The Image Zone/Alamy
NEWS & ANALYSIS
2014 FDA drug approvals The FDA approved 41 new therapeutics in 2014, but the bumper year fell short of the commercial power of the drugs approved in 2013. Asher Mullard The Center for Drug Evaluation and Research (CDER) approved a landmark 41 new therapeutics in 2014, including 11 biologics (TABLE 1). Approvals were up by over 50% from the 27 approved in 2013, and up 30% from the 5-year average of 31.6 per year (FIG. 1). “As a productivity year I’d give it a 3 out of 3,” says Chris Milne, Director of Research at the Tufts Center for the Study of Drug Development in Boston, Massachusetts, USA. He points out that although the US Food and Drug Administration (FDA) approved more drugs in 1996 — with a record of 53 approvals — 1996 was an anomalous year in which a regulatory overhaul and the need to clear a
backlog of applications drove the approval numbers up. “That makes 2014 an even bigger year,” says Milne. In terms of innovation, however, Milne ranked the 2014 approvals as only scoring “a 2 out of 3”. He points out that the list includes a fair amount of competitive bunching, with drug companies seeking approvals for agents that act on the same proven targets and indications. The agency approved four new drugs for type 2 diabetes, for example, but dapagliflozin and empagliflozin
As a productivity year I’d give it a 3 out of 3
NATURE REVIEWS | DRUG DISCOVERY
were respectively the second- and third‑in-class sodium–glucose cotransporter 2 (SGLT2) inhibitors, and albiglutide and dulaglutide were respectively the fourth- and fifth-in-class glucagon-like peptide 1 (GLP1)-receptor agonists. “There is some of that herd mentality here,” he notes. From a commercial perspective, 2014 also looks likely to fall short of the smaller but commercially powerful 2013 approval cohort. The Boston Consulting Group (BCG) tracks a slight larger set of drug approvals — including Center for Biologics Evaluation and Research (CBER) (TABLE 2) and supplemental new drug application (sNDA) approvals — and predicts that 53 notable approvals from 2014 will generate US$48 billion VOLUME 14 | FEBRUARY 2015 | 77
© 2015 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S Table 1 | CDER approvals in 2014 Drug (brand name)
Sponsor
Properties
Indications
Review types
Dapagliflozin (Farxiga)
AstraZeneca
SGLT2 inhibitor
Type 2 diabetes
S
Tasimelteon (Hetlioz)
Vanda
Melatonin-receptor agonist
Non-24-hour sleep–wake disorder
P, O
Elosulfase alfa (Vimizim)
BioMarin
Hydrolytic lysosomal glycosaminoglycan-specific enzyme
Mucopolysaccharidosis type IVA
P, O
Droxidopa (Northera)
Lundbeck
Synthetic amino-acid precursor of noradrenaline; MOA unknown
Light-headedness in patients with neurogenic orthostatic hypotension
P, O, A
Metreleptin (Myalept)
Amylin
Leptin analogue
Leptin deficiency in patients with congenital or acquired generalized lipodystrophy
P, O
Florbetaben‑F18 (Neuraceq)
Piramal Imaging
Radioactive diagnostic agent
Imaging of the brain to estimate density of neuritic amyloid‑β plaques
S
Miltefosine (Impavido)
Knight
MOA unknown
Leishmaniasis
P, O
Apremilast (Otezla)
Celgene
Phosphodiesterase 4 inhibitor
Psoriatic arthritis and plaque psoriasis
S
Albiglutide (Tanzeum)
GlaxoSmithKline
GLP1-receptor agonist
Type 2 diabetes
S
Ramucirumab (Cyramza)
Eli Lilly
VEGFR2 antagonist
Gastric cancer
P, O
Siltuximab (Sylvant)
Janssen Biotech
IL-6-specific antibody
Multicentric Castleman’s disease
P, O
Ceritinib (Zykadia)
Novartis
Kinase inhibitor against ALK, IGF1R, insulin receptor and ROS1
ALK-positive metastatic NSCLC
P, O, B, A
Vorapaxar (Zontivity)
Merck & Co.
Protease-activated receptor 1 antagonist
Thrombotic cardiovascular events
S
Vedolizumab (Entyvio)
Takeda
Integrin-receptor antagonist
Ulcerative colitis and Crohn’s disease
P
Dalbavancin (Dalvance)
Durata
Semisynthetic lipoglycopeptide
ABSSSI
P
Efinaconazole (Jublia)
Dow
Azole antifungal
Onychomycosis of the toenails
S
Tedizolid (Sivextro)
Cubist
Oxazolidinone-class antibacterial
ABSSSI
P
Belinostat (Beleodaq)
Spectrum
Histone-deacetylase inhibitor
Peripheral T-cell lymphoma
P, O, A
Tavaborole (Kerydin)
Anacor
Oxaborole antifungal
Onychomycosis of the toenails
S
Idelalisib (Zydelig)
Gilead Sciences
PI3Kб inhibitor
CLL, B-cell non-Hodgkin lymphoma and SLL
P, O, B, A
Olodaterol (Striverdi Respimat)
Boehringer Ingelheim
Long-acting β2-adrenoceptor agonist
COPD
S
Empagliflozin (Jardiance)
Boehringer Ingelheim
SGLT2 inhibitor
Type 2 diabetes
S
Oritavancin (Orbactiv)
The Medicines Company
Semi-synthetic lipoglycopeptide
ABSSSI
P
Suvorexant (Belsomra)
Merck & Co.
