- Data on Patients with Complex Crohn’s Perianal Fistulas Were Presented at the European Crohn’s and Colitis Organisation (ECCO) 2022 Congress¹

- INSPIRE is the First Observational, Multicenter, Post-Approval, Open-Enrollment Study Designed to Evaluate the Real-World Effectiveness and Safety of Alofisel (darvadstrocel)¹

- Approved in the European Union/European Economic Area, Israel, Switzerland, United Kingdom and Japan, Alofisel, an Expanded Human Allogeneic Adipose-Derived Mesenchymal Stem Cell Therapy, Offers a Potential Cell-Mediated Closure Option for Patients with Complex Crohn’s Perianal Fistulas Who Have Shown an Inadequate Response to at Least One Conventional or Biologic Therapy^3,4,5,6,7,8

Takeda (TSE:4502/NYSE:TAK) today announced the first six-month interim analysis results from INSPIRE, in which clinical remission^* was observed in 65% of patients in both cohorts who were evaluated at 6 months.¹ INSPIRE is a European, observational, multicenter, post-approval, open-enrollment study (EUPAS24267) evaluating the real-world effectiveness and safety of Alofisel (darvadstrocel) in patients with Crohn’s disease (CD) and complex perianal fistulas.^1,2

As of September 2021, 230 patients had enrolled in the ongoing study.¹ The All Treated (AT) cohort consisted of all patients in the study who received Alofisel; the Treated Per Protocol (PP) cohort consisted of all patients in the study who received Alofisel according to protocol recommendation.¹ 138 patients in the All Treated (AT) cohort and 120 patients in the Treated Per Protocol (PP) cohort were six-months post treatment and 66% for AT (92/138) and 58% for PP (69/120) had a six-month visit completed.¹ Among them, 85% (78/92) of the AT cohort and 100% (69/69) of the PP cohort had clinical outcome data available at six-months.¹ Clinical response^† was observed in 73% (57/78) and 74% (51/69) of patients in the AT and PP cohorts, respectively.¹ Clinical remission^* was observed in 65% of patients in both cohorts (AT cohort: 51/78; PP cohort: 45/69).¹

Changes in CD activity, assessed using the Harvey–Bradshaw Index, post-treatment were minimal.¹ Of the 205 patients with complete treatment data, 20% (41/205) had one or more adverse event and 9.3% (19/205) had one or more serious adverse event.¹ There were no reports of ectopic tissue formation and no deaths.¹

“Complex perianal fistulas are a painful, disabling and often embarrassing complication of Crohn’s disease that can be extremely challenging to treat.^9,10,11,12 Despite advances, many patients relapse and do not achieve fistula closure following treatment,¹³” said Professor Oded Zmora, Colon and Rectal Surgeon and Chair of the Department of Surgery, Shamir Medical Center, Tel Aviv, Israel, and Chair of the INSPIRE steering committee. “These promising initial results from the INSPIRE study build knowledge on Alofisel as a treatment option in this area, and I look forward to future analyses with longer follow-up times.”

“We are delighted to present the results of the first interim analysis from the real-world multicenter INSPIRE study. These results are consistent with the pivotal Phase 3 ADMIRE-CD study in terms of efficacy and safety,¹” said Elisabeth Genestin, Senior Global Brand Medical Affairs Director GI Rare Disease, Takeda. “The INSPIRE study aims to include more patients, to promote a better understanding of disease presentation, patient characteristics, patterns of care and clinical outcomes in a large multicenter, heterogenous patient population and we look forward to sharing more data and insights with the community as the study progresses.²”

ADMIRE-CD was a randomized, double-blind, controlled, Phase 3 trial investigating the efficacy and safety of Alofisel for the treatment of complex perianal fistulas in 212 adult patients with non-active/mildly active luminal CD.⁷ A significantly greater proportion of patients in the Alofisel group, compared to the control group, achieved the primary endpoint of combined remission at a 24 week follow-up (51.5% vs 35.6%; a difference of 15.8 percentage points; 97.5% CI 0.5-31.2; P =0.021), and this was maintained over 52 weeks (56.3% vs 38.6%; a difference of 17.7 percentage points; 95% CI 4.2-31.2; P =0.01).¹³ Alofisel treatment was well-tolerated over 52 weeks, with a similar safety profile in the Alofisel group compared to the control group.¹³

