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Hereditary angioedema

Angioedema (BE: angiooedema), also known by its eponym Quincke's edema and the older term angioneurotic edema, is the rapid swelling (edema) of the skin, mucosa and submucosal tissues. Apart from the common form, mediated by allergy, it has been reported as a side effect of some medications, specifically ACE inhibitors. Additionally, there is an inherited form, due to deficiency of the blood protein C1-inhibitor. This form is called hereditary angioedema (HAE) or hereditary angio-neurotic edema (HANE), which is due to C1-esterase inhibitor deficiency. more...

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Cases where angioedema progresses rapidly should be treated as a medical emergency as airway obstruction and suffocation can occur. Rapid treatment with epinephrine, often with an epi-pen, can be life-saving.

Signs and symptoms

The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue, swell up over the period of minutes to several hours. The swelling can also occur elsewhere, typically in the hands. Sometimes, there has been recent exposure to an allergen (e.g. peanuts), and urticaria (hives) develop simultaneously, but many times the cause is idiopathic (unknown). The swelling can be itchy. There may also be slightly decreased sensation in the affected areas due to compression of the nerves.

In severe cases, stridor of the airway occurs, with gasping inspiratory breath sounds and decreasing oxygen levels. Intubation and rapid treatment with epinephrine and antihistamines is required in these situations.

In hereditary angioedema, there is often no direct identifiable cause, although mild trauma and other stimuli can cause attacks. There is usually no associated itch or urticaria. Patients with this syndrome can also have attacks of recurrent abdominal pain, sometimes leading to an unnecessary laparotomy. There is also an increased incidence of autoimmune disease (e.g. lupus erythematosus, glomerulonephritis and hypothyroidism) due to altered activity of the complement system.


The diagnosis is made on the clinical picture. When the patient has been stabilized, complement levels, especially C1-inhibitor and depletion of complement factors 2 and 4, may indicate the presence of hereditary angioedema (see below). Additionally, allergy testing should be undertaken to determine if any allergens need to be avoided in the future. If the patient was on ACE inhibitor medication, this has to be discontinued.


The final common pathway for the development of angioedema seems to be the activation of the bradykinin pathway. This peptide is a potent vasodilator, leading to rapid accumulation of fluid in the interstitium. This is most obvious in the face, where the skin has relatively little supporting connective tissue, and edema develops easily. Bradykinin is released by various cell types in response to numerous different stimuli; it is also a pain mediator.

Various mechanisms that interfere with bradykinin production or degradation can lead to angioedema. ACE inhibitors block the function of kininase II, the enzyme that degrades bradykinin. In hereditary angioedema, bradykinin formation is caused by continuous activation of the complement system due to a deficiency in on of its prime inhibitors, C1-esterase inhibitor (C1INH), and continuous production of kallikrein, another process inhibited by C1INH. This serine protease inhibitor (serpin) normally inhibits the conversion of C1 to C1r and C1s, which - in turn - activate other proteins of the complement system. Additionally, it inhibits various proteins of the coagulation cascade, although effects of its deficiency on the development of hemorrhage and thrombosis appear to be limited.


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Dyax and Genzyme Initiate Pivotal Phase III Trial of Subcutaneously Administered DX-88 for the Treatment of Hereditary Angioedema
From Business Wire, 12/8/05

CAMBRIDGE, Mass. -- Dyax Corp. (Nasdaq:DYAX) and Genzyme Corporation (Nasdaq:GENZ) announced today that patient treatment has begun in their pivotal Phase III clinical trial of Dyax's recombinant plasma kallikrein inhibitor known as DX-88. In this trial, referred to as EDEMA3, DX-88 is being studied for the treatment of patients with hereditary angioedema (HAE), a rare, genetic disease that causes acute attacks of localized swelling and inflammation.

The EDEMA3 trial is being conducted to confirm efficacy of a subcutaneous administration of DX-88 in patients suffering from moderate to severe acute HAE attacks. DX-88 inhibits human plasma kallikrein, which is an enzyme that is thought to be responsible for the activation of molecules that cause swelling and pain associated with HAE.

The evaluation of DX-88 in the HAE indication is being conducted by Dyax under its collaboration with Genzyme Corporation. In this joint venture, Dyax will now receive a $3 million milestone payment from Genzyme for the start of the pivotal trial and will receive an additional $10 million milestone payment upon FDA approval of the compound.

Phase III Design

The Phase III study will be conducted at 47 U.S. and Canadian clinical sites, along with additional clinical sites in Europe and Israel. Dyax and Genzyme expect to have rapid enrollment into the trial and target regulatory approval in the U.S. in 2007, followed by approval in the E.U.

The EDEMA3 study is comprised of two phases: a double-blind, placebo-controlled phase and a repeat dosing phase in which all patients will receive drug. In the first phase, HAE patients will receive either a single 30 mg subcutaneous (SQ) dose of DX-88 or placebo. After patients receive one treatment in the placebo-controlled portion of the study, they then will be eligible for the second phase where they all will receive repeat dosing with SQ DX-88 for any subsequent acute attacks. This trial is planned for 62 patients and will include patients previously exposed to DX-88 as well as naive patients.

"We are very pleased about achieving this significant milestone in our HAE program as planned," stated Henry Blair, Chairman, President and Chief Executive Officer of Dyax. "With our large network of patients and physicians behind us, we believe we can complete this pivotal trial rapidly. Based on the amount of data collected to date and the continued steady progress of this program, it is evident that Dyax, together with Genzyme, is focused on and truly committed to bringing DX-88 to the marketplace as the first subcutaneous treatment for the HAE patient community."

