Shire Receives European Approval for TAKHZYRO™ (lanadelumab) subcutaneous injection, for the Preventive Treatment of Hereditary Angioedema

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Shire Receives European Approval for TAKHZYRO™ (lanadelumab) subcutaneous injection, for the Preventive Treatment of Hereditary Angioedema

-       TAKHZYRO is the first monoclonal antibody for the preventive treatment of Hereditary Angioedema (HAE) in patients 12 years and older available in the European Union
-       In the pivotal study, patients taking TAKHZYRO 300 mg every two weeks had an 87% relative reduction in mean monthly attacks vs. placebo (0.26 vs. 1.97, n=27 vs. n=41)
-       All secondary endpoints (including relative reduction in the number of attacks requiring acute treatment or assessed as moderate or severe) were met
-       According to a post-hoc sensitivity analysis, 77% of patients receiving lanadelumab 300 mg every two weeks were attack-free during the steady-state period of the study

Dublin, Ireland – 30 November 2018 – Shire plc (LSE: SHP, NASDAQ: SHPG), the leading global biotechnology company focused on rare diseases, today announced that the European Commission (EC) has granted Marketing Authorisation for TAKHZYRO™ (lanadelumab) subcutaneous injection, for routine prevention of recurrent attacks of hereditary angioedema (HAE) in patients aged 12 years and older. TAKHZYRO is a first-of-its-kind fully human monoclonal antibody (mAb) that inhibits the activity of plasma kallikrein, an enzyme which is uncontrolled in people with HAE, to help prevent attacks. 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.

"We are delighted to receive today’s European approval. For those with HAE, the burden of disease can significantly impact their day to day life,” said Andreas Busch, Ph.D., Executive Vice President, Head of Research and Development at Shire, "With TAKHZYRO, we can now provide an innovative treatment that has potential to change the way HAE is currently treated.”

The recommended starting dose is 300 mg lanadelumab every two weeks. In patients who are stably attack free on treatment, a dose reduction of 300 mg lanadelumab every four weeks may be considered, especially in patients with low weight.

The Phase III HELP (Hereditary Angioedema Long-term Prophylaxis) Study™ supporting the approval was recently published in JAMA. The primary endpoint was the number of investigator-confirmed HAE attacks over the entire 26-week study duration. TAKHZYRO 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).

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). Patients taking TAKHZYRO 300 mg every two weeks had 83% fewer moderate to severe attacks (vs. placebo), 87% fewer attacks that needed on-demand treatment (vs. placebo) and an 89% attack rate reduction (vs. placebo) from day 14 to 182. A prespecified, exploratory analysis showed that over the entire 26-week study (Days 0-182), 44% (n=12/27) of patients taking TAKHZYRO 300 mg every two weeks were attack-free vs. 2% (n=1/41) of patients taking placebo. Additionally, it is anticipated that TAKHZYRO reaches steady-state after approximately 70 days. A post-hoc sensitivity analysis showed that 77% (n=20/26) of the patients receiving TAKHZYRO 300 mg every two weeks were attack-free during steady-state (day 70-182) vs. 3% of patients on placebo (n=1/37).

Based on an exploratory endpoint, a clinically meaningful improvement in quality of life was observed in 81% of patients treated with TAKHZYRO 300 mg every two weeks compared to 37% of patients in the placebo group [assessed by the Angioedema Quality of Life Questionnaire (AE-QoL)]. The AE-QoL measures the impact of angioedema over a four-week period across four domains: fear/shame, functioning, fatigue/mood, and nutrition.

Henrik Balle Boysen, Executive Director for HAEi said, "On behalf of the HAE community, we welcome today’s news that provides a new option for the prevention of HAE attacks. We are grateful for the time and effort put forth by the patients and researchers who participated in the clinical program that enabled this important addition to the HAE treatment landscape.”

TAKHZYRO has a half-life of approximately two weeks and may be self-administered as one subcutaneous injection every two weeks. In clinical trials, the majority of patients took within 10 to 60 seconds to administer the injection.

Orphan Drug Designation has been maintained by the European Commission.

TAKHZYRO also received approval for the prevention of HAE attacks in people 12 years of age and older in the U.S. on 23 August 2018 and Canada on 19 September 2018. 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. For full Canada Prescribing Information within Canadian Product Monograph, please visit https://www.shirecanada.com/-/media/shire/shireglobal/shirecanada/pdffiles/product%20information/takhzyro-pm-en.pdf.

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.

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 studied: 300 mg every two weeks, 300 mg every four weeks, and 150 mg of TAKHZYRO every four weeks.

Complete results from the Phase 3 HELP Study™ were published in the Journal of the American Medical Association (JAMA) on 27 November 2018.

About TAKHZYRO (lanadelumab)
Lanadelumab is a fully human monoclonal antibody that specifically binds and decreases plasma kallikrein activity. Lanadelumab is produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. TAKHZYRO is approved by the European Medicines Agency (EMA) for routine prevention of recurrent attacks of hereditary angioedema (HAE) in patients aged 12 years and older. TAKHZYRO is formulated for subcutaneous administration and has a half-life of approximately two weeks in patients with HAE. TAKHZYRO is intended for self-administration or administration by a caregiver, only after training by a healthcare professional.

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%)

*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.

Shire’s Commitment to Hereditary Angioedema
Shire is a dedicated, long-term partner to the HAE community with a decade of experience supporting patients. We are committed to serial innovation in HAE and our portfolio of products includes a number of therapy options to help meet the individual needs of those living with the disease. Beyond our focus on developing novel treatments, we provide specialised services and support offerings tailored to the HAE community. Learn more at shire.com.

For further information please contact:

NOTES TO EDITORS

About Shire

Shire is the global biotechnology leader serving patients with rare diseases and specialized conditions. We seek to push boundaries through discovering and delivering new possibilities for patient communities who often have few or no other champions. Relentlessly on the edge of what’s next, we are serial innovators with a diverse pipeline offering fresh thinking and new hope. Serving patients and partnering with healthcare communities in over 100 countries, we strive to be part of the entire patient journey to enable earlier diagnosis, raise standards of care, accelerate access to treatment, and support patients. Our diverse portfolio of therapeutic areas includes Immunology, Hematology, Genetic Diseases, Neuroscience, Internal Medicine and Ophthalmics.
 
Championing patients is our call to action - it brings the opportunity - and responsibility - to change people’s lives.

www.shire.com

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a further list and description of risks, uncertainties and other matters can be found in Shire’s most recent Annual Report on Form 10-K and in Shire’s subsequent Quarterly Reports on Form 10-Q, in each case including those risks outlined in "ITEM1A: Risk Factors”, and in Shire’s subsequent reports on Form 8-K and other Securities and Exchange Commission filings, all of which are available on Shire’s website.

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