NEWS & ANALYSIS 2015 FDA drug approvals FDA approval rate continues to surge, with 45 green lights for new drugs granted in 2015. average peak sales forecast for a 2015 approval is US$900 million. This is down from an average of $1.4 billion in 2014, when the FDA approved Gilead’s record-selling hepatitis C virus combination therapy Harvoni and two highly anticipated cancer immunotherapies (Nat. Rev. Drug Discov. 14, 77–81; 2015). It is 50% higher than the average sales value of the 2009 doldrums (FIG. 2). “It was another great year,” says Michael Ringel, senior partner at BCG. “This is just a tremendous upward trajectory from the lows of 2009. We think it is real, both in terms of the increase in the number of new therapeutic drugs and the recovery of peak sales,” he adds. Sixteen of the new CDER approvals (36% of the cohort) are expected to achieve blockbuster status (FIG. 3).
Asher Mullard Industry and the FDA have had back‑to‑back landmark approval years. The agency’s Center for Drug Evaluation and Research (CDER), which oversees the approval of small molecules and antibodies, approved 45 new drugs in 2015. This marks a 19‑year high, and is up from the previous recent record of 41 drugs in 2014 (FIG. 1; TABLE 1). It is also more than double the approval rate during 2005–2009, when approvals were at their lowest with an average of 22 drugs per year. The 2015 cohort carries solid — although not stellar — commercial potential. Boston Consulting Group (BCG)’s annual analysis of a basket of ‘new therapeutic drugs’ from the CDER and the Center for Biologics Evaluation and Research (CBER; TABLE 2) found that the
By the numbers By therapeutic area, cancer drugs continue to dominate the CDER approval list (FIG. 4). The FDA approved 14 (31%) cancer drugs in 2015. Oncology has accounted for over 30% of the approvals for 3 of the past 4 years (the exception was 2014, when it accounted for only 22% of approvals). Multiple myeloma did particularly well, with four new drug approvals last year, including the first two antibody therapies for this indication (Nat. Rev. Drug Discov. 15, 5–6; 2016). The CBER also approved Amgen’s talimogene laherparepvec, the first cancer-killing virus to gain approval (Nat. Rev. Drug Discov. 14, 369–371; 2015). According to BCG’s analysis, oncology approvals contributed less to the overall value of the 2015 approvals than in previous years. The oncology approval with the most commercial potential of 2015 is
6
60
NMEs BLAs
53
Number of drugs approved
50
39 5 30 5
40
30
25 2
29 1 21 2
35 2
33 6
31 5 27 2
24 5 17 6
24 6
21 6 18 2
20
18 4
21 3 16 2
19 6
30 11
33 12
25 2
15 6
10
0
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Figure 1 | Novel approvals since 1993. New molecular entities (NMEs) and Biologics License Applications (BLAs) approved by the Center for Drug Evaluation and Research (CDER) since 1993. Approvals by the Center for Biologics and Nature Reviews | Evaluation Drug Discovery Research (CBER) are not included in this drug count. Data are from Drugs@FDA and the FDA.
NATURE REVIEWS | DRUG DISCOVERY
VOLUME 15 | FEBRUARY 2016 | 73 © 2016 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S Table 1 | New CDER approvals for 2015 Drug (brand name)
Sponsor
Properties
Indication
Review classification
Edoxaban (Savaysa)
Daiichi Sankyo
Factor Xa inhibitor
Risk of stroke and systemic embolism in NVAF, and deep vein thrombosis
S
Secukinumab (Cosentyx)
Novartis
IL‑17A antagonist
Plaque psoriasis
S
Parathyroid hormone (Natpara)
NPS Pharma
Hormonal injection
Hypocalcaemia in patients with hypoparathyroidism
S, O
Palbociclib (Ibrance)
Pfizer
CDK4 and CDK6 inhibitor
ER‑positive, HER2‑negative advanced breast cancer P, B, A
Lenvatinib (Lenvima)
Eisai
VEGFR inhibitor
