Steady Course Or Changing Tides? 2015 Trial Starts 2016 Clinical Trials Roundup – Steady Course Or Changing Tides?

2016 Clinical Trials Roundup Steady course or changing tides? 2015 Trial Starts 2016 Clinical Trials Roundup – Steady course or changing tides?

Welcome to this year’s roundup where we’ll review clinical trials that initiated in 2015 to elucidate any ongoing, or new, trends within the world of pharma R&D. Here we’ll provide a high-level overview of trial activity, focused on the six major therapeutic areas (TAs) of autoimmune/inflammation, cardiovascular, CNS, infectious disease, metabolic/endocrinology, and oncology, with metrics by TA, trial phase, and disease. We’ll then zoom in on the most active industry sponsors, including a closer look at how they may (or may not be) maximizing their assets. Now, let’s take a look at the new clinical research from 2015, and see how the course of pharma R&D fared.

Doro Shin, MPH Principal Analyst, Infectious & Genitourinary Diseases Manager, Thought Leadership Program

2 April 2016 © Informa UK Ltd 2016 (Unauthorized photocopying prohibited.) Rounding up the 2015 debuts Similar to years past, this annual roundup will hone in on unapproved drug3 clinical research, which comprised Approximately 4,900 Phase I-III trials started in 2015 2,769 of trials starting in 2015 (57%). Involvement across the six TAs.1 Industry sponsors2 were involved from the industry is increased as 77% of trials initiated in the majority of these trials (2934 of 4895 trials, in 2015 with an unapproved drug is linked to an 60%), particularly in autoimmune research (487 of industry sponsor (2143 of 2769 trials). Again, 668 trials, 73%). Oncology had the lowest rate and autoimmune has the largest industry participation (383 just over half of cancer trials included an industry of 424 trials, 90%) while oncology has the lowest (750 sponsor (1110 of 2080 trials). However, there was no of 1064 trials, 70%). (Figure 1) lack of activity for oncology as the therapeutic area clearly leads in absolute trial numbers and comprised Figure 2 provides a more granular look at the 42% of all initiated studies in 2015 (2080 of 4895 unapproved drug trials starting in 2015 with a trials). (Figure 1) breakdown by trial phase for each TA. Trial counts were

Figure 1. Phase I-III Clinical Trials Started in 2015 by Sponsor Type and Drug Status

1200 Unapproved Drug: Non-Industry Unapproved Drug: Industry 1000 Approved Drug: Non-Industry 314 Approved Drug: Industry 800 656 600

41 Trial Count Trial 400 79 750 116 53 395 35 200 360 226 383 140 136 296 253 111 103 104 110 87 134 0 73 72

CNS

Oncology InfectiousDisease Metabolic/ Autoimmune/ Cardiovascular Source: Trialtrove February 2016 Inﬂammation Endocrinology

1Trial counts as of February 11, 2016 and reflects initiated trial activity publically disclosed up to the data pull date. Also, trials that include multiple indications across different therapeutic areas will be counted for each TA it targets. As such, the sum of trial counts for the six TAs will be higher than the total number of Phase I-III trials started in 2015. 2Excludes companies developing generics as well as the generics business of any industry sponsors (i.e. Novartis’ Sandoz or Teva’s generics arm). 3Unapproved drugs have not received regulatory approval for any indication. This excludes drugs that were approved for an initial indication, but are unapproved for additional indications in other patient populations. slightly lower for nearly all TAs in comparison to last of the smaller therapy groups, making up only 7% of year, although this could partially be attributed to an the pipeline.4 earlier data cutoff date. The exceptions were infectious Oncology trial initiations were mostly early stage disease and oncology, both of which had slightly research, with nearly 2/3 of studies in Phase I (42%) to higher trial counts for 2015 in comparison to 2014. I/II (20%). In contrast, only 9% of new cancer trials As usual, oncology continued to reign as the leading were Phase III, which is the lowest percentage across TA by far, with over twice the trials for the runner up, the TAs. The distribution of phases was generally CNS. Cardiovascular research was the least active weighted toward earlier stages of development, which with only 169 unapproved drug trials starting in is in line with the nature of clinical R&D, and Phase I 2015. These trends in trial starts by TA parallel the comprised the largest percentage of initiated trials for makeup of the R&D pipeline by therapy group, which all TAs except autoimmune. Unlike other TAs, was outlined in Ian Lloyd’s recent Pharma R&D autoimmune started an equal number of Phase I and Annual Review. Nearly a third of 2015’s drugs in II trials in 2015. Autoimmune also had the highest active development were anticancer and percentage of Phase III research (25%), so research neurologicals were close to the top, but at a distant within this TA isn’t quite as heavily concentrated in 18% of the pipeline. Cardiovascular drugs were one earlier trial phases. (Figures 2, 3b)

Figure 2. Clinical Trials Started in 2015 with an Unapproved Drug

Phase I Phase I/II Phase II Phase II/III Phase III

Oncology (ONC)

CNS

Autoimmune/Inﬂammation (AI)

Infectious Disease (ID)

Metabolic/Endocrinology (MET)

Cardiovascular (CV)

0 200 400 600 800 1000 1200

Source: Trialtrove February 2016 Trial Count

4The Pharmaprojects Pharma R&D Annual Review 2016, which provides a detailed review of trends in pharmaceutical R&D in 2015, is available to download for free at https://citeline.com/category/whitepapers/.

