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Takeda Submits New Drug Application in Japan for Lanadelumab as a Preventive Treatment for Hereditary Angioedema Attacks

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Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced that it has submitted a New Drug Application (NDA) to the Ministry of Health, Labour and Welfare (MHLW) in Japan for lanadelumab subcutaneous injection, a monoclonal antibody therapy for prophylaxis against attacks of hereditary angioedema (HAE).

HAE is a rare genetic disorder that results in recurrent attacks of oedema – swelling – in various parts of the body, including the abdomen, face, feet, genitals, hands and throat.2,3,4 HAE affects an estimated 1 in 50,000 people worldwide.5 In Japan, it is estimated that between 2,000 and 3,000 people are living with HAE, but only approximately 450 have been diagnosed due to low awareness of the disorder in the country.6

“HAE is unpredictable, debilitating and potentially life-threatening, and recognition of the disease remains low in Japan, meaning there are significant challenges relating to diagnosis and access to effective therapies,” said Naoyoshi Hirota, General Manager, Takeda Development Center, Japan. “Lanadelumab is a fully human monoclonal antibody that specifically binds and decreases plasma kallikrein activity, with a proven efficacy and safety profile as a preventive treatment for HAE attacks. Takeda is committed to bringing important therapies such as lanadelumab to patients with high unmet medical needs around the world. Subject to approval, we are looking forward to providing lanadelumab as a new treatment option for patients in Japan living with HAE.”

Lanadelumab, under the tradename TAKHZYRO®, received its first approval for the prevention of HAE attacks in patients 12 years and older in 2018 and is now available in more than 20 countries with additional regulatory submissions ongoing worldwide.7

The submission of the New Drug Application in Japan is primarily based on results of the global Phase 3 HELP (Hereditary Angioedema Long-term Prophylaxis) Study™ and the Phase 3 HELP Study Open-label Extension (OLE), in addition to interim results of a Phase 3 study evaluating the efficacy and safety of lanadelumab in Japanese subjects.1,8 Combined, these studies have demonstrated the efficacy and safety profile of lanadelumab as a preventive treatment for HAE attacks. If approved, lanadelumab will be available to patients in Japan as a pre-filled syringe presentation.

In the randomized, double-blind, placebo-controlled HELP study, which included 125 people with HAE, lanadelumab reduced the mean number of monthly HAE attacks by 87% relative to placebo when administered at 300 mg every two weeks and 73% relative to placebo when administered at 300 mg every four weeks (adjusted P<0.001).1 A prespecified, exploratory analysis showed that over the entire 26-week study (days 0-182), 44% (n=12/27) of patients taking lanadelumab 300 mg every two weeks were attack-free vs. 2% (n=1/41) of patients taking placebo.1 A post-hoc sensitivity analysis showed that 77% (n=20/26) of the patients receiving lanadelumab 300 mg every two weeks were attack-free during a steady-state (day 70-182) vs. 3% of patients on placebo (n=1/37).1 The most commonly reported treatment-emergent adverse events (excluding HAE attacks) in patients treated with lanadelumab (n=84) during the entire treatment period were injection site pain (42.9%), viral upper respiratory tract infection (23.8%), headache (20.2%), injection site erythema (9.5%), injection site bruising (7.1%), and dizziness (6.0%).1 Most treatment-emergent adverse events (98.5%) were mild to moderate in severity.1 The HELP Study is the largest randomized, controlled clinical prevention study conducted to date in HAE.

The regulatory submission in Japan will be evaluated by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Following its review, the PMDA will issue a report to the Ministry of Health, Labour and Welfare (MHLW) of Japan for a final decision.

Takeda in Hereditary Angioedema
Hereditary Angioedema (HAE), like so many other rare diseases, is highly complex, and patients, their families and caregivers often undergo years of strain trying to understand their disease, get a definitive diagnosis and gain access to the medicines they need. At Takeda we are a committed champion for the patients we serve. Every individual living with HAE is unique and by listening and reacting to their needs, we translate the insights we gain into innovative solutions – from diagnosis to ongoing management. Advancing the science is crucial to the way we operate and we are unafraid to push at the boundaries of success in our mission to accelerate diagnosis and develop transformative and sustainable treatments that will make a difference to the lives of HAE patients, their support networks and those medical professionals who care for them.

About Lanadelumab
Lanadelumab is a fully human monoclonal antibody that specifically binds and decreases plasma kallikrein activity and is indicated for prophylaxis to prevent HAE attacks in patients 12 years and older. Lanadelumab is formulated for subcutaneous administration and has a half-life of approximately two weeks.7 Lanadelumab is intended for self-administration or administration by a caregiver. The patient or caregiver should be trained by a healthcare professional.7

TAKHZYRO® (lanadelumab) Safety Information for Europe
Please consult the TAKHZYRO Summary Product Characteristics (SmPC) before prescribing.

