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

• ClinicalTrials.gov Identifier: NCT04030598
• Recruitment Status: Completed
• First Posted: July 24, 2019
• Results First Posted: September 28, 2022
• Last Update Posted: April 3, 2023
• Sponsor: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Ionis Pharmaceuticals, Inc.

Tracking Information

• First Submitted Date: July 22, 2019
• First Posted Date: July 24, 2019
• Results First Submitted Date: July 26, 2022
• Results First Posted Date: September 28, 2022
• