Pharma R&D Annual Review 2012

Ian Lloyd, Citeline Editorial Director

May is the time when Citelines Annual Review of trends in pharmaceutical R&D is
traditionally conducted. It is a useful opportunity to pause and reflect on how the industry is continuing to evolve, and is also the time when we take the annual snapshot of our data to provide a new timepoint for evaluating trends from our Pharmaprojects Pipeline drug intelligence service. In this article, we examine the data for 2012, look at how it has changed since 2011, and try to put the information into some sort of context. Some of the key points covered in this report include:
Sizeable growth in the overall R&D pipeline A standout year for new active substances GSK replaces Pfizer as the company with

most drugs in development niche companies

launches

Increase in R&D among start-up and Striking acceleration in oncology research

Promising growth of drugs in crucial

Phase III trials

Examining the overall number of Active drugs in the pipeline is always a good place to start, as it gives an overall flavour of the direction in which things are headed. And this year, there is a cheering increase in evidence. After the figures stagnated from 2010 to 2011, the 2012 total number of R&D drugs is up to 10,452, a 7.6% increase from last years figure. Leaving aside the 2007-2008 rise, which is something of an aberration caused by the bringing together of drug data from our original database with that of the then newly-acquired Citeline database of clinical trials (Trialtrove), this represents the largest increase in percentage terms since 2003-2004s 9.0%.

So what does this apparent pipeline growth mean? One thing which is always difficult is the teasing apart of real world changes versus the effect on the figures of improved editorial practices and detection. Clearly, we at Citeline are continuously striving to improve our processes to make our data increasingly comprehensive, and this year has been no exception. However, it seems highly unlikely that this would account for an increase as large as 739 drugs. Our best guess would be that better data collection might account for 2-3.5% of this increase, which would still leave a sizeable growth in the overall reported pipeline, not bad in an era of austerity. So our review of 2012 kicks off on a positive note, and well

Figure 1: ToTal Size oF The pipeline 2001-2012

spend much of the rest of the analysis digging deeper into drug development to look for further trends. But before we slice and dice current drug R&D, lets review the previous year in more detail, looking at those drugs which successfully completed their developmental journey. It seems there are reasons to be cheerful here, too.

entities (NCEs) or new biological entities (NBEs) where the active drug has not had prior approval for human use. As such, this list excludes reformulations of existing active moieties and thus represents a subset of the 72 drugs which we report as making their debuts during the year. While 2011s number of NASs at 33 falls below the 42

New active substances a top-notch year for novel NASs

Table 1 lists all of the new active substances (NASs) which we report as entering the market for the first time during calendar 2011, produced in conjunction with ScripIntelligence.com. NASs are defined as new chemical
Table 1: New Active Substance (NAS) Launches 2011

seen in 2010, this is still above the 10-year average of 29. But the real news is the degree of novelty exhibited by this set of drugs. Whereas the 2010 set contained just three drugs with a mechanism of action not previously approved, this years debutantes boast no fewer than 11, which, at 33% of the total, makes 2011 something of a vintage year, as Table 1 shows.

Generic name (trade name)

company

indication

mechanism of action

country of first launch

month of first launch

first in class

abiraterone (Zytiga)

Johnson & Johnson (originally licensed from BTG) Regeneron

Prostate cancer

17,20 lyase inhibitor and steroid synthesis inhibitor VEGF receptor and human IgG1 Histamine H1 receptor antagonist

US

August

Yes

aflibercept ophthalmic solution (Eylea) alcaftadine (Lastacaft)

Wet age-related macular degeneration Itching associated with allergic conjunctivitis VTE prophylaxis Male sexual dysfunction Hypertension Renal transplant rejection* Systemic lupus erythematosus

US

November

No

Allergan (licensed from Vistakon Pharmaceuticals (Johnson & Johnson)) Bristol-Myers Squibb/ Pfizer JW Pharmaceutical (licensed from Mitsubishi Tanabe Pharma) Takeda Bristol-Myers Squibb

US

March

No

apixaban (Eliquis) avanafil (Zepeed)

Factor Xa inhibitor PDE-5 inhibitor

Germany S Korea

May October

No No

azilsartan medoxomil (Edarbi) belatacept (Nulojix)

Angiotensin II receptor antagonist CD28-mediated T cell co-stimulator inhibitor BLyS inhibitor

US US

April June

No Yes

belimumab (Benlysta)

Human Genome Sciences (licensed to GlaxoSmithKline for joint development and commercialization) Faes Merck & Co Seattle Genetics

US

March

Yes

bilsatine (Drynol) boceprevir (Victrelis) brentuximab vedotin (Adcetris)

Allergic rhinitis Hepatitis-C Hodgkin's lymphoma* and anaplastic large cell lymphoma* Gram-positive infections (community-aquired pneumonia, acute skin and skin structure infections)

H1 receptor antagonist NS3 protease inhibitor CD30-directed antibody-drug conjugate Cell wall synthesis inhibitor

UK and Ireland US US

June May August

No Yes* No

ceftaroline acetate (Teflaro)

Forest Laboratories (licensed from Takeda)

US

March

No

*Orphan indication **Two first-in-class with same new MoA

Generic name (trade name)

company

indication

mechanism of action

country of first launch

month of first launch

first in class

civamide/zucapsaicin (Zuacta)

Valeant Pharmaceuticals (licensed from Sanofi (licensed from Winston Pharmaceuticals)) Pfizer

Osteorarthritis of the knee pain

Vanilloid receptor 1 agonist

Canada

August

No

crizotinib (Xalkori)

ALK-positive non-small cell lung cancer* Ovarian cancer

Anaplastic lymphoma kinase inhibitor Anti-MUC1 immunotherapy Factor Xa inhibitor Vitamin D3 receptor agonist Potassium channel agonist and GABA receptor agonist

US

August

Yes

Cvac

Prima Biomed (licensed from Biomira (now Oncothyreon)) Daiichi Sankyo Roche GlaxoSmithKline licensed from Valeant

Dubai

October

Yes

edoxaban (Lixiana) eldecalcitol (Edirol) ezogabine (Trobalt)

VTE prophylaxis Osteoporosis Epilepsy

Japan Japan Europe (Denmark, Germany, Switzerland, the UK US

July April June

No No No

fidaxomicin (Dificid)

Optimer

Clostridium difficile associateddiarrhoea Restless legs syndrome Acute myocardial infarction Non-small cell lung cancer Melanoma*

Macrocyclic antibiotic (RNA polymerase inhibitor) GABA analogue Mesenchymal stem cell therapy Epidermal growth factor receptor 1 antagonist Cytoxic T-lymphocyte associated protein-4 inhibitor DPP-IV inhibitor Dopamine D2 and 5HT2A/7 receptor antagonist Selective beta3adrenoceptor agonist Non-nucleoside reverse transcriptase inhibitor JAK 1 and 2 kinase inhibitor NS3 protease inhibitor P2Y12 ADP purinoreceptor antagonist VEGF receptor-2 (KDR/flk-1) tyrosine kinase and RET kinase inhibitor B-Raf kinase inhibitor SSRI and 5HT1A partial agonist

July

No

gabapentin enacarbil (Horizant) Hearticellgram-AMI icotinib (Conmana)

GlaxoSmithKline licensed from XenoPort Pharmicell Zhejiang Beta Pharma

US S Korea China

July July August

No Yes No

ipilimumab (Yervoy)

Bristol-Myers Squibb

US

April

Yes

linagliptin (Tradjenta) lurasidone HCl (Latuda) mirabegron (Betanis)

Boehringer Ingelheim/ Lilly Sunovion Pharmaceuticals (Dainippon Sumitomo Pharma) Astellas Pharma

Type 2 diabetes Schizophrenia

US Puerto Rico and the US Japan

May February

No No

Overactive bladder

September

Yes

rilpivirine (Edurant)

