A Study to Assess the Long-Term Safety and Efficacy of Donidalorsen in the Prophylactic Treatment of Hereditary Angioedema (HAE)

December 5, 2025 updated by: Ionis Pharmaceuticals, Inc.

An Open-Label, Long Term Safety and Efficacy Study of Donidalorsen in the Prophylactic Treatment of Hereditary Angioedema (HAE)

The purpose of this study is to evaluate the long-term safety and efficacy of donidalorsen in people with HAE and the effects of donidalorsen on the number of HAE attacks and their impact on quality of life (QoL).

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

This is a Phase 3, multi-center, open-label, global study with donidalorsen in up to approximately 144 participants with HAE-1 (Type I) and HAE-2 (Type II). There are two groups in this study: 1) participants who roll over from another study of donidalorsen (open-label extension [OLE] participants), and 2) new participants who are not rolling over from another study of donidalorsen and were previously maintained on HAE prophylactic therapy with lanadelumab, berotralstat, or a C1-esterase inhibitor (C1-INH). The length of participation in the study is approximately 70 weeks for OLE participants and 76 weeks for other participants. Participants will receive donidalorsen in an Extended Treatment Period for up to an additional 104 weeks.

Study Type

Interventional

Enrollment (Actual)

154

Phase

  • Phase 3

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
      • Edegem, Belgium, 2650
        • Ionis Investigative Site
  • Bulgaria
      • Sofia, Bulgaria, 1431
        • Ionis Investigative Site
      • Sofia, Bulgaria, 1680
        • Ionis Investigative Site
  • Canada
      • Edmonton, Canada, AB T6G 1Z1
        • Ionis Investigative Site
    • Ontario
      • Ottawa, Ontario, Canada, K1H 1E4
        • Ionis Investigative Site
  • France
      • La Tronche, France, 38700
        • Ionis Investigative Site
      • Marseille, France, 13385
        • Ionis Investigative Site
      • Paris, France, 75012
        • Ionis Investigative Site
  • Germany
      • Berlin, Germany, 12203
        • Ionis Investigative Site
      • Frankfurt, Germany, 60590
        • Ionis Investigative Site
      • München, Germany, 81675
        • Ionis Investigative Site
  • Israel
      • Ashkelon, Israel, 7830604
        • Ionis Investigative Site
      • Haifa, Israel, 3104802
        • Ionis Investigative Site
      • Tel Aviv, Israel, 6423906
        • Ionis Investigative Site
  • Italy
      • Catania, Italy, 95123
        • Ionis Investigative Site
      • Napoli, Italy, 80131
        • Ionis Investigative Site
      • Padua, Italy, 35128
        • Ionis Investigative Site
      • Palermo, Italy, 90146
        • Ionis Investigative Site
      • San Donato Milanese, Italy, 20097
        • Ionis Investigative Site
  • Netherlands
      • Amsterdam, Netherlands, 1105
        • Ionis Investigative Site
      • Groningen, Netherlands, 9713 AP
        • Ionis Investigative Site
  • Poland
      • Krakow, Poland, 31-501
        • Ionis Investigative Site
  • Puerto Rico
      • San Juan, Puerto Rico, PR 00927
        • Ionis Investigative Site
  • Spain
      • Barcelona, Spain, 08035
        • Ionis Investigative Site
      • Barcelona, Spain, 08907
        • Ionis Investigative Site
      • Madrid, Spain, 28046
        • Ionis Investigative Site
      • Seville, Spain, 41013
        • Ionis Investigative Site
      • Valencia, Spain, 46026
        • Ionis Investigative Site
  • Turkey (Türkiye)
      • Altındağ, Turkey (Türkiye), 06230
        • Ionis Investigative Site
      • Bornova, Turkey (Türkiye), 35100
        • Ionis Investigative Site
      • Istanbul, Turkey (Türkiye), 34093
        • Ionis Investigative Site
  • United Kingdom
      • Birmingham, United Kingdom, B9 5SS
        • Ionis Investigative Site
      • Bristol, United Kingdom, BS10 5NB
        • Ionis Investigative Site
      • London, United Kingdom, E1 2ES
        • Ionis Investigative Site
  • United States
    • Arizona
      • Paradise Valley, Arizona, United States, 85253
        • Ionis Investigative Site
    • California
      • La Jolla, California, United States, 92037
        • Ionis Investigative Site
      • Santa Monica, California, United States, 90404
        • Ionis Investigative Site
      • Walnut Creek, California, United States, 94598
        • Ionis Investigative Site
    • Florida
      • Tampa, Florida, United States, 33613
        • Ionis Investigative Site
    • Kansas
      • Kansas City, Kansas, United States, 66103
        • Ionis Investigative Site
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Ionis Investigative Site
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • Ionis Investigative Site
      • Detroit, Michigan, United States, 48202
        • Ionis Investigative Site
    • Missouri
      • St Louis, Missouri, United States, 63141
        • Ionis Investigative Site
    • North Carolina
      • Mooresville, North Carolina, United States, 28117
        • Ionis Investigative Site
    • Ohio
      • Cincinnati, Ohio, United States, 45236
        • Ionis Investigative Site
      • Columbus, Ohio, United States, 43235
        • Ionis Investigative Site
    • Pennsylvania
      • Hershey, Pennsylvania, United States, 17033
        • Ionis Investigative Site
    • Texas
      • Dallas, Texas, United States, 75231
        • Ionis Investigative Site
    • Utah
      • Murray, Utah, United States, 84107
        • Ionis Investigative Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

12 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria

  1. Participants and, as applicable, legally authorized representatives (i.e., parent(s)/legal guardian), must provide written and signed informed consent form (ICF).