Orexin-receptor antagonist
Insomnia
S
Peginterferon beta-1A (Plegridy)
Biogen Idec
Long-acting interferon-β1A
Relapsing multiple sclerosis
S
Eliglustat (Cerdelga)
Genzyme
Glucosylceramide-synthase inhibitor
Gaucher’s disease
P, O
Pembrolizumab (Keytruda)
Merck & Co.
PD1-specific antibody
Metastatic melanoma
P, O, B, A
Naloxegol (Movantik)
AstraZeneca
Opioid-receptor antagonist
Opioid-induced constipation
S
Dulaglutide (Trulicity)
Eli Lilly
GLP1-receptor agonist
Type 2 diabetes
S
Sulfur hexafluoride lipid-type A microspheres (Lumason)
Bracco
Ultrasound contrast agent
Cardiovascular imaging
S
Netupitant plus palonosetron (Akynzeo)
Helsinn
An NK1-receptor antagonist plus a 5-HT3-receptor antagonist
Chemotherapy-related nausea
S
Ledipasvir plus sofosbuvir (Harvoni)
Gilead Sciences
An NS5A inhibitor plus an HCV nucleotide-analogue NS5B-polymerase inhibitor
Genotype 1 HCV
P, B
Pirfenidone (Esbriet)
InterMune
MOA unknown
IPF
P, O, B
78 | FEBRUARY 2015 | VOLUME 14
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N E W S & A N A LY S I S Table 1 (cont.) | CDER approvals in 2014 Drug (brand name)
Sponsor
Properties
Indications
Review types
Nintedanib (Ofev)
Boehringer Ingelheim
Kinase inhibitor against PDGFRs, FGFRs, VEGFRs and FLT3
IPF
P, O, B
Blinatumomab (Blincyto)
Amgen
CD19- and CD3-bispecific antibody
B-ALL
P, O, B, A
Finafloxacin (Xtoro)
Alcon
Fluoroquinolone antimicrobial
Acute otitis externa (swimmer’s ear)
P
Olaparib (Lynparza)
AstraZeneca
PARP inhibitor
Advanced BRCA-mutated ovarian cancer
P, O, A
Ombitasvir plus paritaprevir plus dasabuvir plus ritonavir (Viekira Pak)
AbbVie
An NS5A inhibitor plus an NS3Aand NS4A-protease inhibitor plus a non-nucleoside NS5Bpalm-polymerase inhibitor plus a CYP3A inhibitor
Chronic HCV genotype 1 infection
P, B
Ceftolozane plus tazobactam (Zerbaxa)
Cubist
A cephalosporin antibacterial plus a β-lactamase inhibitor
Complicated intra-abdominal infections and complicated urinary tract infections
P
Peramivir (Rapivab)
BioCryst
Neuraminidase inhibitor
Influenza infection
S
Nivolumab (Opdivo)
Bristol-Myers Squibb
PD1 inhibitor
Unresectable or metastatic melanoma
P, O, B, A
5-HT3, serotonin type 3; A, accelerated approval; ABSSSI, acute bacterial skin and skin structure infection; ALK, anaplastic lymphoma kinase; B, breakthrough designation; B‑ALL, B‑cell acute lymphocytic leukaemia; CDER, Center for Drug Evaluation and Research; CLL, chronic lymphocytic leukaemia; COPD, chronic obstructive pulmonary disease; CYP3A, cytochrome P450 3A4; FGFR, fibroblast growth factor receptor; FLT3, receptor-type tyrosine-protein kinase FLT3; GLP1, glucagon-like peptide 1; HCV, hepatitis C virus; IGF1R, insulin-like growth factor 1 receptor; IL‑6, interleukin‑6; IPF, idiopathic pulmonary fibrosis; MOA, mode of action; NK1, substance P; NS, non-structural protein; NSCLC, non-small-cell lung cancer; O, orphan designation; P, priority review; PD1, programmed cell death protein 1; PDGFR, platelet-derived growth factor receptor; PI3Kб, phosphatidylinositol-3-OH kinase; ROS1, proto-oncogene tyrosine-protein kinase ROS; S, standard review; SGLT2, sodium–glucose cotransporter 2; SLL, small lymphocytic lymphoma; VEGFR, vascular endothelial growth factor receptor.
in aggregated peak sales (FIG. 2; see also www.bcgperspectives.com for the full BCG analysis). By comparison, the 36 approvals they tracked from 2013 are expected to earn $53 billion in peak aggregated sales. “2014 was a fantastic year,” says BCG’s Senior Partner, Ulrik Schulze. But he adds that peak sales are probably down from 2013, again in part because many of the new drugs approved in 2014 are entering crowded markets.
Whereas 12 (29%) of the new CDER approvals are set to become blockbusters within 5 years, only 3 (7%) of these are expected to break the $2-billion mark (FIG. 3). The 2013 cohort of approvals included 13 (48%) drugs that were expected to achieve blockbuster status within 5 years of approval, of which 6 (22%) were anticipated to earn over $2 billion in annual sales (Nature Rev. Drug Discov. 13, 85–89; 2014).