Tibotec (Johnson & Johnson) Incyte Corporation Vertex Pharmaceuticals AstraZeneca AstraZeneca

HIV/AIDS

US

September

No

ruxolitinib (Jakafi) telaprevir (Incivek) ticagrelor (Brilinta) vandetanib (Caprelsa)

Myelofibrosis* Hepatitis-C Thrombosis Medullary thyroid cancer*

US US UK US

November May January April

Yes Yes* No No

vemurafenib (Zelboraf) vilazodone (Viibryd)

Roche/Plexxikon (Daiichi Sankyo) Forest Laboratories

Melanoma with BRAF mutation* Major depressive disorder

US US

September June

No No

*Orphan indication **Two first-in-class with same new MoA

Among the refreshingly large amount of drugs with novel mechanisms becoming available to patients last year, several stand out as being real advances. Particularly exciting are two drugs which share the same mechanism, the two anti-hepatitis-C antivirals, boceprevir and telaprevir. These are HCV NS3 protease inhibitors, and represent potentially a major advance in the treatment of hepatitis-C infection, which is estimated to affect 170-200 million people worldwide. Standard HCV therapy has consisted for a number of years of combination therapy with interferon and ribavirin, but has been dogged by lower than desirable cure rates and debilitating side-effects, the latter largely due to the interferon component. These first new small molecules will initially

drug to reach the market first during 2011 which was developed along with its own companion diagnostic was Pfizers crizotinib (Xalkori), the first anaplastic lymphoma kinase inhibitor. Its CD, Abbotts Vysis ALK Break Apart FISH Probe Kit, was approved for use in certain patients with late-stage (locally-advanced or metastatic) nonsmall cell lung cancers (NSCLC) to detect whether they express the abnormal anaplastic lymphoma kinase (ALK) gene and thus are likely to respond to crizotinib therapy. Pfizer itself and several other companies are also developing CDs for crizotinib, in what seems to be an important emerging trend in the industry. One of the most significant releases for 2011 is the first drug specifically approved to treat the disease systemic lupus erythematosus (SLE), rather than just its symptoms. Human Genome Science (HGS) originated the drug belimumab (Benlysta) and jointly developed it with its partner GlaxoSmithKline, which incidentally is currently trying to acquire HGS. It is a monoclonal antibody directed against BLys, a monocyte-derived growth, and was launched in March for SLE. It is one of the 7 agents which were approved in 2011 for orphan indications, and one of four which is both an orphan drug and a first-inclass. It is also one of only 7 biologicals to go on sale during the year, a dramatic reduction from the nineteen in 2010. Notably, there were no novel anti-infective vaccine launches at all during the year, a considerable change from the flurry of flu vaccines which had hit the market during the previous 24 months. However, among these new biologicals were two interesting innovations in the cell therapy arena. South Korean concern Pharmicell successfully completed development of Hearticellgram-AMI, an autologous bone marrow derived mesenchymal stem cell therapy containing mesenchymal stem cells and cells specifically useful for heart regeneration, for the treatment of acute myocardial infarction (AMI). Unusually, it was Dubai that was the first country to approve the other cell therapy, CancerVacs autologous dendritic cell vaccine CVac. Here, a patients blood is primed with its proprietary mannan-MUC1 conjugate before being readministered to stimulate a specific immune response to the cancer antigen MUC1. This approach is approved for use in ovarian cancer and follows similar products CreaVaxRCC and Provenge to the market, these dendritic cell vaccines being launched the previous year for renal and prostate cancer, respectively.