4 April 2016 © Informa UK Ltd 2016 (Unauthorized photocopying prohibited.) The distribution of phases for each TA remained showed the largest change as the proportion of early relatively consistent between 2014 and 2015, although stage research initiated in 2015 decreased by 11% from some shifts were observed. For the most part, phase 2014, while Phase II and III studies increased by 3% distributions were the same or only differed by +/- 5%. and 7%, respectively. Cardiovascular showed the second CNS’ pipeline has seemingly matured as the early stage largest change, primarily in the percentage of Phase III research that was initiated in 2014 progressed in trial initiations which decreased by 8% in 2015. In turn, development, while the balance of cardiovascular proportions increased slightly for Phase I through II/III, research has downshifted to earlier stages. CNS trials with the largest rise seen in Phase I/II. (Figure 3)

Figure 3a. Distribution of Phases of Unapproved Drug Trials per Therapeutic Area in 2014

Phase I Phase I/II Phase II Phase II/III Phase III 100 7% 16% 16% 15% 1% 25% 21% 2% 2% 2% 80 1% 27% 1% 26% 25% 27% 22% 60 29% 20% 4% 5% 9% 6% 40 6%

52% % Trials Per TA Per % Trials 51% 48% 49% 20 39% 45%

0 AI CV CNS ID MET ONC

Figure 3b. Distribution of Phases of Unapproved Drug Trials per Therapeutic Area in 2015

Phase I Phase I/II Phase II Phase II/III Phase III

100 9% 14% 25% 23% 21% 17% 2% 2% 80 3% 2% 1% 2% 23% 27% 25% 31% 60 29% 33% 8% 20% 7% 4% 5% 40 6%

% Trials Per TA Per % Trials 53% 20 41% 45% 46% 42% 33%

0 AI CV CNS ID MET ONC Source: Trialtrove February 2016

© Informa UK Ltd 2016 (Unauthorized photocopying prohibited.) April 2016 5 When looking at trial counts for specific diseases,5 it’s diabetes, pain (nociceptive and neuropathic), and no surprise to see various cancers dominating the top HIV. Also, trial counts for hypertension and indications. In fact, all but five of the 15 diseases with dyslipidemia warrant inclusion among the top 25 the largest trial counts are in oncology. Unspecified diseases, even though cardiovascular was the least solid tumor sits at the top, largely driven by the vast active TA overall. The bulk of cardiovascular research number of Phase I trials, and non-small cell lung appears to be driven by these two indications as a cancer (NSCLC) follows. Both rankings are consistent total of 81 trials were started for hypertension and/or with prior reviews, but respiratory infection studies dyslipidemia in 2015 (6 studies included both, data climb to third place from last year’s sixth place. Other not shown), or 48% of all cardiovascular clinical common non-oncology indications include type 2 research. (Figure 4)

Figure 4. Top 25 Diseases by Trial Count

Unspeciﬁed Solid Tumor NSCLC Respiratory Infections Breast Cancer Non-Hodgkin's Lymphoma Type 2 Diabetes Pain (nociceptive) Acute Myelogenous Leukemia HIV Ovarian Cancer Renal Cancer Melanoma Head/Neck Cancer Colorectal Cancer Pain (neuropathic) Alzheimer's Disease Phase I Asthma Phase I/II Rheumatoid Arthritis Phase II Psoriasis Phase II/III Diabetic Complications Phase III Hypertension HCV Depression Osteoarthritis Dyslipidemia COPD 0 50 100 150 200

Source: Trialtrove February 2016 Trial Count

5Trial counts by disease represent each study that includes the specified indication, including studies that target multiple indications. As such, trials that include more than one disease will be counted for each indication.

