS/%) TABLE 34 GLOBAL MARKET FOR FOSTEMSAVIR, THROUGH 2022 ($ MILLIONS/%) TABLE 35 GLOBAL MARKET FOR GLECAPREVIR/PIBRENTASVIR, THROUGH 2022 ($ MILLIONS/%)

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TABLE HEADING TABLE 36 GLOBAL MARKET FOR IBALIZUMAB, THROUGH 2022 ($ MILLIONS/%) TABLE 37 GLOBAL MARKET FOR TAFENOQUINE, THROUGH 2022 ($ MILLIONS/%) TABLE 38 GLOBAL MARKET FOR V920, THROUGH 2022 ($ MILLIONS/%) TABLE 39 GLOBAL MARKET FOR ONCOLOGY BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) TABLE 40 FDA APPROVED ONCOLOGY BREAKTHROUGH THERAPY DESIGNATION DRUGS, 2013-2015 TABLE 41 GLOBAL MARKET FOR ALENCENSA, THROUGH 2022 ($ MILLIONS/%) TABLE 42 GLOBAL MARKET FOR ARZERRA, THROUGH 2022 ($ MILLIONS/%) TABLE 43 GLOBAL MARKET FOR BLINCYTO, THROUGH 2022 ($ MILLIONS/%) TABLE 44 GLOBAL MARKET FOR DARZALEX, THROUGH 2022 ($ MILLIONS/%) TABLE 45 GLOBAL MARKET FOR GAZYVA, THROUGH 2022 ($ MILLIONS/%) TABLE 46 GLOBAL MARKET FOR IBRANCE, THROUGH 2022 ($ MILLIONS/%) TABLE 47 GLOBAL MARKET FOR IMBRUVICA, THROUGH 2022 ($ MILLIONS/%) TABLE 48 GLOBAL MARKET FOR KEYTRUDA, THROUGH 2022 ($ MILLIONS/%) TABLE 49 GLOBAL MARKET FOR LARTRUVO, THROUGH 2022 ($ MILLIONS/%) TABLE 50 GLOBAL MARKET FOR LENVIMA/KISPLYX, THROUGH 2022 ($ MILLIONS/%) TABLE 51 GLOBAL MARKET FOR LYNPARZA, THROUGH 2022 ($ MILLIONS/%) TABLE 52 GLOBAL MARKET FOR MIDOSTAURIN, THROUGH 2022 ($ MILLIONS/%) TABLE 53 GLOBAL MARKET FOR OPDIVO, THROUGH 2022 ($ MILLIONS/%) TABLE 54 GLOBAL MARKET FOR TAGRISSO, SALES FORECASTS, THROUGH 2022 ($ MILLIONS/%) TABLE 55 GLOBAL MARKET FOR TAFINLAR/MEKINIST, THROUGH 2022 ($ MILLIONS/%) TABLE 56 GLOBAL MARKET FOR TECENTRIQ, THROUGH 2022 ($ MILLIONS/%) TABLE 57 GLOBAL MARKET FOR VENCLEXTA, THROUGH 2022 ($ MILLIONS/%) TABLE 58 GLOBAL MARKET FOR XALKORI, THROUGH 2022 ($ MILLIONS/%) TABLE 59 GLOBAL MARKET FOR ZYDELIG, THROUGH 2022 ($ MILLIONS/%) TABLE 60 GLOBAL MARKET FOR ZYKADIA, THROUGH 2022 ($ MILLIONS/%) TABLE 61 UNDER DEVELOPMENT ONCOLOGY BREAKTHROUGH THERAPY DESIGNATION DRUGS TABLE 62 GLOBAL MARKET FOR ABEMACICLIB, THROUGH 2022 ($ MILLIONS/%) TABLE 63 GLOBAL MARKET FOR AVELUMAB, THROUGH 2022 ($ MILLIONS/%) TABLE 64 GLOBAL MARKET FOR BRIGATINIB, THROUGH 2022 ($ MILLIONS/%) TABLE 65 GLOBAL MARKET FOR CTL019, THROUGH 2022 ($ MILLIONS/%) TABLE 66 GLOBAL MARKET FOR CRS-207 AND GVAX PANCREAS, THROUGH 2022 ($ MILLIONS/%) TABLE 67 GLOBAL MARKET FOR DURVALUMAB, THROUGH 2022 ($ MILLIONS/%) TABLE 68 GLOBAL MARKET FOR EBV-CTL, THROUGH 2022 ($ MILLIONS/%) TABLE 69 GLOBAL MARKET FOR ENTINOSTAT, THROUGH 2022 ($ MILLIONS/%) TABLE 70 GLOBAL MARKET FOR INOTUZUMAB OZOGAMICIN, THROUGH 2022 ($ MILLIONS/%) TABLE 71 GLOBAL MARKET FOR JCAR015, THROUGH 2022 ($ MILLIONS/%) TABLE 72 GLOBAL MARKET FOR KTE-C19, THROUGH 2022 ($ MILLIONS/%) TABLE 73 GLOBAL MARKET FOR LOXO-101, THROUGH 2022 ($ MILLIONS/%) TABLE 74 GLOBAL MARKET FOR NICORD, THROUGH 2022 ($ MILLIONS/%) TABLE 75 GLOBAL MARKET FOR OLMUTINIB, THROUGH 2022 ($ MILLIONS/%) TABLE 76 GLOBAL MARKET FOR NY-ESO, THROUGH 2022 ($ MILLIONS/%) TABLE 77 GLOBAL MARKET FOR PEXIDARTINIB, THROUGH 2022 ($ MILLIONS/%) TABLE 78 GLOBAL MARKET FOR PRACINOSTAT, THROUGH 2022 ($ MILLIONS/%)