Particularly exciting are two drugs which share the same mechanism, the two anti-hepatitis-C antivirals, boceprevir and telaprevir.
be used to up the cure rate, but they may also lead to reductions in adverse events as regimens with lower doses of interferon are explored. Indeed, the agents are the first to be approved of potentially a whole raft of new small molecules in development which, when used in combination, could eventually eliminate the need for interferon entirely. So this could be the beginning of a real game change for HCV therapy. Incidentally, both agents can genuinely be considered first-in-class, since the US FDA granted approvals to both Merck & Co (for boceprevir) and Vertex (for telaprevir) on the same day. Another disease benefitting from two new drugs last year was melanoma. First, Bristol-Myers Squibbs monoclonal ipilimumab (Yervoy) became the first cytotoxic T-lymphocyte associated protein-4 (CTLA4) inhibitor to hit the market in April, and this was followed up in September by Roche/Plexxikons B-Raf kinase inhibitor, vemurafenib (Zelboraf). Both of these drugs have orphan drug status in at least one country. While the latter is not strictly a first-in-class, it is the first B-Raf kinase inhibitor to be approved for melanoma. Also notable about this drug is the fact that it was developed and approved in tandem with a companion diagnostic (CD) - the cobas 4800 BRAF V600 Mutation Test is a PCR-based companion diagnostic assay for use with vemurafenib to identify patients whose tumours carry the mutated BRAF V600 gene. Another novel cancer

Figure 2: pipeline by phaSe, 2012 vS 2011

One further cancer drug introduced last year which has a novel mechanism is Johnson & Johnsons abiraterone (Zytiga), a 17,20 lyase and steroid synthesis inhibitor, which was brought to market for use in prostate cancer. Overall, there were eight anticancer drugs gaining their first approval in a cancer indication. Completing the set of drugs with innovative targets launching during 2011 were Incytes ruxolitinib (Jakafi), the first JAK kinase inhibitor, which was approved for myelofibrosis; BristolMyers Squibbs belatacept (Nulojix), getting the goahead for renal transplant rejection as the first CD28mediated T-cell co-stimulator inhibitor; and mirabegron (Betanis), a selective 3 adrenoceptor agonist for overactive bladder which was developed by Astellas.

The 2012 pipeline by phase growth across the board

Let us now leave 2011 in the past and focus on the current state of the pipeline, as we select a number of ways to slice the R&D pie. The first and most macro of these, is to break it down by phase, to see where in the development cycle that 7.6% growth in the number of compounds is concentrated, as Figure 2 does. What is notable about this years graph is that, leaving aside a negligible drop in the number of drugs currently awaiting registration, there is growth across all phases of development. Its true that the lions share in the increase in the total number of drugs can be found at the preclinical phase, where the rise of 551 drugs represents a big 11.7% increase. It is here that Citelines improvements in detection are probably playing their part most. It is more likely that the increases seen at the clinical phases represent genuine pipeline growth though. In particular, the jump at Phase III of 8.8% is most encouraging, coming as it does on the back of an exceptional 13% rise the previous year. Figure 3 takes a more in-depth look at trends across the three phases of clinical trials over the past five years. This pulls into focus the fact that, after a few years in the doldrums, the Phase III figure is really on the rise. In the latter part of the last decade, there was real concern about the fact that increases in the numbers of drugs at the earlier stages of clinical development were not translating through to Phase III, indicating higher attrition

Overall, there were eight anticancer drugs gaining their first approval in a cancer indication.
Bristol-Myers Squibb and GlaxoSmithKline could be said to be 2011s most successful companies in terms of NAS launches, with three each. Interestingly, all of GSKs were in-licensed, indicating a successful licensing policy at the British multinational. The US was, as usual, by far the most popular territory for drug debuts, with a massive 21 of the 33 (64%) new active substances having the US as their first market. The UK was the top European country in which to launch, but had only three products making their entrances, the same as Japan, in what was a comparatively lean year for both areas. Overall though, the industry can be pleased that the clamour for novel drug launches was addressed well in 2011.

