Citeline Pharma R&D Annual Review 2014 Supplement: New Active Substances Launched During 2013 Ian Lloyd Senior Director, Pharmaprojects/Pipeline and Data Integration

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Following on from our review of trends in the current pharmaceutical R&D pipeline, published in January 2014, this supplement takes a look at the industry’s success stories of 2013 – the drugs which were approved and launched on to the market for the first time during the year. Our survey focuses exclusively on new active substances (NASs): new chemical or biological entities where the active drug had received no prior approval for human use. As such, this list represents a subset of all the first launches which Citeline reported during 2013, excluding as it does the 54 new drug launches with reformulated or non-NAS moieties. Our 2014 Pharma R&D Report was characterized by almost universally positive trends. Pipeline size at all Phases, numbers of companies, novel targets, all had grown and at sometimes quite startling levels. But as I noted at the time, all of this simply means that the industry is spending more, until we add in the final piece of the jigsaw – the industry’s successful output. As such, the overall number of New Active Substances launches each year is a metric keenly observed by the pharma industry as an indication as to whether or not the year just passed was a ‘good year’ or not. Well, the good news seems set to continue, as it looks like 2013 bordered on vintage.

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47 NASs – an all-time high Figure 1 graphs the number of new active substances launched each calendar year since the turn of the millennium. This reveals 2013 to have been a record-breaking year, topping the previous title holder from 2010. However, there is one fairly sizeable caveat. Last year, just as in 2010, the figures are inflated by several new vaccine introductions: eleven in total, and five against influenza alone. The latter are all multivalent vaccines, containing various combinations of H1N1, H3N2 and influenza B antigens, and thus, although all novel, are more variations on a theme rather than each truly novel. In 2010, there were ten vaccines in the list, seven of which were ‘flu vaccines as the industry responded to the emerging H1N1 pandemic.

Figure 1. Number of NAS Launches by Year, 2000-2013, with Numbers Excluding Vaccines Also Shown for 2007-2013

50 45

Vaccines Other NASs

40 35

10

1

30

1

3

11

11

25 20 15 10

38

39

33

31

17

35

29

2000

2001

2002

2003

2004

2005

2006

26

31

26

34

36

36

36

2007

2008

2009

2010

2011

2012

2013

5 0

Source: Pharmaprojects , February 2014 ®

Nevertheless, even if the ‘vaccine-effect’ is stripped out, as we have shown on the graph for the years 2007-2013, 36 new active substances is still a pretty impressive tally for 2013, especially compared to some of the less remarkable outputs of some of years in the mid-2000s. Removing the vaccines also shows that there has actually been considerable consistency over the past few years in the number of non-vaccine NASs, but still has 2013 equalling the previous two years as the best so far.

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The 2013 NAS stats: quality, not just quantity The full list of NASs for 2013 appears in Figure 2. While it’s true that, as we have seen in some previous years, the overall numbers are slightly flattered by a preponderance of new vaccines, it’s the column second from the right which reassures us that last year really was a fine one. ‘First-in-class’ drugs, those where the agent is the first to be marketed with a particular mechanism of action, are more than anything else the bellwether by which the industry’s fortunes are measured. And here, the picture is also bright. No fewer than ten drugs can be considered first-in-class, and we will take a more in-depth look at this subset of drugs in the latter part of this report.

Figure 2. New Active Substance Launches 2013 Generic name

acotiamide hydrochloride

Acofide

Company

Indication

Mechanism of action

Country of first launch

Month of first launch

First in Class

Orphan Drug Status

Zeria/Astellas

Functional dyspepsia

Muscarinic M1/M2 receptor antagonist

Japan

June

No

No

Her1/Her2 antagonist

USA

Sept

No

Yes

DNA inhibitor

USA

May

No

No

USA

June

Yes

Yes

afatinib

Gilotrif

Boehringer Ingelheim

Non-small cell lung cancer with activating EGFR mutations

Alpharadin

Xofigo

Algeta/Bayer

Prostate cancer with bone metastases

bedaquiline

Sirturo

Tibotec (Johnson & Johnson)