"We are extremely excited about treating the first patient in the EDEMA3 trial," remarked the investigational team of Dr. Henry Li and his associate Kelly Bowie of the Institute for Asthma & Allergy in Wheaton, MD. "Currently, there is no treatment for HAE in the United States and with the start of this trial, Dyax and Genzyme are one step closer to a potential drug being approved and on the market for the HAE patient community. We are enthusiastic about our participation in the EDEMA3 trial and look forward to its rapid conclusion."

Cumulative Data

Dyax and Genzyme continue to build upon their clinical data through their extensive DX-88 development program. With regard to clinical data accumulated in the EDEMA trials to date, 303 doses of DX-88 have been administered to 109 angioedema patients. With regard to safety data, 428 doses of DX-88 have now been administered to 177 people.

About Dyax

Dyax Corp. is focused on advancing novel biotherapeutics for unmet medical needs, with an emphasis on cancer and inflammatory indications. Dyax utilizes its proprietary drug discovery technology to identify antibody, small protein and peptide compounds for clinical development.

DX-88 is a recombinant small protein that is currently in clinical trials for its therapeutic potential in two separate indications. In its joint venture with Genzyme Corporation, Dyax has successfully completed two Phase II trials of DX-88 for the treatment of hereditary angioedema (HAE). A third Phase II trial is nearing completion, and a pivotal Phase III trial has just commenced. Independently, Dyax has successfully completed a Phase I/II trial of DX-88 for the prevention of blood loss during heart surgery (CABG procedures) and is in partnering discussions for further development of DX-88 in this indication. A second Dyax compound, DX-890, is being developed by Debiopharm S.A., which has completed two Phase IIa trials and is now conducting a Phase IIb trial of DX-890 in Europe for the treatment of cystic fibrosis. Both compounds have orphan drug designation in the US and EU, and DX-88 also has Fast Track designation in the US for the treatment of HAE.

Dyax identified DX-88 and other compounds in its pipeline using Dyax's patented phage display technology, which rapidly selects compounds that bind with high affinity and specificity to therapeutic targets. Dyax leverages its technology broadly with over 75 revenue generating licenses and collaborations for therapeutic discovery, as well as in non-core areas such as affinity separations, diagnostic imaging, and research reagents.

Dyax Disclaimer

This press release contains forward-looking statements, including statements regarding the potential administration, dosing and therapeutic benefit of DX-88 for HAE, the planned timetable and enrollment for clinical trials of DX-88, and the requirements and plans for regulatory filings and approvals for DX-88 and its position versus other products in development for HAE. Statements that are not historical facts are based on Dyax's current expectations, beliefs, assumptions, estimates, forecasts and projections about the industry and markets in which Dyax competes. The statements contained in this release are not guarantees of future performance and involve certain risks, uncertainties and assumptions, which are difficult to predict. Therefore, actual outcomes and results may differ materially from what is expressed in such forward-looking statements. Important factors which may affect the potential administration, dosing and therapeutic benefit of DX-88 for HAE, the planned timetable and enrollment for clinical trials of DX-88, the requirements and plans for regulatory filings and approvals for DX-88 and its position versus other products in development for HAE include the risks that: DX-88 may not show sufficient therapeutic effect or an acceptable safety profile in clinical trials or could take a significantly longer time to gain regulatory approvals than Dyax expects or may never gain approvals; others may develop technologies or products superior to DX-88 or that are on the market before DX-88; DX-88 may not gain market acceptance; Dyax is dependent on the expertise, effort, priorities and contractual obligations of third parties in the clinical trials, manufacture, marketing, sales and distribution of DX-88; and other risk factors described or referred to in Dyax's most recent Annual Report on Form 10-K and other periodic reports filed with the Securities and Exchange Commission. Dyax cautions investors not to place undue reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this release, and Dyax undertakes no obligations to update or revise these statements, except as may be required by law.

Dyax and the Dyax logo are the registered trademarks of Dyax Corp. EDEMA0, EDEMA1, EDEMA2 and EDEMA3 are trademarks of Dyax Corp.

About Genzyme

One of the world's leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. Founded in 1981, Genzyme has grown from a small start-up to a diversified enterprise with more than 8,000 employees in locations spanning the globe and 2004 revenues of $2.2 billion. With many established products and services helping patients in more than 80 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company's products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant and immune diseases, and diagnostic testing. Genzyme's commitment to innovation continues today with a substantial development program focused on these fields, as well as heart disease and other areas of unmet medical need.

This press release contains forward-looking statements, including statements regarding the potential administration, dosing and therapeutic benefit of DX-88 for HAE; the planned timetable and enrollment for clinical trials of DX-88 and the sites of such trials; the requirements and plans for regulatory filings and approvals for DX-88; and DX-88's position versus other products in development for HAE. These risks and uncertainties include, among others: the timing of discussions with the FDA and the EMEA regarding clinical studies and approval of DX-88; Genzyme's ability to iniate additional trial sites and enroll additional patients; the timing and content of decisions by the FDA and the EMEA related to clinical trials and approval of DX-88; the actual efficacy and safety of DX-88 for HAE; the actual timing and results of clinical trials; further analysis of clinical trial data; and the risks and uncertainties described in reports filed by Genzyme with the Securities and Exchange Commission under the Securities Exchange Act of 1934, as amended, including without limitation the information under the heading "Factors Affecting Future Operating Results" in Genzyme's Quarterly Report on Form 10-Q for the period ended September 30, 2005. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this press release. These statements speak only as of the date of this press release, and Genzyme undertakes no obligation to update or revise these statements.

Genzyme(R) is a registered trademark of Genzyme Corporation. All rights reserved.

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