The potential multi-blockbuster drugs approved in 2014 include the most exciting scientific approvals of the year. Merck & Co.’s pembrolizumab and Bristol-Myers Squibb’s nivolumab are the first programmed cell death protein 1 (PD1)-inhibiting cancer immunotherapies, and oncologists hope that by mixing and matching this class of drugs with other immunotherapies, kinase inhibitors and chemotherapies, they can change the face of
60
NMEs BLAs
53
Number of drugs approved
50
39
40
30
35
30
27
25
25
24
24 21
21
21 20
18
17
18
19
16
15 11
10
0
33
31
30
29
6 2
2
1993
1994
5
5
1 1995
1996
1997
1998
5 2
2
1999
2000
6
6
5 2
2001
2002
Figure 1 | Novel approvals since 1993. This figure shows the new molecular entities (NMEs) and biologics license applications (BLAs) approved by the Center for Drug Evaluation and Research (CDER) since
2003
2004
2005
6
4 2006
2
3
2007
2008
6
6
6 2
2009
2010
2011
2012
2013
2014
1993. Approvals by the Center for Biologics Evaluation and Research (CBER) are not included in this drug count. Data Reviews are from|Drugs@FDA Nature Drug Discovery and the US Food and Drug Administration (FDA).
NATURE REVIEWS | DRUG DISCOVERY
VOLUME 14 | FEBRUARY 2015 | 79 © 2015 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S Table 2 | Selected CBER approvals in 2014 Drug brand name
Sponsor
Properties
Indication
Trumenba
Wyeth/Pfizer
Meningococcal group B vaccine
Meningitis B
Obizur
Baxter
Recombinant porcine antihaemophilic factor
Acquired haemophilia A
Hyqvia
Baxter
Immunoglobulin infusion with recombinant hyaluronidase
Humoral immune defects in adults with primary immunodeficiency
Ruconest
Pharming
Recombinant C1-esterase inhibitor
Hereditary angioedema
Eloctate
Biogen Idec
Recombinant antihaemophilic factor–Fc fusion protein
Haemophilia A
Ragwitek
Merck & Co.
Short ragweed pollen allergen extract
Short ragweed pollen-induced allergic rhinitis
Grastek
Merck & Co.
Timothy grass pollen allergen extract
Grass pollen-induced allergic rhinitis
Oralair
Stallergenes
Sweet vernal grass, orchard grass, perennial rye, Timothy grass and Kentucky Bluegrass mixed pollen allergen extract
Grass pollen-induced allergic rhinitis
Alprolix
Biogen Idec
Recombinant coagulation factor IX–Fc fusion protein
Haemophilia B
CBER, Center for Biologics Evaluation and Research; Fc, crystallizable fragment.
cancer treatment (Nature Rev. Drug Discov. 12, 489–492; 2013). Gilead Sciences’ fixed-dose combination of ledipasvir and sofosbuvir, meanwhile, is the first all-oral therapy for genotype 1 hepatitis C virus (HCV) infection to make it to market from what has been a heated drug-development race (Nature Rev. Drug Discov. 12, 409–411; 2013). Next year could also see late-stage progress on several exciting scientific fronts, including cholesteryl ester transfer protein (CETP) inhibitors, proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors and oncolytic viruses (TABLE 3). The FDA’s first action approval rate was 67% in 2014, down from 78% in 2013 (see TABLE 4 for some of the drugs that received complete response letters or were withdrawn by their sponsors in 2014). 60
Sales
Break-downs The FDA approved 9 (22%) oncology drugs last year (FIG. 4), compared with 9 (33%) in 2013 and 13 (33%) in 2012. “The question is whether you count relative or absolute values,” asks Schulze. “I think we are seeing a burst of innovation in other areas, which by virtue of bringing up the total number of approvals is bringing down the relative share of oncology,” he adds. Infectious diseases also scored 9 (22%) approvals, up from 3 (11%) in 2013. In addition to new HCV and HIV drugs, the infectious-disease additions included 4 antibiotics that were approved under the Qualified Infectious Disease Product (QIDP) programme. Three of these QIDP antibiotics were for the treatment of skin infections.
NTDs
60
40
40
39 36
34 24
28
27
29
32 28
31
20
0
20
51
24
38
25
13
22
29
37
35
53
48
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
Number of NTDs approved
Total peak sales (US$ billions)
53
0
Figure 2 | Aggregated peak drug sales since 2004. Aggregated peak drug sales expectations, as calculated by The Boston Consulting Group (BCG; see ‘R&D Productivity 2014: Year of Nature Reviews | Drug Discovery Breakthroughs’ on www.bcgperspectives.com for full analysis). BCG’s analysis looked at peak sales estimates for 53 new therapeutic drugs (NTDS) that were approved in 2014, including new molecular entities (NMEs) and biologic license applications (BLAs) approved by the Center for Drug Evaluation and Research (CDER), minus the medical imaging approvals, plus certain non-NME approvals from the CDER and the Center for Biologics Evaluation and Research (CBER). Peak sales data for drugs approved in 2014 are wholly forecasted. Actual sales data and updated expectations are used for drugs approved in earlier years.
