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New England Journal of Medicine Publishes Phase 1b Results for Shire's Investigational Treatment for Hereditary Angioedema, a Rare Genetic Disease

Thursday, February 23, 2017 Genetics & Stem Cells News
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CAMBRIDGE, Massachusetts, February 23, 2017 /PRNewswire/ --
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Results Served as Basis for Ongoing Phase 3 Trial  

Shire plc (LSE: SHP, NASDAQ: SHPG), the global leader in rare diseases, today announced the publication of results from the Phase 1b study of lanadelumab (SHP643; formerly DX-2930) in the February 23, 2017 issue of the New England Journal of Medicine (NEJM).
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Lanadelumab is a subcutaneously administered, human monoclonal antibody that specifically binds and inhibits plasma kallikrein, and it is being investigated for the prevention of angioedema attacks in patients with hereditary angioedema (HAE). HAE is a rare, genetic disorder estimated to affect about 1 in 10,000 to 1 in 50,000 people worldwide.[1] The condition results in recurrent, localized edema (swelling). The areas of the body most commonly affected are the extremities, gastrointestinal tract, and upper airways.[2],[3]

"In this Phase 1b study, no serious adverse events or discontinuations due to adverse events were observed at all doses studied. Pre-specified efficacy analyses in patients with at least 2 attacks in the 3 months prior to enrolment demonstrated that from day 8 to day 50, the administration of two doses of lanadelumab (300 or 400 mg) 14 days apart, reduced the rate of attacks by 100% and 88% respectively, when compared with placebo.  In addition, all subjects were attack-free in the 300 mg group and 82% were attack-free in the 400 mg group, compared to 27% in the placebo group," said Dr. Aleena Banerji, Associate Professor, Massachusetts General Hospital, Boston.

"The overall results of this study are encouraging; it should be noted that while the duration of treatment was relatively short and only a small number of patients were investigated, the results supported further Phase 3 investigations, which are currently ongoing," added Dr. Paula Busse, Associate Professor, Mount Sinai Hospital, New York.

"Despite improvements in the management of HAE in recent years, there is still a need for long-acting prophylactic treatment options. At Shire we are proud of our history in HAE and ongoing commitment to the clinical development of lanadelumab, an investigational prophylactic therapy for this rare genetic disease," said Philip J. Vickers, Ph.D., Global Head of Research and Development at Shire.

The complete publication can be found at nejm.org.[4] The main results were previously presented at the American College of Allergy, Asthma, and Immunology (ACAAI) Annual Scientific Meeting in 2015.

A pivotal Phase 3 trial evaluating the safety and efficacy of lanadelumab as a long-acting prophylactic treatment for HAE is currently underway.

With the clinical development of lanadelumab, Shire is building on its legacy in HAE and as the world leader in rare diseases.

About the Study (NCT02093923)[4]

The multicenter, randomized, double-blind, placebo-controlled, multiple-ascending dose study enrolled a total of 37 patients randomized to receive lanadelumab or placebo across four different dosing groups of 30, 100, 300, or 400 mg. Each subject received two doses of lanadelumab or placebo, separated by 14 days, and was followed for 120 days post-dose. The primary objective of the study was to assess the safety and tolerability of multiple subcutaneous administrations of lanadelumab at different dose levels in HAE patients. Secondary and tertiary objectives included characterization of the pharmacokinetics and pharmacodynamics of lanadelumab, evaluation of immunogenicity, and assessments of HAE attack frequency and use of acute attack therapy.

There were no serious adverse events or discontinuations due to adverse events reported in patients treated with lanadelumab. A total of 29% of the patients who received lanadelumab and 38% of those who received placebo had an adverse event that was considered by trial investigators, who were unaware of the trial-group assignments, to be treatment-related. The most common treatment-related adverse events were injection site pain (25% lanadelumab, 23% placebo) and headache (8% lanadelumab, 15% placebo).

