Takeda Pharmaceutical : Submits New Drug Application to Manufacture and Market Darvadstrocel In Japan for Treatment of Complex Perianal Fistulas in Adult Patients with Crohn’s Disease

Osaka, JAPAN, February 10, 2021 -Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) ('Takeda') today announced that it has submitted an application to the Japanese Ministry of Health, Labour and Welfare to manufacture and market darvadstrocel (development code: Cx601) for the treatment of complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn's disease (CD).

The application filing included data from two trials, the Japanese Study Darvadstrocel-3002 and the ADMIRE-CD trial, conducted in Europe and Israel.^1,3 Study Darvadstrocel-3002 is a Phase 3, multicenter, open-label, uncontrolled study investigating the efficacy and safety of darvadstrocel for the treatment of complex perianal fistulas in 22 Japanese adult patients with non-active/mildly active luminal CD.³ Results from Study Darvadstrocel-3002 will be presented at a scientific meeting in the near future. ADMIRE-CD was a randomized, double-blind, controlled, Phase 3 trial investigating the efficacy and safety of darvadstrocel for the treatment of complex perianal fistulas in 212 adult patients with non-active/mildly active luminal CD.¹

Naoyoshi Hirota, General Manager of Takeda Development Center Japan said, 'Complex perianal fistulas in Crohn's disease place a significant burden on patients and are a serious complication that greatly impacts quality of life.^4,5 We are extremely grateful to the patients and healthcare professionals who cooperated in the development of this investigational medicine, and we are proud to have taken this first step toward the potential approval of a cell-mediated closure option^1,2 for adult Crohn's disease patients with complex perianal fistulas in Japan.'

Darvadstrocel received an orphan drug designation from Japan's Ministry of Health, Labour and Welfare on March 13, 2019 for potential efficacy, effects, or performance in treating complex perianal fistulas in adult patients with CD.⁶ Darvadstrocel received central marketing authorization approval in Europe in March 2018 for the treatment of complex perianal fistulas in adult patients with non-active/mildly active luminal CD.⁷

About Complex Perianal Fistulas in Crohn's Disease (CD)

CD is a chronic inflammatory disease of the digestive system,⁸ which affects an estimated 70,000 people in Japan.⁹ People living with CD may experience complex perianal fistulas, which can cause intense pain,⁴ swelling, infection, and anal discharge.⁵ Despite medical and surgical advancements, complex perianal fistulas in CD remain challenging for clinicians to treat¹⁰ and negatively impact quality of life.⁴

About Darvadstrocel

Darvadstrocel is a suspension of allogeneic (or donor-derived) expanded adipose-derived stem cells (eASC) for the treatment of complex perianal fistulas in adult patients with non-active or mildly active luminal CD.² Darvadstrocel was granted orphan drug designation by the European Commission in 2009,⁷ and by the U.S Food and Drug Administration (FDA) in 2017.¹¹ Darvadstrocel received central marketing authorization approval in Europe in March 2018 for the treatment of complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn's disease,⁷ when fistulas have shown an inadequate response to at least one conventional or biologic therapy, and is marketed under the brand name Alofisel in Europe. Darvadstrocel should be used only after conditioning of the fistulas.² In 2019, darvadstrocel received a Regenerative Medicine Advanced Therapy (RMAT) designation from the U.S. FDA for complex perianal fistulas in adults with CD.¹²

Therapeutic Indications

Darvadstrocel is approved in the European Union, 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. Darvadstrocel should be used only after conditioning of the fistulas.

Important Safety Information²

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

Special warnings and special precautions for use
Darvadstrocel 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.

Darvadstrocel is indicated for injection in the fistula tract tissue only. Darvadstrocel 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 darvadstrocel 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.

Darvadstrocel 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 darvadstrocel in pregnant or breast-feeding women. Darvadstrocel 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.

▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See Section 4.8 of the SmPC for how to report adverse reactions.

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.

Disclaimer

Regulatory approval of the product and its use is dependent on the review by Japanese regulatory authorities. The drug information contained herein is intended for the disclosure of Takeda corporate information and is not intended to advertise or promote any prescription drug, including those under development.

Takeda in Gastroenterology

We believe that GI and liver diseases are not just life-disrupting conditions, but diseases that can impact a patient's quality of life.^14,15 Beyond a fundamental need for effective treatment options, we understand that improving patients' lives also depends on their needs being recognized. 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, eosinophilic esophagitis, alpha-1 antitrypsin-associated liver disease, Crohn's disease, and acute pancreatitis, among others. Together with researchers, patient groups and more, we are working to advance scientific research and clinical medicine in GI.

About Takeda Pharmaceutical Company Limited

Takeda Pharmaceutical Company Limited (TSE: 4502/NYSE: TAK) 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 Genetic and Hematology, Neuroscience, and Gastroenterology (GI). 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 healthcare in approximately 80 countries. For more information, visit https://www.takeda.com.