6 April 2016 © Informa UK Ltd 2016 (Unauthorized photocopying prohibited.) Leading captains at the helm companies disclosed 15 trials starting in 2015 each (data not shown). The 20 most active companies were linked to 842 of the 2,769 unapproved drug studies, which is nearly a The balance between early and late stage research third.6 These top sponsors are presented in Figure 5 varied among this cohort of companies, but Phase I with AstraZeneca leading for the third year in a row, research comprised the largest number of trial starts for followed by Johnson & Johnson, Roche, and then the 15 of the 20 top sponsors. Phase II was the largest prior champion of years past, Novartis. The top 20 has number of trials for Novartis (20) and Merck (12), al- changed a bit compared to the prior year as though Phase I research closely followed for Merck (11). Sumitomo, Teva, and Regeneron enter while Astellas, The three companies at the tail end of the top 20, Daiichi Amgen, and Novo Nordisk have exited. However, both Sankyo, Teva, and Regeneron, all had Phase III as the Astellas and Amgen just missed the mark, as these largest amount of their initiated trial activity. (Figure 5)

Figure 5. Top 25 Industry Sponsors by Number of Clinial Trials Started in 2015 with an Unapproved Drug

AstraZeneca Johnson & Johnson Roche Novartis Eli Lilly Pﬁzer Gilead Sciences Takeda GlaxoSmithKline Celgene Merck & Co. AbbVie

Bristol-Myers Squibb Phase I Sanoﬁ Phase I/II Bayer AG Phase II Boehringer Ingelheim Phase II/III Sumitomo Dainippon Pharma Phase III Daiichi Sankyo Teva Regeneron 0 20 40 60 80 100 120

Source: Trialtrove February 2016 Trial Count

6Similar to disease counts, the trial counts by sponsor represent each study that the sponsor was involved in, including collaborative research. Trials that include multiple sponsors will be counted for each company.

© Informa UK Ltd 2016 (Unauthorized photocopying prohibited.) April 2016 7 The distribution of TAs also varied, and some to focus efforts on specific areas. Since oncology appeared to have more diverse interests than others. accounted for the lion share of new clinical research in Diversity was more common among the most active 2015, it follows that it was the primary focus for most sponsors; 8 of the top 10 started at least one trial in companies in this cohort – 13 of the top 20 started each of the six major TAs. Despite efforts in multiple the largest percentage of their trials for anticancer areas, these companies did typically favor a single TA therapies. Other priority TAs were autoimmune, CNS, and demonstrate focus within a diverse pipeline. On and infectious disease. Neither cardiovascular nor the other hand, eleven of the top 20 did not initiate a metabolic comprised the largest proportion of trial single trial in one or more of the six major TAs, opting starts for any of these companies. (Figure 6)

Autoimmune Figure 6. Distribution of Therapeutic Areas for Top Sponsors Starting Unapproved Drug Trials in 2015

Autoimmune Cardiovascular CNS Infectious Disease Metabolic Oncology

AstraZeneca Johnson & Johnson Roche Novartis Eli Lilly Pﬁzer Gilead Sciences Takeda GlaxoSmithKline Celgene Merck & Co. AbbVie Bristol-Myers Squibb Sanoﬁ Bayer AG Boehringer Ingelheim Sumitomo Dainippon Pharma Daiichi Sankyo Teva Regeneron 0 20 40 60 80 100

Source: Trialtrove February 2016 % Trials Per Sponsor

8 April 2016 © Informa UK Ltd 2016 (Unauthorized photocopying prohibited.) For an alternate view of leaders in trial activity, Table 1 second. AstraZeneca is also most prolific for presents the top sponsors by trial count for each of autoimmune and oncology (same ranking as the prior the major TAs. The most prolific sponsors in year), and third place for cardiovascular, consistent autoimmune, infectious disease, and oncology are with the company’s overall ranking in trial counts. also among the most active companies overall, Some shake ups did take place when comparing however, some non-top 20 companies do make an rankings between 2014 and 2015. J&J took over the appearance in the remaining TAs: Chong Kun Dang for leading position for both CNS and infectious disease cardiovascular, Biogen for CNS, and Novo Nordisk and from 2014’s leaders of Pfizer and BMS, respectively. Lexicon for metabolic. Notably, metabolic is the only Pfizer, however, rose in the ranks within TA where a non-top 20 company takes the number cardiovascular, stealing the lead from the prior year’s one spot as Novo Nordisk holds onto their trophy for three way tie between Bayer, Boehringer Ingelheim the third year in a row, but AstraZeneca is a close and Eli Lilly.

Table 1. Top Sponsors per Therapeutic Area for Unapproved Drug Trials starting in 2015

Autoimmune/Inflammation Cardiovascular CNS (n = 425) (n = 169) (n = 474) Sponsor Trials Sponsor Trials Sponsor Trials AstraZeneca 28 Pfizer 8 Johnson & Johnson 30 GlaxoSmithKline 19 AstraZeneca 6 Pfizer 16 Johnson & Johnson 14 Chong Kun Dang 6 Eli Lilly 15 Sanofi 13 Bayer AG 6 Takeda 10 Regeneron 11 Takeda 5 Biogen 10

Infectious Disease Metabolic/Endocrinology Oncology (n = 414) (n = 306) (n = 1064) Sponsor Trials Sponsor Trials Sponsor Trials Johnson & Johnson 29 Novo Nordisk 12 AstraZeneca 64 Gilead Sciences 25 AstraZeneca 11 Roche 52 Merck & Co. 16 Eli Lilly 10 Novartis 40 GlaxoSmithKline 12 Lexicon Celgene 27 9 Pharmaceuticals Bristol-Myers Squibb 12 Eli Lilly 23 Takeda 7 Source: Trialtrove February 2016