Thyroid cancer
P, O
Panobinostat (Farydak)
Novartis
Histone deacetylase inhibitor
Multiple myeloma
P, O, A
Avibactam plus ceftazidime (Avycaz)
Allergan
A β-lactamase inhibitor and a cephalosporin
Complicated intra-abdominal infections and complicated urinary tract infections
P
Isavuconazonium (Cresemba)
Astellas
Azole antifungal
Antifungal
P, O
Dinutuximab (Unituxin)
United Therapeutics
GD2‑binding mAb
Neuroblastoma
P, O
Cholic acid (Cholbam)
Retrophin
A primary bile acid
Bile acid synthesis disorders and peroxisomal disorders
P, O
Ivabradine (Corlanor)
Amgen
Hyperpolarization-activated cyclic nucleotide-gated channel blocker
Chronic heart failure
P
Deoxycholic acid (Kybella)
Kythera
Cytolytic drug
Fat below the chin
S
Eluxadoline (Viberzi)
Allergan
μ‑opioid receptor agonist
Irritable bowel syndrome
P
Cangrelor (Kengreal)
Medicines Company
P2Y12 platelet inhibitor
Myocardial infarction, repeat coronary revascularization, and stent thrombosis
S
Ivacaftor plus lumacaftor (Orkambi)
Vertex
CFTR potentiator plus CFTR corrector
Cystic fibrosis in patients with homozygous DF508 CFTR mutation
P, O, B
Sacubitril plus valsartan (Entresto)
Novartis
A neprilysin inhibitor plus an Chronic heart failure angiotensin II receptor blocker
P
Brexpiprazole (Rexulti)
Otsuka
Atypical antipsychotic
MDD and schizophrenia
S
Alirocumab (Praluent)
Sanofi
PCSK9 inhibitor
LDL lowering
P
Sonidegib (Odomzo)
Novartis
Smoothened inhibitor
Basal cell carcinoma
S
Daclatasvir (Daklinza)
Bristol-Myers Squibb
NS5A inhibitor
HCV
P
Flibanserin (Addyi)
Sprout
Serotonin receptor modulator
Hypoactive sexual desire disorder
S
Evolocumab (Repatha)
Amgen
PCSK9 inhibitor
LDL lowering
S, O
Rolapitant (Varubi)
Tesaro
Neurokinin 1 receptor antagonist
Nausea and vomiting associated with chemotherapy
S
Uridine (Xuriden)
Wellstat
Pyrimidine analogue
Hereditary orotic aciduria
P, O, B
Cariprazine (Vraylar)
Forest
Atypical antipsychotic
Schizophrenia and bipolar 1 disorder
S
Tipiracil plus trifluridine (Lonsurf)
Taiho
Thymidine phosphorylase inhibitor plus a nucleoside metabolic inhibitor
Colorectal cancer
S
Insulin degludec (Tresiba) Novo Nordisk
Long-acting insulin
Diabetes
S
Aripiprazole lauroxil (Aristada)
Alkermes
Extended release atypical antipsychotic
Schizophrenia
S
Idarucizumab (Praxbind)
Boehringer Ingelheim
Dabigatran-binding mAb fragment
Reversal of anticoagulant effects of dabigatran
P, O, B, A
Patiromer sorbitex (Veltassa)
Relypsa
Potassium binder
Hyperkalaemia
S
Asfotase alfa (Strensiq)
Alexion
Alkaline phosphatase
Hypophosphatasia
P, O, B
Trabectedin (Yondelis)
Johnson & Johnson
Alkylating drug
Liposarcoma or leiomyosarcoma
P, O
Mepolizumab (Nucala)
GlaxoSmithKline IL-5 antagonist
Severe asthma
S
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N E W S & A N A LY S I S Table 1 (cont.) | New CDER approvals for 2015 Drug (brand name)
Sponsor
Properties
Indication
Review classification
Elvitegravir plus cobicistat Gilead plus emtricitabine plus tenofovir (Genvoya)
An INSTI plus a CYP3A inhibitor HIV plus two nucleoside analogue reverse transcriptase inhibitors
S
Cobimetinib (Cotellic)
Genentech
MEK inhibitor
Melanoma with BRAFV600E/K mutations
P, O
Osimertinib (Tagrisso)
AstraZeneca
EGFR inhibitor
NSCLC with EGFRT790M mutations
P, O, B, A
Daratumumab (Darzalex) Johnson & Johnson
CD38‑directed mAb
Multiple myeloma
P, O, B, A
Ixazomib (Ninlaro)
Oral proteasome inhibitor
Multiple myeloma
P, O
Necitumumab (Portrazza) Eli Lilly
EGFR antagonist
NSCLC
S, O
Elotuzumab (Empliciti)
Bristol-Myers Squibb
SLAMF7-directed mAb
Multiple myeloma
P, O, B
Sebelipase alfa (Kanuma)
Alexion
Enzyme replacement therapy
LAL deficiency
P, O, B
Alectinib (Alecensa)
Roche
ALK inhibitor
NSCLC
P, O, B, A
Sugammadex (Bridion)
Merck & Co.
