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Pharma R&D Review: What Changed In 2018, What To Look Out For In 2019Ian Lloyd, Senior Director, Pharmaprojects, Pharma IntelligenceAlexandra Shimmings, Executive Editor, Scrip, Pharma IntelligenceApril 17, 2019

AgendaThe drug R&D pipeline in 2019, and how it is changing• Total pipeline size• Success stories of 2018• Top companies• Leading therapies and diseases• Mechanisms and targets• Biotech vs pharma

The outlook for pharma for the year ahead• Launches expected from 2018 drug approvals• Drug approvals to look out for in 2019• Macro issues likely to affect the industry

Pharma intelligence | informa3

The total drug R&D pipeline in 2019


Total pipeline size has grown by 6%

5995 6198 64166994 7360 7406 7737

9217 9605 9737 971310452 10479

1130712300

13718

14872 1526716181

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2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Drug

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Year Source: Pharmaprojects


Successes in 2018 –New active substance drug launches


2018 was the best year on record for New Active Substance launches

Source: Pharmaprojects

37 3629 29

22 26 28 2631

2635 36 37 37

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Other NASs Vaccines


Novel new drug approvals/launches 2018 – Part 1

• Vitrakvi (larotrectinib) from Loxo/Bayer for solid tumors that have a NTRK gene fusion• First tissue-agnostic cancer therapy

• Tibsovo (ivosidenib) from Agios/CStone for acute myelogenous leukemia• The first isocitrate dehydrogenase 1 inhibitor to reach the market

• Copiktra (duvelisib) from Verastem chronic lymphocytic leukemia, small lymphocytic lymphoma and follicular lymphoma

• A dual-acting PI3 kinase delta and gamma inhibitor

• Yivyka (polyinosinicpolycytidylic acid/inactivated virus) for advanced solid tumors• A new immunological approach to cancers launched in Cambodia

Source: Pharmaprojects/Scrip



• Crysvita (burosumab) from Kyowa Hakko Kirin/Ultragenyx for X-linked hypophosphatemia

• Inhibits fibroblast growth factor 23

• Goofice (elobixibat) from Ajinomoto/Mochida/EA Pharma for chronic constipation• An ileal bile acid transport inhibitor and sodium/bile acid contransporter inhibitor

• Lamzede (velmanase alfa) from Chiesi for alpha-mannosidosis• Enzyme replacement therapy for alpha mannosidase II

• Palynziq (pegvaliase) from BioMarin for hyperphenylalaninemia• Pegylated phenylalanine ammonia lyase




• Trogarzo (ibalizumab) from Theratechnologies for HIV infection• Humanized anti-CD4 MAb for heavily treatment-experienced adults

• Xofluza (baloxavir marboxil) from Shionogi/Roche for influenza• CAP-dependent endonuclease

• Luxturna (voretigene neparvovec) from Spark/Novartis for RPE65 mutation-associated retinal dystrophy

• First approved in vivo gene therapy in the US

• Rhopressa (netarsudil) from Aerie Pharmaceuticals for glaucoma• Rho-associated kinase 2 inhibitor




• Cablivi (caplacizumab) from Ablynx for thrombotic thrombocytopenia purpura• A nanobody Factor VIII inhibitor

• Tavalisse (fostamatinib disodium from Rigel for idiopathic thrombocytopenia purpura• Syk tyrosine kinase inhibitor

• Aimovig (erenumb) from Amgen/Novartis• Emgality (galcanezumab) from Eli Lilly• Ajovy (fremanezumab) from Teva

• Calcitonin gene-related peptide inhibitors for migraine prophylaxis



Other selected new drug approvals/launches 2018

• Tegsedi (inotersen) and Onpattro (patisiran) from Ionis/Akcea and Alnylam, respectively for transthyretin-related hereditary amyloidosis

• Antisense and RNAi products for this rare disease

• Epidiolex (cannabidiol) from GW Research for Lennox-Gastaut syndrome and Dravet syndrome

• Types of epilepsy – first for a cannabis-based product in the US

• Three drugs for rare cancers• Xospata (gliteritinib) from Kotobuki/Astellas for refractory acute myeloid leukemia

• Lumoxiti (moxetumomab pasudotox) from AstraZeneca for hairy cell leukemia• Azedra (ultratrace iobenguane (I31) from Molecular Insight for pheochromocytoma

and paraganglioma



Most successful companies for drug launches in 2018



The 2019 drug pipeline in detail


Breakdown of pipeline by phase

8040

2127 2360

1006

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Preclin Phase I Phase II Phase III Pre-reg Registered Launched Suspended

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2018 2019


• 6% rise at Preclinical, 4,001 drugs added to the database• Phase I up 7.2%, Phase II by 9.2%• But Phase III is flat, and Pre-registration/Registered down 9.2%


Trends in drug R&D by clinical phase

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Top 10 pharma companies by pipeline size

Position 2019 (2018)