80 | FEBRUARY 2015 | VOLUME 14
This mini surge of antibiotics, however, was probably primarily due to changes to the acute bacterial skin and skin structure infection (ABSSSI) trial guidelines that were introduced a few years ago, rather than to corrections to the fundamental problems of antibiotic drug development (Nature Rev. Drug Discov. 13, 711–713; 2014). 2014 was the biggest year to date for orphan-drug approvals, with 17 (41%) orphan designees in the approval cohort. By comparison, the agency approved 9 (33%) orphan new molecular entities (NMEs) in 2013, 13 (33%) in 2012 and 11 (37%) in 2011. Every single oncology approval in 2014 was for an orphan indication. The agency also approved 9 (22%) breakthrough designees in 2014. According to the BCG analysis, these agents carried 50% of the commercial potential of the 2014 cohort. Six of the 12 approvals with blockbuster expectations are breakthrough designees, including the 4 drugs with the top sales expectations. With no sign that the FDA is slowing down in awarding breakthrough designations, these are encouraging data for industry (Nature Rev. Drug Discov. 13, 873–875; 2014). The CDER approval list included 11 (27%) biologics, up from just 2 (7%) in 2013 and 6 (15–29%) in each of the years 2009–2012. The agency approved 8 drugs (20%) using the accelerated approval pathway. “This is good,” says Milne, because one aim of the FDA Safety and Innovation Act was to encourage greater use of accelerated approval through the use of surrogate markers. But, because 7 of these drugs were approved for cancer, he adds, there is lots of room for improvement in the use of accelerated approval in other therapeutic areas. www.nature.com/reviews/drugdisc
© 2015 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S 9
8.2
2019 sales in US$ billions
8 7 6
5.3
5 4
3.3
3 1.9
2
1.5
1.4
1.4
1.3
1.2
1
1.1
1.1
0
b b t vir ab ab ne 1A lus zin ma ma ilas pre ir im rp taflo um ido lizu svi uvir* ivolu be gli tux cir en rita onav prem l f o a a i u a r n r i p p S N p i t b A m P sb ero Da Ra lus s ri Led sofo Pem erf ir p plu int g asv buvir e t i P b a Om s das plu
Figure 3 | Anticipated blockbusters approved in 2014. Sales forecasts are average, annual, global estimates for 2019 as compiled by Thomson
sib
lali
Ide
1.0
e
tid
glu
la Du
Oncology Infectious disease Metabolism and endocrinology Neurology Pulmonary
Reuters Cortellis database. *Sales of Gilead’s combination of ledipasvir Drug Discovery plus sofosbuvir are expected to peak at Nature US$12 Reviews billion in|2017.
Table 3 | Selected late-stage drugs to watch in 2015 Drug name
Sponsors
Properties
Indication
Event due in 2015
Secukinumab
Novartis
IL-17-specific antibody
Psoriasis
PDUFA decision in January
Palbociclib
Pfizer
CDK inhibitor
Breast cancer
PDUFA decision in April
Toujeo
Sanofi
Insulin glargine
Diabetes
PDUFA decision in May
Talimogene laherparepvec
Amgen
Oncolytic virus
Melanoma
PDUFA decision in July
Evolocumab
Amgen
PCSK9-specific antibody
Hypercholesterolaemia
PDUFA decision by September
Lumacaftor plus ivacaftor
Vertex
CFTR corrector and CFTR potentiator
Cystic fibrosis
PDUFA decision in November
Alirocumab
Sanofi/ Regeneron
PCSK9-specific antibody
Hypercholesterolaemia
PDUFA decision
LCZ696
Novartis
Angiotensin-receptor inhibitor and neutral-endopeptidase inhibitor
Congestive heart failure
PDUFA decision
Ryzodeg
Novo Nordisk
Co-formulation of insulin degludec and insulin aspart
Diabetes
Cardiovascular outcomes data, to address 2012 complete response letter
Anacetrapib
Merck & Co.
CETP inhibitor
Hypercholesterolaemia
Interim efficacy analysis of Phase III trial
Ocrelizumab
Roche
CD20-specific antibody
Multiple sclerosis
Top-line Phase III data
Baricitinib
Eli Lilly
JAK1- and JAK2- inhibitor
Rheumatoid arthritis
Top-line Phase III data
Event data are from BioMedTracker. CDK, cyclin-dependent kinase; CETP, cholesteryl ester transfer protein; CFTR, cystic fibrosis transmembrane conductance regulator; IL‑17, interleukin‑17; JAK, Janus kinase; PCSK9, proprotein convertase subtilisin kexin type 9; PDUFA, Prescription Drug User Fee Act.
Table 4 | Selected drugs that were rejected or withdrawn* from FDA review in 2014 Drug
Sponsor
Properties
Indications
Cangrelor
The Medicines Company
P2Y12 platelet ADP-receptor inhibitor
Acute coronary syndrome and following coronary artery bypass graft
Serelaxin
Novartis
Agonist for relaxin receptors 1–4
Acute decompensated heart failure
Macrilen
Æterna Zentaris
Ghrelin-receptor agonist
Short stature or growth-hormone deficiency
Daclatasvir*
Bristol-Myers Squibb
NS5A inhibitor
Hepatitis C virus
Daclatasvir plus asunaprevir*
Bristol-Myers Squibb
An NS5A inhibitor plus an NS3 protease inhibitor
Hepatitis C virus
*Indicates agents that were withdrawn. ADP, adenosine diphosphate; NS, non-structural protein.