© Informa UK Ltd 2016 (Unauthorized photocopying prohibited.) April 2016 9 Down to disease – the top 20 edition primarily Phase III for asthma, HCV, and COPD. Nociceptive pain also had a high number of Phase III Similar to the overall disease rankings, unspecified studies, but was evenly balanced by the same solid tumor and NSCLC were the most common for number of Phase I trials (9 each). the top 20 sponsors (Figure 7), and nearly all initiated at least one study for both indications. The exceptions The most popular diseases for this cohort generally were Teva, J&J, and Regeneron, but they remained mirrored interests reflected by the overall trial counts, involved in other anticancer research. Phase I trials and only two indications differed from the top diseases were also common for the top diseases from this across all unapproved drug research. Instead of cohort, especially for unspecified solid tumor (78%), neuropathic pain and diabetic complications, the most Alzheimer’s (68%), and colorectal cancer (68%). A active companies demonstrated a greater interest in few indications appear to have more matured HCV and COPD. (Figure 7) A few rankings changed when compounds in their pipelines and trial activity was comparing Figures 4 and 7, some more noticeable than

Figure 7. Top Diseases for Unapproved Drug Trials Started in 2015 by the Most Active Industry Sponsors*

Unspeciﬁed Solid Tumor NSCLC Breast Cancer Respiratory Infections Non-Hodgkin's Lymphoma

HIV Asthma HCV Renal Cancer Head/Neck Cancer Alzheimer's Disease Rheumatoid Arthritis

Ovarian Cancer Phase I Melanoma Phase I/II COPD Phase II Type 2 Diabetes Phase II/III Phase III Pain (nociceptive) Acute Myelogenous Leukemia Colorectal Cancer Psoriasis 0 10 20 30 40 50 60 70 80

*Set of sponsors determined by total count of unapproved drug trials starting in 2015 Trial Count Source: Trialtrove February 2016

10 April 2016 © Informa UK Ltd 2016 (Unauthorized photocopying prohibited.) others. For instance, type 2 diabetes, which ranked 6th Oncology stands as a key priority, particularly for overall (and first in 2014), fell to number 16 for this AstraZeneca, Roche, and Novartis’ who all included cohort as they initiated only 21% of all 2015 type 2 different cancers as their top diseases. The NSCLC diabetes studies. This decreased level could be due to arena rapidly grew and was a key indication for 11 the number of trials initiated in 2014 that are still companies in 2015 (up from 4 in 2014). Interestingly, ongoing, or possibly because of the flurry of regulatory it appears that the Japanese based Takeda turned activity in 2015. Two new active substances were their honed focus from anticancer therapy to a more launched in Japan for type 2 diabetes7 and the FDA diverse portfolio of indications, starting trials across approved several drugs from Novo Nordisk, Eli Lilly, and multiple TAs in addition to oncology in 2015. In 2014, Sanofi. Or perhaps the FDA safety announcements for all Takeda’s top diseases were within oncology. the DP-4 and SGLT-2 inhibitors dampened new activity (Figure 8) as companies reassessed strategy.8

HCV (from 21 to 7) became more prominent, driven by Investments (or drugs) well utilized? the keen focus from Gilead, Merck, and AbbVie who It’s well known that pharma R&D is a pricey voyage started nearly half of all HCV trials last year (23 of 47). with no guaranteed return and the potential for many Merck was the least active of this group for HCV, but shipwrecks along the way. This cohort invested an only with regards to trial starts as they prepared average of nearly $4.5 billion in R&D efforts, ranging regulatory applications for their recently approved from Sumitomo Dainippon Pharma’s $675 mn to Zepatier. Asthma also moved up in popularity, from 17 Roche’s near $9 bn.9 In Figure 9, we compare this overall to 8 among the top 20 sponsors, partially due figure with the total number of trials started and the to AstraZeneca’s 10 trials that evaluate various number of ongoing trials10 to determine how these monoclonal antibodies among other types of therapy. companies’ investments relate to their clinical efforts. These metrics are intended to serve as an Figure 8 lists the leading indications pursued by each of approximation of whether these dollars are well used, the top 20 sponsors to see where each company as R&D spend does include the significant investments invested their time and energy (and money). Some toward discovery and preclinical development, which shifted gears while others demonstrated unwavering is excluded from this analysis. Also, we do recognize commitment to specific areas in comparison to last that there are other factors besides the amount of year’s review. As previously mentioned, the number of trial activity, such as complexity of the study protocol, new trials has waned a bit for type 2 diabetes, which which feed into the funds that companies need to was a top disease for only Eli Lilly and Sanofi, contrasting pump into their R&D expenditures. the larger efforts of seven companies in 2014. Two of the seven, Astellas and Novo Nordisk, were omitted from this The top spenders exhibited varying levels of ongoing year’s analysis, both of whom had type 2 diabetes as trial activity. Roche’s top dollar commitment to R&D their primary disease in 2014 and continue to actively does support one of the largest numbers of ongoing pursue this indication. (Six of Novo Nordisk’s 13 initiated trial activity (234), but Novartis takes the prize for the trials in 2015 were for type 2 diabetes. Astellas did not most ongoing studies (269), and with a smaller start any type 2 diabetes trials last year, however a amount ($8,181 mn). (We should also note that Roche number of their 2014 initiated studies are still ongoing.). initiated more studies in 2015 than Novartis, which

