Takeda Pharmaceutical

by

Dr. Rainer Steinbach

Rainer studied chemistry and economics in Germany (Bonn, Marburg) and did postdoctoral work at Stanford University (CA, USA). He held various positions (R&D, Market Research, Marketing, Strategic Planning, Sourcing, etc) while working at Rütgers, Novartis, Syngenta, SK, Clariant, Archimica. His international background (he worked out of Belgium, Germany, Italy, Switzerland and the USA) combined with broad experience gained in China and India (he audited more than 200 companies) is the foundation of CAP INTELLIGENCE.

Dr Rainer Steinbach of CAP Intelligence profiles Japan’s most global drugs firm

Takeda is the largest Asian pharmaceuticals company. The company started as early as 1977 to establish major co-operations with Western firms. As a result, it has the most global orientation amongst Japanese pharmaceutical companies. The latest major acquisition, Nycomed, is part of this globalisation strategy.

History

Takeda dates back to 1781, when Chobei Takeda started selling Japanese and Chinese traditional medicines. In 1895, the firm started the first production of pharmaceuticals in Osaka. Research activities started in 1914 and in 1944 fermentation activities were added.

In 1981, the antibiotics Takesulin and Pansporin were launched in Japan. In 1985, Takeda formed TAP Pharmaceuticals, a 50:50 joint venture (JV) in the US with Abbott Laboratories. TAP began marketing the prostate cancer treatment leuprorelin (Lupron) in the same year. 1997 saw the launch in Europe of candesartan celexetil (Blopress/Kensen), an anti-hypertensive agent which is also marketed by AstraZeneca.

In 2008, Takeda acquired Millennium Pharmaceutical of Cambridge, Massachusetts, an oncology research specialist, for $8.8 billion. Larger still was the acquisition of Swiss company Nycomed for €9.6 billion ($13.3 billion) in 2011, not including Nycomed’s US-based dermatological business. Nycomed had itself grown substantially by acquiring the pharmaceuticals interests of Altana in Germany and Bradley Pharmaceuticals in 2007.

The acquired parts of Nycomed had revenues of about €2.84 billion in 2011 and a workforce of about 11,800 employees, plus production locations in 11 countries worldwide. Its revenues were mainly in Europe (48%), Russia (17%) and Latin America (13%), plus other emerging markets. The acquisition also gained Takeda access to romiflumast (Daliresp), a new drug against chronic obstructive pulmonary disease.

In 2012, Takeda acquired URL Pharma, a privately owned company headquartered in Philadelphia and employing about 500, for an upfront payment of $800 million and future performance-based contingent earn out payments. URL’s 2011 revenues amounted of nearly $600 million, over two thirds coming from colchicine (Colcrys), which is used to treat and prevent gout flares. URL Pharma was sold to Sun Pharma in January 2013.

Table 1 – Locations of Takeda sites

Structure

Takeda is a public share company that is listed at the Tokyo and Osaka stock exchange, with the ticker symbol 4502. The main shareholders are financial institutions (33%), foreign investors (30%), some 280,000 individuals (27%) security companies and others (10%). The three biggest single shareholders are Nippon Life Insurance, with 7.1%, Japan Trustee Services Bank (4.4%) and the Master Trust Bank of Japan (4.3%).

The company is headquartered in Osaka, with its European headquarters in London and the American one headquarters Deerfield, Illinois. It has 17 manufacturing sites and three JV manufacturing sites, the most important of which are listed in Table 1. It employs a global workforce of about 30,500. Regional data about this are not published, apart from in Japan itself. CAP Intelligence estimates the workforce split as 31% in Japan, 30% in Europe, 25% in the USA and 14% in the rest of the world.

As of today, the Takeda Group has 61 consolidated companies and 14 affiliates. Major subsidiaries include: Takeda Nycomed Pharmaceuticals, Takeda Europe Holdings (Amsterdam), Takeda USA Holdings (New York), Millennium Chemicals (Cambridge, Massachusetts), Nihon Pharmaceutical, Wako Pure Chemicals and Mizuzawa Industrial Chemicals (all Japan) and Tianjin Takeda Pharmaceuticals (China).

Takeda’s financial year starts on April 1 and ends on March 31. The company’s financial results are reported in Yen, but are given here in US dollars for ease of comparison with other profiled firms. Figure 1 shows revenues, EBITDA, operating income and net earnings for the years since 2002.

