TAKEDA-PHARMACEUTICAL

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK ) (“Takeda”) today announced new data from an ad-hoc analysis of the Phase 3 HELP Study™, designed to evaluate the onset of action for TAKHZYRO^® (lanadelumab) during days 0-69 of treatment. The analysis suggests that TAKHZYRO starts to prevent hereditary angioedema (HAE) attacks during this early treatment phase, with patients experiencing an 80.1% decrease in mean monthly attack rate compared to placebo.¹ The results were presented today (PD0369) during the European Academy of Allergy and Clinical Immunology (EAACI) Congress in Lisbon, Portugal. HAE is a rare, genetic and potentially life-threatening disorder that can result in recurrent attacks of oedema (swelling) in various parts of the body.^2,3

“The unpredictable nature of HAE attacks makes living with the disease physically and emotionally challenging for patients,” said Professor Marcus Maurer, M.D., Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité–Universitätsmedizin Berlin, Germany. “HAE requires an individualised approach to treatment, and it is important that a patient’s treatment plan helps reduce the frequency of attacks. These results are exciting as they suggest that lanadelumab begins to prevent HAE attacks during the initial phase of treatment.”

The ad-hoc analysis evaluated the efficacy of TAKHZYRO compared with placebo during days 0-69 of treatment using the same approach that was used to evaluate the primary and secondary endpoints during the complete study period (days 0-182).¹ Results from the analysis showed that in patients receiving the recommended starting dose of TAKHZYRO 300 mg every two weeks, there was a significant reduction in mean monthly attack rate (80.1% decrease) compared to placebo (Adjusted P<0.001).¹ During this initial treatment phase, patients treated with TAKHZYRO 300 mg every two weeks also experienced fewer severe attacks compared to placebo (7.4% vs. 22%) and were more likely to be HAE attack-free compared to those on placebo (48.1% vs. 7.3%).¹

“Original data from the HELP Study showed that TAKHZYRO was effective in preventing HAE attacks over the entire duration of the study and, according to an exploratory analysis, many patients remained attack-free during the 16-week steady state period,” said Donatello Crocetta, M.D., Franchise Global Medical Unit Head, Rare Immunology and HAE at Takeda. “This new analysis supports previous study findings and builds on our understanding of how quickly TAKHZYRO can begin to help prevent HAE attacks, further supporting its use for appropriate patients as a preventive therapy that can be administered subcutaneously and begins to work rapidly.”

Across all TAKHZYRO treatment arms, (300 mg every two weeks, 300 mg every four weeks, 150 mg every four weeks), there was an improvement in mean monthly attack rate, monthly rate of moderate to severe attacks, monthly rate of attacks requiring acute treatment and the number of attack-free days, versus placebo, during the entire study period.¹

The most commonly observed adverse reactions (52.4%) associated with TAKHZYRO were injection site reactions. Of these, 97% were of mild intensity. Hypersensitivity reaction (mild and moderate pruritus, discomfort and tingling of tongue) was observed (1.2%).⁴

TAKHZYRO 300 mg is approved in the European Union and Australia for the routine prevention of recurrent attacks of HAE in patients aged 12 years and older. TAKHZYRO 300 mg is approved as prophylaxis to prevent attacks of HAE in patients aged 12 years and older in the United States and for the routine prevention of attacks in patients aged 12 years and older in Canada.

The HELP Study™
The HELP (Hereditary Angioedema Long-term Prophylaxis) Study™ was a multicentre, randomised, double-blind, placebo-controlled parallel group trial that evaluated the efficacy and safety of subcutaneously administered TAKHZYRO vs. placebo over 26 weeks in 125 patients 12 years of age or older with HAE.⁴

The primary endpoint of the HELP Study™ was the number of investigator-confirmed HAE attacks over the entire 26-week study duration. TAKHZYRO demonstrated that subcutaneous injections every two or four weeks reduced the mean monthly number of attacks across all three TAKHZYRO treatment arms studies: 300 mg every two weeks, 300 mg every four weeks and 150 mg of TAKHZYRO every four weeks. At 300 mg every two weeks, TAKHZYRO reduced the number of mean monthly HAE attacks by 87% vs. placebo (Adjusted P<0.001).⁴

Secondary endpoints included: 1) number of attacks requiring acute treatment and 2) number of attacks assessed as moderate or severe. Overall, each TAKHZYRO treatment arm demonstrated statistically significant attack rate reductions compared with placebo for all secondary efficacy endpoints (Adjusted P<0.001 for all comparisons), including: attacks requiring acute treatment (74% to 87%) and moderate or severe attacks (70% to 83%).⁴

Complete results from the Phase 3 HELP Study™ were published in the Journal of the American Medical Association (JAMA) on 27 November 2018.⁵

About 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.^2,3,6 Attacks that obstruct the airways can cause asphyxiation and are potentially life-threatening.^3,6 HAE affects an estimated 1 in 10,000 to 1 in 50,000 people worldwide. It is often under-recognised, under-diagnosed and under-treated.^2,7

About TAKHZYRO ^® (lanadelumab)
TAKHZYRO (lanadelumab) 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.⁴

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.⁴

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.

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

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.

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.

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.

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.

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

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.

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.

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.

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.

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 maclo-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 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 bringing Better Health and a Brighter Future to patients by translating science into highly innovative medicines. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Gastroenterology (GI), Neuroscience, and Rare Diseases. 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

¹ Riedl, MA et al. Lanadeluman demonstrates rapid and sustained prevention of hereditary angioedema attacks: Findings from the HELP study. Poster Presentation. European Academy of Allergy and Clinical Immunology. Lisbon, Portugal. June 2019.
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 TAKHZYRO^® (lanadelumab) Summary of Product Characteristics.
⁵ 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.
⁶ Banerji A. The burden of illness in patients with hereditary angioedema. Ann Allergy Asthma Immunol. 2013;111(5):329-336.
⁷ Longhurst HJ, Bork K. Hereditary angioedema: causes, manifestations, and treatment. Br J Hosp Med. 2006;67(12):654-657.

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