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
  • 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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