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TABLE HEADING TABLE 79 GLOBAL MARKET FOR PVS-RIPO, THROUGH 2022 ($ MILLIONS/%) TABLE 80 GLOBAL MARKET FOR RIBOCICLIB, THROUGH 2022 ($ MILLIONS/%) TABLE 81 GLOBAL MARKET FOR RINTEGA, THROUGH 2022 ($ MILLIONS/%) TABLE 82 GLOBAL MARKET FOR ROCILETINIB, THROUGH 2022 ($ MILLIONS/%) TABLE 83 GLOBAL MARKET FOR RUCAPARIB, THROUGH 2022 ($ MILLIONS/%) TABLE 84 GLOBAL MARKET FOR SACITUZUMAB GOVITECAN, THROUGH 2022 ($ MILLIONS/%) TABLE 85 GLOBAL MARKET FOR VOLASERTIB, THROUGH 2022 ($ MILLIONS/%) TABLE 86 GLOBAL MARKET FOR VYXEOS, THROUGH 2022 ($ MILLIONS/%) TABLE 87 FDA APPROVED RARE DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS, 2015-2016 TABLE 88 GLOBAL MARKET FOR RARE DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) TABLE 89 GLOBAL MARKET FOR ILARIS, THROUGH 2022 ($ MILLIONS/%) TABLE 90 GLOBAL MARKET FOR KANUMA, THROUGH 2022 ($ MILLIONS/%) TABLE 91 GLOBAL MARKET FOR STRENSIQ, THROUGH 2022 ($ MILLIONS/%) TABLE 92 UNDER DEVELOPMENT RARE DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS, 2013-2016 TABLE 93 GLOBAL MARKET FOR ALXN-1101, THROUGH 2022 ($ MILLIONS/%) TABLE 94 GLOBAL MARKET FOR FIRDAPSE, THROUGH 2022 ($ MILLIONS/%) TABLE 95 GLOBAL MARKET FOR OLIPUDASE ALFA, THROUGH 2022 ($ MILLIONS/%) TABLE 96 GLOBAL MARKET FOR ZORBLISA, THROUGH 2022 ($ MILLIONS/%) TABLE 97 GLOBAL MARKET FOR SETMELANOTIDE, THROUGH 2022 ($ MILLIONS) TABLE 98 GLOBAL MARKET FOR VTS-270, THROUGH 2022 ($ MILLIONS/%) TABLE 99 FDA APPROVED OTHER BREAKTHROUGH THERAPY DESIGNATION DRUGS, 2015 TABLE 100 GLOBAL MARKET FOR OTHER DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) TABLE 101 GLOBAL MARKET FOR RAPAMUNE BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) TABLE 102 GLOBAL MARKET FOR LUCENTIS BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) TABLE 103 GLOBAL MARKET FOR EYLEA BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) TABLE 104 OTHER DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS AWAITING APPROVAL, 2015-2022 TABLE 105 GLOBAL MARKET FOR DUPILUMAB BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) TABLE 106 GLOBAL MARKET FOR AR101 BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) TABLE 107 GLOBAL MARKET FOR OCALIVA BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) TABLE 108 GLOBAL MARKET FOR VIASKIN PEANUT BREAKTHROUGH THERAPY DESIGNATION DRUGS, THROUGH 2022 ($ MILLIONS/%) TABLE 109 AN OVERVIEW OF THE KEY FEATURES OF THE FDA'S EXPEDITED PROGRAMS TABLE 110 AN OVERVIEW OF THE FDA'S EXPEDITED DEVELOPMENT AND REVIEW PROGRAMS TABLE 111 BREAKTHROUGH THERAPIES CONSIDERATIONS: DRUG DEVELOPMENT TABLE 112 BREAKTHROUGH THERAPY CONSIDERATIONS: MARKETING APPLICATION REVIEW

