Shire Receives Approval of FIRAZYR(R) (icatibant injection) for the Treatment of Hereditary Angioedema (HAE) Attacks in Japan

• FIRAZYR is the first subcutaneous on-demand therapy for HAE in Japan, allowing patients to treat symptoms of acute HAE attacks
• Approval supported by data from dedicated study of HAE patients in Japan
• HAE is a rare, genetic disorder that causes debilitating, painful and sometimes life-threatening swelling in the body

Dublin, Ireland – September 21, 2018 – Shire plc (LSE: SHP, NASDAQ: SHPG) the leading global biotechnology company focused on rare diseases, today announced that the Ministry of Health, Labour and Welfare (MHLW) in Japan has granted manufacturing and marketing authorisation for FIRAZYR^® (icatibant injection), for the acute treatment of hereditary angioedema (HAE) attacks in adult patients with HAE.

HAE is a rare genetic disease characterised by recurrent attacks of localized oedema (swelling). The areas of the body most commonly affected are the extremities, skin, gastrointestinal tract and, less frequently, HAE can cause life-threatening attacks due to obstruction in the upper airways. Symptoms of HAE often present in childhood, and while attacks can occur at any age, early onset may predict a more severe disease course.

“As a long-term partner to the HAE community, we continually strive to bring treatments to those living with HAE around the world,” said Andreas Busch, Ph.D., Executive Vice President, Head of Research and Development at Shire. “HAE attacks can be unpredictable and debilitating and we are delighted that, subject to price listing, we will be able to provide the Japanese HAE community with the first subcutaneous on-demand therapy to treat acute HAE attacks.”

For most people, attacks of HAE are caused by a deficiency of a protein called C1-esterase-inhibitor (C1-INH), either there is not enough of it or it does not function properly. Without sufficient or functional C1-INH, plasma kallikrein in the body is not appropriately controlled. Overactive plasma kallikrein leads to excessive release of bradykinin which causes blood vessels to release fluid, leading to the swelling which characterises HAE. FIRAZYR works by blocking bradykinin from binding to certain receptors in the body, thereby treating the symptoms of acute attacks of HAE.

The use of FIRAZYR in Japanese patients was examined in an open-label, single-arm, Phase 3 study of 8 adult patients with a confirmed diagnosis of HAE who experienced angioedema attacks. During the study, 3 patients self-administered FIRAZYR and 5 patients had FIRAZYR administered by a physician. The primary efficacy endpoint was time to onset of symptom relief (TOSR), defined as a 50% reduction from baseline in patient Visual Analog Scale (VAS) score.

The study showed that FIRAZYR was well tolerated and demonstrated symptom relief during an acute HAE attack through a single injection. Overall, median TOSR was 1.75 hours, and TOSR was similar for patients who self-administered FIRAZYR or who had FIRAZYR administered by a physician. Symptom relief was attained as early as 1 hour after FIRAZYR injection and all patients had symptom relief within 5 hours.

The most common adverse events in patients treated with FIRAZYR were injection site reactions such as erythema, or swelling, which were found to be mild to moderate in severity.

About Hereditary Angioedema
HAE is a rare, genetic disorder estimated to affect about 1 in 10,000 to 1 in 50,000 people worldwide. There are an estimated 2,500 people living with HAE in Japan. The condition results in recurring attacks of oedema (swelling) in various parts of the body, including the abdomen, face, feet, genitals, hands and throat, that can be debilitating and painful. Laryngeal attacks that obstruct the airways are potentially life-threatening due to the risk of asphyxiation.

Management of HAE includes on-demand treatment of swelling attacks to minimise the consequences of the symptoms, and pre-procedure prevention, which is often used before certain surgeries. Long-term prophylaxis (the routine use of medication to prevent episodes of angioedema) may be considered for severely symptomatic patients with HAE.

About FIRAZYR
FIRAZYR is indicated in Japan for the acute treatment of hereditary angioedema (HAE) attacks in adult patients with HAE.

