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

NCT04307381 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: ISIS 721744-CS32020-000197-14
• Study Type: interventional
• Target: 20
• Locations: 2 countries
• Sites: 7

Brief Summary

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).

Conditions

Hereditary Angioedema

Keywords

Hereditary Angioedema; HAE

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (2)

• Percent Change From Baseline in Time-normalized HAE Attack (Per 4 Weeks) Rate

  Up to Week 221

• Percentage of Participants Who Used On-demand Medications

  Up to Week 221

Study Arms (2)

HAE-1/HAE-2

EXPERIMENTAL

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

HAE-nC1-INH

EXPERIMENTAL

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

Interventions

Donidalorsen DRUG

Donidalorsen administered SC

Also known as: ISIS 721744, IONIS-PKK-LRx

HAE-1/HAE-2; HAE-nC1-INH

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Satisfactory completion of ISIS 721744-CS2 (index study) through Week 17 with an acceptable safety and tolerability profile, per Sponsor and Investigator judgement
• Able and willing to participate in a 64-week study
• Females must be non-pregnant, non-lactating and either surgically sterile or post-menopausal
• 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
• 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

You may not qualify if:

• \. 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

Sponsors & Collaborators

• Ionis Pharmaceuticals, Inc.: lead

Study Sites (7)

Ionis Investigative Site

Scottsdale, Arizona, 85251, United States

Location

Ionis Investigative Site

Santa Monica, California, 90404, United States

Location

Ionis Investigative Site

Plymouth, Minnesota, 55446, United States

Location

Ionis Investigative Site

Cincinnati, Ohio, 45231, United States

Location

Ionis Investigative Site

Hershey, Pennsylvania, 17033, United States

Location

Ionis Investigative Site

Dallas, Texas, 75231, United States

Location

Ionis Investigative Site

Amsterdam, 1105 AZ, Netherlands

Location

Related Publications (2)

• 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.

  PMID: 41802598 DERIVED

• 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.

  PMID: 38009241 DERIVED

MeSH Terms

Conditions

Angioedemas, Hereditary

Interventions

donidalorsen; IONIS-PKK-LRx

Condition Hierarchy (Ancestors)

Angioedema; Vascular Diseases; Cardiovascular Diseases; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Urticaria; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Immunologic Deficiency Syndromes

Results Point of Contact

• Title: Ionis Pharmaceuticals, Inc.
• Organization: Ionis Pharmaceuticals, Inc.

globalregulatoryaffairs@ionis.com

760-603-2346

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: March 11, 2020
• First Posted: March 13, 2020
• Study Start: March 31, 2020
• Primary Completion: January 24, 2025
• Study Completion: January 24, 2025
• Last Updated: May 8, 2026
• Results First Posted: May 8, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share

Locations

NL (1); US (6)