Takeda has really shaken things up in the last couple of years. While most companies pin their growth strategy on either an organic (growth based on increasing available resources, expanding clientele, and increasing revenues; usually a long-term process) or an inorganic trend (recognizing key areas of development, divesting areas that are no longer of interest or considered high value, and using those funds to further develop areas of interest), Takeda’s growth strategy is definitely a cocktail of both, which is quite high-risk owing to the high volume of economic burden involved in conducting multiple deals and the promised but as-yet unrealized revenue.

In early 2016, Takeda outlined its research initiatives for Japan and the United States in four main areas of interest (oncology, gastroenterology, CNS, and vaccines1), and since then barely has a week gone by without any news about another step in Takeda’s radical journey. As part of this development strategy, Takeda parted with its pharmaceutical R&D business, by forming a subsidiary strategic business unit, Spera Pharma Inc., and subsequently selling it off to Bushu Pharmaceuticals, thus refining its R&D capabilities.2-5

While Takeda is still expanding by acquiring or partnering with companies, in some cases they are developing outside of its core four areas (e.g., Zika virus vaccine, leishmaniasis6); for the ease of our readers, we are outlining the steps it has taken and deals that it has undergone to execute its aggressive transformation and establish itself as a CNS leader in the United States and Japan, and even Europe.

 

 

Date Headline Details
March 29, 2016 Takeda and Lundbeck Receive CRL for Brintellix (vortioxetine) sNDA ·   Despite FDA lauding Takeda’s use of “Importance of cognitive dysfunction in MDD” as a key aspect of MDD treatment and a suitable aim for drug development, it issued a CRL for Takeda and Lundbeck’s sNDA to include new data about treating certain aspects of cognitive dysfunction in adults with MDD in the clinical trials section of Brintellix (now Trintellix) for its U.S. label.7 News followed on June 23, 2017
April 1, 2016 Takeda and Teva Establish "Teva Takeda Yakuhin Ltd." in Japan ·   This company was formed to meet the growing need in Japan for generics for off-patent drugs.8
May 3, 2016 Brintellix (vortioxetine) Renamed Trintellix (vortioxetine) in U.S. to Avoid Name Confusion ·   Takeda and Lundbeck renamed one of its pioneer antidepressants Trintellix from Brintellix, to avoid potential confusion with AstraZeneca’s Brillinta (a blood thinning drug).9

·   This multimedia campaign included TV, digital, in-office TV and print operation. Despite depression predominantly affecting females, they released two TV advertisements to cater to both genders and develop a sense of familiarity with its users.9

·   This drug faces heavy competition from generically-available products in the depression marketspace.

May 3, 2016 AstraZeneca Completes Acquisition of Takeda’s Respiratory Business ·   AstraZeneca completed its previously announced agreement to acquire the core respiratory business of Takeda.10

·   AstraZeneca had always marketed the COPD medication Daliresp in the United States, since it acquired rights from Actavis in Q1’2015, and the Takeda acquisition would enrich its respiratory portfolio.11

·  This trade also falls in line with Takeda’s plan to have a leaner focus of R&D.

September 12, 2016 Takeda and PRA Health Sciences Announce Transformational Clinical Development and Marketed Product Partnership ·   This collaboration allows Takeda to have a dedicated team focusing on the clinical development of products (pipeline and marketed), to transfer Takeda’s operational expertise, and to simultaneously reduce overall infrastructure costs. This collaboration allows for dynamic allocation of resources as per the necessity.

·   PRA assumes all responsibilities related to all Phase I-IV studies as well as other operational services for all products under the Takeda banner; approximately 300 of Takeda’s R&D employees may choose to relocate to PRA in the United States and Europe.12

September 14, 2016 Takeda Sets Aside Finances for M&A Deals Outside Japan ·   Takeda hired its first non-Japanese CEO Christophe Weber to seek assistance in globalizing the brand.

·   Takeda is looking for potential acquisition deals worth multibillion dollars outside its domestic market (i.e., Japan).13

September 21, 2016 Takeda and Affilogic Enter into Research Collaboration to Develop Nanofitin-Based Therapies in Central Nervous System ·   Takeda entered a research collaboration with Affilogic to use their proprietary Nanofitins platform to develop drug candidates that better target the CNS.

