A Study to Assess the Clinical Efficacy of Donidalorsen (Also Known as IONIS-PKK-LRx and ISIS 721744) in Participants With Hereditary Angioedema

NCT04030598 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: ISIS 721744-CS22019-001044-22
• Study Type: interventional
• Target: 23
• Locations: 2 countries
• Sites: 8

Brief Summary

The purpose of this study was to evaluate the clinical efficacy, safety, and tolerability of donidalorsen in participants with hereditary angioedema (HAE) type 1 (HAE-1), HAE type 2 (HAE-2), or HAE with normal C1-inhibitor (C1-INH) and to evaluate the effect of donidalorsen on plasma prekallikrein (PKK) and other relevant biomarkers.

Conditions

Hereditary Angioedema

Keywords

IONIS PKK-LRx; Donidalorsen

Outcome Measures

Primary Outcomes (1)

• Time-normalized Number of HAE Attacks (Per Month) From Week 1 to Week 17

  The Week 1 to end of on-treatment period HAE attack rate was calculated for each participant as number of HAE attacks occurring from Week 1 to 28 days after the last dose date 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 17

Secondary Outcomes (8)

• Time-normalized Number of Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17

  Week 5 to Week 17

• Time-normalized Number of Moderate or Severe Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17

  Week 5 to Week 17

• Number of Participants With Clinical Response by Week 17

  Week 5 to Week 17

• Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy From Week 5 to Week 17

  Week 5 to Week 17

• Percentage of Cleaved High Molecular Weight Kininogen (cHMWK) Levels at Weeks 9 and 17

  Weeks 9 and 17

Study Arms (3)

Part A: Placebo

PLACEBO COMPARATOR

Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.

Drug: Placebo

Part A: Donidalorsen 80 mg

EXPERIMENTAL

Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.

Drug: Donidalorsen

Part B: Donidalorsen 80 mg

EXPERIMENTAL

Participants with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.

Drug: Donidalorsen

Interventions

Donidalorsen DRUG

Donidalorsen administered SC

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

Part A: Donidalorsen 80 mg; Part B: Donidalorsen 80 mg

Placebo DRUG

Placebo matching solution administered SC

Part A: Placebo

Eligibility Criteria

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

You may qualify if:

• Participants must have experienced a minimum of 2 HAE attacks (assessed by the Angioedema Activity Score \[AAS\] and confirmed by the investigator) during the screening period
• Access to, and the ability to use, ≥ 1 acute medication(s) to treat angioedema attacks

You may not qualify if:

• Anticipated use of short-term prophylaxis for angioedema attacks for a pre-planned procedure during the screening or study periods
• Concurrent diagnosis of any other type of recurrent angioedema, including acquired or idiopathic angioedema
• Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B
• Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated
• Treatment with another investigational drug or biological agent within 1 month or 5 half-lives, whichever is longer, of screening
• Exposure to any of the following medications:
• Angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptive or hormonal replacement therapy) within 4 weeks prior to screening
• Chronic prophylaxis with Lanadelumab within 10 weeks prior to screening
• Oligonucleotides (including small interfering ribonucleic acid \[RNA\]) within 4 months of screening (if single dose received) or within 12 months of screening (if multiple doses received)

Sponsors & Collaborators

• Ionis Pharmaceuticals, Inc.: lead

Study Sites (8)

Medical Research of Arizona

Scottsdale, Arizona, 85251, United States

Location

University of California San Diego (UCSD)

San Diego, California, 92122, United States

Location

AIRE Medical of Los Angeles

Santa Monica, California, 90404, United States

Location

Midwest Immunology Clinical

Plymouth, Minnesota, 55446, United States

Location

Bernstein Clinical Research Center, LLC

Cincinnati, Ohio, 45231, United States

Location

Penn State Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

Location

AARA Research Center

Dallas, Texas, 75231, United States

Location

Amsterdam UMC, loc. AMC

Amsterdam, 1105 AZ, Netherlands

Location

Related Publications (1)

• Fijen LM, Riedl MA, Bordone L, Bernstein JA, Raasch J, Tachdjian R, Craig T, Lumry WR, Manning ME, Alexander VJ, Newman KB, Revenko A, Baker BF, Nanavati C, MacLeod AR, Schneider E, Cohn DM. Inhibition of Prekallikrein for Hereditary Angioedema. N Engl J Med. 2022 Mar 17;386(11):1026-1033. doi: 10.1056/NEJMoa2109329.

  PMID: 35294812 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.

patients@ionisph.com

800-679-4747

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Part A was randomized, double-blind; Part B was open-label.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 22, 2019
• First Posted: July 24, 2019
• Study Start: January 7, 2020
• Primary Completion: January 4, 2021
• Study Completion: March 1, 2021
• Last Updated: April 3, 2023
• Results First Posted: September 28, 2022

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (7); NL (1)