Study Published In The New England Journal Of Medicine Demonstrates Efficacy And Favourable Safety Profile Of Firazyr® (Icatibant) For The Treatment Of Hereditary Angioedema (HAE) Attacks

Icatibant is the first subcutaneous injection for treatment of acute HAE attacks approved in the European Union.

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Shire plc (LSE: SHP, NASDAQ: SHPGY), the global specialty biopharmaceutical company, today announced the publication of results from two Phase III studies of FIRAZYR® (icatibant) in the August 5th issue of the New England Journal of Medicine. The studies, FAST-1 and FAST-2 (For Angioedema Subcutaneous Treatment), were designed to evaluate the effect of icatibant in adult patients with Type 1 or Type 2 hereditary angioedema (HAE) presenting with cutaneous and/or abdominal attacks.

FAST-2 demonstrated that icatibant was well tolerated and provided a significant benefit in the median time to onset of clinically significant symptom relief of either abdominal pain, cutaneous pain or cutaneous swelling compared to tranexamic acid.¹  The findings of the placebo-controlled study, FAST-1, were consistent with respect to tolerability and showed a numerically similar, though non-statistically-significant, benefit for icatibant with respect to the primary endpoint.¹  Open label treatment of laryngeal attacks with icatibant showed median time to first symptom improvement as reported by the patient was 0.6 hours in FAST-1 and 1.0 hours in FAST-2.¹ Laryngeal attacks can be life threatening due to the risk of suffocation as the airways become obstructed by swelling.

“People with HAE live with a persistent anxiety which stems from the unpredictability and variability of their disease,” said Professor Marco Cicardi of the Department of Internal Medicine at the University of Milan. “The publication of this study shows the subcutaneous injection of icatibant to be an effective and well-tolerated treatment for acute attacks of HAE in adults. In addition, patients have the reassurance of being able to carry icatibant with them at all times for any trained healthcare professional to administer subcutaneously in the eventuality of an attack.”

HAE is caused by an absence or dysfunction of C1 esterase inhibitor (C1-INH). Reduced C1-INH activity can lead to elevated plasma levels of bradykinin, the key mediator of HAE symptoms.¹

“Icatibant brings two exciting ‘firsts’ in the symptomatic treatment of acute HAE attacks. It is the first bradykinin B2 receptor antagonist, blocking the effects of bradykinin, the key mediator of HAE symptoms, and the first subcutaneously injectable treatment for HAE approved in Europe,” said Professor Cicardi. “Icatibant has been a positive addition to our treatment options for HAE within Europe.”

Phase III Studies – Overview and Results
In two double-blind, randomized, multicenter trials, the effect of icatibant was evaluated in patients with Type 1 or Type 2 HAE presenting with cutaneous and/or abdominal attacks. In the FAST-2 study, 74 patients received either 30 mg subcutaneous icatibant or oral tranexamic acid 3 g daily for 2 days. In the FAST-1 study, 56 patients received either 30 mg icatibant or placebo. The primary end point for both studies was median time to onset of clinically significant symptom relief. A further eight patients in FAST-1 and three in FAST-2 with laryngeal symptoms were treated with open-label 30 mg subcutaneous icatibant.¹
 
FAST -2
FAST-2 demonstrated that the primary endpoint, the median time to onset of clinically significant symptom relief was significantly shorter for icatibant versus tranexamic acid (2.0 hours vs. 12.0 hours (P<0.001).¹

Median time to first symptom improvement from abdominal pain, cutaneous pain or cutaneous swelling was significantly shorter for icatibant than for tranexamic acid according to both the patient (0.8 hours vs. 7.9 hours, P<0.001) and the investigator (1.5 vs. 6.9 hours, P<0.001).¹

Icatibant also showed a significant difference in median time to almost complete symptom relief versus the tranexemic acid (10.0 hours for icatibant vs 51.0 hours for tranexamic acid (P<0.001).¹

FAST -1
The primary end point of median time to onset of clinically significant symptom relief was 2.5 hours for patients given icatibant and 4.6 hours for patients given placebo, a difference that was not statistically significant (P=0.14).¹

However, median time to first symptom improvement from abdominal pain, cutaneous pain or cutaneous swelling was significantly shorter for icatibant than placebo according to both the patient (0.8 hours vs. 16.9 hours, P<0.001) and investigator (1.0 versus 5.7 hours, P<0.001).¹

The lack of significance for the primary endpoint in the FAST-1 trial may be attributed to the stringent definition of that endpoint in particular the inclusion of patients who received rescue medication in the analysis and the specification that only one symptom (index symptom) be assessed in defining symptom relief.¹