^* clinical remission is defined as closure despite gentle finger compression of all external openings treated with darvadstrocel that were draining at baseline

^† clinical response is defined as closure despite gentle finger compression of ≥50% of external openings treated with darvadstrocel that were draining at baseline

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About Alofisel

Alofisel is a suspension of expanded allogeneic (donor-derived), adipose-derived mesenchymal stem cells (eASC) for the treatment of complex perianal fistulas in adult patients with non-active or mildly active luminal CD.³ In March 2018, Alofisel became the first allogeneic stem cell therapy to receive central marketing authorization approval in the European Union.^3,14 In 2019, darvadstrocel received a Regenerative Medicine Advanced Therapy (RMAT) designation from the U.S. FDA for complex perianal fistulas in adult patients with CD.¹⁵ In September 2021, Alofisel became the first expanded human allogeneic adipose-derived mesenchymal stem cell therapy to be approved in Japan.^4,16

Therapeutic Indications

Alofisel is approved in the European Union/European Economic Area, Israel, Switzerland and the United Kingdom for the treatment of complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn’s disease, when fistulas have shown an inadequate response to at least one conventional or biologic therapy.^3,5,6 Alofisel should be used only after conditioning of the fistulas.^3,5,6

In Japan, Alofisel is indicated for the treatment of complex perianal fistulas in patients with non-active or mildly active luminal Crohn’s disease (CD).^4,16 This product is indicated for the treatment of patients who have shown an inadequate response to at least one existing medicinal treatment.^4,16

Important Safety Information³

Contraindications

Hypersensitivity to the active substance, bovine serum or to any of the excipients.

Special warnings and special precautions for use

Alofisel may contain trace amounts of either gentamicin or benzylpenicillin and streptomycin. This should be considered in patients with known hypersensitivity to these classes of antibiotics. Local anesthesia is not recommended due to the unknown effect of local anesthetics on the injected cells.

The injection of any substance other than sodium chloride 9 mg/mL (0.9%) (e.g. hydrogen peroxide, methylene blue, iodine solutions or hypertonic glucose solutions) through the fistula tracts is not allowed before, during, or after the injection of darvadstrocel as this may compromise cell viability.

Alofisel is indicated for injection in the fistula tract tissue only. Alofisel must not be administered using a needle thinner than 22G. Thinner gauge needles can cause cell disruption during injection and may compromise cell viability.

As Alofisel is a living stem cell therapy, it cannot be sterilized, and therefore could contain potentially infected biological material, although the risk is considered to be low and controlled in the manufacturing process. Patients should be followed up for potential signs of infection after administration.

Alofisel should only be administered by specialist physicians experienced in the diagnosis and treatment of conditions for which Darvadstrocel is indicated.

Fertility, Pregnancy & Lactation

No data is available from the use of Alofisel in pregnant women. Alofisel is not recommended during pregnancy and in women of childbearing potential who are not using contraception. As a precautionary measure, darvadstrocel is not recommended for administration during breast-feeding.

Adverse reactions include: Common (≥1/100 to <1/10): anal abscess, proctalgia, anal fistula and procedural pain. Conditioning of fistulas has been associated with proctalgia and procedural pain.

For EU audiences, please see the Summary of Product Characteristics (SmPC) for Alofisel^®▼.

Please consult with your local regulatory agency for approved labeling in your country.

Takeda in Gastroenterology

We believe that gastrointestinal (GI) and liver diseases are not just life-disrupting conditions, but diseases that can impact a patient’s quality of life.^17,18 Beyond a fundamental need for effective treatment options, we understand that improving patients’ lives also depends on their needs being recognized.^17,18 With nearly 30 years of experience in gastroenterology, Takeda has made significant strides in addressing GI patient needs with treatments for inflammatory bowel disease (IBD), acid-related diseases, short bowel syndrome (SBS), and motility disorders. We are making significant strides toward closing the gap on new areas of unmet needs for patients who have celiac disease, alpha-1 antitrypsin-associated liver disease and Crohn’s disease, among others. Together with researchers, patient groups and more, we are working to advance scientific research and clinical medicine in GI.