Figure 3: CliniCal pipeline by phaSe , May 2007-May 2012

rates at Phase II and a serious issue for the industry trying to deliver new drugs. This stumbling block seems to have largely gone away in the last couple of years. There may be a hint of a tail-off in the numbers at Phase II, but any concern about this should be somewhat offset by an expansion this year at Phase I. So the longer term trend data on drugs in clinical trials is looking pretty healthy.

reflecting the fact that it has been rationalizing its global R&D, including closing its major UK R&D centre at Sandwich, Kent. It also announced in February last year a strategic shift in research and development, focusing on a smaller number of research areas where it sees the potential for greatest impact. Pfizer remains the company which originated the most drugs, however, but only holds on to the runner-up position overall due to a small drop in pipeline numbers at third-placed Merck & Co, which is now snapping at its heels. Novartis also cements its place in the exclusive 200+ club, with its 9% increase putting it right behind Pfizer and Merck. Elsewhere in the Top 10, the big news is that for the first time, we have a Japanese company joining the elite. Takeda rises five places to bask at number seven, its elevation due in no small part to its acquisition of Nycomed last September.

Top companies GSK regains its crown as top companies loosen their stranglehold
We now move to examining the pipeline by company, looking first at the biggest 25 pharma companies by pipeline size. As Table 2 shows, GlaxoSmithKline has returned to the summit after two years of being displaced by Pfizer, despite reporting a small drop in its number of R&D products. Pfizers portfolio has indeed contracted substantially, with a drop of over 20%,

Table 2: Top 25 companies by pipeline size 2012

position 2012 (2011)

company

no of r&d products 2012 (2011)

no of oriGinated products

1 (2) 2 (1) 3 (3) 4 (4) 5 (5) 6 (6) 7 (12) 8 (9) 9 (8) 10 (7)

GlaxoSmithKline Pfizer Merck & Co Novartis Hoffmann-La Roche Sanofi Takeda Bristol-Myers Squibb AstraZeneca Johnson & Johnson

257 (269) 225 (284) 223 (236) 218 (200) 198 (183) 178 (182) 149 (103) 146 (149) 144 (167) 142 (171)

147 152 150 151 147 91 80 113 85 85

position 2012 (2011)

company

no of r&d products 2012 (2011)

no of oriGinated products

11 (10) 12 (11) 13 (13) 14 (17) 15 (15) 16 (14) 17 (16) 18 (20) 19 (18) 20 (19) 21 (-) 22 (24) 23 (-) 24 (21) 25 (23)

Eli Lilly Astellas Abbott Amgen Bayer Daiichi Sankyo Eisai Teva Boehringer Ingelheim Merck KGaA Celgene Kyowa Hakko Kirin Gilead Sciences Mitsubishi Tanabe Pharma Shionogi

125 (131) 104 (108) 96 (96) 91 (68) 91 (91) 89 (93) 79 (74) 78 (48) 69 (67) 58 (62) 52 (-) 48 (42) 47 (-) 47 (45) 45 (43)

102 66 67 79 62 52 45 35 48 21 33 21 33 27 24

Elsewhere in the Top 20, Johnson & Johnson and AstraZeneca are down and Amgen is up, while Tevas purchase of Cephalon swells its pipeline by 30 drugs, but this is only enough to pull it up two places in the table. Outside the Top 20 but making their entrances into the Top 25, we find Celgene and Gilead, which replace Ligand and Dainippon Sumitomo Pharma which duck out this year. With relatively few major mergers and acquisitions, and consequently more shuffling around in position rather than wholesale changes, its instructive to look at the Top 10 as a whole and its changing relationship with the global industry. Last year, the Top 10 increased their grip on pharma R&D, with drugs originated by them accounting
Figure 4: ToTal nuMber oF CoMpanieS wiTh aCTive r&D 2000-2012

for 13.4% of the total pipeline, up from 12.4% the previous year. This year however, there has been a dramatic reversal of fortune, with this proportion sliding back significantly to 11.5%. So it appears that the big boys stranglehold has been loosened strikingly and the trend of previous years overturned. While big pharma continues to face an uncertain future, our 2012 survey reveals that there has been an unprecedented burst in the total number of companies involved in pharma R&D, as Figure 4 shows. This year we report 2,705 active companies, an increase of 318, or 13.3%, from the same point in 2011. Only in 2002-2003 has there been larger percentage growth, but

this was an increase of only 190 companies in real terms. Undoubtedly, better detection of emerging companies has played its part here, and it is interesting to note that this year, there are 953 companies with a single product in their pipeline (up from 862 last year) and 459 companies with two products in their pipeline (from 341 in 2011). This would imply that at