TAKHZYRO treatment should be initiated under the supervision of a physician experienced in the management of patients with hereditary angioedema (HAE). TAKHZYRO may be self-administered or administered by a caregiver only after training on SC injection technique by a healthcare professional.7

Contraindication
Hypersensitivity to the active substance or to any of the excipients.7

Warnings and Precautions
Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.7

Hypersensitivity reactions have been observed. In case of a severe hypersensitivity reaction, administration of TAKHZYRO must be stopped immediately and appropriate treatment must be initiated.7

General: TAKHZYRO is not intended for treatment of acute HAE attacks. In case of a breakthrough HAE attack, individualized treatment should be initiated with an approved rescue medication. There are no available clinical data on the use of lanadelumab in HAE patients with normal C1-INH activity.7

Interference with coagulation test: Lanadelumab can increase activated partial thromboplastin time (aPTT) due to an interaction of lanadelumab with the aPTT assay. The reagents used in the aPTT laboratory test initiate intrinsic coagulation through the activation of plasma kallikrein in the contact system. Inhibition of plasma kallikrein by lanadelumab can increase aPTT in this assay. None of the increases in aPTT in patients treated with TAKHZYRO were associated with abnormal bleeding adverse events. There were no differences in international normalised ratio (INR) between treatment groups.7

Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium-free'.7

Interactions
No dedicated drug-drug interaction studies have been conducted. Based on the characteristics of lanadelumab, no pharmacokinetic interactions with co-administered medicinal products is expected.7

As expected, concomitant use of the rescue medication C1 esterase inhibitor results in an additive effect on lanadelumab-cHMWK response based on the mechanism of action (MOA) of lanadelumab and C1 esterase inhibitor.7

Immunogenicity
Treatment with lanadelumab has been associated with development of treatment emergent anti-drug antibodies (ADA) in 11.9% (10/84) of subjects. All antibody titres were low. The ADA response was transient in 20% (2/10) of ADA positive subjects. 2.4% (2/84) of lanadelumab-treated subjects tested positive for neutralizing antibodies.7

The development of ADA including neutralising antibodies against TAKHZYRO did not appear to adversely affect the pharmacokinetic (PK) and pharmacodynamics (PD) profiles or clinical response.7

Adverse Reactions
The most commonly observed adverse reaction (52.4%) associated with TAKHZYRO was injection site reactions (ISR) including injection site pain, injection site erythema and injection site bruising. Of these ISRs, 97% were of mild intensity, 90% resolved within 1 day after onset with a median duration of 6 minutes.7

Hypersensitivity reaction (mild and moderate pruritus, discomfort and tingling of tongue) was observed (1.2%)

Very common
(frequency ≥1/10):

Injection site reactions*

Common
(≥1/100 to <1/10):

Hypersensitivity**, dizziness, rash maculo-papular, myalgia, alanine aminotransferase increased, aspartate aminotransferase increased.

*Injection site reactions include: pain, erythema, bruising, discomfort, haematoma, haemorrhage, pruritus, swelling, induration, paraesthesia, reaction, warmth, oedema and rash.
** Hypersensitivity includes: pruritus, discomfort and tingling of tongue.

For full U.S. Prescribing Information, including the approved indication and important safety information, please visithttps://www.shirecontent.com/PI/PDFs/TAKHZYRO_USA_ENG.pdf.

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 health care in approximately 80 countries. 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.

The companies in which Takeda directly and indirectly owns investments are separate entities. In this press release, “Takeda” is sometimes used for convenience where references are made to Takeda and its subsidiaries in general. Likewise, the words “we”, “us” and “our” are also used to refer to subsidiaries in general or to those who work for them. These expressions are also used where no useful purpose is served by identifying the particular company or companies.

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/reports/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.

1 Banerji A, Riedl MA, Bernstein JA, et al; for the HELP Investigators. Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks: a randomized clinical trial. JAMA. 2018;320(20):2108-2121.
2 Cicardi M, Bork K, Caballero T, et al; on behalf of HAWK (Hereditary Angioedema International Working Group). Evidence based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy. 2012; 67(2):147-157.
3 Zuraw BL. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-1036.
4 Banerji A. The burden of illness in patients with hereditary angioedema. Ann Allergy Asthma Immunol. 2013;111(5):329-336.
5 Longhurst HJ, Bork K. Hereditary angioedema: causes, manifestations, and treatment. Br J Hosp Med. 2006;67(12):654-657.
6 Hide M, Horiuchi T, et al. Management of hereditary angioedema in Japan: Focus on icatibant for the treatment of acute attacks. Allergol Int. 2021 Jan;70(1):45-5.
7 TAKHZYRO® (lanadelumab) European Summary of Product Characteristics.
8 Efficacy and Safety of Lanadelumab (SHP643) in Japanese Participants With Hereditary Angioedema (HAE). https://clinicaltrials.gov/ct2/show/NCT04180163. Accessed January 2021.

Contact information

Media Contacts:
Japanese Media
Kazumi Kobayashi
kazumi.kobayashi@takeda.com
+81 (0) 3-3278-2095

Media Outside Japan
Emily Bunting
Emily.bunting@takeda.com
+41 79 866 9703

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