  2. Participants must have access to, and the ability to use, ≥ 1 acute medication(s) (e.g., plasma-derived or recombinant C1-INH concentrate or a bradykinin receptor (BK) 2-receptor antagonist) to treat angioedema attacks.

    Open-Label Extension Participants ONLY:

  3. Satisfactory completion of ISIS 721744-CS5 (randomized placebo-controlled index study) through Week 25 or participants who are allowed to exit ISIS 721744-CS5 study per protocol with an acceptable safety and tolerability profile.

    New (not previously on donidalorsen) Participants ONLY:

  4. Participants must be aged ≥ 12 years at the time of informed consent and, as applicable, assent.
  5. Participants must have a documented diagnosis of HAE-1/HAE-2.
  6. Participants must be on a stable dose (≥ 12 weeks) of prophylaxis treatment with lanadelumab or berotralstat or SC C1-esterase inhibitor prior to the Screening Period.

Exclusion Criteria

Open-Label Extension Participants:

  1. Have any new condition or worsening of an existing condition or change or anticipated change in medication.

    New (not previously on donidalorsen) Participants ONLY:

  2. Concurrent diagnosis of any other type of recurrent angioedema, including acquired, idiopathic angioedema or HAE with normal C1-INH (also known as HAE Type III).
  3. Anticipated change in the use of concurrent androgen or tranexamic acid prophylaxis used to prevent angioedema attacks.
  4. Any clinically-significant abnormalities in screening laboratory values.
  5. Malignancy within 5 years of Screening, except for non-melanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma that has been successfully treated.
  6. Hypersensitivity to the active substance (donidalorsen) or to any of the excipients.
  7. Treatment with another investigational drug (non-oligonucleotide) or biological agent within 1 month of Screening or 5 half-lives of investigational agent, whichever is longer.
  8. Recent history of, or current drug or alcohol abuse.
  9. Participated in a prior donidalorsen study.

  10. Exposure to any of the following medications:

    1. Angiotensin-converting enzyme (ACE) inhibitors or any estrogen containing medications with systemic absorption.
    2. Oligonucleotides (including small interfering ribonucleic acid [siRNA]) within 4 months of Screening if single dose received, or within 12 months of Screening if multiple doses received. This exclusion does not apply to vaccines.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: OLE Participants
Group 1 and Group 2 participants will be administered donidalorsen by SC injection for up to 157 weeks.
Drug: Donidalorsen
Donidalorsen will be administered by SC injection.
Other Names:
  • ISIS 721744
  • IONIS-PKK-LRx

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Percentage of Participants with at Least One Treatment-emergent Adverse Event (TEAE), Graded by Severity
Time Frame: Up to approximately 70 weeks, plus 104 weeks for Group 1; up to approximately 76 weeks, plus 104 weeks for Group 2
Up to approximately 70 weeks, plus 104 weeks for Group 1; up to approximately 76 weeks, plus 104 weeks for Group 2

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time-normalized Number of Investigator-confirmed HAE Attacks (per Month)
Time Frame: Week 1 to Week 157 for Group 1 and Group 2
Week 1 to Week 157 for Group 1 and Group 2
Percentage of Investigator-confirmed HAE Attack-free Participants
Time Frame: Week 1 to Week 157 for Group 1 and Group 2
Week 1 to Week 157 for Group 1 and Group 2
Time-normalized Number of Moderate or Severe Investigator-confirmed HAE Attacks (per Month)
Time Frame: Week 1 to Week 157 for Group 1 and Group 2
Week 1 to Week 157 for Group 1 and Group 2
Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy
Time Frame: Week 1 to Week 157 for Group 1 and Group 2
Week 1 to Week 157 for Group 1 and Group 2
Angioedema Quality of Life (AE-QoL) Questionnaire Total Score
Time Frame: Up to 157 weeks for Group 1 and Group 2
The AE-QoL questionnaire is a validated tool to assess symptom-specific health-related QOL impairment in participants suffering from recurrent angioedema. The AE-QoL is a self-administered questionnaire comprising 17 questions across 4 domains: functioning, fatigue/mood, fears/shame, and food. The responses are scored from 1 to 5 where, 1 = never, 2 = rarely, 3 = sometimes, 4 = often, 5 = very often. Total and domain scores range from 0 to 100, with higher scores indicating greater impairment.
Up to 157 weeks for Group 1 and Group 2

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ionis Pharmaceuticals, Inc.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 13, 2022

Primary Completion (Estimated)

December 1, 2026

Study Completion (Estimated)

March 1, 2027

Study Registration Dates

First Submitted

May 23, 2022

First Submitted That Met QC Criteria

May 23, 2022

First Posted (Actual)

May 26, 2022

Study Record Updates

Last Update Posted (Estimated)

December 12, 2025

Last Update Submitted That Met QC Criteria

December 5, 2025

Last Verified

December 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ISIS 721744-CS7
  • 2022-000757-93 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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