Figure 5: global DiSTribuTion oF CoMpanieS aCTive in pharMa r&D

least two thirds of the additional companies are new or small companies. Thus the pharma industrys tail of niche companies is getting ever longer. While a relatively quiet period for M&A is also contributed to this phenomenon, it is still notable that the global financial crisis does not seem to be significantly inhibiting the ability of companies to establish themselves. Nonetheless, we would present this continued growth of in the number of companies of being a highly positive sign for the long-term health of the industry. The vast majority of the newer companies are US-based, feeding into the general dominance of America in the pharma arena, as the pie chart of companies by HQ country in Figure 5 shows. US-based pharma and biotech companies account for half of the entire global set. Europe together has 26%, with the UK being the

single biggest contributor with just under a fifth of the continents R&D companies. The Asia/Pacific region now accounts for 19% of companies, of which Japan contributes 4%, indicating that in the emerging markets in the region, pharma R&D is still somewhat in its infancy. This will be an interesting metric to watch in the coming years.

Top therapy areas, diseases, and mechanisms of action/targets the cancer juggernaut accelerates
Moving from the companies to their therapeutic focuses, we see a striking increase in the number of compounds under development for cancer. As Figure 6 shows, while all therapeutic areas show a modest growth in their pipeline sizes, anticancers considerably outperform the typical growth rate. Indeed, now 29.5% of all R&D drugs

Figure 6: pipeline by Therapy group

have an oncology focus. The boom for cancer is back on; last year, the cancer proportion rose from 26.8% to 28% after falling back for the first time the previous year. But this years rise makes 2010 look like an aberration, with an increase of 362 drugs marking a 13.3% expansion in the cancer pipeline considerably higher than the general growth rate, and an acceleration of the growth rate. Neurologicals consolidate their position as the second most popular therapeutic area, but with just a 4.4% growth rate. Anti-infectives remain third, but as last year, the gain in this area is fairly minimal. Also included in this graph are the numbers of drugs which are new formulations of older drugs and those which are biotechderived. While the former is almost flat, the latter also shows a sizeable swell in numbers. Biotech drugs this year account for 26.7% of all R&D projects, up from

25.6%, and after a few years of languishing around the 22-23% mark, there is once again a clear trend to move into biotech. Trends in individual therapeutic categories not surprisingly reflect those seen in the previous graph, as Table 3 of the top 25 shows. Unlike in previous years, the vast majority of the leading therapeutic categories are exhibiting growth, with a handful showing little change. The only category to display a definite drop is prophylactic anti-infective vaccines, which surrender their Top 3 spot accordingly. Outside of the cancer arena, antiinflammatories post a significant surge and the related area musculoskeletal is a Top 25 newcomer this year. Biotech-related categories, such as those for recombinant drugs and monoclonal antibodies, also increase as one would expect.

Table 3: Top 25 Therapeutic Categories

position 2012 (2011)

therapy

no of r&d products 2012 (2011)

trend

1 (1) 2 (2) 3 (4) 4 (5) 5 (3) 6 (6) 7 (9) 8 (7) 9 (11) 10 (8) 11 (10) 12 (13) 13 (15) 14 (12) 15 (14) 16 (19) 17 (16) 18 (18) 19 (20) 20 (-) 21 (24) 22 (-) 23 (23) 24 (19) 25 (21)

Anticancer, other Anticancer, immunological Analgesic, other Antidiabetic Prophylactic vaccine, anti-infective Anti-inflammatory Antiviral, other Recombinant vaccine Ophthalmological Cognition enhancer Cardiovascular Immunosuppressant Recombinant, other Formulation, fixed-dose combinations GI inflammatory/bowel disorders Monoclonal antibody, human Neuroprotective Monoclonal antibody, other Antiarthritic, other Musculoskeletal Neurological Monoclonal antibody, humanized Antiparkinsonian Antiasthma Symptomatic antidiabetic