About Takeda

Takeda is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to discover and deliver life-transforming treatments, guided by our commitment to patients, our people and the planet. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Genetics and Hematology, Neuroscience, and Gastroenterology. We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people’s lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries and regions. For more information, visit https://www.takeda.com.

Important Notice

For the purposes of this notice, “press release” means this document, any oral presentation, any question and answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited (“Takeda”) regarding this release. This press release (including any oral briefing and any question-and-answer in connection with it) is not intended to, and does not constitute, represent or form part of any offer, invitation or solicitation of any offer to purchase, otherwise acquire, subscribe for, exchange, sell or otherwise dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or other securities are being offered to the public by means of this press release. No offering of securities shall be made in the United States except pursuant to registration under the U.S. Securities Act of 1933, as amended, or an exemption therefrom. This press release is being given (together with any further information which may be provided to the recipient) on the condition that it is for use by the recipient for information purposes only (and not for the evaluation of any investment, acquisition, disposal or any other transaction). Any failure to comply with these restrictions may constitute a violation of applicable securities laws.

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Forward-Looking Statements

This press release and any materials distributed in connection with this press release may contain forward-looking statements, beliefs or opinions regarding Takeda’s future business, future position and results of operations, including estimates, forecasts, targets and plans for Takeda. Without limitation, forward-looking statements often include words such as “targets”, “plans”, “believes”, “hopes”, “continues”, “expects”, “aims”, “intends”, “ensures”, “will”, “may”, “should”, “would”, “could” “anticipates”, “estimates”, “projects” or similar expressions or the negative thereof. These forward-looking statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those expressed or implied by the forward-looking statements: the economic circumstances surrounding Takeda’s global business, including general economic conditions in Japan and the United States; competitive pressures and developments; changes to applicable laws and regulations, including global health care reforms; challenges inherent in new product development, including uncertainty of clinical success and decisions of regulatory authorities and the timing thereof; uncertainty of commercial success for new and existing products; manufacturing difficulties or delays; fluctuations in interest and currency exchange rates; claims or concerns regarding the safety or efficacy of marketed products or product candidates; the impact of health crises, like the novel coronavirus pandemic, on Takeda and its customers and suppliers, including foreign governments in countries in which Takeda operates, or on other facets of its business; the timing and impact of post-merger integration efforts with acquired companies; the ability to divest assets that are not core to Takeda’s operations and the timing of any such divestment(s); and other factors identified in Takeda’s most recent Annual Report on Form 20-F and Takeda’s other reports filed with the U.S. Securities and Exchange Commission, available on Takeda’s website at: https://www.takeda.com/investors/sec-filings/ or at www.sec.gov. Takeda does not undertake to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results or statements of Takeda in this press release may not be indicative of, and are not an estimate, forecast, guarantee or projection of Takeda’s future results.

Medical information

This press release contains information about products that may not be available in all countries, or may be available under different trademarks, for different indications, in different dosages, or in different strengths. Nothing contained herein should be considered a solicitation, promotion or advertisement for any prescription drugs including the ones under development.

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References

¹ Zmora O, Baumgart DC, Faubion W et al. P603 INSPIRE: 6-month interim analysis from an observational post-marketing registry on the effectiveness and safety of darvadstrocel in patients with Crohn’s disease and complex perianal fistulas. J Crohn’s Colitis. 2022;16:i536-i537

² An observational post-marketing registry on the effectiveness and safety of darvadstrocel in patients with Crohn's disease and complex perianal fistulas (INSPIRE). European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP). Available at https://www.encepp.eu/encepp/viewResource.htm?id=44173. Last updated: November 2021 Last accessed: February 2022

³Alofisel Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/alofisel-epar-product-information_en.pdf. Last updated August 6, 2021. Last accessed February 2022.

⁴ Japan Pharmaceuticals and Medical Devices Agency. Products Approved in FY 2021: Regenerative Medical Products. Available at: https://www.pmda.go.jp/files/000244758.pdf. Last accessed: February 2022.