A modified gamma cyclodextrin
Reversal of neuromuscular blockade during surgery
P
Selexipag (Uptravi)
Actelion
Prostacyclin receptor agonist
Pulmonary arterial hypertension
S, O
Lesinurad (Zurampic)
AstraZeneca
URAT1 inhibitor
Gout
S
Takeda
A, accelerated; ALK, anaplastic lymphoma kinase; B, breakthrough; CDER, Center for Drug Evaluation and Research; CDK, cyclin-dependent kinase; CFTR, cystic fibrosis transmembrane conductance regulator; CYP3A; cytochrome P450, 3A; EGFR, epidermal growth factor receptor; ER, oestrogen receptor; GD2, disialoganglioside; HCV, hepatitis C virus; IL-5, interleukin 5; INSTI, integrase strand transfer inhibitor; LAL, lysosomal acid lipase; LDL, low-density lipoprotein; mAb, monoclonal antibody; MDD, major depressive disorder; MEK, MAPK/ERK kinase; NSCLC, non-small-cell lung cancer; NVAF, non-valvular atrial fibrillation; O, orphan; P, priority; P2Y12, P2Y purinergic receptor 12; PCSK9, proprotein convertase subtilisin/kexin type 9; S, standard; SLAMF7, signalling lymphocytic activation molecule family 7; URAT1, urate anion exchanger 1; VEGFR, vascular endothelial growth factor receptor.
Pfizer’s first‑in‑class cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor palbociclib, which is forecast to achieve peak sales of $4.8 billion (Nat. Rev. Drug Discov. 14, 130–146; 2015). Other potential moneymakers in 2015 include three drugs that could be prescribed by family doctors rather than specialists. “That is actually quite unusual, because there has been a bit of a drought in this space,” says Ulrik Schulze, senior partner at BCG. Novartis’s Entresto, a combination of sacubitril plus valsartan for the treatment of chronic heart failure, could achieve peak global sales of nearly $5 billion. As such, it could advance the case for outcome-based
pricing in the USA (Nat. Rev. Drug Discov. 14, 665–667; 2015). Relatively fast approvals for two potentially lucrative lipid-lowering drugs — first‑in‑class proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors alirocumab, from Sanofi and Regeneron, and evolocumab, from Amgen — meanwhile demonstrate the benefits of using human genetics to validate therapeutic targets (Nat. Rev. Drug Discov. 12, 581–594; 2013). Approvals for orphan-designated drugs for rare diseases hit their highest level ever. The CDER approved 21 (47%) drugs with orphan indications in 2015, up from 17 (41%) in 2014 and 9 (33%) in 2013. As in 2014, over
half of these orphan drugs were cancer drugs, reflecting the ability to split cancer indications into narrower and narrower segments. Although the breakthrough designation programme is just 3 years old, the number of breakthrough approvals stabilized last year. The CDER approved 10 (22%) drugs with a breakthrough designation in 2015, compared with 9 (22%) in 2014. John Jenkins, Director of the Office of New Drugs at the CDER, noted in a December presentation on new drug approvals that the pace of requests for breakthrough designation, and the proportion of requests that are granted, have remained steady.
Table 2 | Selected new CBER approvals for 2015 Drug name
Sponsor
Properties
Indication
Bexsero
GlaxoSmithKline
Meningococcal group B vaccine
Immunization against Neisseria meningitidis serogroup B
Anthrasil
Cangene
Anthrax immune globulin
Anthrax inhalation
Quadracel
Sanofi
Diphtheria and tetanus toxoids and acellular pertussis vaccine
Immunization against diphtheria, tetanus, pertussis and poliomyelitis
Ixinity
Cangene
Coagulation factor IX
Haemophilia B
Raplixa
ProFibrix
Fibrin sealant
Bleeding during surgery
Anavip
Instituto Bioclon
Equine-derived antivenom
Rattlesnake envenomation
Nuwiq
Octapharma
Recombinant anti-haemophilic factor
Haemophilia A
Coagadex
Bio Products
Coagulation factor X
Factor X deficiency
Imlygic
Amgen
Genetically modified oncolytic virus
Melanoma
CBER, Center for Biologics Evaluation and Research.