AdenosinetriphosTuberculosis phate synthase inhibitor

cabozantinib

Cometriq

Exelixis/ Bristol-Myers Squibb

Thyroid cancer

MET, VEGFR-2, RET and VEGFR tyrosine kinase inhibitor

USA

January

No

Yes

canagliflozin

Invokana

Mitsubishi Tanabe/ Johnson & Johnson

Type 2 diabetes

Sodium/glucose cotransporter 2 inhibitor

USA

May

No

No

crofelemer

Fulyzaq

Diarrhoea in HIV/AIDS Napo Pharmaceuticals patients on ART

CF transmembrane conductance regulator antagonist

USA

April

No

No

dabrafenib

Tafinlar

GlaxoSmithKline

Melanoma

B-raf kinase inhibitor

USA

June

No

Yes

dapagliflozin

Forxiga

Bristol-Myers Squibb/ AstraZeneca

Type 2 diabetes

Sodium/glucose cotransporter 2 inhibitor

UK

January

Yes

No

dimethyl fumarate

Tecfidera

Biogen Idec

Relapsingremitting multiple sclerosis

Transcription factor Nrf2 stimulant

USA

April

No

No

dolutegravir

Tivicay

Shionogi/ GlaxoSmithKline/Pfizer

Infection, HIV/AIDS

HIV integrase inhibitor

USA

Sept

No

No

Sanofi/Merck & Co

Prophylaxis of diphtheria, tetanus, Immunostimulant pertussis, polio, HiB and hepatitis-B

No

No

DTaP-IPV-HBPRP-T vaccine

4

Trade name

Hexyon

Germany July

Figure 2. New Active Substance Launches 2013 (continued) Generic name

Trade name

Company

Indication

Mechanism of action

Country of first launch

Month of first launch

First in Class

Orphan Drug Status

Bio Farma

Prophylaxis of diphtheria, tetanus, Immunostimulant pertussis, HiB and hepatitis-B

Indonesia August

No

No

Breo Ellipta

GlaxoSmithKline/ Theravance

Chronic obstructive pulmonary disease

Corticosteroid agonist

USA

October

No

No

ibrutinib

Imbruvica

Pharmacyclics/ Johnson & Johnson

Mantle cell lymphoma

Bruton's tyrosine kinase inhibitor

USA

Nov

Yes

Yes

influenza vaccine, inactivated quadrivalent

Fluarix Tetra

GlaxoSmithKline

Influenza virus prophylaxis

Immunostimulant

USA

Sept

No

No

influenza vaccine, live attenuated quadrivalent

FluMist quadrivalent

AstraZeneca

Influenza virus prophylaxis

Immunostimulant

USA

July

No

No

influenza vaccine, seasonal quadrivalent

FluLaval quadrivalent

GlaxoSmithKline

Influenza virus prophylaxis

Immunostimulant

USA

Nov

No

No

influenza vaccine, seasonal recombinant

Flublok

Protein Sciences

Influenza virus prophylaxis

Immunostimulant

USA

Sept

No

No

influenza vaccine, spilt-virion quadrivalent

Fluzone QIV

Sanofi

Influenza virus prophylaxis

Immunostimulant

USA

Sept

No

No

insulin degludec

Tresiba

Novo Nordisk

Type 1 & 2 diabetes

Long-acting insulin

UK

March

No

No

istradefylline

Nouriast

Kyowa Hakko Kirin/Roche

Parkinson’s disease

Adenosine A2a receptor antagonist

Japan

May

No

No

itolizumab

Alzumab

Biocon

Psoriasis

CD6 antagonist

India

August

Yes

No

Japanese encephalitis virus vaccine

JENVAc

Bharat Biotech

Japanese encephalitis virus prophylaxis

Immunostimulant

India

October

No

No

lixisenatide

Lyxumia

Zealand/Sanofi

Type 2 diabetes

Glucagon-like peptide 1 agonist

UK

March

No

No

lobeglitazone

Duvie

Chong Kun Dang

Type 2 diabetes

Peroxisome proliferator-activated receptor alpha/ gamma agonist

S Korea

October

No

No

Microsomal trigylceride transfer protein inhibitor

USA

January

Yes

Yes

DTP-HB-Hib vaccine, Bio Farma

Pentabio

fluticasone furoate + vilanterol*

lomitapide

Juxtapid

Aegerion

Homozygous familial hypercholesterolaemia

lorcaserin hydrochloride

Belviq

Arena

Obesity

5 Hydroxytryptamine 2C receptor agonist

USA

June

No

No

Loxosceles Immune F(Ab)2, Instituto Bioclon

Reclusmyn

Bioclon

Brown recluse spider envenomation

Immunostimulant

Mexico

Sept

No

No

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Figure 2. New Active Substance Launches 2013 (continued) Country of first launch