CompanyNo of Drugs in Pipeline

2019 (2018)No of Originated

Drugs 2019

1 (1) Novartis 219 (223) 131

2 (9) Takeda 211 (164) 99

3 (2) Johnson & Johnson 208 (216) 112

4 (3) AstraZeneca 194 (205) 111

5 (4) Sanofi 192 (179) 93

6 (5) Roche 189 (191) 106

7 (7) GlaxoSmithKline 177 (191) 99

8 (6) Merck & Co. 176 (191) 86

9 (4) Pfizer 163 (192) 96

10 (11) Eli Lilly 124 (121) 74Source: Pharmaprojects

• Novartis stays top, with Takeda up to 2nd due to Shire acquisition• Bristol-Myers Squibb + Celgene would be joint third• Only 2 other Top 10 companies grew pipeline size – Sanofi and Lilly


Top 10

Top 25

Companies with 1 or 2 drugs

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Big Pharma vs small companies – how the balance is shifting


• Top 10 companies only originating 6.5% of drugs now, was over 13% in 2011• Top 25 providing 11.0%, down from 18.3% in 2011• Companies with 1 or 2 drugs (2,302 companies, 53% of total) provide >19% of pipeline


1198 13131503 1576 1621 1633

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• 4.6% increase in companies, up from a 3.3% increase last year• 772 new companies identified through 2018 (up from 670 in 2017)• Therefore, 533 companies exited due to M&A, failure or hibernation

Total companies involved in pharma R&D



The R&D pipeline by Therapeutic Area

5212

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2018 2019

• Oncology up by 9.3%, Biotech by 14.1%• Neurologicals +6.6%, Alimentary/Metabolic +7.6%• But Anti-infectives only up 1.4% and Musculoskeletals by 0.9%



Cancer taking an ever bigger slice of the R&D pie

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The rise and fall and rise of gene therapy

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Active League Table Position


• Peak of 275 projects in 2003, followed by a decline• Steep rise post-2014, success or Luxturna, CAR-T, CRISPR etc


Top 10 diseases/indications


DiseaseNumber of Active Drugs

2019 (2018)Trend

1 (1) Cancer, breast 774 (727) ↑

2 (2) Cancer, lung, non-small cell 586 (544) ↑

3 (3) Cancer, colorectal 535 (503) ↑

4 (4) Cancer, ovarian 442 (434) ↔

5 (5) Cancer, pancreatic 438 (430) ↔

6 (8) Alzheimer's disease 405 (381) ↑

7 (6) Diabetes, Type 2 382 (407) ↓

8 (7) Cancer, prostate 366 (381) ↓

9 (9) Cancer, brain 360 (361) ↔

10 (11) Cancer, melanoma 357 (346) ↔Source: Pharmaprojects

• Breast cancer up 6.5%, NSCLC in 2nd up 7.7%. Cancers now 14 of the Top 20• Alzheimer’s and T2 Diabetes only non-cancer indications in Top 10


Top diseases/indications – 11-25Position

2019 (2018)Disease

Number of Active drugs 2019 (2018)

Trend

11 (12) Cancer, leukaemia, acute myelogenous 338 (326) ↔12 (10) Arthritis, rheumatoid 335 (352) ↓13 (17) Cancer, myeloma 283 (254) ↑14 (15) Cancer, head and neck 283 (258) ↑15 (19) Cancer, gastrointestinal, stomach 276 (242) ↑16 (13) Cancer, liver 273 (272) ↔17 (18) Parkinson's disease 271 (252) ↑18 (14) Pain, nociceptive, general 266 (262) ↔19 (16) Psoriasis 260 (256) ↔20 (22) Cancer, lymphoma, non-Hodgkin's 231 (215) ↔21 (-) Non-alcoholic steatohepatitis 222 (-) ↑

22 (21) Cancer, renal 221 (218) ↔23 (20) Asthma 196 (224) ↓24 (25) Infection, HIV/AIDS 189 (177) ↔25 (-) Cancer, bladder 179 (-) ↑



Increasing focus on rare diseases

299326

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No of RareDiseases


• 580 rare diseases being investigated now, up from 389 in 2013• No of drugs for rare diseases up from 4,615 in 2018 to 4,953 now


Top 10 Mechanisms of Action (Pharmacologies)


Mechanism of Action (Pharmacology)Number of Active Drugs

2019 (2018)% of Compounds

PR/R/L

1 (2) Immuno-oncology therapy 1875 (1332) 1.62 (1) Immunostimulant 1387 (1501) 10.2

3 (11) T cell stimulant 404 (106) 1.74 (3) Immune checkpoint inhibitor 327 (211) 3.75 (4) Immunosuppressant 199 (208) 30.7

6 (5) Angiogenesis inhibitor 186 (169) 17.7

7 (6)Vascular endothelial growth factor (VEGF) receptor antagonist 149 (138) 14.8

8 (7) Apoptosis stimulant 131 (116) 15.39 (10) Radiopharmaceutical 122 (108) 8.210 (9) Opioid mu receptor agonist 116 (110) 37.9


