OASIS-HAE: A Study to Evaluate the Safety and Efficacy of Donidalorsen (ISIS 721744 or IONIS-PKK-LRx) in Participants With Hereditary Angioedema (HAE)

A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ISIS 721744 in Patients With Hereditary Angioedema (HAE)

The purpose of this study was to evaluate the safety and efficacy of donidalorsen in participants with HAE and effect of donidalorsen on the quality and pattern of HAE attacks and their impact on quality of life (QoL).

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema
• Intervention / Treatment: Drug: Donidalorsen; Drug: Placebo

Detailed Description

This was a Phase 3, multi-center, double-blind, randomized, placebo-controlled study of donidalorsen in 91 participants. Participants were randomly assigned in a 2:1 ratio to Cohort A (donidalorsen or placebo every 4 weeks) or Cohort B (donidalorsen or placebo every 8 weeks), respectively. Within each Cohort, participants were randomized in a 3:1 ratio to receive donidalorsen or matching-placebo. The study included an up to 8-week Screening Period, a 24-week Treatment Period, and an up to 13-week Post-treatment Period.

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Phase 3

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1020
    • Ionis Investigative Site
  • Brussels, Belgium, 1200
    • Ionis Investigative Site
  • Edegem, Belgium, 2650
    • Ionis Investigative Site
• Bulgaria
  • Sofia, Bulgaria, 1431
    • Ionis Investigative Site
  • Sofia, Bulgaria, 1680
    • Ionis Investigative Site
• Canada
  • Edmonton, Canada, T6G 2G3
    • Ionis Investigative Site
  • Ontario
    • Ottawa, Ontario, Canada, K1G6C6
      • Ionis Investigative Site
• Denmark
  • Odense, Denmark, 5000
    • 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
  • Munich, Germany, 81675
    • Ionis Investigative Site
• Israel
  • Ashkelon, Israel, 78278
    • Ionis Investigative Site
  • Haifa, Israel, 3104802
    • Ionis Investigative Site
  • Tel Aviv, Israel, 6423906
    • Ionis Investigative Site
• Italy
  • Catania, Italy, 95124
    • Ionis Investigative Site
  • Milan, Italy, 20138
    • Ionis Investigative Site
  • Napoli, Italy, 80131
    • Ionis Investigative Site
  • Padova, Italy, 35128
    • Ionis Investigative Site
  • Palermo, Italy, 90146
    • Ionis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Ionis Investigative Site
  • Groningen, Netherlands, 9713 GZ
    • Ionis Investigative Site
• Poland
  • Kraków, Poland, 31-503
    • Ionis Investigative Site
• Spain
  • Barcelona, Spain, 08035
    • Ionis Investigative Site
  • Barcelona, Spain, 8907
    • Ionis Investigative Site
  • Madrid, Spain, 28046
    • Ionis Investigative Site
  • Sevilla, Spain, 41013
    • Ionis Investigative Site
  • Valencia, Spain, 46026
    • Ionis Investigative Site
• Turkey
  • Ankara, Turkey, 6230
    • Ionis Investigative Site
  • Istanbul, Turkey, 34093
    • Ionis Investigative Site
  • İzmir, Turkey, 35100
    • 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 1FR
    • Ionis Investigative Site
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Ionis Investigative Site
  • California
    • San Diego, California, United States, 92122
      • Ionis Investigative Site
    • Santa Monica, California, United States, 90404
      • Ionis Investigative Site
    • Walnut Creek, California, United States, 94598
      • Ionis Investigative Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Ionis Investigative Site
  • Florida
    • Tampa, Florida, United States, 33613
      • Ionis Investigative Site
  • Kansas
    • Kansas City, Kansas, United States, 66205
      • Ionis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Ionis Investigative Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Ionis Investigative Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Ionis Investigative Site
  • Ohio
    • Columbus, Ohio, United States, 43235
      • Ionis Investigative Site
    • Toledo, Ohio, United States, 43617
      • 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

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria

1. Participants, or their legally appointed and authorized representatives, must provide written and signed informed consent form (ICF)/assent
2. Participants must be aged ≥ 12 years at the time of informed consent and, as applicable, assent
3. Participants must have a documented diagnosis of hereditary angioedema type 1 (HAE-1)/hereditary angioedema type 2 (HAE-2)

4. Participants must:

   1. Experience a minimum of 2 HAE attacks (confirmed by the Investigator) during the Screening Period
   2. Be willing to complete the participant reported outcomes (PRO) assessments throughout the study
5. Participants must have access to, and the ability to use acute medication(s) to treat angioedema attacks

Key Exclusion Criteria

1. 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)
2. Any clinically-significant abnormalities in screening laboratory values that would render a participant unsuitable for inclusion in the study
3. Treatment with another investigational drug or biological agent within 1 month or 5 half-lives, whichever is longer, of Screening
4. Participated in a prior ISIS 721744 study