In the year to March 2013, earnings fell by 13.3% to $16.57 billion, but EBITDA was up by 6.1% to $5.52 million and operating income was 27.4% up to $4.28 billion while earnings more than doubled to $3.48 million. Consequently, the net profit margin shot up from the 8% mark in the previous two years to 21.2%.

Figure 1 – Takeda’s revenues & profits ($ billion), 2011-2013 fiscal years

Main activities

Takeda is overwhelmingly focused on ethical products, which account for 90% of its revenues. Within this, cardiovascular and metabolic therapies account for 74%, followed by oncology with 13.5% and inflammatory with the other 2.5%. The remainder of its revenues is split between consumer healthcare products, including cold remedies and vitamin-containing products (4%), and others (6%). The company’s five best selling products account for close to $10 billion in sales, more than half of the total (Figure 2).

Sales are 47% in Japan, 23% in North America, 16% in Europe, 4% each in the rest of Asia, Russia and the CIS and Latin America and 2% in the rest of the world. As the Japanese market will not deliver major growth opportunities, the company’s objective is to be strongly present in emerging markets, especially China and Russia. Sales and marketing efforts have been intensified to this end. In fiscal 2012, Takeda all started an e-commerce website for direct selling in Japan called the Takeda Online Shop as part of the consumer healthcare business.

Takeda’s stated vision is “to embody global pharmaceutical leadership through innovation, culture, and growth, guided by an unwavering commitment to significantly improve the lives of patients”. Its strategy includes:

• A strong focus on emerging markets
• An improved presence in China and Korea
• The integration of Nycomed and reducing over-reliance on the Japanese and American markets
• Leveraging Nycomed’s strength in emerging markets to drive growth and combine the strength of both companies
• Securing a top market share by establishing new products and maximising the sales of the existing portfolio
• Concentration of management resources into new core therapeutic areas of metabolic and cardiovascular disease, oncology and diseases of the central nervous system (CNS), plus exploring further immunology and inflammatory medications
• Increasing promotional efficiency
• Making strategic investments actively and flexibly, while pursuing all opportunities, including M&A, product acquisition and the introduction of pipeline drugs

Takeda is one of the few Japanese pharmaceuticals companies that have a truly global presence. Because of this, in addition to its Japanese competitors, such as Astellas, Eisai, Mitsubishi, Otsuka, Shionogi, Taiho and Teijin, it also competes with all the major international companies, including generics companies. The strongest competitors in its main area of cardiovascular and metabolic drugs are AstraZeneca, Bayer, Bristol-Myers Squibb (BMS), Boehringer Ingelheim (BI), Daiichi Sankyo, Dainippon Sumitomo, Merck & Co., Novartis, Pfizer and Sanofi.

Table 2 – Takeda’s leading brands by sales, 2010-2013 fiscal years

R&D structure

About 6,000 Takeda employees work in R&D. In 2012-2013, the company invested more than $3.9 billion in R&D, almost 21% of total revenues. It has R&D sites in: Osaka and Fujisawa in Japan; Palo Alto, San Diego, Deerfield, Cambridge, Bozeman and Fort Collins in the US; Cambridge and London, UK; Roskilde, Denmark; Konstanz, Germany; Singapore; Guangzhou, China; and, Sao Jerônimo in Brazil.

Following the opening of the new drug discovery research centre, the Shonan Research Centre in Osaka, a new R&D structure was implemented in early 2011, creating ‘Drug Discovery Units (DDUs)’, with research functions around each of the four core research activities of metabolic diseases, oncology, CNS-related diseases and inflammatory diseases.

In addition, R&D alliances continue to form a key part of Takeda’s strategy. This has included alliances with Advinus Therapeutics in India, Seattle Genetics, Sage Bionetworks, Xoma and Zinfandel Pharma in the US and BC Cancer Agency in Canada. The company has stated that R&D expenditure over the next three years will be divided as follows between different therapeutic areas: oncology 31%, cardiovascular and metabolic 27%, CNS 14%, immunology and respiratory 12%, general medicine and vaccines 16%.

Clinical development

As of July 2013, Takeda had more than 40 products in clinical development, with the main emphasis on cardiovascular and metabolic indications and oncology. These comprised 14 compounds in Phase I, six (all NMEs) in Phase II and 12 (including seven NMEs) in Phase III.