3% 5% 5% 7%
22%
7% 7%
22%
10%
12%
Oncology Infectious disease Metabolism and endocrinology Neurology Gastroenterology
Dermatology Pulmonary Lysosomal storage disease Imaging Cardiology
Figure 4 | Approvals by therapeutic area. Nature Reviews | Drug Discovery
NATURE REVIEWS | DRUG DISCOVERY
VOLUME 14 | FEBRUARY 2015 | 81 © 2015 Macmillan Publishers Limited. All rights reserved
NEWS & ANALYSIS
2014 FDA drug approvals The FDA approved 41 new therapeutics in 2014, but the bumper year fell short of the commercial power of the drugs approved in 2013. Asher Mullard The Center for Drug Evaluation and Research (CDER) approved a landmark 41 new therapeutics in 2014, including 11 biologics (TABLE 1). Approvals were up by over 50% from the 27 approved in 2013, and up 30% from the 5-year average of 31.6 per year (FIG. 1). “As a productivity year I’d give it a 3 out of 3,” says Chris Milne, Director of Research at the Tufts Center for the Study of Drug Development in Boston, Massachusetts, USA. He points out that although the US Food and Drug Administration (FDA) approved more drugs in 1996 — with a record of 53 approvals — 1996 was an anomalous year in which a regulatory overhaul and the need to clear a
backlog of applications drove the approval numbers up. “That makes 2014 an even bigger year,” says Milne. In terms of innovation, however, Milne ranked the 2014 approvals as only scoring “a 2 out of 3”. He points out that the list includes a fair amount of competitive bunching, with drug companies seeking approvals for agents that act on the same proven targets and indications. The agency approved four new drugs for type 2 diabetes, for example, but dapagliflozin and empagliflozin
As a productivity year I’d give it a 3 out of 3
NATURE REVIEWS | DRUG DISCOVERY
were respectively the second- and third‑in-class sodium–glucose cotransporter 2 (SGLT2) inhibitors, and albiglutide and dulaglutide were respectively the fourth- and fifth-in-class glucagon-like peptide 1 (GLP1)-receptor agonists. “There is some of that herd mentality here,” he notes. From a commercial perspective, 2014 also looks likely to fall short of the smaller but commercially powerful 2013 approval cohort. The Boston Consulting Group (BCG) tracks a slight larger set of drug approvals — including Center for Biologics Evaluation and Research (CBER) (TABLE 2) and supplemental new drug application (sNDA) approvals — and predicts that 53 notable approvals from 2014 will generate US$48 billion VOLUME 14 | FEBRUARY 2015 | 77
© 2015 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S Table 1 | CDER approvals in 2014 Drug (brand name)
Sponsor
Properties
Indications
Review types
Dapagliflozin (Farxiga)
AstraZeneca
SGLT2 inhibitor
Type 2 diabetes
S
Tasimelteon (Hetlioz)
Vanda
Melatonin-receptor agonist
Non-24-hour sleep–wake disorder
P, O
Elosulfase alfa (Vimizim)
BioMarin
Hydrolytic lysosomal glycosaminoglycan-specific enzyme
Mucopolysaccharidosis type IVA
P, O
Droxidopa (Northera)
Lundbeck
Synthetic amino-acid precursor of noradrenaline; MOA unknown
Light-headedness in patients with neurogenic orthostatic hypotension
P, O, A
Metreleptin (Myalept)
Amylin
Leptin analogue
Leptin deficiency in patients with congenital or acquired generalized lipodystrophy
P, O
Florbetaben‑F18 (Neuraceq)
Piramal Imaging
Radioactive diagnostic agent
Imaging of the brain to estimate density of neuritic amyloid‑β plaques
S
Miltefosine (Impavido)
Knight
MOA unknown
Leishmaniasis
P, O
Apremilast (Otezla)
Celgene
Phosphodiesterase 4 inhibitor
Psoriatic arthritis and plaque psoriasis
S
Albiglutide (Tanzeum)
GlaxoSmithKline
GLP1-receptor agonist
Type 2 diabetes
S
Ramucirumab (Cyramza)
Eli Lilly
VEGFR2 antagonist
Gastric cancer
P, O
Siltuximab (Sylvant)
Janssen Biotech
IL-6-specific antibody
Multicentric Castleman’s disease
P, O
Ceritinib (Zykadia)
Novartis
Kinase inhibitor against ALK, IGF1R, insulin receptor and ROS1
ALK-positive metastatic NSCLC
P, O, B, A
Vorapaxar (Zontivity)
Merck & Co.
Protease-activated receptor 1 antagonist
Thrombotic cardiovascular events
S
Vedolizumab (Entyvio)
Takeda
Integrin-receptor antagonist
Ulcerative colitis and Crohn’s disease
P
Dalbavancin (Dalvance)
Durata
Semisynthetic lipoglycopeptide
ABSSSI
P
Efinaconazole (Jublia)
Dow
Azole antifungal
Onychomycosis of the toenails
S
Tedizolid (Sivextro)
Cubist
Oxazolidinone-class antibacterial
ABSSSI
P
Belinostat (Beleodaq)
Spectrum
Histone-deacetylase inhibitor
Peripheral T-cell lymphoma
P, O, A
Tavaborole (Kerydin)
Anacor
Oxaborole antifungal
Onychomycosis of the toenails
S
Idelalisib (Zydelig)
Gilead Sciences
PI3Kб inhibitor
CLL, B-cell non-Hodgkin lymphoma and SLL
P, O, B, A
Olodaterol (Striverdi Respimat)
Boehringer Ingelheim
Long-acting β2-adrenoceptor agonist
COPD
S
Empagliflozin (Jardiance)
Boehringer Ingelheim
SGLT2 inhibitor
Type 2 diabetes
S
Oritavancin (Orbactiv)
The Medicines Company
Semi-synthetic lipoglycopeptide
ABSSSI
P
Suvorexant (Belsomra)
Merck & Co.