·   In exchange, Takeda is financing Affliogic’s research, and Affliogic is eligible to receive additional development and sales milestone payments and royalties.14

October 6, 2016 Takeda's Digital Innovation 'Shark Tank' Challenge Yields Creative Help for Depression ·   Takeda partnered with MedStartr to receive its services in shortlisting digital submissions for its Depression Care Challenge, which would assist patients with depression beyond the clinic.15

·   The winning idea was EllieGrid, which pairs a combination of a smart pillbox and a digital reminder app with personalized prompts that would notify the caregiver and/or the patient to take a pill and when the pill was taken. Developers won a total of $50,000. Takeda was assessing this product’s fit in their treatment portfolio, which possibly competes with Pfizer’s Moodivator.16

November 2, 2016 Takeda and Lundbeck Report Negative Trial Results for Brintellix in Adult ADHD ·   In this 12-week Phase II study (Clincialtrials.gov NCT02327013, accessed May 30, 2018)17 evaluating Trintellix/Brintellix’s efficacy in adults with ADHD (n = 227), the drug failed to separate from placebo.

·   Lundbeck reported extremely low or no exposure to Trintellix/Brintellix in more than 30% of its patients which diluted the overall result.18

December 15, 2016 Takeda Announces Sale of Shareholding in Wako Pure Chemical Industries, Ltd. to Fujifilm Corporation ·   Takeda gains $1 billion in cash by selling off its approximately 72% stake in Wako Pure Chemical Industries Pvt. Ltd. To FujiFilm Holdings.19

·   This deal potentially allows Takeda to further narrow its focus on its four-chosen core therapeutic areas.

January 18, 2017 Takeda and Ovid Therapeutics Announce Innovative Clinical Development and Commercialization Collaboration for TAK-935 in Rare Pediatric Epilepsies ·   Takeda entered into a collaboration agreement with rare neurological disease specialized company, Ovid Therapeutics, to develop and commercialize TAK-935 in rare pediatric epilepsies.

·   TAK-935 is presently in a Phase I/II trial for rare epileptic encephalopathies including Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex, and has completed several Phase I studies.

·   Takeda and Ovid will share the commercialization costs and profits equally. Ovid may be eligible for milestone payments based on advancements. 20

February 15, 2017 PRA Health Sciences and Takeda Partnership Expands to Japan ·   Takeda and PRA Health Sciences partnership now expands to include Japan.

·   This joint venture, much like its role in the United States, will manage the entire developmental pipeline, provide pharmacovigilance, and additional services to assist Takeda Development Center Japan as closely as possible.21

February 20, 2017 Takeda Announces Further Details of Splitting off (Simple Absorption-type Split) of Japan Consumer Healthcare Business Unit ·   Takeda transfers its Japan Consumer Healthcare Business Unit to Takeda Consumer Healthcare Company Limited, to better cater to the various needs of the highly volatile consumer market.22
February 23, 2017 Takeda and Cognition Kit Partner in Study to Pilot Wearable Software in Patients With MDD ·   Takeda and Cognition Kit have partnered to develop a customized Apple Watch app that monitors around-the-clock cognitive functions of patients with MDD.

·  The study enrolled patients with mild to moderate depression (n = 30; aged 18-65 years) who have been prescribed at least one antidepressant. This study aims to compare the difference in automated data collection vs. self-reported assessment of feasibility and compliance, and overall better understand how mood and cognition is comprehended on wearable technology vs. traditional methods. At the time, results were expected in late 2017.23 News followed on November 17, 2017.

April 7, 2017 Takeda Announces Splitting Off a Part of Takeda Development Center Japan Businesses ·   Takeda transfers a portion of its consumer business unit, Takeda Development Center Japan, to PRA.24
April 10, 2017 Takeda Sells Additional Long-Listed Products in Japan to Teva Takeda Yakuhin Ltd. ·   Takeda sells off 7 of its long-listed products in Japan to Teva Takeda Yakuhin for 28.5 billion yen, freeing up more of its assets which it can re-invest in its focus areas.25
May 31, 2017 Construction to Start on GCP2 Production Facility at Takeda Ireland Limited Site in Grange Castle ·   Takeda started construction of its new $40 million manufacturing plant in early 2017.26

·   It has also sought planning permission to expand an existing site.

June 12, 2017 Numerate and Takeda Enter Agreement to Generate Novel Clinical Candidates Using AI-Driven Drug Discovery ·   Takeda signs a multi-year contract with Numerate, a computational drug-discovery company, to help identify new therapies in the four therapeutic areas Takeda has refocused on.

