2. Academic Validation
  3. A phase 2 open-label extension study of prekallikrein inhibition with donidalorsen for hereditary angioedema

A phase 2 open-label extension study of prekallikrein inhibition with donidalorsen for hereditary angioedema

  • Allergy. 2024 Mar;79(3):724-734. doi: 10.1111/all.15948.
Remy S Petersen 1,  Laura Bordone 2,  Marc A Riedl 3,  Raffi Tachdjian 4 5,  Timothy J Craig 6 7,  William R Lumry 8,  Michael E Manning 9,  Jonathan A Bernstein 10,  Jason Raasch 11,  Bruce L Zuraw 12,  Yiwen Deng 2,  Kenneth B Newman 2,  Veronica J Alexander 2,  Cindy Lui 2,  Eugene Schneider 2,  Danny M Cohn 1
Affiliations

Affiliations

  • 1 Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • 2 Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
  • 3 University of California San Diego, La Jolla, California, USA.
  • 4 Department of Pediatrics, University of California, Los Angeles, California, USA.
  • 5 Providence Saint John's Health Center, Santa Monica, California, USA.
  • 6 Department of Medicine, Pediatrics, and Biomedical Sciences, Pennsylvania State University, Hershey, Pennsylvania, USA.
  • 7 Vinmec International Hospital, Times City, Hanoi, Vietnam.
  • 8 Allergy and Asthma Research Associates Research Center, Dallas, Texas, USA.
  • 9 Medical Research of Arizona, Scottsdale, Arizona, USA.
  • 10 Department of Internal Medicine, University of Cincinnati College of Medicine, and Bernstein Clinical Research Center, Cincinnati, Ohio, USA.
  • 11 Midwest Immunology Clinic, Plymouth, Minnesota, USA.
  • 12 Division of Rheumatology, Allergy, and Immunology, Department of Medicine, University of California San Diego, La Jolla, California, USA.
PMID: 38009241 DOI: 10.1111/all.15948
Abstract

Background: Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, recurrent, often disabling swelling attacks. In a randomized phase 2 study, donidalorsen reduced HAE attack frequency and improved patient quality-of-life (ISIS721744-CS2, NCT04030598). We report the 2-year interim analysis of the phase 2 open-label extension (OLE) study (ISIS 721744-CS3, NCT04307381).

Methods: In the OLE, the on-treatment study period consisted of fixed (weeks 1-13, donidalorsen 80 mg subcutaneously every 4 weeks [Q4W]) and flexible (weeks 17-105, donidalorsen 80 mg Q4W, 80 mg every 8 weeks [Q8W], or 100 mg Q4W) dosing periods. The primary outcome was incidence and severity of treatment-emergent adverse events (TEAEs). The secondary outcomes included efficacy, pharmacodynamic, and quality-of-life assessments.

Results: Seventeen patients continued in the OLE study. No serious TEAEs or TEAEs leading to treatment discontinuation were reported. Mean monthly HAE attack rate was 96% lower than the study run-in baseline rate (mean, 0.06/month; 95% confidence interval [CI], 0.02-0.10; median, 0.04 on-treatment vs. mean, 2.70/month; 95% CI, 1.94-3.46; median, 2.29 at baseline). Mean monthly attack rate for Q8W dosing (n = 8) was 0.29 (range, 0.0-1.7; 95% CI, -0.21 to 0.79; median, 0.00). Mean plasma prekallikrein and D-dimer concentrations decreased, and Angioedema Quality of Life Questionnaire total score improved from baseline to week 105 with donidalorsen.

Conclusion: The 2-year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated. There was durable efficacy with a 96% reduction in HAE attacks.

Keywords

AE-QoL; HAE attack; HAE safety; HAE treatment; clinical trial; donidalorsen; hereditary angioedema; ligand-conjugated antisense oligonucleotide; long-term prophylaxis; plasma kallikrein; quality-of-life.

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