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TABLE HEADING TABLE 113 CDER BREAKTHROUGH THERAPY DESIGNATION REQUESTS RECEIVED BY FISCAL YEAR COHORT: JULY 9, 2012*-SEPTEMBER 30, 2015 TABLE 114 CDER BREAKTHROUGH THERAPY DESIGNATION REQUESTS RECEIVED BY FISCAL YEAR COHORT: OCTOBER 1, 2015-SEPTEMBER 30, 2016 TABLE 115 CDER BREAKTHROUGH THERAPY DESIGNATION APPROVALS DATA AS OF DECEMBER 31, 2015 TABLE 116 CUMULATIVE CBER BREAKTHROUGH THERAPY DESIGNATION REQUESTS RECEIVED BY FISCAL YEAR COHORT: JULY 9, 2012*-DECEMBER 31, 2015 TABLE 117 CBER BREAKTHROUGH THERAPY DESIGNATION REQUESTS RECEIVED BY FISCAL YEAR COHORT: OCTOBER 1, 2015-SEPTEMBER 30, 2016 TABLE 118 CUMULATIVE CBER BREAKTHROUGH THERAPY APPROVAL DATA AS OF SEPTEMBER 30, 2016 TABLE 119 MOST RECENTLY ANNOUNCED BREAKTHROUGH THERAPY DESIGNATIONS DATA AS OF FEBRUARY 29, 2016

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LIST OF FIGURES FIGURE TITLE SUMMARY FIGURE GLOBAL MARKET FOR BREAKTHROUGH THERAPY DESIGNATION DRUGS, BY THERAPY, 2015-2022 ($ MILLIONS) FIGURE 1 BREAKTHROUGH THERAPY REQUESTS GRANTED BY DIVISION, 2015* (%) FIGURE 2 PRIME SCHEME APPLICATIONS AND ELIGIBILITY FIGURE 3 PRIME DRUG BY TYPE OF APPLICATION AND THERAPEUTIC AREA FIGURE 4 PRIME DRUG APPLICATIONS, THERAPEUTIC AREA FIGURE 5 FDA APPROVALS, BREAKTHROUGH THERAPY DESIGNATION AND DESIGNATION RESCINDED, BY STATUS, 2012-2016 (NUMBER) FIGURE 6 FDA APPROVALS, BREAKTHROUGH DESIGNATION AND DESIGNATION RESCINDED, BY THERAPY AREA, 2012-2016 (NUMBER) FIGURE 7 CARDIOVASCULAR BREAKTHROUGH THERAPY DESIGNATION DRUGS, BY STAGE (NUMBER) FIGURE 8 CNS BREAKTHROUGH THERAPY DESIGNATION DRUGS, BY STAGE, 2016 (NUMBER) FIGURE 9 INFECTIOUS DISEASE BREAKTHROUGH THERAPY DESIGNATION DRUGS, BY STAGE, 2016 (NUMBER) FIGURE 10 CANCER DRUGS WITH BREAKTHROUGH THERAPY DESIGNATION, BY CANCER TYPE, 2016 (NUMBER OF APPROVED BTD DRUGS) FIGURE 11 CANCER BREAKTHROUGH THERAPY DESIGNATION, BY COMPANY, 2016 (NO. OF BTD IN ONCOLOGY) FIGURE 12 TREATMENT ALGORITHM FOR ALL PATIENTS FIGURE 13 ENTINOSTAT MECHANISM OF ACTION FIGURE 14 RARE DISEASE BREAKTHROUGH THERAPY DESIGNATION DRUGS, BY STAGE, 2016 FIGURE 15 OTHER DISEASES BREAKTHROUGH THERAPY DESIGNATION DRUGS, BY STAGE, 2016 (NUMBER) FIGURE 16 COMPARISON OF APPROVAL TIMES STANDARD VERSUS BREAKTHROUGH DESIGNATION (MONTHS) FIGURE 17 COMPARISON OF STANDARD AND BREAKTHROUGH THERAPY APPROVAL TIMES (MONTHS)

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