An Open-label Trial With Plasma Prekallikrein Oligonucleotide Antisense Therapy To Control Angioedema Attacks In Hereditary Angioedema Patients With Normal C1-inhibitor

Hereditary angioedema with normal C1-inhibitor (nC1-INH-HAE) is a very rare condition, characterized by recurrent and unpredictable swellings which are disabling and potentially fatal. There are currently no approved prophylactic treatments for this condition. In a phase 2 study, we assessed efficacy and safety following treatment with oligonucleotide antisense therapy targeted against plasma prekallikrein (PKK-LRx) in patients with nC1-INH-HAE. Patients with nC1-INH-HAE were eligible if they had either one of the established mutations associated with nC1-INH-HAE in the genes encoding for factor XII, plasminogen or angiopoietin-1, or a clinical diagnosis of bradykinin-mediated angioedema confirmed with threshold-stimulated kallikrein activity and an investigator confirmed response to acute use of a bradykinin targeted treatment. All patients had two or more angioedema attacks during the run-in period which lasted maximally eight weeks. Eligible patients received four unblinded doses of 80 mg PKK-LRx every 4 weeks over a 16-week treatment period. The primary endpoint was the time-normalized number of angioedema attacks per month during the treatment period compared to baseline. Three patients met the eligibility criteria for enrollment based on the results of the threshold-stimulated kallikrein activity assay. The mean monthly attack rate was 4.23 (95% confidence interval [CI] -2.56 to 11.03) at baseline and 1.52 during the treatment period (95% CI -3.99 to 7.04); mean difference -76% (95% confidence interval: -146.45 to -5.59). The treatment was well tolerated with no severe adverse events. Prophylactic treatment with PKK-LRx in patients with nC1-INH-HAE was well tolerated and resulted in significantly improved disease control.