In HAE patients, the pharmacokinetic profile of lanadelumab is linear, dose-dependent, and exhibits a half-life of approximately 14 days, typical of a human monoclonal antibody. The pharmacodynamic profile of lanadelumab was assessed by plasma levels of cleaved high molecular weight kininogen (cHMWK). Pharmacodynamic results confirm plasma kallikrein inhibition in a dose and time-dependent manner, and suggest doses of 300 mg or greater have the potential to normalize cHMWK levels based on levels of cHMWK approaching that observed in healthy subjects.  

About HAE 

HAE is a rare genetic disease characterized by recurrent and spontaneous episodes of swelling (edema), typically affecting the extremities, abdomen, face, throat and/or genitourinary tract.[2],[3] Swelling of the throat can be life-threatening due to asphyxiation.[5]-[7] In most cases, the disease is caused by a deficiency of functional C1-esterase inhibitor. This deficiency eventually results in excessive bradykinin production. Bradykinin is a vasodilator responsible for the characteristic symptoms of localized swelling, inflammation, and pain in HAE.[8]  

About Lanadelumab 

Unopposed activation of the kallikrein-kinin cascade leads to uncontrolled generation of plasma kallikrein, resulting in excessive bradykinin production.

Lanadelumab is an investigational human monoclonal antibody that specifically binds and inhibits plasma kallikrein, and it is being developed for the prevention of angioedema attacks in adult patients with HAE. Lanadelumab is formulated for subcutaneous administration with a half-life of approximately 14 days in patients with HAE.[4]

About Shire 

Shire is the leading global biotechnology company focused on serving people with rare diseases and other highly specialized conditions. We strive to develop best-in-class products, many of which are available in more than 100 countries, across core therapeutic areas including Hematology, Immunology, Neuroscience, Ophthalmics, Lysosomal Storage Disorders, Gastrointestinal / Internal Medicine / Endocrine and Hereditary Angioedema; and a growing franchise in Oncology.

Our employees come to work every day with a shared mission: to develop and deliver breakthrough therapies for the hundreds of millions of people in the world affected by rare diseases and other high-need conditions, and who lack effective therapies to live their lives to the fullest.

http://www.shire.com

Forward-Looking Statements 

Statements included herein that are not historical facts, including without limitation statements concerning future strategy, plans, objectives, expectations and intentions, the anticipated timing of clinical trials and approvals for, and the commercial potential of, inline or pipeline products 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, Shire's results could be materially adversely affected. The risks and uncertainties include, but are not limited to, the following:

