New Data from the Phase 3 HELP Study™ Open-Label Extension Evaluating Safety and Efficacy of TAKHZYRO® (lanadelumab) for Hereditary Angioedema Patients to be Presented at European Academy of Allergy and Clinical Immunology (EAACI) Hybrid Congress

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced results from two final analyses from the Phase 3 HELP (Hereditary Angioedema Long-term Prophylaxis) Study^™ Open-label Extension (OLE), which evaluated the long-term safety (primary endpoint) and efficacy of TAKHZYRO^® (lanadelumab) 300 mg every two weeks for up to 2.5 years. In the first analysis, the mean (min, max) reduction in the attack rate compared to baseline observed in the study population (N=212) was of 87.4 percent (-100; 852.8), and the median reduction was 97.7 percent and patients received treatment for a mean (standard deviation) duration of 29.6 (8.2) months.¹ At steady state – day 70 to the end of the treatment period – attack rates were further reduced to a mean of 92.4 percent and a median reduction of 98.2 percent.^2,3 An additional analysis further suggests TAKHZYRO was a well-tolerated treatment that prevented HAE attacks over an extended planned 132 week treatment period across specific HAE patient demographic and disease characteristic subgroups.³ These data are being presented at the 2021 European Academy of Allergy and Clinical Immunology (EAACI) Hybrid Congress in Krakow, Poland and Madrid, Spain.

“Hereditary angioedema is a lifelong condition and research shows that concerns about another attack can limit the way patients lead their lives,” said Prof. Markus Magerl, M.D., Department of Dermatology, Venereology and Allergology, Charité – Universitätsmedizin in Berlin, Germany. “The efficacy of TAKHZYRO to prevent HAE attacks over the long term will be an important consideration for patients and physicians as they develop a treatment plan for patients that is focused on reducing the number of HAE attacks.”

The original Phase 3 HELP Study was conducted in 125 patients aged 12 years and older over 26 weeks, making it the largest randomized, controlled prevention study in HAE, with the longest active treatment duration, to date.⁴ The HELP Study OLE was designed to evaluate the long-term safety (primary endpoint) and efficacy of TAKHZYRO for up to 2.5 years. The complete results were based on data collected between May 2016 and October 2019 and included 109 rollover patients who were originally evaluated in the HELP Study, and 103 eligible non-rollover patients who did not participate in the initial study but had experienced at least one HAE attack within the previous 12 weeks.¹

Attack-free status during steady state of lanadelumab treatment in patients with hereditary angioedema: findings from the HELP open-label extension study (Electronic Poster Presentation: Abstract #342)

Results from the HELP Study OLE found that TAKHZYRO sustained efficacy in the prevention of HAE attacks by reducing attack rates in a treatment period of up to 132 weeks. TAKHZYRO, which has a half-life of approximately 14 days, is expected to reach steady state at approximately 70 days. The HELP Study OLE analysis of attack-free status during the steady state period showed that the efficacy of TAKHZYRO 300 mg administered subcutaneously every two weeks in rollover patients was consistent with the original findings from the HELP Study.²

The mean (min, max) reduction in the attack rate compared to baseline observed in the study population (N=212) was of 87.4 percent (-100; 852.8), and the median reduction was 97.7 percent (98.0 percent rollovers, 96.9 percent non-rollovers).^1,2 At steady state, attack rates were further reduced to a mean of 92.4 percent (-100, 0.44) comprised of 92.7 percent rollovers (-100, -40.9) and 91.9 percent non-rollovers (-100, 0.44) and a median reduction of 98.2 percent (98.4 percent rollovers, 97.3 percent non-rollovers). During the first six months of treatment after day 70 during the steady-state period, 58.6 percent of patients (n=119) were attack-free, 54.7 percent rollovers and 62.9 percent non-rollovers. The maximum duration of attack-free period after day 70 ≥ 6 months was 83.7 percent and ≥ 12 months was 70 percent. The means of the average and maximum duration of attack-free period during steady state were 14.8 and 18.6 months, respectively, with 70.0 percent of patients (n=142) having a maximum duration of attack-free period greater than 12 months.²

Long-term prevention of attacks with lanadelumab across subgroups of patients with hereditary angioedema (HAE): final results from the HELP open-label extension study (Oral Presentation: Abstract #392)

