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NEWS & ANALYSIS

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Where do new medicines originate from in the EU? p92

Court clears the way for Nexium alternative p94

2013 FDA drug approvals Although the FDA’s 27 new approvals are down from the 15‑year high of 2012, the newcomers pack powerful commercial potential.

Novo Nordisk

Asher Mullard

NPG

Mads Krogsgaard Thomsen discusses two decades leading research at Novo Nordisk p96

Biosimilar competition: lessons from Europe p99

The US Food and Drug Administration (FDA)’s Center for Drug Evaluation and Research (CDER) approved 25 small molecules and 2 biologics in 2013, making by most counts for an average year. While critics bemoaned the 31% decline in approvals from the 39 of 2012, the FDA emphasized that the success rate is on par with long-term averages (FIG. 1). John Jenkins, Director of the Office of New Drugs at the FDA, pointed out at a meeting in December that the agency has approved an average of 28 new drugs per year since 2009, and 26 drugs per year since 2003. Last year’s 27 approvals (TABLE 1), falling squarely between the 5- and 10‑year averages, was likely just a “regression to the mean following an outlier”, he suggested.

Jenkins also noted that the first-cycle approval rate is stable (at around 70%), and that the decline is therefore unlikely to be due to changes in the agency’s risk tolerance. There were also fewer new molecular entities (NMEs) to act on last year, he said. As of 30 November the FDA had acted on 41 potential NMEs (including first filings and resubmissions) in 2013, compared with 50 for the full year in 2012.

It was not, at first glance, a terrifically different year than the last couple of years

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The community, suffering a comedown from the optimism brought on by last year’s approval bonanza, is divided on how to interpret these stats. Some see dark days ahead, and the overall approval rate was down to around 60% in 2013 at the end of November from nearly 80% in 2012 and 2011 (see TABLE 2 for some of the potential NMEs that the FDA rejected in 2013). Others see it as business as usual. “It was not, at first glance, a terrifically different year than the last couple of years,” says Chris Milne, director of research at the Tufts Center for the Study of Drug Development in Boston, Massachusetts, USA. A few, digging beyond the crude ‘approval number’ metric, see cause for optimism. Analysts at Boston Consulting Group (BCG) argue that the financial prospects for the newest batch of approvals are at a 9‑year high. VOLUME 13 | FEBRUARY 2014 | 85

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A step closer to European clinical trial reform p91

N E W S & A N A LY S I S 60

NMEs BLAs

53

Number of drugs approved

50

39

40

30

35 30

29 25

33

31

27 24

20

18

17

10

6 2

2

1993

1994

5

5

1

6

5 2

2

1999

2000

25

24 21

21

21

6

18

5

4

2

19

16

15 6 2

3

2007

2008

6

6

6 2

0 1995

1996

1997

1998

2001

2002

Figure 1 | FDA NME 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

Each year, BCG analysts compile their own approval list — discounting medical imaging approvals and including certain additional approvals from both the CDER and the Center for Biologics Evaluation and Research (CBER) — and then calculate the cumulative peak sales value of the newest therapeutics. This year, they identified 36 medicines that are cumulatively worth US$37 billion in peak annual sales, the highest aggregate value the analysts have seen since 2004 (FIG. 2). “The story of productivity is not as bad as people make out,” says BCG analyst David Greber. These data put the average peak sale value of a new approval at just over $1 billion. Of course, peak sales estimates often fail to reflect reality (Nature Rev. Drug Discov. 12, 737–738; 2013). But, says BCG analyst Ulrik Schulze, the differences between forecasts and real sales are often on the order of rounding errors when considered in the context of large companies’ balance sheets. And industry as a whole tends to underestimate the value of the largest products, he adds. Schulze attributes the increasing value over the past few years to a combination of luck, scientific opportunity and better pipeline management brought on by research and development (R&D) reorganizations. Not all consultants are as sanguine. A separate analysis from Deloitte and Thomson Reuters last year looked at the Phase III pipelines of a set of 12 large pharmaceutical companies, and found that peak sales estimates for this broader set of

2003

2004

2005

2006

2009

2010

2011

2012

2013

Center for Biologics Evaluation and Research (CBER) are not included in Nature Reviews | Drug Discovery this drug count. Data for NMEs are from [email protected], data for BLAs are directly from the US Food and Drug Administration (FDA).