Month of first launch

First in Class

Orphan Drug Status

Endothelin A & B receptor antagonist

USA

Nov

No

Yes

Meningococcal/ Haemophilus influenza infection

Immunostimulant

USA

Dec

No

No

Amgen

Lipodystrophy

Leptin receptor agonist

Japan

July

No

Yes

ApoB-100 inhibitor

USA

March

Yes

Yes

Generic name

Trade name

macitentan

Opsumit

Actelion

Pulmonary arterial hypertension

meningitis C/Y + Hib vaccine

MenHibrix

GlaxoSmithKline

metreleptin

Myalept

Company

Indication

Mechanism of action

mipomersen sodium

Kynamro

Isis Pharmaceuticals/Sanofi

Homozygous familial hypercholesterolaemia

mite allergy therapeutic

Acarovac Plus

Allergy Therapeutics

Mite allergy

Immunosuppressant

Spain

October

No

No

Sinovac Biotech

Mumps prophylaxis

Immunostimulant

China

February

No

No

mumps vaccine ocriplasmin

Jetrea

ThromboGenics/Novartis

VitreomacuPlasmin stimulant lar adhesion

USA

January

Yes

No

ospemifene

Osphena

Hormos Medical (QuatRx)

Selective estrogen Dyspareunia receptor modulator

USA

May

No

No

pomalidomide

Pomalyst

Celgene

Multiple myeloma

Angiogenesis inhibitor

USA

May

No

Yes

riociguat

Adempas

Bayer

Pulmonary arterial hypertension

Guanylate cyclase stimulant

Canada

Sept

No

Yes

racotumomab

Vaxira

CMI/Recombio

Small cell lung cancer

Immunostimulant

Argentina

May

No

No

Peroxisome proliferator-activatIndia ed receptor alpha/ gamma agonist

Sept

No

No

saroglitazar

Lipaglyn

Zydus Cadila

Diabetic dyslipidemia and hypertriglyceridemia

simeprevir

Olysio

Medivir/ Johnson & Johnson

Hepatitis-C infection

HCV NS3 protease inhibitor

Canada, Japan & USA

Dec

No

No

sofosbuvir

Sovaldi

Gilead

Hepatitis-C infection

HCV-NS5B polymerase inhibitor

USA

Dec

Yes

No

teduglutide

Gattex

NPS Pharmaceuticals/ Takeda

Short bowel syndrome

Glucagon-like peptide 2 agonist

USA

February

Yes

Yes

trametinib

Mekinist

GlaxoSmithKline

Melanoma

MEK inhibitor

USA

October

Yes

Yes

trastuzumab emtansine

Kadcyla

Genentech (Roche)/ ImmunoGen

Breast cancer

Microtubule inhibitor

USA

March

No

No

typhoid conjugate vaccine

Typbar-TCV Bharat Biotech

Typhoid prophylaxis

Immunostimulant

India

August

No

No

*vilanterol is the NAS here Source: Pharmaprojects ®, February 2014

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Figure 3 breaks down the NASs drugs by the major Therapeutic Group to which each belongs. Anti-infectives took over from anticancers last year as the therapeutic group with the largest number of NASs, although as happened in 2010, the figures are fattened by a number of influenza vaccines (five) and by vaccines as a whole (eleven). This led cancer to once again generate the most novel molecules, although the oncology yield, at nine drugs, is down on the fourteen seen in 2012. In contrast, the Alimentary/Metabolic area had a bumper year, itself producing ten NASs, focused unsurprisingly on the diabetes arena. It was another troubling year for Neurology though; last year, the second largest therapeutic area in terms of pipeline size could only deliver a paltry two new drugs to the market, even worse than the three seen the previous twelve months. Something of renaissance for Cardiovascular this time though – entirely absent in 2012, it produced five new drugs based around dyslipidaemia and pulmonary arterial hypertension.

Figure 3. 2013 NAS Launches by Therapeutic Group

2

1 1

Alimentary/Metabolic Cardiovascular

10

Dermatological Genitourinary

9

Immunological Anti-infective

5

Anticancer Neurological Respiratory

1 1

2

15

Sensory

Source: Pharmaprojects ®, February 2014

No change though, in which country led the way in terms of hosting the most NAS first launches, with the USA’s hegemony intensified this year and accounting for almost two in every three introductions, as shown in Figure 4. Europe’s presence here appears to have waned, to the benefit of the rest of the world. This year, almost a quarter of first launches took place is this set of non-traditional markets, with a diverse range of territories featuring, including Indonesia, China, and a number in India.

