MA-TAKEDA-PHARMACEUTICAL

Takeda (TSE:4502/NYSE:TAK) today announced that it has received approval from the Ministry of Health, Labour and Welfare (MHLW) for TAKHZYRO^® (lanadelumab) subcutaneous injection 300mg syringes for prophylaxis against acute attacks of hereditary angioedema (HAE) in adult and pediatric patients 12 years of age and older in Japan.¹

Hereditary angioedema (HAE) is a rare genetic disorder that results in recurring attacks of oedema – swelling – in various parts of the body, including the abdomen, face, feet, genitals, hands and throat. The swelling can be debilitating and painful. ^2,3,4 Attacks that obstruct the airways can cause asphyxiation and are potentially life threatening.^2,5 . HAE affects an estimated 1 in 50,000 people worldwide.² 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.³

This approval 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 results of a Phase 3 study evaluating the efficacy and safety of TAKHZYRO in Japanese patients. Combined, these studies have demonstrated the efficacy and safety profile of TAKHZYRO as a preventive treatment for HAE attacks.^1,6,7

“In addition to the burden of debilitating and potentially life-threatening HAE attacks, the unpredictable nature of this disease presents significant challenges to patients and their support networks,” said Naoyoshi Hirota, general manager, Takeda Development Center, Japan. “We hope TAKHZYRO, a new treatment option for patients in Japan living with HAE, along with the efficacy and safety profile as a preventive treatment showcased across global studies and within a Japan-specific Phase 3 study, will contribute to HAE treatment.”

TAKHZYRO received its first approval for the prevention of HAE attacks in patients 12 years and older in 2018 in the United States and in the European Union, and is now approved in more than 50 countries. TAKHZYRO is intended for self-administration or administration by a caregiver once trained by a healthcare professional.⁴ TAKHZYRO is supported by a robust clinical development program, which includes one of the largest prevention studies in HAE with the longest active treatment duration⁷ with additional regulatory submissions ongoing worldwide.

About the HELP Study^6,7
In the randomized, double-blind, placebo-controlled HELP study, which included 125 patients 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). 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. 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). 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%). Most treatment-emergent adverse events (98.5%) were mild to moderate in severity. The HELP Study™ and HELP OLE is the largest randomized, controlled clinical prevention study conducted to date in HAE.

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 bold in our mission to accelerate diagnosis and develop treatments that will make a difference to the lives of HAE patients, their support networks and those medical professionals who care for them.

TAKHZYRO^® (lanadelumab) Injection

TAKHZYRO is a fully human monoclonal antibody that specifically binds and decreases plasma kallikrein and is indicated for routine prophylaxis against acute attacks of HAE in patients aged 12 years and older. It was studied in one of the largest prevention studies in HAE with the longest active treatment duration, and TAKHZYRO consistently demonstrated HAE attack reduction. TAKHZYRO is formulated for subcutaneous administration and has a half-life of approximately two weeks. ⁴

Product name	TAKHZYRO subcutaneous injection 300 mg syringes
Generic name	Lanadelumab (Genetical Recombination)
Indications and effects	Prophylaxis against acute attacks of hereditary angioedema (HAE)
Dosage and Administration	The recommended dosage for adult patients and pediatric patients aged 12 years and older is 300 mg of lanadelumab (genetical recombination) injected subcutaneously every 2 weeks. For patients who remain HAE attack-free with symptoms well-controlled, 300 mg of lanadelumab may be injected subcutaneously every 4 weeks.

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 (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 and regions. For more information, visit https://www.takeda.com .

TAKHZYRO Safety Information for Europe

Please consult the TAKHZYRO Summary of Product Characteristics (SmPC) before prescribing.

Guidance for use
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 subcutaneous (SC) injection technique by a healthcare professional.

Contraindication
Hypersensitivity to the active substance or to any of the excipients.⁴

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. ⁴

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. ⁴

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. ⁴

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. ⁴

Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium-free'. ⁴

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.

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. ⁴

Immunogenicity
Treatment with lanadelumab has been associated with development of treatment emergent antidrug 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 neutralising antibodies. ⁴

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. ⁴

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. ⁴

Hypersensitivity reaction (mild and moderate pruritus, discomfort and tingling of tongue) was observed (1.2%)⁴

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. ⁴

** Hypersensitivity includes: pruritus, discomfort and tingling of tongue. ⁴

For European Union Summary of Product Characteristics, please visit https://www.ema.europa.eu/en/documents/product-information/takhzyro-epar-product-information_en.pdf.

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

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

Disclaimer
The drug information contained herein is intended to disclose corporate information. Nothing contained in this document should be considered a solicitation, promotion, or indication for any prescription drug, including those currently under development.

References

1. Package insert of TAKHZYRO subcutaneous injection 300 mg syringes.
2. Longhurst HJ, Bork K. Hereditary angioedema: causes, manifestations, and treatment. Br J Hosp Med. 2006;67(12):654-657.
3. 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.
4. TAKHZYRO^® (lanadelumab) European Summary of Product Characteristics.
5. Banerji A. The burden of illness in patients with hereditary angioedema. Ann Allergy Asthma Immunol. 2013;111(5):329-336.
6. Banerji A, Riedl MA, Bernstein JA, et al. Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks: a randomized clinical trial. JAMA. 2018;320(20):2108-2121. doi:1001/jama.2018.16773
7. Banerji A, Bernstein JA, Johnston DT, et al. Long-term prevention of hereditary angioedema attacks with lanadelumab: the HELP OLE Study. Allergy. 2022;77(3)979-990. doi:10.1111/all.15011

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