• Immuno-oncology now the most popular strategy, despite only 1.6% of drugs in late stage development • T cell stimulant, covering CAR-T and some vaccines, up to number 3


The rise of immuno-oncology as a drug development strategy

399

889

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1875

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Drug count

Year



Top 10 Drug protein targets


TargetNumber of Active Drugs

2019 (2018)Trend

1 (1) opioid receptor, mu 1 147 (140) ↑2 (2) erb-b2 receptor tyrosine kinase 2 [HER-2] 135 (120) ↑3 (3) vascular endothelial growth factor A 131 (119) ↑4 (5) tumour necrosis factor 123 (113) ↑5 (7) epidermal growth factor receptor 121 (107) ↑

6 (4)nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor) 113 (113) ↔

7 (6)prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) [COX-2] 112 (107) ↔

8 (8) insulin receptor 104 (99) ↔9 (10) glucagon-like peptide 1 receptor 94 (80) ↑10 (9) opioid receptor, kappa 1 91 (88) ↔


• Mu1 opioid receptor (pain/constipation) stays top• Only 2 cancer targets in Top 10. Two diabetes targets also feature


Number of new drug protein targets identified by year

72

107

92

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179

89

68

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113

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Number of new targets

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Biologicals advance towards 40% of R&D

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Biotech Non-Biotech Source: Pharmaprojects


The outlook for pharma for the year ahead


Selected key drugs approved late 2018/early 2019

• Ultomiris (ravulizumab) from Alexion for adults with paroxysmal nocturnal hemoglobinuria• Complement inhibitor, approved in US early Dec (was launched Jan 2019)

• Elzonris (tagraxofusp) from Stemline Therapeutics for blastic plasmacytoid dendritic cell neoplasm• Targeted therapy of human IL-3 recombinantly fused to truncated diphtheria toxin (was launched Jan 2019)

• Tyvyt (sintilimab) from Innovent and Lilly for Hodgkin’s lymphoma• PD-1 antagonist launched in China in Feb 2019

• Esketamine from Johnson & Johnson for treatment-resistant depression• Received US approval Mar 2019 after mixed clinical results



Important approvals expected in 2019 – Part 1

• Tenapanor hydrochloride from Ardelyx for irritable bowel syndrome with constipation• First-in-class selective Sodium/hydrogen exchange (NH3E) inhibitor

• Selinexor from Karyopharm for multiple myeloma• A first-in-class inhibitor of the nuclear export protein, XPO1

• Givosiran from Alnylam for acute hepatic porphyria • A subcutaneous RNAi therapeutic which targets aminolevulinate synthase

• Lefamulin from Nabriva for community-acquired bacterial pneumonia• A potent oral and iv antibacterial with favorable pharmacokinetics



Important approvals expected in 2019 – Part 2 (biologicals)

• Brolucizumab from Novartis for wet age-related macular degeneration• Has the potential to extend the dosing intervals for intravitreal anti-VEGF therapy to once every 12wk

• Zolgensma (nasemnogene abeparvovec) from Novartis for spinal muscular atrophy• A one-time gene therapy which replaces the defective SMN1 gene

• Zynteglo (LentiGlobin) from Bluebird Bio for transfusion-dependent ß-thalassemia• Uses a lentiviral vector to deliver the human beta-globin gene transfer

• Lisocabtagene maraleucel from Celgene for diffuse large B-cell lymphoma• CAR-T therapy acquired with Juno Therapeutics



Other wider issues likely to affect pharma in 2019

• Political upheaval• Brexit – uncertainty

• Impact Of US government shutdown

• Growth slowdown in China and ongoing China vs US trade war

• M&A picture uncertain• High valuations remain a barrier

• Effects of US tax reform not clear cut

• Likely one or two big mergers, others focused on acquiring specific drugs or technology

• Pricing & market access• Real-world pricing: drugs reimbursed based on their benefits, not manufacturing costs

• High pricing ‘acceptable’ for curative therapies?



What does 2019 hold for biopharma? Therapeutic advances

• New Approaches• Gene therapies

• Microbiome gaining importance

• Genomic testing

• Oncology • New I-O combos: CAR-Ts + antibody/drug conjugates

• Targeting disease resistant to 1L therapies

• Tumor-agnostic: targeting common gene mutations rather than tumor types

• CNS• Much activity in Parkinson’s, on disease-modifying alpha-synuclein inhibitors

• Year of anticipation in Alzheimer’s – 2020 readouts on beta-amyloid-targeting MAbs


Global R&D And Clinical Trends: What Changed In 2018, And What To Look Out For In 2019 -Summary

• The R&D pipeline continues to grow at a healthy rate

• This might be sustainable, as the past few years have delivered healthy numbers of new drugs

• Phase II failure rate remains a barrier

• Limited big M&A is underway, although top companies continue to lose share

• Cancer, and immuno-oncology in particular, ever more dominant

• In 2018 in R&D, pharma scored a try;

now it needs a conversion!

Thanks for your attention!

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