Figure 4. 2013 NAS Launches by Region

Japan

4

RoW Europe USA

11

29 5 * NB: The NAS first launched in Canada, Japan and USA has been counted in each set of figures Source: Pharmaprojects ®, February 2014

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In terms of the most successful company, GlaxoSmithKline would appear to be the clear winner here, being behind seven of the NASs, although again, vaccines cloud the issue, accounting for three of the company’s successes. Elsewhere, two other Top 10 pharma companies have involvement in four NAS launches each. Johnson & Johnson and its subsidiaries came to this particular party, buoyed by some shrewd in-licensing, and is joined by Sanofi. But Pfizer almost misses out entirely, only showing up all as part of the ViiV Healthcare joint-venture it contributes to with GSK to develop the two companies’ anti-HIV franchises. Among the Top 10 pharma companies in terms of pipeline size, all of which are represented in this list, this gives Pfizer the worst NAS launch to pipeline size ratio in 2013.

The novel NASs of 2013 So let us turn to the drugs themselves, and focus particularly on the novel NASs. With ten drugs falling into this class, 2013 fell just shy of 2012’s impressive twelve, but this still made it an extremely good year. One of the most exciting prospects is Gilead’s Sovaldi (sofosbuvir) for hepatitis-C. It’s beginning to look as though, as the nineties are remembered as the years which revolutionized HIV/AIDS treatment with the introduction of combination therapy HAART, this decade will be the one where a paradigm shift occurs in HCV therapy. We are the midst of a move away from the unpleasant and patchily effective interferon-α/ ribavirin regimens, into a bright new interferon-free future, with effective and well tolerated oral combination therapies hitting the virus at a number of targets. Sovaldi adds another one of these, the viral NS5B polymerase, to the armoury. Not only this, but Sovaldi is expected to become something of a blockbuster with some analysts forecasting up to $5 billion in sales this calendar year. It joins the two NS3 protease inhibitors, Victrelis and Incivek, which were launched in 2011, which were themselves joined during the year by a third drug hitting the same target, Medivir/Tibotec’s Olysio (simeprevir). This means that there are now four of these new generation of oral small molecule drugs on the market, and importantly, a second target. So at last, we are probably not far away from simple, oral, multitarget based combination therapies, similar to those which have revolutionized AIDS – with the added benefit that hepatitis-C therapy can be curative. Sticking with infections – and with Tibotec – another novel NAS this year is Sirturo (bedaquiline). This drug is a welcome additional option in the fight against a disease which had been well treated by anti-infective combination therapy until a few years ago, but is now bedevilled by multidrug resistant (MDR) strains and is therefore making an unwelcome comeback: tuberculosis. It is approved specifically for use in MDR TB, and targets the mycobacterial ATP synthase oligomeric subunit c. It is also one of the many NASs to come to the market with orphan drug status this year, a topic which we will return to later. It may have surrendered its lead as top NAS provider to infectious disease thanks to the vaccines, but cancer remains a leader in providing novel drugs. Last year, it produced two novel NASs, with kinases coming to the fore as targets – a measure of how much more we now understand about the disease processes which trigger and fuel cancer. Chief among these is GlaxoSmithKline’s Mekinist (trametinib), the first MEK (mitogen-activated protein kinase kinase) 1 and 2 inhibitor, which was launched in the US as an orphan drug for melanoma. It was a good year for this dangerous skin cancer, with another new therapy, the B-raf kinase inhibitor Tafinlar (dabrafenib) also debuting in the US. The second novel oncological NAS is Imbruvica (ibrutinib), jointly-developed by Pharmacyclics and Janssen (Johnson & Johnson). This is a small molecule selective Bruton’s kinase inhibitor, launched late in the year in the US for mantle cell lymphoma, a subtype of non-Hodgkin’s lymphoma. This drug not only has orphan drug status but additionally has breakthrough therapy status, joining the aforementioned Sovaldi as the only two drugs to receive this newer expedited review designation which was introduced during 2013.

