An Extension Study of Donidalorsen (IONIS-PKK-LRx) in Participants With Hereditary Angioedema

An Open-Label Extension Study of ISIS 721744 in Patients With Hereditary Angioedema

The purpose of this study was to evaluate the safety and efficacy of extended dosing of donidalorsen administered subcutaneously (SC), with alternative dosing and/or dose frequency with donidalorsen in participants with hereditary angioedema (HAE).

Study Overview

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

Detailed Description

This was an open-label extension study of donidalorsen in 20 participants with HAE. The length of participation in the study was approximately 68 weeks, which included an up to 4-week qualification period, a 52-week treatment period, and a 12-week post-treatment period. Following the Week 53 treatment period visit, participants received donidalorsen in an extended treatment period for up to an additional 156 weeks. Participants taking part in the extended treatment period entered the 12-week post-treatment period after completion of, or early termination from, the extended treatment period.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Ionis Investigative Site
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Ionis Investigative Site
  • California
    • Santa Monica, California, United States, 90404
      • Ionis Investigative Site
  • Minnesota
    • Plymouth, Minnesota, United States, 55446
      • Ionis Investigative Site
  • Ohio
    • Cincinnati, Ohio, United States, 45231
      • Ionis Investigative Site
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Ionis Investigative Site
  • Texas
    • Dallas, Texas, United States, 75231
      • Ionis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Satisfactory completion of ISIS 721744-CS2 (index study) through Week 17 with an acceptable safety and tolerability profile, per Sponsor and Investigator judgement
2. Able and willing to participate in a 64-week study
3. Females must be non-pregnant, non-lactating and either surgically sterile or post-menopausal
4. Males must be surgically sterile or abstinent* or if engaged in sexual relations with a female of child-bearing potential, participant is utilizing an acceptable contraceptive method
5. Participants must have access to, and the ability to use, ≥ 1 acute medication(s) (e.g., plasma-derived or recombinant C1- inhibitor (C1-INH) concentrate or a bradykinin-2 [BK-2] antagonist) to treat angioedema attacks

Exclusion Criteria:

1. Have any new condition or worsening of an existing condition or change or anticipated change in medication, which in the opinion of the Investigator would make the participant unsuitable for enrollment, or could interfere with the participant participating in or completing the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HAE-1/HAE-2; Participants with hereditary angioedema Type I/Type II (HAE-1/HAE-2) who received placebo or donidalorsen, 80 milligrams (mg), SC once every 4 weeks, in the previous study ISIS 721744-CS2 (NCT04030598), received donidalorsen, 80 mg, SC once every 4 weeks, from Week 1 to Week 13 (Fixed Dosing Period). Starting From Week 17 (Flexible Dosing Period), participants had 3 different dosing options as: 80 mg every 4 weeks, 80 mg every 8 weeks for participants who were attack-free for ≥12 weeks, 100 mg every 4 weeks for participants who were not attack-free for ≥12 weeks up to Week 53 based on the investigator and sponsor medical monitor recommendation. Participants continued flexible dosing from Week 53 for up to approximately 209 weeks.	Drug: Donidalorsen; Donidalorsen administered SC; Other Names: ISIS 721744; IONIS-PKK-LRx
Experimental: HAE-nC1-INH; Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) who received donidalorsen, 80 mg, SC, once every 4 weeks, in the previous study ISIS 721744-CS2 (NCT04030598), continued to receive donidalorsen, 80 mg, SC once every 4 weeks, from Week 1 to Week 13 (Fixed Dosing Period). Starting From Week 17 (Flexible Dosing Period), participants had 2 different dosing options as: 80 mg every 4 weeks, and 100 mg every 4 weeks for participants who were not attack-free for ≥12 weeks up to Week 53 based on the investigator and sponsor medical monitor recommendation. Participants continued flexible dosing from Week 53 for up to approximately 209 weeks.	Drug: Donidalorsen; Donidalorsen administered SC; Other Names: ISIS 721744; IONIS-PKK-LRx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not the AE is considered related to the medicinal (investigational) product. TEAEs were defined as those AEs that either started or worsened in severity on or after the date/time of first administration of study drug in this OLE Study. TEAEs included both serious and non-serious TEAEs.	Up to Week 221
Percentage of Participants With Clinically Meaningful Changes in Clinical Laboratory Assessments	Clinical laboratory tests including clinical chemistry, hematology, coagulation, complement, inflammatory, urinalysis were performed. The percentage of participants with clinically meaningful changes were reported. Clinical meaningfulness was determined by the investigator.	Up to Week 221
Percentage of Participants With Clinically Meaningful Changes in Vital Signs	Vital sign measurements including heart rate, respiratory rate, body temperature, systolic and diastolic blood pressure and pulse pressure were assessed. Percentage of participants with clinically meaningful changes in the vital signs were reported. Clinically meaningfulness was determined by the investigator.	Up to Week 221
Percentage of Participants With Clinically Meaningful Changes in Electrocardiograms (ECGs) Parameters	The ECG parameters included ventricular rate, PR interval, QRS duration, QTc, QT corrected using the Fridericia's formula (QTcF), QT corrected using the Bazett's formula (QTcB), and overall interpretation. Percentage of participants with clinically meaningful changes in the ECG parameters were reported. Clinical meaningfulness was determined by the investigator.	Up to Week 221
Percentage of Participants Who Received At Least One Concomitant Medication	Concomitant medications include medications that participants were exposed to on or after the first dose of ISIS 721744 in the OLE study. Percentage of participants who received at least one concomitant medication were reported.	Up to Week 221

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Time-normalized HAE Attack (Per 4 Weeks) Rate	HAE attack rate was calculated for each participant as the number of HAE attacks occurring during the respective period divided by the number of days the participant contributed to this 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). A negative change from baseline in HAE attacks indicates an improvement in HAE attacks.	Up to Week 221
Percentage of Participants Who Used On-demand Medications	The most commonly used on-demand medications during the On-Treatment Period were C1 esterase inhibitors (human) and icatibant, which were allowed per-protocol for treatment of acute attacks.	Up to Week 221

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Manning ME, de Lange M, Bernstein JA, Craig T, Lumry WR, Raasch J, Tachdjian R, Bordone L, Deng Y, Newman KB, Cohn DM. Donidalorsen for hereditary angioedema: Long-term results from a 4-year phase 2 open-label extension study. Ann Allergy Asthma Immunol. 2026 Mar 7:S1081-1206(26)00095-5. doi: 10.1016/j.anai.2026.02.019. Online ahead of print.
• Petersen RS, Bordone L, Riedl MA, Tachdjian R, Craig TJ, Lumry WR, Manning ME, Bernstein JA, Raasch J, Zuraw BL, Deng Y, Newman KB, Alexander VJ, Lui C, Schneider E, Cohn DM. 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. Epub 2023 Nov 27.

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2020
• Primary Completion (Actual): January 24, 2025
• Study Completion (Actual): January 24, 2025

Study Registration Dates

• First Submitted: March 11, 2020
• First Submitted That Met QC Criteria: March 11, 2020
• First Posted (Actual): March 13, 2020

Study Record Updates

• Last Update Posted (Actual): May 8, 2026
• Last Update Submitted That Met QC Criteria: April 17, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: HAE; Hereditary Angioedema
• 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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin and Connective Tissue Diseases; Angioedema; Angioedemas, Hereditary; donidalorsen; IONIS-PKK-LRx
• Other Study ID Numbers: ISIS 721744-CS3; 2020-000197-14 (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
• product manufactured in and exported from the U.S.: Yes