Hereditary Angioedema (HAE)

Active clinical trials in patients with hereditary angioedema (HAE) are evaluating the use of donidalorsen, lanadelumab, and berotralstat (BCX7353). Novel biologics are also in different phases of development and are discussed below. 

Extension Study of Donidalorsen

The purpose of the extension study (NCT04307381) is to follow up on the results of a phase 2 trial, published in March 2022, of a novel treatment with an antisense oligonucleotide, donidalorsen. The phase 2 trial found that treatment with donidalorsen reduces the production of plasma prekallikrein and the number of angioedema attacks.1 The extension study, funded by Ionis Pharmaceuticals, will evaluate the safety and efficacy of extended dosing of subcutaneously administered donidalorsen in patients with HAE. Participants will receive donidalorsen for up to 157 weeks and be assessed for treatment-emergent adverse events (TEAEs), time-normalized number of HAE attacks per month, and plasma prekallikrein levels, among other outcomes. The expected completion date is April 2024.2 

Lanadelumab for Japanese People With HAE

This study (NCT04687137) is an expanded access program in which Japanese patients with HAE are being granted access to lanadelumab, an unlicensed treatment, on compassionate grounds. Lanadelumab is a monoclonal antibody against plasma kallikrein. It was initially evaluated in the SHP643-302 study, in which it was found to be beneficial in preventing HAE attacks. Enrolled patients will receive the experimental treatment and be monitored for TEAEs.3


The EMPOWER trial (NCT03845400) aims to compare the HAE attack rate before and after the start of lanadelumab treatment in persons with HAE type 1 or 2 in the United States and Canada. Patients will receive the study drug and be followed for 24 or 36 months. The primary outcome measure is the number of HAE attacks before and after lanadelumab treatment. Secondary outcome measures include the dose and frequency of lanadelumab injections, the proportion of participants who discontinue treatment, and the number of hospitalizations due to HAE attacks, among others. It is estimated to conclude in December 2023.4

Long-term Safety Study of BCX7353

Berotralstat (BCX7353) is a second-generation, synthetic, orally administered small-molecule plasma kallikrein inhibitor that was approved by the US Food and Drug Administration (FDA) in 2020 to prevent HAE attacks in patients up to 12 years old.5 The long-term use of BCX7353 for prophylaxis is being evaluated in 386 participants with HAE, who receive the drug for 96 weeks. TEAEs, the rate of acute attacks during treatment, patients’ reported quality of life, and their satisfaction with treatment will be measured during the study period. The proposed completion date is February 2024.6 

Novel Biologics

Two novel biologics, NTLA-2002 and CSL312, are being studied in patients with HAE. 

NTLA-2002 is a gene-editing therapy in which a proprietary in vivo lipid nanoparticle delivery technology, developed by Intellia Therapeutics, is used to knock out the LKLB1 gene in the liver.7 A phase 1/2 study (NCT05120830) is currently underway to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of NTLA-2002 in adults with HAE. TEAEs will be studied in phase 1, and the number of HAE attacks per month will be determined over a 6-week period in phase 2; these are the primary outcome measures. Secondary outcome measures include change from baseline in the total plasma kallikrein protein level and the number of HAE attacks per month, among others.8 

CSL312 (garadacimab) is a fully humanized, anti-activated factor XII immunoglobulin G4 monoclonal antibody. In a phase 2 study, garadacimab reduced the number of monthly HAE attacks vs placebo.9 A phase 3 study is currently evaluating the long-term safety and efficacy of CSL312 in the prophylactic treatment of HAE. Primary outcome measures include number and percentage of subjects with TEAEs, TEAE rates per injection, and TEAE rates per subject-year over a 32-month study period. Secondary outcome measures include the time-normalized number of HAE attacks, percentage reduction in the number of attacks, and the number of subjects experiencing at least a 50%, 70%, or 90% reduction or a 100% reduction in the time-normalized number of HAE attacks during treatment vs during the run-in period, among others. 


1. Fijen LM, Riedl MA, Bordone L, et al. Inhibition of prekallikrein for hereditary angioedema. N Engl J Med. 2022;386(11):1026-1033. doi:10.1056/NEJMoa2109329

2. An extension study of donidalorsen (IONIS-PKK-LRx) in participants With hereditary angioedema. April 1, 2020. Updated April 11, 2022. Accessed July 3, 2022.

3. Expanded access program with lanadelumab for Japanese people with hereditary angioedema. February 10, 2021. Updated June 3, 2022. Accessd July 3, 2022.

4. A study of lanadelumab in persons with hereditary angioedema (HAE) type I or II in North America (EMPOWER). March 30, 2019. Updated December 27, 2021. Accessed June 3, 2022.

5. Manning ME, Kashkin JM. Berotralstat (BCX7353) is a novel oral prophylactic treatment for hereditary angioedema: review of phase II and III studies. Allergy Asthma Proc. 2021;42(4):274-282. doi:10.2500/aap.2021.42.210034

6. BioCryst Pharmaceuticals. An open-label study to evaluate the long-term safety of daily oral BCX7353 in subjects With type I and II hereditary angioedema.; 2020. Accessed June 30, 2022. A long term safety study of BCX7353 in hereditary angioedema. February 16, 2018. Updated December 17, 2020.

7. Intellia Therapeutics announces first quarter 2022 financial results and highlights recent company progress. News release. Intellia Therapeutics; May 5, 2022.

8. NTLA-2002 in adults with hereditary angioedema (HAE). December 10, 2021. Updated May 4, 2022.

9. Craig T, Magerl M, Levy DS, et al. Prophylactic use of an anti-activated factor XII monoclonal antibody, garadacimab, for patients with C1-esterase inhibitor-deficient hereditary angioedema: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2022;399(10328):945-955. doi:10.1016/S0140-6736(21)02225-X

Reviewed by Hasan Avcu, MD, on 6/30/2022.