NATURE REVIEWS | DRUG DISCOVERY
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N E W S & A N A LY S I S
Sales
Total peak sales (US$ billions)
60
Regulatory rejection rates were at an all-time low. As of the end of November, the CDER had only issued two complete response letters that denied approvals to
NTDs
60
58
53 39
40
28
24
20
0
29
26
32
28
40
34
31
20
27
37
26
13
19
31
35
32
46
66
51
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
Number of NTDs approved
Five (50%) of the breakthrough approvals are forecast to achieve blockbuster status, compared with six (66%) in 2014.
0
Blockbuster sales (US$ billions)
Figure 2 | Aggregated peak drug sales since 2005. Aggregated peak drug sales expectations, as calculated by the Boston Consulting Group (BCG). BCG’s analysis looked at| peak estimates Nature Reviews Drug sales Discovery for 58 new therapeutic drugs (NTDs) from 2015, including approvals from both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). Peak sales data for drugs approved in 2015 are wholly forecasted. Actual sales data and updated expectations are used for drugs approved in earlier years.
would‑be new drugs. In 2009, by contrast, the CDER issued 22 complete response letters over the course of the year. Jenkins said that the agency has not lowered its approval criteria. “We are not a rubber stamp,” he said. He attributed the change to more meetings with drug sponsors, better applications, and targeted and orphan drugs that offer a clearer benefit–risk balance. Next year could be another big approval year. The FDA received 40 new molecular entity (NME) and Biologics Licence Application (BLA) filings in 2015, compared with 41 in 2014. Many of these will be reviewed over the course of the year to make up the 2016 approval cohort. This year’s new drugs could include a first exon-skipping drug for Duchenne muscular dystrophy, a first‑in‑class B cell lymphoma 2 (BCL-2) inhibitor and anti‑PDL1 (programmed cell death 1 ligand 1) antibodies (TABLE 3). 2%
4%
5
*
*
4% 31%
7%
NMEs BLAs
4
2% 2%
3
7%
2
* 1 0
n
rta
sv
lu
lp
i itr
b cu
Sa
sa al
lib
l Pa
ft ca
ac
um
sl
lu
p or
7%
*
9% 7%
or
a e b ir ib ab dec ab mib ab ab ab ad ol ni sv oy ur atin rti ta env um raz um zum azo um cum glu n i a e c v n l s p i n c m um otu G Ix pi iro volo n de cuk Le Le Osi at Da Al ex i El E ar Se ul Br D s In
aft
ic
c bo
*
Inborn errors Haematology Dermatology Pulmonary Sexual health Anaesthesia Rheumatology
Oncology Cardiology Infectious disease Metabolism and endocrinology Psychiatry Gastroenterology
Iva
Figure 3 | Anticipated blockbusters approved in 2015. Sales forecasts are average, annual, global consensus sales estimates for 2020 as reported by Thomson Reuters’ Cortellis database on 31 December 2015. BLA, Biologics Licence Application; NME, new Nature molecular entity.| *Drugs with Reviews Drug Discovery breakthrough designation.
9%
9%
Figure 4 | Approvals by therapeutic area. Nature Reviews | Drug Discovery
Table 3 | Selected new drugs to watch Drug
Companies
Properties
Indications
Status
Eteplirsen
Sarepta
Exon-skipping oligonucleotide
Duchenne muscular dystrophy
PDUFA date in February
Venetoclax*
AbbVie
First‑in‑class BCL-2 inhibitor
Chronic lymphocytic leukaemia
PDUFA date in April
Andexanet alfa*
Portola
Universal factor Xa inhibitor antidote
Reversing the activity of factor Xa inhibitors
PDUFA date in August
Baricitinib
Eli Lilly
JAK/STAT inhibitor
Rheumatoid arthritis
PDUFA date in January 2017
Ocrelizumab
Roche
Second generation anti‑CD20 mAb
Multiple sclerosis
Filing anticipated in first quarter of 2016
Atezolizumab* and durvalumab
Roche and Anti‑PDL1 mAbs AstraZeneca
Bladder cancer and NSCLC
Filings anticipated in first half of 2016
KTE‑C19* and CTL019*
Kite Pharma and Novartis
Blood cancers
Filings anticipated in 2016
CD19-targeting CAR T cell therapies
BCL-2, B cell lymphoma 2; CAR, chimeric antigen receptor; EGFR, epidermal growth factor receptor; JAK, Janus kinase; NSCLC, non-small-cell lung cancer; PDL1, programmed cell death 1 ligand 1; PDUFA, Prescription Drug User Fee Act; STAT, signal transducer and activator of transcription. *Drugs with publicly disclosed breakthrough designations.