7Data provided by Ian Lloyd’s Pharmaprojects Pharma R&D Annual Review 2016 NAS Supplement, which provides a detailed review of the New Active Substances that were launched in 2015 and is available to download for free at https://citeline.com/category/whitepapers/. 8http://www.fda.gov/ForPatients/Illness/Diabetes/default.htm 9R&D expenditures derived from the Scrip league tables, available to Scrip Intelligence subscribers at http://www.scripintelligence.com/home/ marketdata/Scrip-League-Tables-361800. For non-subscribers, a free preview is available at http://marketing.scripintelligence.com/ scrip100-2015/. 10 Includes all trials, regardless of start date, that were ongoing in Trialtrove as of March 9, 2016.

AstraZeneca Unspecified Solid Tumor (17) NSCLC (15) Asthma (10)

Johnson & Respiratory Infections (15) Depression (13) HIV (9) Johnson Breast Cancer (13) Roche NSCLC (11) Non-Hodgkin's Lymphoma (9) Unspecified Solid Tumor (13) Novartis NSCLC (12) Breast Cancer (9) Unspecified Cancer (7) Alzheimer's Disease (5) NSCLC (5) Psoriasis (5) Eli Lilly Migraine (6) Breast Cancer (4) Type 2 Diabetes (5) Unspecified Cancer (5) Unspecified Solid Tumor (5) Alzheimer's Disease (4) Other Bacterial Vaccines (4) Pfizer NSCLC (8) Dyslipidemia (5) Pain (nociceptive) (4) Schizophrenia (4) Unspecified Cancer (4) HCV (10) Non-Hodgkin's Lymphoma (5) Arrhythmia (4) Gilead Sciences HIV (10) Diabetic Complications (4) Hypertension (4) Hyperuricemia/Gout (3) Takeda Schizophrenia (6) Renal Cancer (4) Unspecified Solid Tumor (3) Renal Disease (4) Rheumatoid Arthritis (4) Atopic Dermatitis (4) HIV (3) GlaxoSmithKline COPD (7) Respiratory Infections (4) Psoriasis (3) Acute Myelogenous Myelodysplastic Syndrome (3) Non-Hodgkin's Leukemia (4) NSCLC (3) Celgene Lymphoma (6) Crohn's Disease (4) Ulcerative Colitis (3) Unspecified Solid Tumor (4) HCV (5) Head/Neck Cancer (3) HIV (4) Merck & Co. NSCLC (5) Respiratory Vaccines (3) Melanoma (4) Respiratory Infections (5) Unspecified Solid Tumor (3) Breast Cancer (4) Non-Hodgkin's Lymphoma (3) AbbVie HCV (8) CNS, Glioblastoma (4) NSCLC (3) Rheumatoid Arthritis (4) Unspecified Solid Tumor (3) Acute Myelogenous Leukemia (3) Head/Neck Cancer (3) Bristol-Myers HIV (11) NSCLC (4) Squibb Ovarian Cancer (3) Pancreas (3) Unspecified Solid Tumor (3)

12 April 2016 © Informa UK Ltd 2016 (Unauthorized photocopying prohibited.) Asthma (3) Multiple Myeloma (3) Sanofi Atopic Dermatitis (4) Multiple Sclerosis (3) Rheumatoid Arthritis (3) Type 2 Diabetes (3) Bayer AG Unspecified Solid Tumor (8) Non-Hodgkin's Lymphoma (7) Asthma (3) Alzheimer's Disease (4) Boehringer Crohn's Disease (3) Ingelheim NSCLC (4) Rheumatoid Arthritis (3) COPD (3) Sumitomo Unspecified Solid Tumor (5) Liver Cancer (3) Dainippon Myelodysplastic Syndrome (3) Diabetic Complications (3) Daiichi Sankyo Pain (neuropathic) (6) Unspecified Solid Tumor (4) NSCLC (3) Teva Asthma (5) Asthma (3) Regeneron Atopic Dermatitis (4) Rheumatoid Arthritis (3)