FAST-1 & FAST-2: Effective treatment of laryngeal attacks
The administration of icatibant in patients with laryngeal attacks resulted in a patient reported median time to symptom improvement of 0.6 and 1.0 hours in FAST-1 and FAST-2 respectively.¹

No drug-related serious adverse events were reported.¹ Although almost all icatibant treated patients experienced injection site reactions such as redness of skin, itching and in some cases burning and pain,¹ these were generally mild to moderate in severity, short-lived and resolved spontaneously.¹

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About Icatibant
Icatibant is the first subcutaneous injection for the symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults (with a C1-esterase-inhibitor deficiency).  Icatibant was approved in the European Union on July 15, 2008 for EU member states and is now approved in 36 countries around the world. The active substance, icatibant, is a specific bradykinin B2 receptor antagonist. It represents a novel and targeted approach to the treatment of HAE attacks by blocking effects of bradykinin, the key mediator of oedema formation. Icatibant provides rapid* symptom improvement and shortens the duration of an attack.²   Icatibant is a synthetic decapeptide (a peptide containing ten amino acids). The drug is supplied in a pre-filled 3 ml syringe and should be administered subcutaneously by a healthcare professional. Icatibant can be stored at up to 25 degrees Celsius without refrigeration.

Icatibant is not available in all countries and prescribing information may differ between countries.  Please consult your local prescribing information.

[ * Median time to first symptom improvement reported by the patient was 48 minutes in FAST 1 (P<0.001) and FAST 2 (P<0.001)¹; Median time to end of attack was 8.5 hours in FAST 1 (P=0.08) and 10.0 hours in FAST 2 (P<0.001)¹]

About Hereditary Angioedema (HAE)
HAE is a rare genetic disease characterised by recurrent sudden attacks of oedema (swelling) of the skin (hands, arms, feet, legs, thighs, face, genitals) or the mucous membranes (gastrointestinal tract, larynx or voicebox).³  The swelling can be disfiguring and painful, especially in case of abdominal attacks. Laryngeal attacks are potentially life-threatening due to the risk of suffocation. Unlike angioedemas caused by allergic reactions, signs and symptoms such as hives and itching do not occur in HAE. Patients often first notice redness or tingling over the area of skin that will be affected by swelling, before the HAE attack.³ HAE is caused by an inherited deficiency in a protein called C1-esterase inhibitor (C1-INH).³

Normally, C1-INH is involved in the regulation of the so called complement system which helps the body  to fight off infections. C1-INH also controls the activity of enzymes of the fibrinolytic, clotting and kinin pathways. C1-INH deficiency results in an increased release of a peptide called bradykinin, which is the key mediator of symptoms in HAE.¹ Bradykinin is a naturally occurring peptide in the blood and an increase in its levels within the blood causes a widening of spaces within the cell walls of blood vessels, and swelling/ oedema occurs. Blocking the B2 receptors of the bradykinin interrupts its action and stops the progression of further swelling/ oedema so the HAE attack subsides.^3,4

About Shire PLC
Shire’s strategic goal is to become the leading specialty biopharmaceutical company that focuses on meeting the needs of the specialist physician. Shire focuses its business on attention deficit hyperactivity disorder (ADHD), human genetic therapies (HGT) and gastrointestinal (GI) diseases as well as opportunities in other therapeutic areas to the extent they arise through acquisitions. Shire’s in-licensing, merger and acquisition efforts are focused on products in specialist markets with strong intellectual property protection and global rights. Shire believes that a carefully selected and balanced portfolio of products with strategically aligned and relatively small-scale sales forces will deliver strong results.

For further information on Shire, please visit the Company’s website: www.shire.com

"SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995
Statements included herein that are not historical facts are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, the Company’s results could be materially adversely affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of research, development, approval, reimbursement, manufacturing and commercialization of the Company’s Specialty Pharmaceutical and Human Genetic Therapies products, as well as the ability to secure and integrate new products for commercialization and/or development; government regulation of the Company’s products; the Company’s ability to manufacture its products in sufficient quantities to meet demand; the impact of competitive therapies on the Company’s products; the Company’s ability to register, maintain and enforce patents and other intellectual property rights relating to its products; the Company’s ability to obtain and maintain government and other third-party reimbursement for its products; and other risks and uncertainties detailed from time to time in the Company’s filings with the Securities and Exchange Commission.

References

¹ Cicardi M, Banerji A et al. Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema. N Engl J Med 2010;363:532-41
² FIRAZYR® Summary of Product Characteristics http://www.ema.europa.eu
³ Agostoni A et al. J Allergy Clin Immunol 2004;114 (Suppl):S51-131
⁴ Kaplan A, Kusumam J.The bradykinin-forming cascade and its role in hereditary angioedema. Ann Allergy Asthma Immunol. 2010;104:193-204