1729 (1488) 886 (773) 538 (535) 511 (507) 509 (544) 454 (410) 394 (377) 392 (399) 388 (342) 374 (382) 369 (351) 359 (326) 349 (295) 348 (331) 326 (297) 284 (251) 281 (260) 275 (250) 270 (243) 265 (-) 253 (215) 248 (-) 248 (224) 245 (245) 244 (234)

h h n n i h h n h n n h h n h h h h h h h h h n n

This year, we have also taken our examination of the therapeutic focus of the pipeline to an even more forensic level, by producing for the first time a Top 25 of individual diseases or indications. Note that Table 4 has had stripped out from it any of our very general indication terms which include the word unspecified to produce a ranking for specific diseases only. This analysis reinforces our earlier conclusions in that more than half of the Top 25 diseases are oncology indications. Breast cancer comes out top as the single most targeted disease. Type 2 diabetes, one of the fastest-growing health problems in the developing world, takes the runner-up position from prostate and colorectal cancers. Interestingly, Alzheimers disease is now the sixth most targeted indication, despite, or perhaps because of, the relative lack of success in this area.
Table 4: Top 25 Specific Indications

Interestingly, Alzheimers disease is now the sixth most targeted indication, despite, or perhaps because of, the relative lack of success in this area.
So what are the top strategies which pharma R&D is adopting? This year, we have included both a table of the top mechanisms of action (MoAs), based on our own proprietary hierarchical classification system, and one of the top protein targets assigned to drugs, per the NCBIs internationally recognized public database of genes and their protein products, Gene. The first table includes more general terms where the precise target is as yet unknown, such as Angiogenesis inhibitor and Apoptosis stimulant; the second only reports precise protein targets coded for by a single gene. Thus, in

position 2012

indication

no of r&d products 2012

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Cancer, breast Diabetes, Type 2 Cancer, prostate Cancer, colorectal Arthritis, rheumatoid Alzheimer`s disease Cancer, lung, non-small cell Pain, general Cancer, pancreatic Cancer, ovarian Cancer, melanoma Asthma Infection, hepatitis-C virus Cancer, brain Infection, HIV/AIDS Psoriasis Pain, neuropathic Parkinson`s disease Cancer, liver Cancer, myeloma Cancer, lymphoma, non-Hodgkin`s Cancer, leukaemia, acute myelogenous Cancer, renal Chronic obstructive pulmonary disease Obesity

434 355 349 332 316 312 308 295 289 263 241 219 211 198 184 176 175 174 173 167 165 154 151 145 145

Table 5, you can see that a large amount of R&D drugs are still ascribed general mechanisms, with only two of the Top 10 MoAs relating directly to a precise target. This gives a more general view of the areas in which R&D is being conducted, with many of the Top 10 mechanisms referring to general processes involved in oncogenesis. In Table 6, we zoom in to the precise targets, where we find the mu opioid receptor, a binding site for analgesics, to be the single most popular target for drug development. Its striking that the first cancer target in the listing is not found until we reach the number eight position. Thus these two tables taken in tandem demonstrate how many anticancer projects are undertaken where the precise target for the drug is as yet unknown or at least, undisclosed. This year, the total number of targets which are or have been investigated for drug development has risen to

2,384, indicating that there were 179 new targets identified and beginning investigation during the past twelve months. This is still an impressive level of innovation, but notably, is only half the amount from the previous year. But there is context here, as 2011s figure was artificially inflated by the 289 new bacterial targets which we had added to the database. Leaving these aside, and taking into account that the rate of addition has generally been around 100 per year, we are left with 2011-12 looking like a highly innovative year for the pharma industry. Focusing on protein targets solely for drugs in active development, we see more positive signs, with a jump from 1,323 to 1,404. Removing the bacterial targets from the equation, this figure had actually declined during the previous year, albeit for the first time, so it is good to see that the current pipeline once again has a greater range of targets in its sights than ever before.