*Top diseases limited to indications with at least 3 or more trials Source: Trialtrove February 2016

could correlate with higher expenditures.) The second Next, let’s look at how this cohort maximizes another largest spender, Pfizer, supports approximately the type of asset: the unapproved drugs in active clinical same number of ongoing trials as J&J who spent $2.2 development. Table 2 captures the counts for active billion less yet initiated the second highest number of drugs11 and ongoing trials as well as the calculated trials in 2015. Turning toward the smaller companies, ratio of ongoing trials per pipeline drug. Since multiple Sumitomo’s investments support a healthy number of candidates are sometimes evaluated within a single ongoing studies (42) and trial starts (21), especially in trial, again, this metric intends to merely approximate comparison to Regeneron and Teva who both fed how assets are being utilized. nearly twice as much into R&D with less or similar As a whole, these companies averaged 1.4 ongoing trials amounts of trial activity. for each unapproved drug in active development. In the same vein as last year’s review, AstraZeneca Celgene exhibits the highest trial density for their drugs remains noteworthy as they support, in addition to (3.2), followed by Sumitomo (2.1) and AstraZeneca (2.0). starting, a large number of clinical trials with a much While GlaxoSmithKline possesses the largest inventory of smaller R&D spend than some of their counterparts unapproved drugs, their ratio (0.9) is similar to both BMS (244 ongoing trials, $5,579 mn). With a comparable and Merck (0.8, each), who have lower drug counts. budget, the number of trials that GSK initiated and Despite their smaller portfolio, Regeneron appears to be currently supports are 34% and 56% of AstraZeneca’s making good use of their assets. With a ratio of 1.6, their respective totals. ratio exceeds Roche’s (1.5), who has a significantly larger

11Data pulled from Pharmaprojects in February 2016. Unapproved drugs have not been approved for any indication and are listed in Phase I-III development or pre-registration in Pharmaprojects. Compounds in pre-registration, also known as pre-approval, are drugs where registration documents have been submitted but not yet approved.

Unapproved drug trials started in 2015 All ongoing unapproved drug trials* 2014 R&D Spend

300 10000

250 8000

200

6000

150

Trial Count Trial 4000 R&D Spend ($m) Spend R&D 100

2000 50

0 0

Teva Roche Pﬁzer Eli Lilly Takeda AbbVie Sanoﬁ Novartis Celgene Bayer AG Regeneron AstraZeneca Merck & Co. Daiichi Sankyo Gilead SciencesGlaxoSmithKline Johnson & Johnson Bristol-Myers Squibb CNS Boehringer Ingelheim *Includes all trials, regardless of start date and trial phase, ongoing as of March 9, 2016 Source: Trialtrove February/March 2016, Scrip November 2015 Sumitomo Dainippon Pharma

count of drugs. At the tail end, Teva has the largest multiple parties across the industry. The majority of number of active drugs relative to their ongoing trials, their jointly sponsored studies are with other with the lowest ratio of 0.2. biopharmaceutical companies, but over 40% list cooperative groups and/or academic/medical centers The level of ongoing activity for Celgene and as collaborators. Among Celgene’s industry Regeneron is likely aided by both companies’ partnerships, the most studies are conducted with penchant for collaboration. Approximately half of Acceleron, Agios, and OncoMed. (Data not shown) Celgene’s and all of Regeneron’s ongoing trials are jointly sponsored, but with different approaches. Regeneron’s collaborative work can be attributed Land ahoy – where have these solely to their long standing relationship with Sanofi to ships headed? develop fully human monoclonal antibodies for The United States continues to be the most frequented various indications. In contrast, Celgene works with clinical trial destination by far, overall and for each of

14 April 2016 © Informa UK Ltd 2016 (Unauthorized photocopying prohibited.) the TAs included in our analysis. (Table 3) The extreme Location preferences outside the US vary among the popularity of the US comes as no surprise, especially TAs, and interest in emerging markets remains. China, since the US hosts the headquarters for 48% of R&D as well as South Korea, are common destinations for companies4 and served as the first market for 63% of all TAs except autoimmune and CNS. Some Eastern the new active substances launched during 2015.7 The European countries, particularly Poland, and Russia remaining countries that comprise the 7 major were also top locations. Seemingly, autoimmune trials markets (France, Germany, Italy, Spain, UK, and Japan) eschewed the East Asian market for Eastern Europe dominate the top 10 ex-US countries overall, and most since it was the only TA to have multiple Eastern European countries in their top trial locations. make frequent appearances across the individual TAs. However, only two areas include all 7 of the 7 major For the 10 most active sponsors from our cohort, some markets (7MM) as top locations: metabolic and similar themes emerge along with some differences. oncology. The US still dominates as a destination, as well as the

Table 2. Ratio of Ongoing Unapproved Drug Trials to Unapproved Drugs in Active Clinical Development