·  Numerate will use its AI-driven platform for lead design/optimization and ADME (absorption, distribution, metabolism, and excretion)/toxicity modeling for these candidates.

·   Financial terms were not disclosed publicly but include a combination of milestone and royalty payments. Read more here.27

June 23, 2017 Lundbeck and Takeda Receive Complete Response Letter from the FDA for Trintellix (vortioxetine) sNDA ·   Takeda and Lundbeck receive their second CRL issued by the FDA with regards to their sNDA to revise Trintellix’s prescribing information to include clinical trial results for treating cognitive dysfunction in adults with MDD.28 News followed on May 2, 2018.
June 29, 2017 Takeda Submits an NDA for Rasagiline Mesylate for the Treatment of Parkinson’s Disease in Japan ·   Takeda submits an NDA for rasagiline mesylate to the Ministry of Health, Labour and Welfare in Japan for the treatment of PD.

·   The NDA filing was based on results from its Phase II/III and Phase III study conducted in patients with early-stage PD.

·   Takeda acquired commercialization rights from Teva in 2014.29

July 21, 2017 Takeda and Schrödinger Announce Multi-year, Multi-Target Research Collaboration ·   Schrödinger, a company that specializes in computational method-driven drug discovery, will collaborate with Takeda to discover therapies that align with Takeda’s four therapy areas of focus.

·   The agreement allows Takeda to exclusively license these emerging therapies at a pre-decided value of up to $170 million per program.30

August 29, 2017 AstraZeneca and Takeda join forces to develop MEDI1341 ·   AstraZeneca and Takeda entered into an agreement to co-develop, co-commercialize, and share the risks and finances involved in developing MEDI1341 for PD.

·   While Takeda usually enters into a joint venture with organizations that have different capabilities than their own, this unusual joint venture is driven by the high failure rate associated with developing a PD drug.

·   AstraZeneca will lead the Phase I clinical trials of MEDI1341 which began as expected in late 2017. Takeda will pay AstraZeneca, which includes initial 2017 revenues and additional development and sales milestones.31

November 6, 2017 Takeda, Lundbeck, and Advocate Health Care Research Study Aims to Improve Patient-Provider Engagement in MDD Treatment using Digital Technology ·   Takeda, Lundbeck U.S., and Advocate Health Care Research joined forces to understand how to better use technology to aid people with MDD.

·  The Advocate Pathway (mobile) App allows the patient to record their change in medication, mood swings, compliance, and side effects.

·  This data can be shared with an HCP, which could help provide an improved customized treatment plan.

·  This study spans 18 weeks, and improvements will be measured at study start and end using end points developed by Advocate Health Care Research specifically for this study.32

November 17, 2017 Takeda and Cognition Kit Present Results from Digital Wearable Technology Study in Patients with MDD ·     Takeda and Cognition Kit announces that they will present the results from their MDD-5003 pilot study at the 2017 CNS Summit Meeting in Boca Raton, Florida.33
December 1, 2017 Takeda Announces the Sale of the Tokyo Takeda Building Currently Used as Takeda’s Tokyo Headquarters ·   Takeda’s real estate subsidiary sells off the company’s Tokyo headquarters to Takashimaya Company Limited for the price of 49.5 billion yen.

·   This trade will be completed by the end of March 2019.34 News followed on March 20, 2018.

January 5, 2018 Takeda and Denali Therapeutics Collaborate to Develop and Commercialize Therapies for Neurodegenerative Diseases ·   Takeda and Denali Therapeutics agree to develop and bring to market up to three drugs addressing neurodegenerative disorders, including a drug targeting Alzheimer’s disease (AD).

·   Denali’s proprietary ATV platform will be used to develop programs that will aim for a genetically validated target and increase drug levels in the brain.

·   Denali will incur all development and costs involved prior to IND filing for each of the three programs. Takeda may co-develop and co-commercialize all programs, and upon exercising this option, developmental costs will be shared equally. Takeda will be responsible for late-stage development efforts.

·   Takeda will pay Denali $150 million initially and an additional $90 million on achieving pre-defined milestones.35

January 25, 2018 Takeda and Zinfandel Pharmaceuticals Discontinue TOMMORROW Trial Following Planned Futility Analysis ·   Following a negative interim futility analysis, Takeda and Zinfandel agreed to terminate the global Phase III TOMORROW trial being conducted for pioglitazone, aiming to delay the onset of mild cognitive impairment due to AD, due to insufficient treatment effect.