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As noted earlier, it was a stellar year for Alimentary/Metabolic drugs, lit up particularly by a dazzling five new diabetes therapeutics. Of these, Bristol-Myers Squibb/AstraZeneca’s Forxiga (dapagliflozin) was the novel one, the first sodium/glucose cotransporter 2 inhibitor to the market, launching in the UK back in January. Hot on its heels in May came Invokana (canagliflozin), the second drug in this class, from Mitsubishi Tanabe and Johnson & Johnson. The market for these SGLT2 inhibitors looks set to get ever more crowded: since the turn of the year, Astellas’ ipragliflozin has been approved in Japan, where Roche’s tofogliflozin and Taisho’s luseogliflozin are awaiting approval too. Meanwhile, empagliflozin from Boehringer Ingelheim is in the regulatory queue in the US. In the related area of hypercholesterolaemia, there were actually two first-in-class drugs: Juxtapid (lomitapide) and Kynamro (mipomersen sodium). Both have been approved initially for the relatively narrow indication of homozygous familial hypercholesterolaemia, with the former a microsomal triglyceride transfer protein inhibitor, and the latter an ApoB-100 inhibitor. Kynamro is also interesting by dint of being an antisense therapy. Isis Pharmaceuticals, the developer of Kynamro, launched the first ever antisense therapy, Vitravene, in 1998, but was forced to withdraw it for commercial reasons following the dwindling in the numbers of cases of opportunistic cytomegalovirus retinitis brought about by successful HAART in HIV/ AIDS patients. It must therefore be delighted to return antisense therapy to the family of successfully marketed drug types, particularly as this class of drugs has had a somewhat chequered history. Biocon’s Alzumab (itolizumab) for psoriasis distinguishes itself in a couple of ways. Firstly, not only does it have a novel mechanism as the first CD6 antagonist, but it appears to have no visible competitors as such in the pipeline: the only other drugs targeting this antigen have ceased development. Secondly, it is a new active substance developed by an Indian company, still something of a comparative rarity. We expect new molecules originating in developing countries such as India or China to become increasingly common as the decade continues. Completing the ten novel NASs are Thrombogenics and Novartis’ Jetrea (ocriplasmin), a plasmin stimulant for the treatment of vitreomacular adhesion; and NPS Pharmaceuticals/Takeda’s Gattex (teduglutide), a glucagon-like peptide 2 agonist for short bowel syndrome. As well as the ten first-in-class drugs, three drugs in the table are those which have a mechanism of action which has been launched before, but are the first example of this mechanism being used to treat their particular disease target. These are Fulyzaq (crofelemer), the first CF transmembrane conductance regulator antagonist to be used in diarrhoea; Belviq (lorcaserin hydrochloride), a 5-HT2C agonist for obesity; and Adempas (riociguat) a guanylate cyclase stimulant for the therapy of pulmonary arterial hypertension.

We are the midst of a move away from the unpleasant and patchily effective interferon-α/ribavirin regimens, into a bright new interferon-free future, with effective and well tolerated oral combination therapies hitting the virus at a number of targets. 9

Another bumper batch of orphan drugs As well as novelty, we have also recorded this year in our table which of the 47 NASs have been approved for diseases for which they have orphan drug status. There are a twelve such orphan drugs from 2013, not quite reaching the heights of 2012’s fourteen, but very much confirming the trend for companies to focus increasingly on drugs for niche diseases, for which they can frequently command a high price. The performance of biotech drugs was also in-line with that seen last year. With ten biotech drugs among the NASs, we saw the same number as in 2012, although biotech’s contribution as a % fell slightly to 21%, slightly below but still broadly similar to the proportion of the overall pipeline which is covered by biologicals. So 2013 saw a record-breaking number of NASs, impressive novelty, and even the possibility of a good old-fashioned blockbuster in the shape of Gilead’s Sovaldi. Not much to complain about there then, and coming on the back on the almost entirely upward-facing statistics from our earlier Pharma R&D Annual Report, arguably the best set of statistics which a single year has produced to date. Yet the nagging doubt remains that pipeline size growth, and therefore, expenditure, continues to expand at a higher rate than NAS product, and thus new revenue, generation. Whilst it might seem contrary to kick the industry in a successful year, it really should be reaping proportionally as much as it sows. Still 47 NASs is undoubtedly impressive. In cricket, when a batsman reaches the landmark of 50 runs, it is customary for them to pause, raise their bat aloft, and acknowledge the crowd’s warm applause for reaching such a notable score. The pharmaceutical industry may not quite be there yet, but will be heading to the pavilion viewing its knock during 2013 as a pretty decent innings. Thanks to Alexandra Shimmings of Scrip Intelligence, and Michael Lanthier from the Office of Planning at the U.S. Food and Drug Administration (FDA), for help in compiling and refining the NAS list.

Yet the nagging doubt remains that pipeline size growth, and therefore, expenditure, continues to expand at a higher rate than NAS product, and thus new revenue, generation.

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