# of ongoing trials Sponsor Unapproved drugs Ongoing trials per drug AstraZeneca 123 244 2.0 Johnson & Johnson 118 140 1.2 Roche 156 234 1.5 Novartis 152 269 1.8 Eli Lilly 92 116 1.3 Pfizer 149 141 0.9 Gilead Sciences 39 75 1.9 Takeda 57 77 1.4 GlaxoSmithKline 157 137 0.9 Celgene 35 111 3.2 Merck & Co. 107 88 0.8 AbbVie 52 100 1.9 Bristol-Myers Squibb 95 79 0.8 Sanofi 102 59 0.6 Bayer AG 65 94 1.4 Boehringer Ingelheim 38 52 1.4 Daiichi Sankyo 48 68 1.4 Sumitomo Dainippon Pharma 20 42 2.1 Teva 51 47 0.9 Regeneron 16 26 1.6

Notes: Trial counts includes all trials, regardless of start date, ongoing as of March 9, 2016. Unapproved drugs are listed in Phase I-III development or pre-registration. Source: Trialtrove February/March 2016, Pharmaprojects March 2016

Overall Autoimmune/Inflammation Cardiovascular CNS Country Trials Country Trials Country Trials Country Trials

United States 1583 United States 225 United States 70 United States 275 Germany 105 China 24 United Kingdom 62 United Kingdom 398 United Kingdom 102 United Kingdom 23 Germany 56

Germany 390 Canada 88 Germany 19 Canada 53 Poland 79 South Korea 18 Spain 45 Canada 337 Hungary 65 Japan 17 France 41 Spain 297 France 63 Australia 16 Belgium 41 Spain 62 Canada 15 Netherlands 36 France 296 Czech Republic 59 Netherlands 14 Australia 36 Australia 259 Belgium 58 France 12 Poland 33 Australia 57 Poland 11 Italy 29 Belgium 248 Russia 11 China 240

Italy 228 Infectious Disease Metabolic/Endocrinology Oncology Japan 228 Country Trials Country Trials Country Trials United States 188 United States 133 United States 732 United Kingdom 62 Germany 39 United Kingdom 137 Canada 48 Japan 33 Spain 133 China 48 China 29 Germany 132 Russia 48 United Kingdom 28 France 131 Germany 47 Canada 23 Canada 119 Belgium 41 Russia 22 China 112 France 40 South Korea 20 Australia 106 Spain 35 Spain 20 Italy 102 Australia 35 Italy 19 South Korea 101 South Korea 28 France 17 Japan 97 New Zealand 28 Sweden 17

Source: Trialtrove February 2016

16 April 2016 © Informa UK Ltd 2016 (Unauthorized photocopying prohibited.) other 7MM countries. Poland also makes the cut for half as well, but was barely beat by Novartis. of these companies and South Korea for four. (The Based on these averages, it’s apparent that some South Korean market is still a focus for AstraZeneca, sponsors appear to focus on specific markets and limit Roche, and Pfizer; all included the country as a top the geographic scope of their initiated studies, even location in last year’s review as well.) However, while for later phase development. For instance, Sumitomo China was a top destination overall and for various TAs, opted to include only a single country in their Phase none of these companies included China frequently III trials. In fact, Sumitomo only used one or two enough to be included in Table 4. Newly initiated countries, primarily the US and Japan, across all newly research in China was primarily sponsored by China initiated research in 2015 regardless of trial phase. based groups, likely due to the regulatory challenges in GSK also cast a smaller net compared to their conducting clinical studies within the country. counterparts and averaged 5.3 countries for their Although some emerging markets remain a target for Phase III studies, well below the overall Phase III these sponsors, the focus on South America appears to average of 14.9. Furthermore, their overall average have dimmed. Previously, Roche, GSK, and Takeda has decreased in comparison to previous years. Prior turned to Brazil and Argentina to identify patients for average number of countries per trial were 3.5 in 2013 trials initiated in 2014, which was not the case for and 4.2 in 2014, which shrank to 2.3 in 2015. studies started last year. Instead other unique locations appeared as targets. One was South Africa, which GSK The two most active sponsors, AstraZeneca and J&J, included in a handful of their autoimmune and generally used fewer countries per trial than the infectious disease studies. Another was New Zealand, averages calculated for the overall group. Both used which was a top location for Gilead, and also across all fewer countries overall, and for their Phase II and III infectious disease studies. The company appears to be studies specifically. AstraZeneca also had a lower driving infectious disease activity here; Gilead initiated average for their Phase I trials. Perhaps both a third of the new trials in New Zealand, primarily for companies limited the geographic scope of their their ongoing work in HCV, while the remaining trials initiated research as a strategy to facilitate their large were split among 10 different companies. number of trial starts and mitigate costs, which was reflected in their lower R&D spend (Table 5). Similar to last year, the average number of countries involved per trial continues to be relatively stable.12 Although the companies included in the analysis Wrapping up the round up differs slightly, the average number of countries used As interests in the industry and a company’s focus ebb by the top 20 was 5.3 in 2013, 4.7 in 2014, and 5.5 in and flow over time, it’s no surprise to see fluctuations 2015. Country utilization does vary widely among the in new clinical trials activity in 2015 for some diseases different sponsors, from Sumitomo’s 1.2 to Bayer’s and sponsors and stability in others. But for the most 10.3. This year, we also provide a breakdown by trial part, most of pharma R&D held a steady course. phase to get a better sense of the geographic breadth Oncology and AstraZeneca both continue to lead the for the larger, global trials, which are typically Phase R&D landscape, which will likely continue with the huge III. (Table 5) The overall mean of 5.5 appears to reflect and ongoing interest in immune-oncology. The 7MM the typical trial size for Phase II research, which remain of high interest, as do East Asia and Eastern averaged 5.7 countries among this cohort. In contrast, Europe, but the average number of countries used per Phase III studies averaged 14.9 countries, with some trial was nearly the same as prior years. Although 2016 companies including over 30 countries. Bayer has just begun, over 600 initiated trials for unapproved incorporated the largest mean number of countries drugs across the 6 TAs have already been disclosed, into their trials, overall and for Phase II and III trials. which is on track for another busy year. Stay tuned via The company nearly had the lead for Phase I research Trialtrove, and we’ll see how the year unfolds.

