Hereditary Angioedema (HAE)

What is HAE? | Current Treatment for HAE? | Why DX-88 in HAE?
Clinical Trial Status

What is HAE?
Hereditary angioedema (HAE) is an acute inflammatory condition characterized by episodes of severe, often painful swelling affecting the extremities (hands, feet, face, etc.), the gastrointestinal tract, the genitalia, and in potentially life-threatening cases, the larynx. HAE is caused by low or dysfunctional levels of C1 esterase inhibitor (C1-INH), a naturally occurring molecule that inhibits kallikrein and other serine proteases in the blood.

Published estimates on the prevalence of HAE range from 1 in 10,000 to 1 in 50,000 adults and children around the world, with no known correlation to gender, ethnicity or geography.

HAE attacks vary in frequency and severity among patients, and each attack may manifest differently. The triggers of HAE attacks are not well understood, although factors such as physical trauma, stress, hormonal changes, oral surgery and cold weather are relatively well documented.

Untreated, HAE can be fatal; a laryngeal attack can rapidly close the airways, and facial attacks can progress to laryngeal. Abdominal attacks of HAE are extremely painful and often lead to nausea and vomiting caused by obstruction and swelling in the intestinal wall. Peripheral attacks are visually disfiguring. All types of HAE attacks are debilitating, affecting the activities of patients’ daily lives. On average, HAE patients have 12 attacks per year, which generally persist for 2 to 5 days before resolving on their own.

HAE is caused by an autosomal dominant mutation, which means that a parent with the disease has a 50% chance of passing it on to his or her offspring. Spontaneous mutations resulting in HAE occur, but more often, a patient with HAE represents one of several family members with the condition. Therefore, once a patient is properly diagnosed, a cluster of family members can also be identified.

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Current Treatment of HAE
There is no marketed therapy for acute attacks of HAE in the United States. However, some adults with severe HAE manage the frequency of attacks with the chronic use of anabolic steroids. While this may reduce the number of attacks in some patients, steroids are ineffective during an attack and are associated with serious side-effects.

In some European countries, there is a marketed product for HAE. This product is human plasma-derived C1-INH, which replaces the missing or dysfunctional protein. However, it is isolated from human plasma and carries the potential risk of blood-borne pathogens. It is also a non-specific inhibitor of kallikrein, which is thought to be the most relevant target in HAE.

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Why DX-88 in HAE?
Kallikrein is a key enzyme in the inflammatory cascade. It liberates bradykinin, a molecule that causes local leakage of fluid from the blood vessels into the tissues and is capable of producing the swelling and pain associated with HAE.

DX-88 is a small protein that powerfully and specifically inhibits kallikrein in laboratory experiments. Unlike C1-INH, it does not inhibit any other blood enzymes against which it was tested. Because it bypasses the C1-INH pathway, it shows potential in treating not just HAE but also other less common forms of non-allergic angioedema, and the acquired forms of angioedema (AAE) that can occur secondary to blood malignancies or autoimmune disease.

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Clinical Trial Status of DX-88 in HAE

Trial Status
Dyax has completed three Phase 2 clinical trials, referred to as EDEMA0, EDEMA1^®, and EDEMA2^SM, and a Phase 3 trial, EDEMA3^®, to evaluate DX-88 for its potential to treat HAE.  A second Phase 3 trial, known as EDEMA4^®, is ongoing.

Completed Phase 2 Trials
EDEMA0, a 9-patient, multicenter, Phase 2, open-label dose-escalation study of DX-88 in HAE was initiated in 2001 at several European sites. Initial results from this study were announced in March 2003, demonstrating that all patients had clinical improvement of HAE attacks within four hours of treatment. The drug was generally well tolerated with the exception of an allergic reaction in one patient, whose HAE symptoms were resolved.

EDEMA1, a 48-patient, multicenter, Phase 2, placebo-controlled, single dose, dose-escalation study was completed in May 2004. Initial results from this lead trial were announced in June 2004 and demonstrated that DX-88 was significantly more efficacious than placebo in producing clinical improvement of HAE attacks within 4 hours of dosing (p=0.0169). Positive final results from EDEMA1 were announced in November 2004. The final results demonstrated that DX-88 was effective at treating HAE attacks at all anatomic locations, including life-threatening laryngeal attacks.

EDEMA2, a 77-patient, multicenter, Phase 2, open-label, repeat dosing trial was completed in January 2006. Two routes of administration, intravenous (IV) and subcutaneous (SC), were administered. The final results from the EDEMA2 trial were presented at the ACAAI Conference in November 2006 and reported on 240 HAE attacks in 77 patients using intravenous (IV) and subcutaneous (SC) routes of administration. Final results indicated that DX-88 provided substantial therapeutic benefit and can elicit rapid clinical response for HAE patients.

Completed Phase 3 Trial
EDEMA3, a 72-patient, multicenter, Phase 3, placebo-controlled trial was completed in November 2006. Topline results were announced in April 2007. The results showed that the primary and secondary endpoints demonstrated statistical significance. In addition, the overall safety results showed that DX-88 continues to be well tolerated. The trial was conducted to determine the efficacy of the 30 mg fixed subcutaneous (SC) dose of DX-88 for patients suffering from moderate to severe acute HAE attacks. The EDEMA3 trial was comprised of two phases: a double-blind, placebo-controlled phase and a repeat dosing phase. In the first phase, HAE patients received either a single 30 mg SC dose of DX-88 or placebo. After patients received one treatment in the placebo-controlled portion of the study, they were eligible for the second phase where they received repeat dosing with SC DX-88 for any subsequent acute attacks.

Second Phase 3 Trial
EDEMA4, a second Phase 3 trial, was initiated in April 2007 and is being conducted under a special protocol assessment (SPA). The trial design is based on EDEMA3 with an addition of a 4-hour rescue. The purpose of this trial is to further support the validity of the patient reported outcome (PRO) methodology and to confirm efficacy and safety.

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Orphan Drug Designation
DX-88 has orphan drug designation in the U.S. and E.U. for the treatment of angioedema.

Fast Track Designation
DX-88 has Fast Track designation in the U.S. for the treatment of acute attacks of HAE.