Orexin-receptor antagonist
Insomnia
S
Peginterferon beta-1A (Plegridy)
Biogen Idec
Long-acting interferon-β1A
Relapsing multiple sclerosis
S
Eliglustat (Cerdelga)
Genzyme
Glucosylceramide-synthase inhibitor
Gaucher’s disease
P, O
Pembrolizumab (Keytruda)
Merck & Co.
PD1-specific antibody
Metastatic melanoma
P, O, B, A
Naloxegol (Movantik)
AstraZeneca
Opioid-receptor antagonist
Opioid-induced constipation
S
Dulaglutide (Trulicity)
Eli Lilly
GLP1-receptor agonist
Type 2 diabetes
S
Sulfur hexafluoride lipid-type A microspheres (Lumason)
Bracco
Ultrasound contrast agent
Cardiovascular imaging
S
Netupitant plus palonosetron (Akynzeo)
Helsinn
An NK1-receptor antagonist plus a 5-HT3-receptor antagonist
Chemotherapy-related nausea
S
Ledipasvir plus sofosbuvir (Harvoni)
Gilead Sciences
An NS5A inhibitor plus an HCV nucleotide-analogue NS5B-polymerase inhibitor
Genotype 1 HCV
P, B
Pirfenidone (Esbriet)
InterMune
MOA unknown
IPF
P, O, B
78 | FEBRUARY 2015 | VOLUME 14
www.nature.com/reviews/drugdisc © 2015 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S Table 1 (cont.) | CDER approvals in 2014 Drug (brand name)
Sponsor
Properties
Indications
Review types
Nintedanib (Ofev)
Boehringer Ingelheim
Kinase inhibitor against PDGFRs, FGFRs, VEGFRs and FLT3
IPF
P, O, B
Blinatumomab (Blincyto)
Amgen
CD19- and CD3-bispecific antibody
B-ALL
P, O, B, A
Finafloxacin (Xtoro)
Alcon
Fluoroquinolone antimicrobial
Acute otitis externa (swimmer’s ear)
P
Olaparib (Lynparza)
AstraZeneca
PARP inhibitor
Advanced BRCA-mutated ovarian cancer
P, O, A
Ombitasvir plus paritaprevir plus dasabuvir plus ritonavir (Viekira Pak)
AbbVie
An NS5A inhibitor plus an NS3Aand NS4A-protease inhibitor plus a non-nucleoside NS5Bpalm-polymerase inhibitor plus a CYP3A inhibitor
Chronic HCV genotype 1 infection
P, B
Ceftolozane plus tazobactam (Zerbaxa)
Cubist
A cephalosporin antibacterial plus a β-lactamase inhibitor
Complicated intra-abdominal infections and complicated urinary tract infections
P
Peramivir (Rapivab)
BioCryst
Neuraminidase inhibitor
Influenza infection
S
Nivolumab (Opdivo)
Bristol-Myers Squibb
PD1 inhibitor
Unresectable or metastatic melanoma
P, O, B, A
5-HT3, serotonin type 3; A, accelerated approval; ABSSSI, acute bacterial skin and skin structure infection; ALK, anaplastic lymphoma kinase; B, breakthrough designation; B‑ALL, B‑cell acute lymphocytic leukaemia; CDER, Center for Drug Evaluation and Research; CLL, chronic lymphocytic leukaemia; COPD, chronic obstructive pulmonary disease; CYP3A, cytochrome P450 3A4; FGFR, fibroblast growth factor receptor; FLT3, receptor-type tyrosine-protein kinase FLT3; GLP1, glucagon-like peptide 1; HCV, hepatitis C virus; IGF1R, insulin-like growth factor 1 receptor; IL‑6, interleukin‑6; IPF, idiopathic pulmonary fibrosis; MOA, mode of action; NK1, substance P; NS, non-structural protein; NSCLC, non-small-cell lung cancer; O, orphan designation; P, priority review; PD1, programmed cell death protein 1; PDGFR, platelet-derived growth factor receptor; PI3Kб, phosphatidylinositol-3-OH kinase; ROS1, proto-oncogene tyrosine-protein kinase ROS; S, standard review; SGLT2, sodium–glucose cotransporter 2; SLL, small lymphocytic lymphoma; VEGFR, vascular endothelial growth factor receptor.
in aggregated peak sales (FIG. 2; see also www.bcgperspectives.com for the full BCG analysis). By comparison, the 36 approvals they tracked from 2013 are expected to earn $53 billion in peak aggregated sales. “2014 was a fantastic year,” says BCG’s Senior Partner, Ulrik Schulze. But he adds that peak sales are probably down from 2013, again in part because many of the new drugs approved in 2014 are entering crowded markets.
Whereas 12 (29%) of the new CDER approvals are set to become blockbusters within 5 years, only 3 (7%) of these are expected to break the $2-billion mark (FIG. 3). The 2013 cohort of approvals included 13 (48%) drugs that were expected to achieve blockbuster status within 5 years of approval, of which 6 (22%) were anticipated to earn over $2 billion in annual sales (Nature Rev. Drug Discov. 13, 85–89; 2014).