AstraZeneca Johnson & Johnson Roche Novartis Country Trials Country Trials Country Trials Country Trials United States 89 United States 50 United States 61 United States 51 United Kingdom 34 Belgium 36 Spain 30 Germany 30 Germany 27 United Kingdom 27 France 27 France 25 Canada 24 Spain 27 Germany 24 Spain 23 South Korea 23 Germany 26 Canada 23 Canada 22 Spain 19 France 25 United Kingdom 23 Italy 21 Australia 18 Canada 20 Italy 22 Netherlands 20 Belgium 17 Netherlands 19 South Korea 20 Australia 17 Japan 17 Poland 18 Netherlands 20 Singapore 16 Italy 16 Italy 15 Australia 20 Japan 15

Poland 15 Sweden 14 Poland 17 Belgium 15

France 15 Taiwan 15

Gilead Sciences Takeda GlaxoSmithKline Celgene Country Trials Country Trials Country Trials Country Trials United States 43 United States 27 United States 20 United States 37 Canada 20 Japan 11 United Kingdom 7 Canada 14 Germany 19 United Kingdom 9 Germany 6 Germany 12 France 18 Spain 6 Canada 6 Italy 12 United Kingdom 18 South Korea 4 Netherlands 3 France 10 New Zealand 14 Italy 4 South Africa 3 Netherlands 9 Australia 11 Russia 4 Czech Republic 3 Spain 9 Spain 10 Canada 3 Russia 3 United Kingdom 8 Italy 10 Czech Republic 3 Romania 3 Belgium 8

Puerto Rico 8 Germany 3 Japan 3 Australia 7

Source:Belgium Trialtrove February 20168 Poland 3 Hungary 6

12Trials included in this analysis are limited to studies that disclosed specific countries as locations rather than regions.

18 April 2016 © Informa UK Ltd 2016 (Unauthorized photocopying prohibited.) Table 5. Average Number of Countries Disclosed per Trial Across Most Active Industry Sponsors*

Eli Lilly Average Number of Countries/Trial Country Trials Company Overall Phase I Phase II Phase III United States 45 AstraZeneca 4.3 1.4 3.5 12.8 France 13 Johnson & Johnson 4.6 2.0 5.3 10.3 Canada 13 Roche 7.5 1.9 9.7 19.0 Spain 12 Novartis 8.3 2.9 8.0 20.2 Eli Lilly 4.0 1.3 6.5 9.9 Germany 12 Pfizer 4.1 1.2 3.3 14.0 Japan 12 Gilead Sciences 5.6 2.0 7.6 8.3 United Kingdom 11 Takeda 2.8 1.3 3.2 13.3 Belgium 10 GlaxoSmithKline 2.3 1.1 3.8 5.3 Italy 8 Celgene 6.1 1.7 4.9 22.3 Hungary 7 Merck & Co. 5.1 1.5 4.2 15.7 Poland 7 AbbVie 8.2 1.3 11.3 17.3 Bristol-Myers Squibb 3.4 1.0 5.4 10.3 Sanofi 5.8 1.2 9.2 11.5 Bayer AG 10.3 2.8 11.8 32.8 Pfizer Boehringer Ingelheim 6.5 1.3 8.5 31.5 Country Trials Daiichi Sankyo 4.8 1.0 2.2 11.4 Sumitomo Dainippon United States 48 1.2 1.3 1.3 1.0 Pharma Belgium 14 Teva 8.8 2.3 5.0 17.8 United Kingdom 12 Regeneron 7.2 1.4 4.0 13.6 South Korea 9 Spain 9 *Trials limited to those disclosing specific countries as locations. Source: Trialtrove February 2016 Japan 9 France 8 Hungary 7 Australia 7 Canada 7 Germany 6 Poland 6

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