  • Shire's products may not be a commercial success;
  • increased pricing pressures and limits on patient access as a result of governmental regulations and market developments may affect Shire's future revenues, financial condition and results of operations;
  • Shire conducts its own manufacturing operations for certain of its products and is reliant on third party contract manufacturers to manufacture other products and to provide goods and services.  Some of Shire's products or ingredients are only available from a single approved source for manufacture.  Any disruption to the supply chain for any of Shire's products may result in Shire being unable to continue marketing or developing a product or may result in Shire being unable to do so on a commercially viable basis for some period of time;
  • the manufacture of Shire's products is subject to extensive oversight by various regulatory agencies.  Regulatory approvals or interventions associated with changes to manufacturing sites, ingredients or manufacturing processes could lead to significant delays, an increase in operating costs, lost product sales, an interruption of research activities or the delay of new product launches;
  • certain of Shire's therapies involve lengthy and complex processes, which may prevent Shire from timely responding to market forces and effectively managing its production capacity;
  • Shire has a portfolio of products in various stages of research and development. The successful development of these products is highly uncertain and requires significant expenditures and time, and there is no guarantee that these products will receive regulatory approval;
  • the actions of certain customers could affect Shire's ability to sell or market products profitably. Fluctuations in buying or distribution patterns by such customers can adversely affect Shire's revenues, financial conditions or results of operations;
  • Shire's products and product candidates face substantial competition in the product markets in which it operates, including competition from generics;
  • adverse outcomes in legal matters, tax audits and other disputes, including Shire's ability to enforce and defend patents and other intellectual property rights required for its business, could have a material adverse effect on the combined company's revenues, financial condition or results of operations;
  • inability to successfully compete for highly qualified personnel from other companies and organizations;
  • failure to achieve the strategic objectives with respect to Shire's acquisition of NPS Pharmaceuticals, Inc., Dyax Corp. ("Dyax") or Baxalta Inc. ("Baxalta") may adversely affect Shire's financial condition and results of operations;
  • Shire's growth strategy depends in part upon its ability to expand its product portfolio through external collaborations, which, if unsuccessful, may adversely affect the development and sale of its products;
  • a slowdown of global economic growth, or economic instability of countries in which Shire does business, as well as changes in foreign currency exchange rates and interest rates, that adversely impact the availability and cost of credit and customer purchasing and payment patterns, including the collectability of customer accounts receivable;
  • failure of a marketed product to work effectively or if such a product is the cause of adverse side effects could result in damage to the Shire's reputation, the withdrawal of the product and legal action against Shire;
  • investigations or enforcement action by regulatory authorities or law enforcement agencies relating to Shire's activities in the highly regulated markets in which it operates may result in significant legal costs and the payment of substantial compensation or fines;
  • Shire is dependent on information technology and its systems and infrastructure face certain risks, including from service disruptions, the loss of sensitive or confidential information, cyber-attacks and other security breaches or data leakages that could have a material adverse effect on Shire's revenues, financial condition or results of operations;
  • Shire incurred substantial additional indebtedness to finance the Baxalta acquisition, which may decrease its business flexibility and increase borrowing costs;
  • difficulties in integrating Dyax or Baxalta into Shire may lead to the combined company not being able to realize the expected operating efficiencies, cost savings, revenue enhancements, synergies or other benefits at the time anticipated or at all; and other risks and uncertainties detailed from time to time in Shire's filings with the Securities and Exchange Commission, including those risks outlined in "ITEM 1A: Risk Factors" in Shire's Quarterly Report on Form 10-Q for the quarter ended September 30, 2016.
All forward-looking statements attributable to us or any person acting on our behalf are expressly qualified in their entirety by this cautionary statement. Readers are cautioned not to place undue reliance on these forward-looking statements that speak only as of the date hereof. Except to the extent otherwise required by applicable law, we do not undertake any obligation to update or revise forward-looking statements, whether as a result of new information, future events or otherwise.

References 

  1. Longhurst, Hilary. Hereditary Angioedema: Causes, Manifestations and Treatment. British Journal of Hospital Medicine. 2006; 67:654-57
  2. Cicardi M, et al. Classification, diagnosis and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy. 2014;69(5):602-16
  3. Bork K, et al. Hereditary angioedema: New findings concerning symptoms, affected organs, and course. Am J Med. 2006; 119(3): 267-74
  4. Banerji A, et al. Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis. N Engl J Med 2017;376:717-728
  5. Bork K, et al. Asphyxiation by laryngeal edema in patients with hereditary angioedema. Mayo Clin Proc. 2000; 75: 349-354
  6. Bork K, et al. Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. Arch Intern Med. 2003; 163: 1229-1235
  7. Bork K, et al. Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency. J Allergy Clin Immunol 2012;130:692-7
  8. Kaplan AP and Joseph K. The bradykinin-forming cascade and its role in hereditary angioedema. Ann Allergy Asthma Immunol 2010;104:193-204.
For further information please contact: 

Investor Relations Ian Karp [email protected] +1-781-482-9018 Robert Coates [email protected] +44-1256-894874

Media         Annabel Cowper [email protected] +41-79-630-8619 Charles Catalano [email protected] +1-513-575-6978

SOURCE Shire plc

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