late-stage assets fell from $816 million in 2010 to $466 million in 2013 (Nature Rev. Drug Discov. 13, 9; 2014). But consensus sales forecasts from Thomson Reuters Cortellis support the view that many of the 2013 approvals offer exceptional earning potential. Thirteen (48%) of the new approvals are set to achieve over $1 billion in annual sales within 5 years, including six (22%) destined for multibillion dollar sales (TABLE 3). Broad breakdowns As in previous years, orphan drugs and cancer drugs dominate. The agency approved nine orphan NMEs in 2013 (33% of the list), in line with 2012 (33%) and 2011 (37%). The agency approved eight cancer drugs in 2013 (30%), also on par with 2012 (33%) and 2011 (27%). Six of the cancer approvals were also for orphan indications. Other therapeutic areas that saw multiple successes included metabolic and endocrinological therapies (two type 2 diabetes drugs and a dyslipidaemia drug), antivirals (two hepatitis C virus (HCV) drugs and an HIV drug) and medical imaging products (three approvals). See FIG. 3 for a full breakdown of the approvals by therapeutic area. 2013 was a good year for companion diagnostic developers, at least in terms of their importance in drug development. Companion diagnostic data backed three new oncology approvals — GlaxoSmithKline (GSK)’s dabrafenib, GSK’s trametinib and Boehringer Ingelheim’s afatinib — with

86 | FEBRUARY 2014 | VOLUME 13

FDA-approved companion diagnostic language incorporated into their drug labelling. These approvals, following 2 years on from the companion-diagnosticsupported approvals of Pfizer’s anaplastic lymphoma kinase (ALK) inhibitor crizotinib and Roche’s BRAF inhibitor vemurafenib, provide encouragement that the slow drip is set to become a steady trickle. “Over the next 5 years, we are looking at reaching three to five companion diagnostic approvals a year,” says Milne. “That is pretty good.” In 2012 the FDA noted that many of the approvals (41%) went to emerging sponsors, companies receiving their first drug approval. Although the FDA did not analyse the approvals by sponsor type in 2013, established drug companies appear to have done better in 2013. Small-molecule milestones Several approvals stood out from the pack in terms of scientific novelty, clinical importance or commercial potential. Gilead’s sofosbuvir, for example, combined all three attributes. It is the first‑in‑class NS5B polymerase inhibitor and the first of a bursting pipeline of drugs angling for the potentially lucrative all-oral HCV market (Nature Rev. Drug Discov. 12, 409–411; 2013). Sofosbuvir is initially only approved in the all-oral combination setting for genotype 2 and 3 HCV, but analysts anticipate the FDA will eventually approve it for all-oral use in genotype 1 HCV, the most common form of HCV in the United States. They predict the drug will earn $6.8 billion in annual global sales by 2018. (Sales data in this article are www.nature.com/reviews/drugdisc

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N E W S & A N A LY S I S Table 1 | CDER’s novel approvals in 2013 Drug (brand) Alogliptin (Nesina) Mipomersen (Kynamro)

Company Takeda Genzyme

Pomalidomide (Pomalyst) Ado-trastuzumab emtansine (Kadcyla)* Ospemifene (Osphena)

Celgene Genentech Shionogi

Properties DPP4 inhibitor Oligonucleotide inhibitor of apolipoprotein B100 synthesis Immunomodulatory antineoplastic agent HER2‑targeted antibody and microtubule inhibitor conjugate Oestrogen receptor modulator

Technetium TC 99m tilmanocept (Lymphoseek kit) Gadoterate meglumine (Dotarem) Dimethyl fumarate (Tecfidera) Canagliflozin (Invokana) Fluticasone; vilanterol (Breo Ellipta) Radium RA 223 dichloride (Xofigo) Dabrafenib (Tafinlar)

Navidea

Radioactive diagnostic agent

Guerbet

Gadolinium-based contrast agent

Biogen Idec Janssen GSK

MOA unknown; activates NRF2 pathway SGLT2 inhibitor Corticosteroid plus LABA

Bayer

Trametinib (Mekinist)

GSK

Alpha particle-emitting radioactive therapeutic Kinase inhibitor with activity against BRAFV600E, BRAFV600K, BRAFV600D, wild-type BRAF and other kinases MEK1 and MEK2 kinase inhibitor

Afatinib (Gilotrif)

Boehringer Ingelheim

EGFR (ERBB1), HER2 (ERBB2), and HER4 (ERRB4) kinase inhibitor

Dolutegravir (Tivicay)

ViiV

Vortioxetine (Brintellix) Bazedoxifene acetate plus oestrogens (Duavee)

Takeda Pfizer

HIV1 integrase strand transfer inhibitor Serotonin reuptake inhibitor Conjugated oestrogens with an oestrogen receptor modulator