The potential multi-blockbuster drugs approved in 2014 include the most exciting scientific approvals of the year. Merck & Co.’s pembrolizumab and Bristol-Myers Squibb’s nivolumab are the first programmed cell death protein 1 (PD1)-inhibiting cancer immunotherapies, and oncologists hope that by mixing and matching this class of drugs with other immunotherapies, kinase inhibitors and chemotherapies, they can change the face of
60
NMEs BLAs
53
Number of drugs approved
50
39
40
30
35
30
27
25
25
24
24 21
21
21 20
18
17
18
19
16
15 11
10
0
33
31
30
29
6 2
2
1993
1994
5
5
1 1995
1996
1997
1998
5 2
2
1999
2000
6
6
5 2
2001
2002
Figure 1 | Novel approvals since 1993. This figure shows the new molecular entities (NMEs) and biologics license applications (BLAs) approved by the Center for Drug Evaluation and Research (CDER) since
2003
2004
2005
6
4 2006
2
3
2007
2008
6
6
6 2
2009
2010
2011
2012
2013
2014
1993. Approvals by the Center for Biologics Evaluation and Research (CBER) are not included in this drug count. Data Reviews are from|Drugs@FDA Nature Drug Discovery and the US Food and Drug Administration (FDA).
NATURE REVIEWS | DRUG DISCOVERY
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N E W S & A N A LY S I S Table 2 | Selected CBER approvals in 2014 Drug brand name
Sponsor
Properties
Indication
Trumenba
Wyeth/Pfizer
Meningococcal group B vaccine
Meningitis B
Obizur
Baxter
Recombinant porcine antihaemophilic factor
Acquired haemophilia A
Hyqvia
Baxter
Immunoglobulin infusion with recombinant hyaluronidase
Humoral immune defects in adults with primary immunodeficiency
Ruconest
Pharming
Recombinant C1-esterase inhibitor
Hereditary angioedema
Eloctate
Biogen Idec
Recombinant antihaemophilic factor–Fc fusion protein
Haemophilia A
Ragwitek
Merck & Co.
Short ragweed pollen allergen extract
Short ragweed pollen-induced allergic rhinitis
Grastek
Merck & Co.
Timothy grass pollen allergen extract
Grass pollen-induced allergic rhinitis
Oralair
Stallergenes
Sweet vernal grass, orchard grass, perennial rye, Timothy grass and Kentucky Bluegrass mixed pollen allergen extract
Grass pollen-induced allergic rhinitis
Alprolix
Biogen Idec
Recombinant coagulation factor IX–Fc fusion protein
Haemophilia B
CBER, Center for Biologics Evaluation and Research; Fc, crystallizable fragment.
cancer treatment (Nature Rev. Drug Discov. 12, 489–492; 2013). Gilead Sciences’ fixed-dose combination of ledipasvir and sofosbuvir, meanwhile, is the first all-oral therapy for genotype 1 hepatitis C virus (HCV) infection to make it to market from what has been a heated drug-development race (Nature Rev. Drug Discov. 12, 409–411; 2013). Next year could also see late-stage progress on several exciting scientific fronts, including cholesteryl ester transfer protein (CETP) inhibitors, proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors and oncolytic viruses (TABLE 3). The FDA’s first action approval rate was 67% in 2014, down from 78% in 2013 (see TABLE 4 for some of the drugs that received complete response letters or were withdrawn by their sponsors in 2014). 60
Sales
Break-downs The FDA approved 9 (22%) oncology drugs last year (FIG. 4), compared with 9 (33%) in 2013 and 13 (33%) in 2012. “The question is whether you count relative or absolute values,” asks Schulze. “I think we are seeing a burst of innovation in other areas, which by virtue of bringing up the total number of approvals is bringing down the relative share of oncology,” he adds. Infectious diseases also scored 9 (22%) approvals, up from 3 (11%) in 2013. In addition to new HCV and HIV drugs, the infectious-disease additions included 4 antibiotics that were approved under the Qualified Infectious Disease Product (QIDP) programme. Three of these QIDP antibiotics were for the treatment of skin infections.
NTDs
60
40
40
39 36
34 24
28
27
29
32 28
31
20
0
20
51
24
38
25
13
22
29
37
35
53
48
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
Number of NTDs approved
Total peak sales (US$ billions)
53
0
Figure 2 | Aggregated peak drug sales since 2004. Aggregated peak drug sales expectations, as calculated by The Boston Consulting Group (BCG; see ‘R&D Productivity 2014: Year of Nature Reviews | Drug Discovery Breakthroughs’ on www.bcgperspectives.com for full analysis). BCG’s analysis looked at peak sales estimates for 53 new therapeutic drugs (NTDS) that were approved in 2014, including new molecular entities (NMEs) and biologic license applications (BLAs) approved by the Center for Drug Evaluation and Research (CDER), minus the medical imaging approvals, plus certain non-NME approvals from the CDER and the Center for Biologics Evaluation and Research (CBER). Peak sales data for drugs approved in 2014 are wholly forecasted. Actual sales data and updated expectations are used for drugs approved in earlier years.
