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
Pharma intelligence | informa4
Total pipeline size has grown by 6%
5995 6198 64166994 7360 7406 7737
9217 9605 9737 971310452 10479
1130712300
13718
14872 1526716181
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019
Drug
cou
nt
Year Source: Pharmaprojects
Pharma intelligence | informa5
Successes in 2018 –New active substance drug launches
Pharma intelligence | informa6
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
57
4334
47
61
6 0
0 2
14 3 1
111
8 1 311
6
3
7
7
7
0
10
20
30
40
50
60
70
80
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Drug
cou
nt
Other NASs Vaccines
Pharma intelligence | informa7
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
Pharma intelligence | informa8
Novel new drug approvals/launches 2018 – Part 2
• 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
Source: Pharmaprojects/Scrip
Pharma intelligence | informa9
Novel new drug approvals/launches 2018 – Part 3
• 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
Source: Pharmaprojects/Scrip
Pharma intelligence | informa10
Novel new drug approvals/launches 2018 – Part 4
• 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
Source: Pharmaprojects/Scrip
Pharma intelligence | informa11
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
Source: Pharmaprojects/Scrip
Pharma intelligence | informa12
Most successful companies for drug launches in 2018
Source: Pharmaprojects/Scrip
Pharma intelligence | informa13
The 2019 drug pipeline in detail
Pharma intelligence | informa14
Breakdown of pipeline by phase
8040
2127 2360
1006
214 150
1199
52
8520
22812576
1009
199 152
1273
600
1000
2000
3000
4000
5000
6000
7000
8000
9000
Preclin Phase I Phase II Phase III Pre-reg Registered Launched Suspended
Drug
cou
nt
2018 2019
Source: Pharmaprojects
• 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%
Pharma intelligence | informa15
Trends in drug R&D by clinical phase
2127
2360
1006
2281
2576
1009
0
500
1000
1500
2000
2500
3000
Phase I Phase II Phase III
Drug
cou
nt
2007200820092010201120122013201420152016201720182019
Source: Pharmaprojects
Pharma intelligence | informa16
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
Pharma intelligence | informa17
Top 10
Top 25
Companies with 1 or 2 drugs
5
7
9
11
13
15
17
19
21
23
25
2011 2012 2013 2014 2015 2016 2017 2018 2019
% o
f tot
al p
ipel
ine
Year
Big Pharma vs small companies – how the balance is shifting
Source: Pharmaprojects
• 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
Pharma intelligence | informa18
1198 13131503 1576 1621 1633
17691965 2084
22072387
2705 27452984
3286
3687
40034134
4323
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019
Com
pany
cou
nt
Year
• 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
Source: Pharmaprojects
Pharma intelligence | informa19
The R&D pipeline by Therapeutic Area
5212
4751
2604
2238
2237
2073
1597
929
916
893
859
828
643
630
271
124
5697
5422
2775
2270 24
07
2173
1611
962
977
920
882
892
665
664
260
113
0
1000
2000
3000
4000
5000
6000
Drug
cou
nt
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%
Source: Pharmaprojects
Pharma intelligence | informa20
Cancer taking an ever bigger slice of the R&D pie
26.8
28.0
29.530.1
29.3 29.3
30.4
32.6
34.1
35.2
20.0
22.0
24.0
26.0
28.0
30.0
32.0
34.0
36.0
2010 2011 2012 2013 2014 2015 2016 2017 2018 2019
% o
f pip
elin
e w
hich
is O
ncol
ogy
Year Source: Pharmaprojects
Pharma intelligence | informa21
The rise and fall and rise of gene therapy
0
5
10
15
20
250
100
200
300
400
500
600
700
800
900
1000
Rank
ing
Drug
cou
nt
Year
Active League Table Position
Source: Pharmaprojects
• Peak of 275 projects in 2003, followed by a decline• Steep rise post-2014, success or Luxturna, CAR-T, CRISPR etc
Pharma intelligence | informa22
Top 10 diseases/indications
Position 2019 (2018)
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
Pharma intelligence | informa23
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 (-) ↑
Source: Pharmaprojects
Pharma intelligence | informa24
Increasing focus on rare diseases
299326
394369
434
348
50
157182 188
250269
389
440476
509546
580
0
100
200
300
400
500
600
700
2013 2014 2015 2016 2017 2018
Drug
cou
nt
Year
Orphan DrugStatus Granted
Expedited ReviewStatus Granted
No of RareDiseases
Source: Pharmaprojects
• 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
Pharma intelligence | informa25
Top 10 Mechanisms of Action (Pharmacologies)
Position 2019 (2018)
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
Source: Pharmaprojects
• 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
Pharma intelligence | informa26
The rise of immuno-oncology as a drug development strategy
399
889
1332
1875
0 200 400 600 800 1000 1200 1400 1600 1800 2000
2016
2017
2018
2019
Drug count
Year
Source: Pharmaprojects
Pharma intelligence | informa27
Top 10 Drug protein targets
Position 2019 (2018)
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) ↔
Source: Pharmaprojects
• Mu1 opioid receptor (pain/constipation) stays top• Only 2 cancer targets in Top 10. Two diabetes targets also feature
Pharma intelligence | informa28
Number of new drug protein targets identified by year
72
107
92
102
97
67
179
89
68
77
113
116
75
97
0 20 40 60 80 100 120 140 160 180 200
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
Number of new targets
Year
Source: Pharmaprojects
Pharma intelligence | informa29
Biologicals advance towards 40% of R&D
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%19
95
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
Biotech Non-Biotech Source: Pharmaprojects
Pharma intelligence | informa30
The outlook for pharma for the year ahead
Pharma intelligence | informa31
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
Source: Pharmaprojects/Scrip
Pharma intelligence | informa32
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
Source: Pharmaprojects/Scrip
Pharma intelligence | informa33
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
Source: Pharmaprojects/Scrip
Pharma intelligence | informa34
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?
Source: Pharmaprojects/Scrip
Pharma intelligence | informa35
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
Source: Pharmaprojects/Scrip
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!