Riociguat (Adempas)

Bayer

Soluble guanylyl cyclase stimulator

Macitentan (Opsumit) Flutemetamol F-18 (Vizamyl)

Actelion GE Healthcare

Endothelin receptor antagonist Radioactive diagnostic agent

Obinutuzumab (Gazyva)*

Genentech

Eslicarbazepine (Aptiom)

Sunovion

Ibrutinib (Imbruvica) Luliconazole (Luzu)

Pharma­cyclics Medicis

Humanized CD20‑specific monoclonal antibody MOA unknown, but thought to involve voltage-gated sodium channels Bruton’s tyrosine kinase inhibitor Azole antifungal

Simeprevir (Olysio)

Janssen

HCV NS3/4A protease inhibitor

Sofosbuvir (Sovaldi)

Gilead

Umeclidinium and vilanterol (Anoro Ellipta)

GSK

HCV nucleotide analogue NS5B polymerase inhibitor Anticholinergic and a LABA

GSK

Indication Type 2 diabetes Homozygous familial hypercholesterol­ aemia Multiple myeloma HER2‑positive metastatic breast cancer

Review S S, O

Moderate to severe dyspareunia due to menopause Lymphatic mapping in patients with breast cancer or melanoma Contrast agent to visualize disruption of the blood–brain barrier Relapsing forms of multiple sclerosis Type 2 diabetes Chronic obstructive pulmonary disease

S

Castration-resistant prostate cancer

P

Unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test Unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test First-line treatment of patients with metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test HIV1 infection in adults and children, in combination with other antiretroviral agents Major depressive disorder Moderate to severe vasomotor symptoms associated with menopause and prevention of postmenopausal osteoporosis Persistent or recurrent chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension Pulmonary arterial hypertension PET imaging of the brain to estimate β-amyloid neuritic plaque density in patients who are being evaluated for Alzheimer’s disease Previously untreated chronic lymphocytic leukaemia Partial-onset seizures

S, O

Mantle cell lymphoma Interdigital tinea pedis, tinea cruris and tinea corporis caused by Trichophyton rubrum and Epidermophyton floccosum Chronic HCV infection, as a component of a combination antiviral treatment regimen Chronic HCV infection, as a component of a combination antiviral treatment regimen Chronic obstructive pulmonary disease

P, O, B S

S, O P

S P S S S

S, O P, O

P S S P, O S, O S

P, O, B S

P P, B S

*Biologics license application. B, breakthrough designation status; CDER, Center for Drug Evaluation and Research; DPP4, dipeptidyl peptidase 4; EGFR, epidermal growth factor receptor; FDA, US Food and Drug Administration; GSK, GlaxoSmithKline; HCV, hepatitis C virus; LABA, long-acting β2‑adrenergic receptor agonist; MEK, MAPK/ERK kinase; MOA, mechanism of action; NME, new molecular entity; NRF2, NFE2‑related factor 2; NSCLC, non-small-cell lung cancer; O, orphan status; P, priority review; S, standard review. SGLT2, sodium-dependent glucose cotransporter 2.

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N E W S & A N A LY S I S Table 2 | Selected drugs that received complete response letters in 2013 Drug

Company

Properties

Indication

Insulin degludec (with and without insulin aspart)

Novo Nordisk

Long-acting basal insulin (plus fast-acting insulin)

Type 1 and 2 diabetes

Elvitegravir*

Gilead

HIV integrase inhibitor

HIV

Cobicistat*

Gilead

Cytochrome p450 inhibitor

HIV

Suvorexant

Merck

Dual orexin receptor antagonist

Insomnia

Cariprazine

Forest

Dopamine D3 and D2 receptor partial agonist

Schizophrenia and bipolar 1 disorder

Flibanserin

Sprout

5‑HT1A receptor agonist and 5‑HT2A receptor antagonist

Female sexual arousal disorder

Genzyme

CD52‑targeting monoclonal antibody

Multiple sclerosis

Alemtuzumab



*Elvitegravir and cobicistat were both approved in 2012 as components of Gilead’s Quad pill Stribild, but were rejected last year as individual agents. ‡ Alemtuzumab was filed as a supplemental biologics license application because it was previously approved for chronic lymphocytic leukaemia (CLL). 5‑HT, 5‑hydroxytryptamine (serotonin).

than the other available oral and injectable therapeutic options. Analysts forecast over $6 billion in annual sales by 2019. GSK picked up five approvals from the FDA last year (counting the approval granted to ViiV), more than any other drug developer in 2013. The company’s two new chronic obstructive pulmonary disease (COPD) combination treatments, Breo Ellipta and Anoro Ellipta, are both forecast to generate multibillion dollars in annual sales. But in terms of scientific novelty, trametinib is their drug to watch.

