NEMJ Publishes Positive Results of Ionis’ Experimental Antisense Therapy for HAE

Rare Daily Staff

Ionis Pharmaceuticals reported positive results from a compassionate-use study of its experimental antisense therapy for patients living with severe bradykinin-mediated angioedema The New England Journal of Medicine.

Hereditary angioedema (HAE) is a rare autosomal dominant disease that results in recurrent, painful attacks of swelling affecting the arms, legs, face, intestinal track, and airway. Without preventive treatment, attacks can be frequent and severe and, in some patients, life-threatening. The majority of HAE cases are caused by genetic mutations that lead to either a deficiency (Type 1 HAE) or dysfunction (Type 2 HAE) of C1 esterase inhibitor (C1-INH), which regulates multiple pathways, including the kallikrein-kinin and contact system. In the third, especially rare form of the disorder (Type 3 HAE or HAE-nC1-INH), which occurs predominantly in women, and in which the cause is often unknown, patients have a higher frequency of facial, pharyngeal and tongue swelling.

The compassionate-use study evaluated IONIS-PKKRx and IONIS-PKK-LRx in patients living with severe bradykinin-mediated angioedema. IONIS-PKKRx and IONIS-PKK-LRx are experimental antisense medicines designed to reduce the production of prekallikrein, or PKK, which plays a key role in the activation of inflammatory mediators associated with acute attacks of HAE. In the study, researchers found that the drugs reduced plasma prekallikrein activity levels and showed evidence of clinical efficacy in reducing the number of breakthrough attacks per month in patients over the course of the treatment, including complete resolution in a patient with Type 1 HAE.

Physicians have long prescribed prophylactic treatment approaches, including C1-INH replacement therapies, and more recently inhibitors of plasma kallikrein, to prevent and reduce the severity of HAE attacks. Ionis says that its experimental antisense medicine, IONIS-PKK-LRx, has the potential to provide significant efficacy with the convenience of once per month low volume subcutaneous injections.

In the study, two patients–Patient 1 with Type 1 HAE and Patient 2 with Type 3 HAE–were first treated with IONIS-PKKRx for a period of 12 to 16 weeks, after which they received IONIS-PKK-LRx at a dose of 80 mg every three to four weeks for seven to eight months at the time of data analysis. During treatment with the ligand-conjugated IONIS-PKK-LRx and the unconjugated parent drug, IONIS-PKKRx, there was a clinically meaningful reduction in HAE attack rates in both patients. Plasma prekallikrein activity levels decreased substantially following treatment.

“The results of this study are encouraging and support continued development of IONIS-PKK-LRx as a potential treatment in patients with severe hereditary angioedema for whom current therapies offer limited therapeutic benefit,” said Richard Geary, executive vice president of development for Ionis and a co-author on the paper published in NEJM.

Photo: Richard Geary, executive vice president of development for Ionis and a co-author on the paper published in NEJM.