Eight products, including three NMEs, had been submitted for approval and submissions had been filed for: vedolizumab, a monoclonal antibody developed to treat Crown’s disease and ulcerative colitis (Figure 2a); vortioxetine an anti-depressant co-developed with Lundbeck to treat generalised anxiety disorder; and, BLB-750, a vaccine developed to prevent pandemic influenza. Amongst the developmental drugs in Phase III are:

• Alisertib (MLN8237, Figure 2b), a developmental kinase inhibitor to treat non-small lung cancer, breast cancer, ovarian cancer and T-cell lymphoma
• Fasiglifam (TAK-875, Figure 2c), an experimental drug against diabetes mellitus, belonging to the group of fatty acid receptor agonists
• Ixazomib (MLN7908, Figure 2d), a protease inhibitor developed to treat multiple myeloma and relapsed primary amyloidosis
• Orteronel (TAK 700, Figure 2e), an experimental non-steroidal proteasome inhibitor developed to treat prostate cancer
• Trebananib (AMG 386), a developmental antineoplastic immunoglobulin that is being co-developed with Amgen
• Trelagliptin (SYR-472, Figure 2f), a long-acting dipeptidyl peptidase-4 inhibitor developed to treat Type 2 diabetes
• Vonoprazan (TAK-438, Figure 2g) an acid blocker developed to treat peptic ulcer and other acid-related diseases

Figure 3 – Pipeline drugs at Takeda

Key products

The main market products from Takeda have already been listed above in Table 2. The five most important by sales in the most recent fiscal year are as follows in alphabetical order, with the generic name first and the brand name in brackets after. Further information about the rest of the portfolio is available from CAP Intelligence.

Bortezomib (Velcade, Figure 3a) belongs to the class of targeted intra-cellular tumour therapeutics. It was the first therapeutic protease inhibitor ever approved and was originally developed by Myogenics, a company that was sold to Leukosite. This firm was in turn acquired by Millennium, which ultimately became part of Takeda.

Amongst others, bortezomib is approved against multiple myeloma and mantle cell lymphoma. Chemically, it is an N-protected dipeptide. The protection group contains a boron atom which binds the catalytic site of the 26S proteasome that regulates protein expression. Bortezomib is co-marketed with Johnson & Johnson (J&J) under the same trade name Velcade. Pharmstandard markets it in Russia.

Depending on the specific indication multiple myeloma, competing drugs include: other targeted tumour therapeutics, such as lenalidomide (Revlimid), pomalidomide (Pomast) and thalidomide (Thalidomide), all by Celgene; enzyme inhibitors, such as carfilzomib (Kyprolix by Onyx); and, topomerase inhibitors, such as doxorubicin (Doxil/Caelyx) by J&J.

Candesartan (Blopress/Kensen, Figure 3b) belongs to the class of angiotensin II receptor antagonists (ARBs) or ‘sartans’, which are chemically 2-tetrazoylbiphenyl derivatives. The drug is used for treatment of hypertension (high blood pressure). Depending on the specific indication, competing drugs include:

• Other sartans, such as irbesartan (Avarpro/Avalide by BMS, Approvel by Sanofi or Irbetan by Shionogi), olmesartan (Olmetec by Daiichi Sankyo), telmisartan (Micardis by BI) and valsartan (Diovan by Novartis)
• Angiotensin-converting enzyme inhibitors  or ‘prils’, such as benazepril (Lotensin by Novartis), captopril (Capoten by BMS), enalapril (Vasotec by Merck & Co.), fosinopril (Monopril by BMS), lisinopril (Prinivil by Merck & Co., Zestril by AstraZeneca), perindopril (Coversyl by Servier), quinapril (Accupril by Pfizer), ramipril (Tritace by Sanofi, Altace by King), zofenopril (Zofenopril, Zopranol or Zantipres by Menarini)
• Renin inhibitors or ‘kirens’, such as aliskiren (Tekturna/Rasilez by Novartis)
• Drugs from other classes, such as calcium channel blockers

Figure 3 – Key market products by Takeda

Lansoprazole (Takepron/Ogast/Lansox, Figure 4c) belongs to the sub-group or proton pump inhibitors (PPIs) or ‘prazoles’ in the class of drugs for acid-related disorders. PPIs reduce acid secretion by inhibiting the enzyme ATPase in gastric parientel cells.