·   Additionally, this study was investigating the validity of a generic biomarker to determine patient disease risk.36

February 20, 2018 Takeda Deepens Commitment to Develop Innovative Treatments for Neurological Diseases ·   Wave and Takeda entered a co-development and co-commercialization program in Huntington’s Disease (WVE-120101 and WVE-120102, which selectively target mutant huntingtin), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) [WVE-3972-01, targets C9ORF72] and spinocerebellar ataxia type 3 (SCA3) [ATXN3 gene-targeted therapy], with Takeda having additional rights to license multiple preclinical programs targeted at AD and PD.

·   Takeda will pay Wave a total of at least $230 million ($110 million in cash, $60 million in equities, and at least $60 million in research support over a period of four years).

·  If all six programs bear fruit, then Takeda will pay Wave Life Sciences a total of $2 billion in cash milestone payments, including $1 billion in precommercial milestone payments.37

February 27, 2018 MindStrong Health and Takeda Partner to Explore Development of Digital Biomarkers for Mental Health Conditions ·   MindStrong continuously aggregates data on brain function via a smartphone app and classifies them as digital biomarkers.

·   Takeda plans to use the collected intel about biomarkers that are associated with mental health conditions to better identify these diseases (particularly schizophrenia and TRD) and predict the likelihood of novel therapies to induce remission in patients with these conditions.

·   The companies expect that the outcomes resulting from this partnership will yield advances in the clinical assessment of mentally ill patients with limited treatment options.38

March 20, 2018 Completion of Takeda Global Headquarters ·   The new office building in Tokyo will serve as the company’s global HQ.39
March 27 –May 8, 2018 Takeda and Shire Acquisition ·   After five consistently increasing bids for Shire from Takeda, Shire agrees to be acquired in its entirety (apart from its Oncology Business which it sold to Servier in 2018). The final offer stands at $64 billion.40,41

·   The companies received an extension from U.K. authorities to make a firm offer by May 8, 2018.

·   Shire shareholders would own approximately 50% of the enlarged company as per the latest proposal.42

May 2, 2018 Takeda and Lundbeck Announce the Acceptance of Their sNDA by the U.S. FDA for Trintellix ·   U.S. FDA approved the sNDA for Trintellix’s label to include data on the benefits of the drug to cognitive function in acute MDD based on results from the FOCUS and CONNECT studies.

·   The dataset on which the new label content is based is from the largest repeated clinical trial in patients with MDD.43

June 8, 2018 Positive Clinical Phase III Results of Vortioxetine in Japanese Patients ·  Takeda and Lundbeck reported positive results from their pivotal Phase III study (Clincaltrials.gov NCT02389816, accessed on June 12, 2018) with vortioxetine in adults (n = 490) with MDD in Japan.44

·  Later in 2018, Takeda plans to initiate regulatory filing of vortioxetine in Japan. Read more here.45

 

Conclusion

Takeda has historically been a big domestic player in the Japanese drug market. However, it started losing business due to multiple drugs under its umbrella going generic (e.g., Actos) and had reported its lowest profit in 15 years in 2015 (which was considered within Takeda as an “investment year”) 47, which is also coincidentally when it announced their strategy of globalizing their company brand. Its first step towards globalization was to internationalize certain functions (e.g., manufacturing) and revamp the organization structure by initiating foreign hires, including non-family and a non-Japanese CEO (an uncommon practice in Japan), Mr. Christophe Weber. He was hired with the expectations to spearhead Takeda’s vision into action by drumming up business in the form of mergers, acquisitions, collaborations, and out-of-the-box research partnerships, aiding in improving overall profitability. In the duration since he assumed his role as CEO in 2015, Takeda has had a total of 180 such partnerships48 (including more than 56 partnerships for early-line products)49 and is still looking for more such revenue-generating enterprises.

Takeda has shifted from a being a company with an extensive line of drugs to one with a more intensive approach, which involved trimming down its therapy areas, shedding its generics business (cheap drugs catering to a lot of people) in exchange for originator products (more expensive drugs that cater to a more targeted population [e.g., hemophilia]). However, the most talked-about deal of Takeda’s in recent times is its effort to acquire Shire, in part because the high financial risk involved, which highlights the CEO’s aggressive growth vision for Takeda. This acquisition also implies how compellingly Takeda is trying to establish itself as an international brand offering novel emerging drugs, especially because multiple drugs within its current portfolio have faced/are facing patent expiries, and the domestic market is shrinking as well (i.e., the Japanese government has promoted use of generics for managing patients).