In general, the recommended dose of FIRAZYR is 30 mg administered subcutaneously in adults. Additional doses may be administered at intervals of at least 6 hours if response is inadequate or if symptoms recur. No more than 3 doses may be administered within any 24 hour period.

The active substance, icatibant, is a specific bradykinin B2 receptor antagonist. It represents a novel, targeted, subcutaneously-administered approach to the treatment of HAE attacks designed to block the effects of bradykinin, the key mediator of oedema formation. FIRAZYR is a synthetic decapeptide (a peptide containing ten amino acids).

Important Safety Information in Japan

Contraindications
Patients with hypersensitivity to ingredients of FIRAZYR.

Precautions

Careful Administration (FIRAZYR should be carefully administered to the following patients.)
(1) Under ischemic conditions, a deterioration of cardiac function and a decrease in coronary blood flow could theoretically arise from antagonism of bradykinin receptor type 2. Caution should therefore be observed in the administration of FIRAZYR to patients with acute ischemic heart disease or unstable angina pectoris

(2) Although there is evidence to support a beneficial effect of B2 receptor blockade immediately following a stroke, there is a theoretical possibility that icatibant may attenuate the positive late phase neuroprotective effects of bradykinin. Accordingly, caution should be observed in the administration of icatibant to patients in the weeks following a stroke.

Adverse reactions
Among the total of 8 subjects who received this product in a clinical study conducted in Japan, injection site reactions have been reported in 7 subjects (87.5%). No clinically meaningful changes related to this product were observed in clinical laboratory values.

In foreign Phase 3 clinical studies in HAE (113 patients), injection site reactions has been reported in 110 patients who were administered FIRAZYR (97.3%).

Serious hypersensitivity (Incidence unknown*)
Patients should be monitored carefully since serious hypersensitivity such as anaphylaxis, etc. may occur. If such a reaction is observed, treatment should immediately be discontinued and appropriate measures should be taken.
* The incidence of these adverse reactions is unknown because they are derived from the safety information of post-marketing in the overseas.

Other Adverse Reactions
>10% Injection site reactions (bruising, hematoma, burning, erythema, hypoesthesia, irritation, numbness, oedema, pain, pressure sensation, pruritus, swelling, urticaria, and warmth) (96.7%).

<10% Nausea, rash, erythema, pruritus, dizziness, headache, pyrexia, transaminases increased.

Use in the Elderly
Elderly patients (≥65 years) are likely to have increased systemic exposure to FIRAZYR compared to younger (18-45 years) patients. Accordingly, FIRAZYR should be administered carefully with monitoring the patient conditions sufficiently.

Use during Pregnancy, Delivery or Lactation
For pregnant women or women who may be pregnant, FIRAZYR should be administered only when therapeutic benefits justifies the potential risks. [The safety of this drug for use during pregnancy has not been established. Animal studies showed increase of pre-implantation loss, post-implantation loss and embryofetal death rates, and delaying parturition]

Breastfeeding women who are receiving icatibant should avoid breastfeeding. [It is unknown whether icatibant is excreted in human breast milk. Systemic absorption of icatibant in infants is not expected after oral exposure through breast milk. However, caution should be observed when FIRAZYR is administered to breastfeeding women].

Pediatric Use
Safety of this drug in premature infants, neonates, infants or young children less than 2 years of age has not been established. In the daily administration study of icatibant with juvenile rats, delaying of preputial separation and testes toxicity in males, and increase of pre-implantation loss in untreated females paired with icatibant-dosed males, have been observed.

Overdose
In a clinical study evaluating a 90mg dose, the adverse events were the same as seen with the approved dosage. In another study, a dose of 3.2mg/kg intravenously (approximately 8 times the therapeutic dose) caused transient erythema, itching, flushing or hypotension on healthy subjects. No therapeutic intervention was necessary.

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 specialized 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, Haematology, 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.

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