Trametinib is a first‑in‑class MAPK/ERK kinase (MEK) inhibitor that overcame the problems of bioavailability, pharmacokinetics and toxicity that sunk its many experimental predecessors (Nature Rev. Drug Discov. 11, 819–820; 2012). However, trametinib is entering the increasingly competitive metastatic melanoma space, and analysts expect sales to be under $800 million by 2019. GSK is testing the MEK inhibitor in combination with various other therapeutics — including a BRAF inhibitor, a phosphoinositide 3‑kinase (PI3K) inhibitor,

100

50

NMEs

Sales 40

80

36

35 32 28

60

46

34

30 23

20

20

13

2004

31 30

24

40

0

27

29

29

2005

2006

2007

2008

40

33

37

20

Number of NMEs

Total peak sales (US$ billion)

consensus annual global sales forecasts from two or more analysts, compiled by Thomson Reuters Cortellis and accurate as of 2 January.) Sofosbuvir is also the third of three novel drugs approved through the new breakthrough therapy designation pathway, which was created to speed up and streamline clinical testing. Because these experimental drugs were already well advanced in development when they were granted their breakthrough designations, the new pathway probably only minimally accelerated their approval (Nature Rev. Drug Discov. 12, 891–893; 2013). Pharmacyclics and Janssen’s ibrutinib — another breakthrough-designated drug — is another highlight. The first‑in‑class Bruton’s tyrosine kinase (BTK) inhibitor, which entered the clinic in 2009, picked up its first green light for mantle cell lymphoma, an aggressive form of B cell non-Hodgkin’s lymphoma. But compelling data in other indications, including chronic lymphocytic leukaemia (CLL), are fuelling annual sales forecasts of $4.5 billion for the drug by 2019. Ibrutinib is also an irreversible kinase inhibitor. Its approval, along with that granted to afatinib earlier in the year, marks a turning point for these once-shunned irreversible agents (Nature Rev. Drug Discov. 12, 649–651; 2013). Biogen Idec’s dimethyl fumarate (formerly BG‑12) also looks set to become a clinical and commercial success. Dimethyl fumarate has a history of prior use as an approved anti-psoriasis drug in Germany and in preventing the growth of mold in furniture. Biogen Idec gave new life to this very small (with a molecular mass of only 144 Da) small molecule by getting it approved in the United States as the third oral drug for multiple sclerosis. The drug’s mechanisms of action remain unclear, but its combined efficacy and safety profile make it competitive or better

26

17 10

2009

2010

2011

2012

2013

0

Figure 2 | Aggregate peak drug sales since 2004.  Aggregate peak drug sales expectations, Nature | Drug Discovery as calculated by Boston Consulting Group (BGC). BCG’s analysis is based onReviews 36 approvals, made up of the Center for Drug Evaluation and Research (CDER)’s new molecular entities (NMEs), minus the medical imaging approvals, plus certain non-NME approvals from both the CDER and the Center for Biologics Evaluation and Research (CBER). This year, the additional approvals were: Protein Science’s Flubok; GlaxoSmithKline’s FluLaval; Forest’s Fetzima (extended-release levomilnacipran); Novo Nordisk’s NovoEight (recombinant factor VIII); Baxter’s Rixubis (recombinant factor IX); CSL’s Kcentra (Prothrombin Complex Concentrate); Cangene’s BAT (botulism antitoxin); Novo Nordisk’s Tretten (coagulation factor XIII); Takeda’s Kazano (alogliptin plus metformin); Merck’s Liptruzet (ezetimibe plus atorvastatin); Takeda’s Oseni (alogliptin plus pioglitazone); and Novartis’s Simbrinza (brinzolamide plus brimonidine tartrate). Whereas peak sales data for drugs approved in 2013 are wholly forecasted, actual peak sales data are used where available for drugs approved in earlier years.