Despite Takeda’s active absorption of companies and remodeling of itself, the company’s CNS-specific pipeline is in early stages of development, with just two Phase II CNS drugs (i.e., TAK-935 and TAK-831) in its pipeline50 (and three drugs in Phase III across all indications covered in its areas of focus), which will translate into delayed revenue generation (if at all).

TAK-935 is being co-developed by Takeda and Ovid Therapeutics. It is a highly selective cholesterol 24-hydroxylase inhibitor that is being developed for the treatment of rare pediatric epilepsies.51 The compound showed positive safety, tolerability, and PK profiles in preclinical and four Phase I clinical studies conducted in healthy subjects52-55 and is conducting a Phase I/II study to establish its safety and tolerability as an adjunctive therapy in managing developmental and/or epileptic encephalopathies (see “Disease Landscape & Forecast – Epilepsy”).56

TAK-831 is a D-amino-acid oxidase inhibitor that is being developed to treat negative and cognitive symptoms of schizophrenia.57 Takeda is conducting two Phase II studies58,59 to establish the efficacy, safety and tolerability, and PK/PD of TAK-831 at multiple dose levels in adults with schizophrenia (see “Disease Landscape & Forecast – Schizophrenia”). It is also being investigated in adults with Friedreich Ataxia and was awarded orphan drug designation for this indication in December 2017.63 It is currently in a Phase II proof-of-concept clinical trial (see “Disease Landscape & Forecast – Friedreich Ataxia).60 Note, Takeda terminated part 3 of its four-part Phase I study because of patient discomfort during the CSF sample collection process; no serious adverse events were reported during the remaining parts.61 These upcoming late-stage CNS drugs targeting underserved CNS patient populations plays well into Takeda’s current strategy.

At the same time, one cannot overlook how well Takeda has adhered to its vision and has been dedicated to investing in its diverse research partnerships—including using artificial intelligence to better analyze treatment targets, and to identify “beyond the pill” technologies, which have the potential to help drug developers better understand the problem patients are facing first-hand and in somewhat of a real-time scenario (i.e., from data collected via mobile phone apps) than via a third party (i.e., through physician assumptions or primary market surveys for patients), data collection methods which have their own limitations [e.g., geographical bias in surveys, whereas mobile apps reach a broad pool of smartphone users, who will require only basic guidance on maneuvering the app).

As per DRG’s Company and Drug Insights62, Takeda’s 2017 ethical drug sales reached $15 billion worldwide, placing it within the top 20 pharmaceutical companies, though its revenue curve will be stymied in the recent years (i.e., 2019-20) due to drug genericization. Simultaneously, though Shire’s worldwide ethical drugs sales were valued at $14 billion in 2017, they are expected to grow steadily over the next few years owing to its robust late-phase pipeline. This acquisition of Shire by Takeda would possibly result in Takeda steadying its revenue during this duration, courtesy of consistent revenues from Shire’s blockbuster drug, Vyvanse/Elvanse, which also includes the drug’s upcoming launch in Japan (it is presently registered there)65, complemented with recent drug approvals (i.e., SHP-660 in hemophilia A)64, seven registered drugs, and 15 Phase III drugs.65

 

 

In the last several years of its more than 200-year existence, Takeda has undergone considerable restructuring in terms of its operations, functions, executive leadership, pretty much everything you can put a finger on. While the fruits of Takeda’s efforts have yet to be borne out in full, the initiatives the company has undertaken to date signify a distinct determination and drive to bring its revised strategy into focus. It will certainly be interesting to see how all these measures will benefit the company, but for now, it seems like a promising enterprise.

 

References:

  1. Takeda, press release, July 29, 2016
  2. Takeda, press release, February 28, 2017
  3. Takeda, press release, May 14, 2017
  4. Takeda, press release, May 15, 2017
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  10.   AstraZeneca, press release, December 16, 2015
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  63. Orphan Drug Designations and Approvals, FDA, December 6, 2017
  64. Form 10-K, Shire, December 31, 2017
  65. Shire Pipeline, accessed June 4, 2018

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