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Asher Mullard Industry and the FDA have had back‑to‑back landmark approval years. The agency’s Center for Drug Evaluation and Research (CDER), which oversees the approval of small molecules and antibodies, approved 45 new drugs in 2015. This marks a 19‑year high, and is up from the previous recent record of 41 drugs in 2014 (FIG. 1; TABLE 1). It is also more than double the approval rate during 2005–2009, when approvals were at their lowest with an average of 22 drugs per year. The 2015 cohort carries solid — although not stellar — commercial potential. Boston Consulting Group (BCG)’s annual analysis of a basket of ‘new therapeutic drugs’ from the CDER and the Center for Biologics Evaluation and Research (CBER; TABLE 2) found that the
By the numbers By therapeutic area, cancer drugs continue to dominate the CDER approval list (FIG. 4). The FDA approved 14 (31%) cancer drugs in 2015. Oncology has accounted for over 30% of the approvals for 3 of the past 4 years (the exception was 2014, when it accounted for only 22% of approvals). Multiple myeloma did particularly well, with four new drug approvals last year, including the first two antibody therapies for this indication (Nat. Rev. Drug Discov. 15, 5–6; 2016). The CBER also approved Amgen’s talimogene laherparepvec, the first cancer-killing virus to gain approval (Nat. Rev. Drug Discov. 14, 369–371; 2015). According to BCG’s analysis, oncology approvals contributed less to the overall value of the 2015 approvals than in previous years. The oncology approval with the most commercial potential of 2015 is
6
60
NMEs BLAs
53
Number of drugs approved
50
39 5 30 5
40
30
25 2
29 1 21 2
35 2
33 6
31 5 27 2
24 5 17 6
24 6
21 6 18 2
20
18 4
21 3 16 2
19 6
30 11
33 12
25 2
15 6
10
0
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Figure 1 | Novel approvals since 1993. New molecular entities (NMEs) and Biologics License Applications (BLAs) approved by the Center for Drug Evaluation and Research (CDER) since 1993. Approvals by the Center for Biologics and Nature Reviews | Evaluation Drug Discovery Research (CBER) are not included in this drug count. Data are from Drugs@FDA and the FDA.
NATURE REVIEWS | DRUG DISCOVERY
VOLUME 15 | FEBRUARY 2016 | 73 © 2016 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S Table 1 | New CDER approvals for 2015 Drug (brand name)
Sponsor
Properties
Indication
Review classification
Edoxaban (Savaysa)
Daiichi Sankyo
Factor Xa inhibitor
Risk of stroke and systemic embolism in NVAF, and deep vein thrombosis
S
Secukinumab (Cosentyx)
Novartis
IL‑17A antagonist
Plaque psoriasis
S
Parathyroid hormone (Natpara)
NPS Pharma
Hormonal injection
Hypocalcaemia in patients with hypoparathyroidism
S, O
Palbociclib (Ibrance)
Pfizer
CDK4 and CDK6 inhibitor
ER‑positive, HER2‑negative advanced breast cancer P, B, A
Lenvatinib (Lenvima)
Eisai
VEGFR inhibitor
Thyroid cancer
P, O
Panobinostat (Farydak)
Novartis
Histone deacetylase inhibitor
Multiple myeloma
P, O, A
Avibactam plus ceftazidime (Avycaz)
Allergan
A β-lactamase inhibitor and a cephalosporin
Complicated intra-abdominal infections and complicated urinary tract infections
P
Isavuconazonium (Cresemba)
Astellas
Azole antifungal
Antifungal
P, O
Dinutuximab (Unituxin)
United Therapeutics
GD2‑binding mAb
Neuroblastoma
P, O