5. Exposure to any of the following medications:

   1. Angiotensin-converting enzyme (ACE) inhibitors or any estrogen containing medications with systemic absorption within 4 weeks prior to Screening
   2. Chronic prophylaxis with Takhzyro, Haegarda, Cinryze and Ruconest or Orladeyo within 5 half-lives prior to Screening
   3. 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
6. Recent history (3 years) of, or current drug or alcohol abuse

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Pooled Placebo; Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Weeks 1, 5, 9, 13, 17, and 21) or 8 weeks (Weeks 1, 9, and 17)	Drug: Donidalorsen; Donidalorsen was administered by SC injection.
Experimental: Cohort A: Donidalorsen 80 mg; Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.	Drug: Donidalorsen; Donidalorsen was administered by SC injection.
Experimental: Cohort B: Donidalorsen 80 mg; Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.	Drug: Placebo; Donidalorsen-matching placebo was administered by SC injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25	The time-adjusted HAE attack rate was calculated as number of IC HAE attacks occurring from Week 1 to Week 25, divided by the number of days the participant contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx).	Week 1 to Week 25

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25	The time-adjusted HAE attack rate was calculated as number of IC HAE attacks occurring from Week 5 to Week 25, divided by the number of days the participant contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx).	Week 5 to Week 25
Percentage of IC HAE Attack-Free Participants From Week 5 to Week 25	An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Percentages are rounded off to the nearest decimal.	Week 5 to Week 25
Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25	The time-adjusted HAE attack rate was calculated as number of investigator-confirmed moderate or severe HAE attacks occurring from Week 5 to Week 25, divided by the number of days the participant contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx).	Week 5 to Week 25
Number of Participants With a Clinical Response From Week 5 to Week 25	Clinical response was defined as a ≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline in HAE attack rate from Week 5 to Week 25. The HAE attack rate between Week 5 and Week 25 for each participant is calculated as number of HAE attacks occurring from Week 5 to week 25 divided by the number of days the participant contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Baseline= Run-in period which is the period from screening to the last day prior to Study Day 1.	Week 5 to Week 25
IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25	Time-adjusted HAE attack rate is calculated as number of IC HAE attacks requiring acute therapy occurring from Week 5 to Week 25, divided by number of days the participant contributed to period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). HAE attacks requiring acute therapy included those attacks with following concomitant medications c1 esterase inhibitors (human and recombinant), plasma kallikrein inhibitor (human), and bradykinin antagonist.	Week 5 to Week 25
Percentage of Participants Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25	The AECT is a validated participant-reported outcome instrument to assess disease activity in participants with recurrent angioedema. The questionnaire consists of 4 questions asking about the frequency and severity of angioedema experienced in last 4 weeks. Each question has 5 response choices with total score ranging from 0 to 16. The AECT can be used to identify participants with poorly controlled disease by working with a cutoff value of greater than or equal to 10 points. Participants who score less than 10 points (0-9) in the AECT have poorly controlled disease whereas participants with well-controlled disease score 10-16 points. Percentages are rounded off to the nearest decimal.	Week 25
Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25	The AE-QoL questionnaire is a validated tool to assess symptom-specific health-related QOL impairment in participants suffering from recurrent angioedema. It is a self-administered questionnaire comprising 17 questions across 4 domains: functioning, fatigue/mood, fears/shame, and food. The responses are scored from 0 to 4 where, 0 = never, 1 = rarely, 2 = occasionally, 3 = often, 4 = very often. The AE-QoL domain scores and total score were calculated by using the following formula: (Sum score of all completed items) / (maximum sum score of all possible items) × 100. Total scores ranges from 0 to 100, with higher scores indicating greater impairment. Negative change from baseline indicates improvement. The calculated domain and total scores were not raw scores but linear transformations to a 0 to 100 scale. Baseline is defined as the score on Study Day 1.	Week 25

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Riedl MA, Tachdjian R, Lumry WR, Craig T, Karakaya G, Gelincik A, Stobiecki M, Jacobs JS, Gokmen NM, Reshef A, Gompels MM, Manning ME, Bordone L, Newman KB, Treadwell S, Wang S, Yarlas A, Cohn DM; OASIS-HAE Team. Efficacy and Safety of Donidalorsen for Hereditary Angioedema. N Engl J Med. 2024 Jul 4;391(1):21-31. doi: 10.1056/NEJMoa2402478. Epub 2024 May 31.

Study record dates

Study Major Dates

• Study Start (Actual): December 3, 2021
• Primary Completion (Actual): November 9, 2023
• Study Completion (Actual): November 9, 2023

Study Registration Dates

• First Submitted: November 18, 2021
• First Submitted That Met QC Criteria: November 18, 2021
• First Posted (Actual): December 1, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 13, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: HAE
• Additional Relevant MeSH Terms: Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Immune System Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immunologic Deficiency Syndromes; Skin Diseases; Urticaria; Skin Diseases, Vascular; Angioedema; Angioedemas, Hereditary
• Other Study ID Numbers: ISIS 721744-CS5; 2021-002571-19 (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