88 | FEBRUARY 2014 | VOLUME 13

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N E W S & A N A LY S I S Table 3 | New approvals with billion-dollar potential Drugs

Company

Forecast (billions of $US)*

Sofosbuvir (Sovaldi)

Gilead

6.8‡

Dimethyl fumarate (Tecfidera)

Biogen Idec

6

Ibrutinib (Imbruvica)

Pharmacyclics

4.5

Ado-trastuzumab emtansine (Kadcyla)

Genentech

4.1

Umeclidinium and vilanterol (Anoro Ellipta)

GlaxoSmithKline

3.1

Fluticasone and vilanterol (Breo Ellipta)

GlaxoSmithKline

2.8

Pomalidomide (Pomalyst)

Celgene

1.8

Canagliflozin (Invokana)

Janssen

1.6

Obinutuzumab (Gazyva)

Genentech

1.5

Dolutegravir (Tivicay)

ViiV

1.4

Afatinib (Gilotrif)

Boehringer Ingelheim

1.3§

Macitentan (Opsumit)

Actelion

1

Alogliptin (Nesina)

Takeda

1||

*All forecasts are consensus, annual, global sales estimates for 2019, as compiled by Thomson Reuters Cortellis, except where indicated otherwise. ‡The sofosbuvir sales estimates are for 2018. §The afatinib sales forecasts are from BioMedTracker, for 2018. ||The alogliptin sales forecast is for 2017, after which the drug is forecast to lose blockbuster status.

a cytotoxic T lymphocyte antigen 4 (CTLA4) inhibitor and a cyclin-dependent kinase (CDK) inhibitor — to increase its market share and expand its label. Janssen’s canagliflozin, the first-FDA approved sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor, is entering the even more crowded type 2 diabetes space. Analysts, nevertheless, are forecasting sales of $1.6 billion for the drug by 2019. AstraZeneca and Bristol-Myers Squibb actually filed their SGLT2 inhibitor dapagliflozin before Janssen filed canagliflozin. The FDA rejected the first filing of dapagliflozin in 2012 because of a possible bladder cancer signal, but approved the drug in January 2014. Although Genzyme and Isis’s mipomersen is an innovative product, it looks set to disappoint on the commercial front. Mipomersen is the second antisense drug to be approved and the only one currently on the market. (Isis discontinued the first, fomivirsen, in 2005 when its market evaporated.) Mipomersen also acts on a novel target, binding apolipoprotein B mRNA, reducing protein synthesis and thereby lowering low-density lipoprotein (LDL) levels. But after years of setbacks the sponsors lowered their first approval hopes and settled for an LDL cholesterol-lowering green light only in the narrow orphan homozygous familial hypercholesterolaemia population. Regulators in the European Union (EU) rejected mipomersen because of its side-effect profile. Analysts forecast annual sales of around $200 million for the drug by 2019.

Only two mAbs The FDA approved only two novel monoclonal antibodies (mAbs) last year, down from six annual mAb approvals in each of the past 4 years. But, says Milne, given the emphasis on mAbs in industry’s pipeline, this change is more likely to be a “quirk than a new trend”. Genentech’s ado-trastuzumab emtansine is the third success from the growing antibody–drug conjugate (ADC) pipeline (Nature Rev. Drug Discov. 12, 329–332; 2013). The FDA approved the ADC for patients with HER2‑positive metastatic breast cancer who have already been treated with trastuzumab and a taxane. Genentech, a subsidiary of Roche, is already testing the mAb as a first-line treatment for metastatic disease and in combination with its pertuzumab, a HER dimerization inhibitor, to expand its drug label. With trastuzumab due to come off patent in the EU in 2014, Genentech’s aim is to make its older blockbuster obsolete before it faces serious competition from biosimilars. (Trastuzumab comes off patent in the United States in 2019.) Analysts predict annual sales of $4.1 billion for ado-trastuzumab emtansine by 2019. Genentech’s CD20‑targeting obinutuzumab is another oncologic biosimilar beater. The FDA approved the mAb, dubbed the ‘son of rituximab’, for previously untreated CLL. Roche’s CD20‑targeting rituximab came off patent in the EU last year and is set to come off patent in the United States in 2016.

To stave off competition in CLL at least, Genentech secured obinutuzumab’s approval by showing in a head-to-head trial that it was better than the established blockbuster rituximab. Analysts forecast annual sales of $1.5 billion for obinutuzumab by 2019. Obinutuzumab is also the first breakthrough-designated drug approved, and the first glyco-engineered mAb approved in the United States.

4%

4%

7%

30%

7%

7% 7% 11% 11%

11%

Oncology Metabolic and endocrinology Medical imaging Antivirals Cardiology Neurology Respiratory Women’s health Psychiatry Dermatology

Figure 3 | Approvals by therapeutic area. Nature Reviews | Drug Discovery

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2013 FDA drug approvals.

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