Cholic acid (Cholbam)
Retrophin
A primary bile acid
Bile acid synthesis disorders and peroxisomal disorders
P, O
Ivabradine (Corlanor)
Amgen
Hyperpolarization-activated cyclic nucleotide-gated channel blocker
Chronic heart failure
P
Deoxycholic acid (Kybella)
Kythera
Cytolytic drug
Fat below the chin
S
Eluxadoline (Viberzi)
Allergan
μ‑opioid receptor agonist
Irritable bowel syndrome
P
Cangrelor (Kengreal)
Medicines Company
P2Y12 platelet inhibitor
Myocardial infarction, repeat coronary revascularization, and stent thrombosis
S
Ivacaftor plus lumacaftor (Orkambi)
Vertex
CFTR potentiator plus CFTR corrector
Cystic fibrosis in patients with homozygous DF508 CFTR mutation
P, O, B
Sacubitril plus valsartan (Entresto)
Novartis
A neprilysin inhibitor plus an Chronic heart failure angiotensin II receptor blocker
P
Brexpiprazole (Rexulti)
Otsuka
Atypical antipsychotic
MDD and schizophrenia
S
Alirocumab (Praluent)
Sanofi
PCSK9 inhibitor
LDL lowering
P
Sonidegib (Odomzo)
Novartis
Smoothened inhibitor
Basal cell carcinoma
S
Daclatasvir (Daklinza)
Bristol-Myers Squibb
NS5A inhibitor
HCV
P
Flibanserin (Addyi)
Sprout
Serotonin receptor modulator
Hypoactive sexual desire disorder
S
Evolocumab (Repatha)
Amgen
PCSK9 inhibitor
LDL lowering
S, O
Rolapitant (Varubi)
Tesaro
Neurokinin 1 receptor antagonist
Nausea and vomiting associated with chemotherapy
S
Uridine (Xuriden)
Wellstat
Pyrimidine analogue
Hereditary orotic aciduria
P, O, B
Cariprazine (Vraylar)
Forest
Atypical antipsychotic
Schizophrenia and bipolar 1 disorder
S
Tipiracil plus trifluridine (Lonsurf)
Taiho
Thymidine phosphorylase inhibitor plus a nucleoside metabolic inhibitor
Colorectal cancer
S
Insulin degludec (Tresiba) Novo Nordisk
Long-acting insulin
Diabetes
S
Aripiprazole lauroxil (Aristada)
Alkermes
Extended release atypical antipsychotic
Schizophrenia
S
Idarucizumab (Praxbind)
Boehringer Ingelheim
Dabigatran-binding mAb fragment
Reversal of anticoagulant effects of dabigatran
P, O, B, A
Patiromer sorbitex (Veltassa)
Relypsa
Potassium binder
Hyperkalaemia
S
Asfotase alfa (Strensiq)
Alexion
Alkaline phosphatase
Hypophosphatasia
P, O, B
Trabectedin (Yondelis)
Johnson & Johnson
Alkylating drug
Liposarcoma or leiomyosarcoma
P, O
Mepolizumab (Nucala)
GlaxoSmithKline IL-5 antagonist
Severe asthma
S
74 | FEBRUARY 2016 | VOLUME 15
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N E W S & A N A LY S I S Table 1 (cont.) | New CDER approvals for 2015 Drug (brand name)
Sponsor
Properties
Indication
Review classification
Elvitegravir plus cobicistat Gilead plus emtricitabine plus tenofovir (Genvoya)
An INSTI plus a CYP3A inhibitor HIV plus two nucleoside analogue reverse transcriptase inhibitors
S
Cobimetinib (Cotellic)
Genentech
MEK inhibitor
Melanoma with BRAFV600E/K mutations
P, O
Osimertinib (Tagrisso)
AstraZeneca
EGFR inhibitor
NSCLC with EGFRT790M mutations
P, O, B, A
Daratumumab (Darzalex) Johnson & Johnson
CD38‑directed mAb
Multiple myeloma
P, O, B, A
Ixazomib (Ninlaro)
Oral proteasome inhibitor
Multiple myeloma
P, O
Necitumumab (Portrazza) Eli Lilly
EGFR antagonist
NSCLC
S, O
Elotuzumab (Empliciti)
Bristol-Myers Squibb
SLAMF7-directed mAb
Multiple myeloma
P, O, B
Sebelipase alfa (Kanuma)
Alexion
Enzyme replacement therapy
LAL deficiency
P, O, B
Alectinib (Alecensa)
Roche
ALK inhibitor
NSCLC
P, O, B, A
Sugammadex (Bridion)
Merck & Co.
