Abstract
Hereditary angioedema (HAE) is an autosomal dominant disorder that results in a deficiency of C1 esterase inhibitor (C1-INH), with a 1/10,000 to 1/50,000 prevalence worldwide (Nzeako 2001). Affected individuals manifest with recurrent attacks of intense, massive, localized non-pitting edema, without an allergic component, responding poorly to epinephrine and steroids. Prophylaxis include antifibrinolytic or androgens. A worrisome potentially fatal complication is laryngeal edema, which currently has no abortive therapy available.
C1-INH is a serine protease inhibitor that also regulates kinin generation. Angioedema results from uncontrolled activation of the classical complement pathway generating vasoactive peptide or contact system activation release of bradykinin from high molecular weight kininogen. Knockout mouse data supports the role of bradykinin for the edema generation. However, other mediators may be involved. C1-INH gene disruption in mice showed increased vascular permability, which was reversed by intravenous C1-INH, bradykinin, and plasma kallikrein inhibitor (Hun 2002). Therefore, DX-88 (Dyax Corporation), a recombinant polypeptide inhibitor of plasma kallikrein, was used as an abortive agent for the treatment of acute attacks in HAE. We describe our institution’s experience in treating an HAE family, affected father with his two affected daughters, with DX-88 in a jointly conducted adult and pediatric hematology clinical trial. EDEMA I is an ascending four dose placebo controlled study to assess the efficacy and tolerability of DX-88 for acute attacks of HAE. Patients presented for treatment within 4 hours of a moderately severe acute attack and were observed for 8 hours. All three presented with abdominal attacks. The first daughter, on Oxandrin prophylaxis, presented with cramping, gnawing abdominal pain, associated nausea and rash. Subjective resolution of nausea, cramping and rash occured within 1 hour of treatment. The abdominal distention had partial resolution with continuing response up to 8 hours.
The second daughter had more severe recurrent symptoms associated with her menses. She used imported C1-INH concentrate for acute attacks. She presented with mid to upper abdominal cramping and nausea. She had no resolution of symptoms with treatment. Her abdominal attack of 10/10 pain increased with nausea. She subsequent developed erythema marginatum.. The study was stopped 4 hours post dose. She was admitted for narcotic pain medication for symptomatic relief. The father, on Oxandrin prophylaxis, presented with abdominal attack, left hand and scrotal edema, and extensive erythema marginatum; reticular rash over the neck, back, arms, and shoulder. The attacks improved within 1 hour of treatment with significant resolution within 2 hours. The rash and abdominal symptoms resolved completely. The left hand and scrotal edema had partial resolution typical of his disease course, with continuing response up to 8 hours.
HAE families have debilitating acute attacks despite prophylaxis. Replacement therapy with C1-INH concentrate is not commercially available in the United States. We treated an HAE family with DX-88 for acute attacks. Two had responses and the non responder was a potential placebo. The treatment was well tolerated. Longer follow up for safety and efficacy with ideal drug dosing are needed. Trial results are currently being analyzed. DX-88 is a promising, non plasma based, treatment for acute attacks of patients with HAE.
Oral Plasma Kallikrein Inhibitor BCX7353 is Safe and Effective as an On-Demand Treatment of Angioedema Attacks in Hereditary Angioedema (HAE) Patients: Results of the ZENITH-1 Trial