Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema.

N Engl J Med

From the Division of Hematology, Oncology, and Hemostaseology, Department of Children and Adolescents, Angioedema Center, University Hospital Frankfurt (E.A.-P.), and the Fraunhofer Institute for Molecular Biology and Applied Ecology, Translational Medicine and Pharmacology (J. Graff), Frankfurt, the Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin (M. Magerl, M. Maurer), and the Department of Otorhinolaryngology and Head and Neck Surgery, Ulm University Medical Center, Ulm (J. Greve) - all in Germany; the Department of Dermatology and Allergy Center, Odense University Hospital, Odense, Denmark (A.B.); Public Health Institution University Clinic of Dermatology, School of Medicine, University Sts. Cyril and Methodius, Skopje, Macedonia (V.G.-P.); the Department of Clinical Immunology, University Hospital Zurich, Zurich, Switzerland (U.C.S.); Assistance Publique-Hôpitaux de Paris Hôpital Saint Antoine, Sorbonne Université, Paris (O.F.), and the Department of Dermatology, Université de Montpellier, Montpellier (A.D.-T.) - both in France; the Allergy and Immunology West Midlands, Birmingham Heartlands Hospital, Birmingham (A.H.), Barts Health NHS Trust-Royal London Hospital, London (H.J.L.), the National Institute for Health Research Southampton Clinical Research Facility, Southampton (W.R.), and the North Bristol NHS Trust, Southmead Hospital, Bristol (M. Gompels) - all in the United Kingdom; the Department of Dermatology, Medical University of Vienna, Vienna (T.K.), and the Department of Dermatology and Venereology, Medical University of Graz, Graz (W.A.) - both in Austria; the Hungarian Angioedema Reference Center, 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary (H.F.); the Allergology Unit, Department of Internal Medicine, Hospital Universitario Bellvitge de L'Hospitalet de Llobregat (R.L.) and Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (M. Guilarte), Barcelona, Hospital General Universitario Gregorio Marañón, Biomedical Research Network on Rare Diseases (Centro de Investigación Biomédica en Red de Enfermedades Raras)-Unit 761, Institute for Health Research, Gregorio Marañon, Madrid (M.L.B.), and Hospital Universitario Virgen del Rocío, Seville (T.G.-Q.) - all in Spain; the Division of Allergy and Clinical Immunology, University of Salerno, Salerno (M.T.), the Department of Medicine, University of Padua, Padua (M. Cancian), and Azienda Socio Sanitaria Territoriale Fatebenefratelli Sacco-Università degli Studi di Milano, Milan (A.Z., M. Cicardi) - all in Italy; the Department of Clinical Immunology and Allergy, Royal Adelaide Hospital, Adelaide, SA (W.B.S.), and Campbelltown Hospital, Immunology and Allergy, Western Sydney University, Sydney (C.K.) - both in Australia; and BioCryst Pharmaceuticals (S.D., M. Cornpropst, D.C., P.C., W.S.) and PharStat (L.F.) - both in Durham, NC.

Published: July 2018

Hereditary angioedema is a serious genetic condition that leads to severe swelling due to mutations affecting the C1 inhibitor, which can be addressed by the oral drug BCX7353 that inhibits plasma kallikrein.
In a clinical trial involving 77 patients, BCX7353 was tested in four daily doses (62.5 mg to 350 mg) compared to a placebo to prevent angioedema attacks over 28 days, focusing on attack rates and patient quality of life.
Results showed that daily doses of 125 mg or higher significantly reduced the number of angioedema attacks and improved quality of life, while mild gastrointestinal side effects were the main adverse events reported.

Background: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks.

Methods: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life.

Results: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups.

Conclusions: Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972 .).

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http://dx.doi.org/10.1056/NEJMoa1716995	DOI Listing

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