A modified gamma cyclodextrin
Reversal of neuromuscular blockade during surgery
P
Selexipag (Uptravi)
Actelion
Prostacyclin receptor agonist
Pulmonary arterial hypertension
S, O
Lesinurad (Zurampic)
AstraZeneca
URAT1 inhibitor
Gout
S
Takeda
A, accelerated; ALK, anaplastic lymphoma kinase; B, breakthrough; CDER, Center for Drug Evaluation and Research; CDK, cyclin-dependent kinase; CFTR, cystic fibrosis transmembrane conductance regulator; CYP3A; cytochrome P450, 3A; EGFR, epidermal growth factor receptor; ER, oestrogen receptor; GD2, disialoganglioside; HCV, hepatitis C virus; IL-5, interleukin 5; INSTI, integrase strand transfer inhibitor; LAL, lysosomal acid lipase; LDL, low-density lipoprotein; mAb, monoclonal antibody; MDD, major depressive disorder; MEK, MAPK/ERK kinase; NSCLC, non-small-cell lung cancer; NVAF, non-valvular atrial fibrillation; O, orphan; P, priority; P2Y12, P2Y purinergic receptor 12; PCSK9, proprotein convertase subtilisin/kexin type 9; S, standard; SLAMF7, signalling lymphocytic activation molecule family 7; URAT1, urate anion exchanger 1; VEGFR, vascular endothelial growth factor receptor.
Pfizer’s first‑in‑class cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor palbociclib, which is forecast to achieve peak sales of $4.8 billion (Nat. Rev. Drug Discov. 14, 130–146; 2015). Other potential moneymakers in 2015 include three drugs that could be prescribed by family doctors rather than specialists. “That is actually quite unusual, because there has been a bit of a drought in this space,” says Ulrik Schulze, senior partner at BCG. Novartis’s Entresto, a combination of sacubitril plus valsartan for the treatment of chronic heart failure, could achieve peak global sales of nearly $5 billion. As such, it could advance the case for outcome-based
pricing in the USA (Nat. Rev. Drug Discov. 14, 665–667; 2015). Relatively fast approvals for two potentially lucrative lipid-lowering drugs — first‑in‑class proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors alirocumab, from Sanofi and Regeneron, and evolocumab, from Amgen — meanwhile demonstrate the benefits of using human genetics to validate therapeutic targets (Nat. Rev. Drug Discov. 12, 581–594; 2013). Approvals for orphan-designated drugs for rare diseases hit their highest level ever. The CDER approved 21 (47%) drugs with orphan indications in 2015, up from 17 (41%) in 2014 and 9 (33%) in 2013. As in 2014, over
half of these orphan drugs were cancer drugs, reflecting the ability to split cancer indications into narrower and narrower segments. Although the breakthrough designation programme is just 3 years old, the number of breakthrough approvals stabilized last year. The CDER approved 10 (22%) drugs with a breakthrough designation in 2015, compared with 9 (22%) in 2014. John Jenkins, Director of the Office of New Drugs at the CDER, noted in a December presentation on new drug approvals that the pace of requests for breakthrough designation, and the proportion of requests that are granted, have remained steady.
Table 2 | Selected new CBER approvals for 2015 Drug name
Sponsor
Properties
Indication
Bexsero
GlaxoSmithKline
Meningococcal group B vaccine
Immunization against Neisseria meningitidis serogroup B
Anthrasil
Cangene
Anthrax immune globulin
Anthrax inhalation
Quadracel
Sanofi
Diphtheria and tetanus toxoids and acellular pertussis vaccine
Immunization against diphtheria, tetanus, pertussis and poliomyelitis
Ixinity
Cangene
Coagulation factor IX
Haemophilia B
Raplixa
ProFibrix
Fibrin sealant
Bleeding during surgery
Anavip
Instituto Bioclon
Equine-derived antivenom
Rattlesnake envenomation
Nuwiq
Octapharma
Recombinant anti-haemophilic factor
Haemophilia A
Coagadex
Bio Products
Coagulation factor X
Factor X deficiency
Imlygic
Amgen
Genetically modified oncolytic virus
Melanoma
CBER, Center for Biologics Evaluation and Research.
NATURE REVIEWS | DRUG DISCOVERY
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N E W S & A N A LY S I S
Sales
Total peak sales (US$ billions)
60
Regulatory rejection rates were at an all-time low. As of the end of November, the CDER had only issued two complete response letters that denied approvals to
NTDs
60
58
53 39
40
28
24
20
0
29
26
32
28
40
34
31
20
27
37
26
13
19
31
35
32
46
66
51
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
Number of NTDs approved
Five (50%) of the breakthrough approvals are forecast to achieve blockbuster status, compared with six (66%) in 2014.
