Hereditary angioedema (HAE) is one of the more puzzling phenomena in immunology, in part because, even though it’s an autoimmune disease involving complement dysregulation, it’s generally treated by allergists because its symptoms impersonate those of severe allergic reactions. At the American Academy of Allergy, Asthma, and Immunology’s annual meeting — cancelled because of concerns surrounding COVID-19 coronavirus — more than two dozen abstracts on HAE were to be presented. Here are some of the highlights.

Lanadelumab Trial Extension

Several of the scheduled abstracts involved lanadelumab (Takhzyro), approved in 2018 for prevention of HAE attacks, and in particular on results from an open-label extension of the product’s main phase III registration trial.

Among the findings from the extension:

• Monthly attack rates declined dramatically — by upwards of 90% in all groups stratified by baseline attack frequency. Even patients with baseline rates below 1 per month still showed median reductions of 92%; median reduction was greater in other groups (abstract #318)

• Among 21 adolescent patients in the extension, attack rates declined about 90% from baseline and about half experienced treatment-emergent adverse events, although none were serious or severe (abstract #319)

• Nearly 60% of patients in the extension were completely free of attacks for 12 months or more, and 78% remained attack-free for periods of at least 6 months (abstract #322)

The extension included 212 patients, about half of whom came over from the phase III HELP study after completing the double-blind phase (“rollovers”) while the other half were newly enrolled. In the extension, rollovers received the drug at 300 mg on day 0, then every 2 weeks following their first attack. Nonrollovers who had at least one attack in the previous 12 weeks prior to enrollment received 300 mg every 2 weeks.

Cluster Attacks Despite Treatment

One feature of HAE is that attacks may not be isolated, but instead are repeated with intervals of a few days — even among patients on prophylactic medications. Ulrich Strassen, MD, of Technische Universität in Munich, sought to investigate this phenomenon with an eye toward identifying risk factors and predictors (abstract #334).

Strassen and colleagues examined records of 15 patients treated in their clinic group from 2015 to 2018 who had experienced attacks coming less than a week apart after treatment, which the group termed “cluster attacks.” Two-thirds of these were tied to “exogenous stimuli” mostly following mental or physical stresses. A few came during menstrual periods. Time to repeat attacks appeared shorter for patients who took “on-demand” therapy versus scheduled prophylactic dosing, and the former group also needed more redosing to bring attacks under control.

On-demand treatment may not be optimal for patients who develop cluster attacks, Strassen concluded; a switch to regular prophylaxis should be considered in such patients.

ITP as a Consequence of HAE?

HAE pathology mainly involves an excess of C1 complement, but other factors are dysregulated as well. One of those can be deficiency in C4 complement. Other patients with C4 deficiency have shown increased susceptibility to autoimmune and hematologic disease, including immune thrombocytopenia (ITP).

This condition hasn’t traditionally been associated with HAE, but Abeer Hegazi and Paul Keith of McMaster University in Hamilton, Ontario, found a patient with both ITP and HAE and decided to investigate further.

The patient was a 37-year-old woman with symptoms consistent with HAE. She was diagnosed and, in 2010, began taking C1 inhibitor therapy administered every 3 months or so. Her endogenous C4 as well as C1 inhibitor levels were low prior to beginning therapy. Two years after starting C1 inhibitor replacement, she developed low platelet counts; this recurred 3 years later and was identified as ITP. Her C1 inhibitor dosing was increased and no subsequent ITP episodes were seen.

Hegazi and Keith concluded that HAE patients showing low C4 levels may be at risk for ITP as well. In these patients, “future consideration” should be given to a treat-to-C4-target strategy for C1 inhibitor dosing, rather than merely seeking to block the kallikrein activation that causes HAE symptoms.

Last Updated March 17, 2020