Table 5: Top 20 Mechanisms Of Action

position 2012 (2011)

mechanism of action (pharmacoloGy)

no of r&d products 2012 (2011)

% pr/r/l*

1 (1) 2 (2) 3 (3) 4 (4) 5 (5) 6 (10) 7 (6) 8 (7) 9 (9) 10 (13) 11 (14) 12 (11) 13 (16) 14 (12) 15 (8) 16 (-) 17 (-) 18 (15) 19 (17) 20 (18)

Immunostimulant Angiogenesis inhibitor Apoptosis stimulant Immunosuppressant Cell cycle inhibitor Opioid mu receptor agonist Protein kinase inhibitor DNA inhibitor Cyclooxygenase 2 inhibitor Mitotic inhibitor Cyclooxygenase 1 inhibitor Tyrosine kinase inhibitor (TKI) Tubulin inhibitor Vascular endothelial growth factor (VEGF) receptor antagonist Protease/peptidase inhibitor Corticosteroid agonist Tumour necrosis factor alpha antagonist DNA topoisomerase II inhibitor PI3 kinase inhibitor Sodium channel antagonist

1191 (1127) 198 (206) 158 (180) 150 (148) 142 (131) 120 (93) 119 (131) 102 (98) 101 (95) 81 (73) 81 (72) 81 (89) 79 (69) 77 (79) 76 (95) 76 (-) 75 (-) 71 (72) 68 (69) 67 (68)

7 9 8 29 15 24 18 19 30 15 30 20 14 16 39 42 16 24 0 30

*% of drugs with this activity in Pre-registration, Registered or Launched

Table 6: Top 25 Drug Protein Targets

position 2012

[except where italicized, added for clarity])

tarGet (official entrezGene name

no of r&d products 2012

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

opioid receptor, mu 1 prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) [COX-2] polyprotein, hepatitis-C virus prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase) [COX-1] nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor) gag-pol, HIV-1 opioid receptor, kappa 1 v-erb-b2 erythroblastic leukaemia viral oncogene homologue 2, neuro/ glioblastoma derived oncogene homologue (avian) [erbB2] tumour necrosis factor glucagon-like peptide 1 receptor dopamine receptor D2 insulin receptor epidermal growth factor receptor kinase insert domain receptor (a type III receptor tyrosine kinase) [VEGFR2] opioid receptor, delta 1 tubulin, beta class 1 adrenergic, beta-2-, receptor, surface estrogen receptor 1 interferon (alpha, beta and omega) receptor 2 amyloid beta (A4) precursor protein progesterone receptor mechanistic target of rapamycin (serine/threonine kinase) [mTOR] solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 [5HT transporter] androgen receptor membrane-spanning 4-domains, subfamily A, member 1 [CD20]

142 103 102 97 95 74 74 66 65 62 61 60 57 56 56 56 51 51 50 49 46 45 45 43 43

Many positive signs

So, in summing up our 2012 data, we find ourselves in the unusual position of seeing positive signs in virtually every metric. We come in off the back of an acceptable number of NAS launches sweetened by an exceptionally high level of first-in-class drugs, to find a pipeline swollen by 7.6%, with increases across all phase of development, including a sizeable one at the crucial Phase III stage. This is highly significant, as moving from Phase II to Phase III has proved to be one of the biggest hurdles for drugs to overcome in recent years. The industry is also growing in terms of the number of
ian lloyd, Editorial Director

companies involved in R&D, particularly at the level of start-up and niche companies. More drug targets are being investigated than ever before. Perhaps one note of caution might be sounded as to whether the industry is in danger of putting too many of its eggs in the oncology basket, but this seems somewhat churlish in the face of a generally positive outlook. Of course, there is a potentially apposite phrase in the warning that one swallow does not make a summer, but this just makes the prospect of next years set of data even more tantalizing. Let us see where we are in twelve months time.

Ian would like to thank Patrick Newton, Citeline Cardiovascular Drug Analyst, for producing much of the data contained in this report.

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