0
Blockbuster sales (US$ billions)
Figure 2 | Aggregated peak drug sales since 2005. Aggregated peak drug sales expectations, as calculated by the Boston Consulting Group (BCG). BCG’s analysis looked at| peak estimates Nature Reviews Drug sales Discovery for 58 new therapeutic drugs (NTDs) from 2015, including approvals from both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). Peak sales data for drugs approved in 2015 are wholly forecasted. Actual sales data and updated expectations are used for drugs approved in earlier years.
would‑be new drugs. In 2009, by contrast, the CDER issued 22 complete response letters over the course of the year. Jenkins said that the agency has not lowered its approval criteria. “We are not a rubber stamp,” he said. He attributed the change to more meetings with drug sponsors, better applications, and targeted and orphan drugs that offer a clearer benefit–risk balance. Next year could be another big approval year. The FDA received 40 new molecular entity (NME) and Biologics Licence Application (BLA) filings in 2015, compared with 41 in 2014. Many of these will be reviewed over the course of the year to make up the 2016 approval cohort. This year’s new drugs could include a first exon-skipping drug for Duchenne muscular dystrophy, a first‑in‑class B cell lymphoma 2 (BCL-2) inhibitor and anti‑PDL1 (programmed cell death 1 ligand 1) antibodies (TABLE 3). 2%
4%
5
*
*
4% 31%
7%
NMEs BLAs
4
2% 2%
3
7%
2
* 1 0
n
rta
sv
lu
lp
i itr
b cu
Sa
sa al
lib
l Pa
ft ca
ac
um
sl
lu
p or
7%
*
9% 7%
or
a e b ir ib ab dec ab mib ab ab ab ad ol ni sv oy ur atin rti ta env um raz um zum azo um cum glu n i a e c v n l s p i n c m um otu G Ix pi iro volo n de cuk Le Le Osi at Da Al ex i El E ar Se ul Br D s In
aft
ic
c bo
*
Inborn errors Haematology Dermatology Pulmonary Sexual health Anaesthesia Rheumatology
Oncology Cardiology Infectious disease Metabolism and endocrinology Psychiatry Gastroenterology
Iva
Figure 3 | Anticipated blockbusters approved in 2015. Sales forecasts are average, annual, global consensus sales estimates for 2020 as reported by Thomson Reuters’ Cortellis database on 31 December 2015. BLA, Biologics Licence Application; NME, new Nature molecular entity.| *Drugs with Reviews Drug Discovery breakthrough designation.
9%
9%
Figure 4 | Approvals by therapeutic area. Nature Reviews | Drug Discovery
Table 3 | Selected new drugs to watch Drug
Companies
Properties
Indications
Status
Eteplirsen
Sarepta
Exon-skipping oligonucleotide
Duchenne muscular dystrophy
PDUFA date in February
Venetoclax*
AbbVie
First‑in‑class BCL-2 inhibitor
Chronic lymphocytic leukaemia
PDUFA date in April
Andexanet alfa*
Portola
Universal factor Xa inhibitor antidote
Reversing the activity of factor Xa inhibitors
PDUFA date in August
Baricitinib
Eli Lilly
JAK/STAT inhibitor
Rheumatoid arthritis
PDUFA date in January 2017
Ocrelizumab
Roche
Second generation anti‑CD20 mAb
Multiple sclerosis
Filing anticipated in first quarter of 2016
Atezolizumab* and durvalumab
Roche and Anti‑PDL1 mAbs AstraZeneca
Bladder cancer and NSCLC
Filings anticipated in first half of 2016
KTE‑C19* and CTL019*
Kite Pharma and Novartis
Blood cancers
Filings anticipated in 2016
CD19-targeting CAR T cell therapies
BCL-2, B cell lymphoma 2; CAR, chimeric antigen receptor; EGFR, epidermal growth factor receptor; JAK, Janus kinase; NSCLC, non-small-cell lung cancer; PDL1, programmed cell death 1 ligand 1; PDUFA, Prescription Drug User Fee Act; STAT, signal transducer and activator of transcription. *Drugs with publicly disclosed breakthrough designations.
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