Lansoprazole is used to treat stomach ulcers, peptic ulcers and gastroesophagal reflux. The originator drug is marketed by Takeda but is now generic, being marketed as Lansul and Lansoptol by Krka, Lansopran by Sawai and Opiren by Almirall and as an over-the-counter drug by Novartis under the name Prevacid 24H. Depending on the specific indication, lansoprazole competes with:

• Other PPIs, such as dexlansoprazole (Dexilant Takeda), Nexium by AstraZeneca, omeprazole (Losec and Prilosec, also by Astra Zeneca, plus generic versions), pantoprazole (by Nycomed) and rabeprazole (Aciphex and Pariet by J&J)
• H2-antagonists (‘tidines’), such as cimetidine (Tagamet by Glaxo Smithkline (GSK)), famotidine (Pepicidine and Pepcid by J&J and Merck & Co., Gaster by Astellas, loratidine (Claritin by Schering Plough and Shionogi), nizatidine (Tazac by Eli Lilly), ranitidine (Zantac by GSK)
• Prostaglandins or ‘prosts’, such as misoprostol (Cytotex by Pfizer)
• Non-classified drugs, such as repabimide (e.g. Mucosta by Otsuka), teprenone (Seftac by Sawai, Selbex by Eisai), etc.

Leuprorelin (Leuplin/Enatoe, Figure 3d) is an analogue to the gonadotropin-releasing hormone (GnRH) and acts as agonist at pituitary GnRH receptors. It regulates down the secretion of gonadotropins-luteinizing hormones (LHs) and follicle-stimulating hormones (FSHs), reducing estradiol and testosterone levels in both sexes.

Leuprolin is marketed by various companies, such as Eligard by Sanofi and Astellas and Vidadur by Bayer. Competing GnRH medications include goserelin (Zalodex by AstraZeneca), buserelin (Suprefact by Sanofi), histrelin (Vantas and Supprelin by Elan), triptorelin (Decapentyl by Ipsen, Gonapeptyl by Ferring, Trelstar by Watson), deslorelin (Ovuplant by Peptech) and nafarelin (Synarel by Pfizer).

Pioglitazone (Actos/Glustin/Zanctos, Figure 3e) belongs to the sub group of insulin sensitisers in the class of anti-diabetic drugs. These work against the core problem of Type II diabetes, insulin resistance. In India, the drug is marketed by Zydus Cadila. Depending on the specific indication, competing drugs include:

• Insulin sensitisers, such as metformin (e.g. Glucophage by Merck & Co. or Daiichi Sankyo; Glycoran by Nippon Shinyaku; Metgluco/Melbin by Dainippon Sumitomo, etc.) and ‘glitazones’, such as rosiglitazone (Avandia by GSK)
• Insulin secretagogues, which trigger the release of insulin by inhibiting the K-ATPase channel of the pancreatic beta cells, including sulfonyl ureas, such as glimeripide (Amaryl by Sanofi), glipizide (Gluctrol by Pfizer), gliclazide (Diamicron Servier), glibenclamide (e.g. Glimel by Dong-A), etc; meglitinides or ‘glinides’, such as nateglinide (e.g. Starlix by Par), repaglinide (e.g. Prandin by Novo Nordisk), glucagon-like peptide 1 analogues, such as exenatide (Byetta/Bydurone by Amylin and Eli Lilly), liraglutide (Victoza by Novo Nordisk) and lixenatide (Lyxumia by Sanofi); and, dipeptidyl dipetidase-4 inhibitors, such as linagliptin (Trajenta by Eli Lilly and BI), sitagliptin (Januvia by Merck), saxagliptin (Onglyza by AstraZeneca and BMS), vidagliptin (Galvus by Novartis), etc.
• Insulin analogues, including long-acting insulins, such as insulin glargine (Lantus by Sanofi) and insulin detemir (Levemir by Novo Nordisk), and short-acting insulins, such as insulin lispro (Humalog by Eli Lilly) or insulin glulisine (Apidra by Sanofi), etc.
• Alpha-glucosidase inhibitors, such as acarbose (Glucobay by Bayer), miglitol (Diastabol by Sanofi), voglibose (Basen by Takeda) and other non-classified drugs
• Sodium-glucose transport protein inhibitors, such as canaglifozin (Invokanna by Jansssen) and empaglifozin, which is under investigation by Eli Lilly and BI
• Amylin analogues, such as pramlintide (Symlin by Amylin)

 http://www.specchemonline.com/articles/view/takeda-pharmaceutical#.U6fUjUCs_yV

Contact:

Dr Rainer Steinbach
CEO
CAP Intelligence
Tel: +49 231 73 56 84
E-mail: rainer.steinbach@cap-intelligence.de
Website: http://www.cap-intelligence.de