In a further HELP Study OLE analysis, treatment with TAKHZYRO 300 mg every two weeks was well-tolerated and effectively reduced attack rates over an extended treatment period across different patient demographic and disease characteristics, including patient age, gender, race, HAE type, body mass index, history of long-term prophylaxis use, and baseline attack rate.³

The safety profile of TAKHZYRO was comparable across all evaluated subgroups with treatment-related TEAEs occurring in 54.7 percent of patients (n=116) and the most common being injection-site pain.³

“For more than a decade, we’ve listened to the HAE community to further understand the need for long-term, preventive targeted therapies and have committed our resources to developing treatment options,” said Neil Inhaber, M.D., Vice President, Global Medical Head, HAE and Transplant at Takeda. “These analyses further assert the important role TAKHZYRO can play in the lives of people who live with HAE.”

About The HELP Study^™ Open-label Extension

The HELP (Hereditary Angioedema Long-term Prophylaxis) Study^™ Open-label Extension (OLE) is an evaluation of the long-term efficacy and safety of TAKHZYRO in hereditary angioedema (HAE) patients of at least 12 years of age and older. Two hundred and twelve patients received treatment with TAKHZYRO at the start of the OLE Study (109 rollover patients originally evaluated in the HELP Study and who continued into the OLE, and 103 eligible patients who did not participate in the HELP Study but who had experienced at least one attack in the last 12 weeks). Rollover patients received a dose of 300 mg TAKHZYRO on Day 0 and then every two weeks after their first attack. Non-rollover patients were treated with one 300 mg dose every two weeks, beginning on Day 0. One hundred and ninety-six participants completed at least 12 months of treatment and 173 participants completed at least 30 months of treatment.¹

About Hereditary Angioedema

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.^5,6,7 Attacks that obstruct the airways can cause asphyxiation and are potentially life threatening.^7,8 HAE affects an estimated 1 in 50,000 people worldwide. It is often under recognized, under diagnosed and under treated.^5,7,8

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.

About TAKHZYRO^® (lanadelumab)

TAKHZYRO^® (lanadelumab) is indicated for routine prevention of recurrent attacks HAE in patients aged 12 years and older. TAKHZYRO is a fully human monoclonal antibody that specifically binds and decreases plasma kallikrein activity. TAKHZYRO is produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.⁹

TAKHZYRO is formulated for subcutaneous administration and has a half-life of approximately two weeks in patients with HAE. TAKHZYRO is intended for the self-administration or administration by a caregiver, only after training by a healthcare professional.⁹

TAKHZYRO is not intended for treatment of acute HAE attacks.⁹

Depending on regional marketing authorization, TAKHZYRO is available as a 300 mg dose in a vial or pre-filled syringe. Please consult local prescribing information for more information.

TAKHZYRO 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.⁹

Contraindication

Hypersensitivity to the active substance or to any of the excipients.⁹

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.⁹

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.⁹

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.⁹

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.⁹

Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium-free'.⁹

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.⁹

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.⁹

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.⁹

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.⁹

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.⁹

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 maculopapular, 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 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.

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

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Medical information

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¹ Banerji A, Hao J, Ming Y et al; Long-Term Efficacy and Safety of Lanadelumab: Final Results from the HELP Open-Label Extension Study. ACAAI 2020.
² Magerl M, Johnston D, et al. Attack-free status during steady state of lanadelumab treatment in patients with hereditary angioedema: findings from the HELP open-label extension study. EAACI 2021.
³ Maurer M, Bernstein J, et al. Long-term prevention of attacks with lanadelumab across subgroups of patients with hereditary angioedema (HAE): final results from the HELP open-label extension study. EAACI 2021.
⁴ 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.
⁵ 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.
⁶ Zuraw BL. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-1036.
⁷ Banerji A. The burden of illness in patients with hereditary angioedema. Ann Allergy Asthma Immunol. 2013;111(5):329-336.
⁸ Longhurst HJ, Bork K. Hereditary angioedema: causes, manifestations, and treatment. Br J Hosp Med. 2006;67(12):654-657.
⁹ TAKHZYRO (lanadelumab) European Summary of Product Characteristics.

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