⁵ Ministry of Health Israel. The Israeli Drug Registry. Alofisel. Available at: https://data.health.gov.il/drugs/alonim/Rishum_18_484505220.pdf. Last updated December 2020. Last accessed February 2022.

⁶ Swissmedic. Alofisel^®, Suspension zur Injektion (Darvadstrocelum). Available at: https://www.swissmedic.ch/swissmedic/en/home/humanarzneimittel/authorisations/new-medicines/alofisel_suspensionzurinjektion_darvadstrocelum.html. Last updated December 27, 2018. Last accessed February 2022.

⁷ Panés J, García-Olmo D, Van Assche G, et al. ADMIRE CD Study Group Collaborators. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016;24;388(10051):1281-90.

⁸ García-Olmo D, Gilaberte I, Binek M, et al. Follow-up study to evaluate the long-term safety and efficacy of darvadstrocel (mesenchymal stem cell treatment) in patients with perianal fistulizing Crohn's disease: ADMIRE-CD Phase 3 randomized controlled trial. Dis Colon Rectum. 2021. Online ahead of print.

⁹ Marzo M, Felice C, Pugliese D, et al. Management of perianal fistulas in Crohn’s disease: An up-to-date review. World J Gastroenterol. 2015; 21(5): 1394-1403

¹⁰ Aguilera-Castro L, Ferre-Aracil C, Garcia-Garcia-de-Paredes A, et al. Management of complex perianal Crohn’s disease. Annals of Gastroenterology. 2017; 30: 33-44.

¹¹ Geltzeiler C, Wieghard N and Tsikitis V. Recent developments in the surgical management of perianal fistula for Crohn’s disease. Ann Gastroenterol. 2014; 27(4): 320-330.

¹² Spinelli A, Yanai H, Lӧnnfors S et al. EFCCA. P435 The impact of perianal fistula in Crohn’s disease on quality of life: results of a patient survey conducted in Europe. J Crohn’s Colitis . 2021;15: S436-S437.

¹³ Panés J, García-Olmo D, Van Assche G et al. ADMIRE CD Study Group Collaborators. Long-term efficacy and safety of stem cell therapy (Cx601) for complex perianal fistulas in patients with Crohn's disease. Gastroenterology. 2018 Apr;154(5):1334-1342.e4.

¹⁴ Takeda Pharmaceutical Company Ltd. TiGenix and Takeda announce Alofisel ^® (darvadstrocel) receives approval to treat complex perianal fistulas in Crohn’s disease in Europe. Available at https://www.takeda.com/newsroom/newsreleases/2018/tigenix-and-takeda-announce-alofisel-receives-approval-in-europe/. Last accessed February 2022.

¹⁵ RMAT Designation Letter, May 2019. Takeda Pharmaceuticals USA, Inc.

¹⁶ Takeda Pharmaceutical Company Ltd. Takeda receives approval to manufacture and market Alofisel ^®▼ (darvadstrocel) in Japan for treatment of complex perianal fistulas in patients with non-active or mildly active luminal Crohn’s disease. Available at https://www.takeda.com/newsroom/newsreleases/2021/takeda-receives-approval-to-manufacture-and-market-alofisel-darvadstrocel-in-japan-for-treatment-of-complex-perianal-fistulas-in-patients-with-non-active-or-mildly-active-luminal-crohns-disease/. Last accessed February 2022.

¹⁷ Center for Drug Evaluation and Research (CDER) & the FDA. The Voice of the patient/functional gastrointestinal disorder. 2016. Available at: https://www.fda.gov/media/95140/download. Last accessed February 2022.

¹⁸ Jones R, Hunt C, Stevens R, et al. Management of common gastrointestinal disorders: quality criteria based on patients’ views and practice guidelines. Br J Gen Pract. 2009;59:e199-208.

Copyright 2022 Takeda Pharmaceutical Company Limited. All rights reserved. Takeda and the Takeda Logo are registered trademarks of Takeda Pharmaceutical Company Limited.

Date of preparation: February 2022

C-ANPROM/INT/ALOFI/0117

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