80 | FEBRUARY 2015 | VOLUME 14
This mini surge of antibiotics, however, was probably primarily due to changes to the acute bacterial skin and skin structure infection (ABSSSI) trial guidelines that were introduced a few years ago, rather than to corrections to the fundamental problems of antibiotic drug development (Nature Rev. Drug Discov. 13, 711–713; 2014). 2014 was the biggest year to date for orphan-drug approvals, with 17 (41%) orphan designees in the approval cohort. By comparison, the agency approved 9 (33%) orphan new molecular entities (NMEs) in 2013, 13 (33%) in 2012 and 11 (37%) in 2011. Every single oncology approval in 2014 was for an orphan indication. The agency also approved 9 (22%) breakthrough designees in 2014. According to the BCG analysis, these agents carried 50% of the commercial potential of the 2014 cohort. Six of the 12 approvals with blockbuster expectations are breakthrough designees, including the 4 drugs with the top sales expectations. With no sign that the FDA is slowing down in awarding breakthrough designations, these are encouraging data for industry (Nature Rev. Drug Discov. 13, 873–875; 2014). The CDER approval list included 11 (27%) biologics, up from just 2 (7%) in 2013 and 6 (15–29%) in each of the years 2009–2012. The agency approved 8 drugs (20%) using the accelerated approval pathway. “This is good,” says Milne, because one aim of the FDA Safety and Innovation Act was to encourage greater use of accelerated approval through the use of surrogate markers. But, because 7 of these drugs were approved for cancer, he adds, there is lots of room for improvement in the use of accelerated approval in other therapeutic areas. www.nature.com/reviews/drugdisc
© 2015 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S 9
8.2
2019 sales in US$ billions
8 7 6
5.3
5 4
3.3
3 1.9
2
1.5
1.4
1.4
1.3
1.2
1
1.1
1.1
0
b b t vir ab ab ne 1A lus zin ma ma ilas pre ir im rp taflo um ido lizu svi uvir* ivolu be gli tux cir en rita onav prem l f o a a i u a r n r i p p S N p i t b A m P sb ero Da Ra lus s ri Led sofo Pem erf ir p plu int g asv buvir e t i P b a Om s das plu
Figure 3 | Anticipated blockbusters approved in 2014. Sales forecasts are average, annual, global estimates for 2019 as compiled by Thomson
sib
lali
Ide
1.0
e
tid
glu
la Du
Oncology Infectious disease Metabolism and endocrinology Neurology Pulmonary
Reuters Cortellis database. *Sales of Gilead’s combination of ledipasvir Drug Discovery plus sofosbuvir are expected to peak at Nature US$12 Reviews billion in|2017.
Table 3 | Selected late-stage drugs to watch in 2015 Drug name
Sponsors
Properties
Indication
Event due in 2015
Secukinumab
Novartis
IL-17-specific antibody
Psoriasis
PDUFA decision in January
Palbociclib
Pfizer
CDK inhibitor
Breast cancer
PDUFA decision in April
Toujeo
Sanofi
Insulin glargine
Diabetes
PDUFA decision in May
Talimogene laherparepvec
Amgen
Oncolytic virus
Melanoma
PDUFA decision in July
Evolocumab
Amgen
PCSK9-specific antibody
Hypercholesterolaemia
PDUFA decision by September
Lumacaftor plus ivacaftor
Vertex
CFTR corrector and CFTR potentiator
Cystic fibrosis
PDUFA decision in November
Alirocumab
Sanofi/ Regeneron
PCSK9-specific antibody
Hypercholesterolaemia
PDUFA decision
LCZ696
Novartis
Angiotensin-receptor inhibitor and neutral-endopeptidase inhibitor
Congestive heart failure
PDUFA decision
Ryzodeg
Novo Nordisk
Co-formulation of insulin degludec and insulin aspart
Diabetes
Cardiovascular outcomes data, to address 2012 complete response letter
Anacetrapib
Merck & Co.
CETP inhibitor
Hypercholesterolaemia
Interim efficacy analysis of Phase III trial
Ocrelizumab
Roche
CD20-specific antibody
Multiple sclerosis
Top-line Phase III data
Baricitinib
Eli Lilly
JAK1- and JAK2- inhibitor
Rheumatoid arthritis
Top-line Phase III data
Event data are from BioMedTracker. CDK, cyclin-dependent kinase; CETP, cholesteryl ester transfer protein; CFTR, cystic fibrosis transmembrane conductance regulator; IL‑17, interleukin‑17; JAK, Janus kinase; PCSK9, proprotein convertase subtilisin kexin type 9; PDUFA, Prescription Drug User Fee Act.
Table 4 | Selected drugs that were rejected or withdrawn* from FDA review in 2014 Drug
Sponsor
Properties
Indications
Cangrelor
The Medicines Company
P2Y12 platelet ADP-receptor inhibitor
Acute coronary syndrome and following coronary artery bypass graft
Serelaxin
Novartis
Agonist for relaxin receptors 1–4
Acute decompensated heart failure
Macrilen
Æterna Zentaris
Ghrelin-receptor agonist
Short stature or growth-hormone deficiency
Daclatasvir*
Bristol-Myers Squibb
NS5A inhibitor
Hepatitis C virus
Daclatasvir plus asunaprevir*
Bristol-Myers Squibb
An NS5A inhibitor plus an NS3 protease inhibitor
Hepatitis C virus
*Indicates agents that were withdrawn. ADP, adenosine diphosphate; NS, non-structural protein.
3% 5% 5% 7%
22%
7% 7%
22%
10%
12%
Oncology Infectious disease Metabolism and endocrinology Neurology Gastroenterology
Dermatology Pulmonary Lysosomal storage disease Imaging Cardiology
Figure 4 | Approvals by therapeutic area. Nature Reviews | Drug Discovery
NATURE REVIEWS | DRUG DISCOVERY
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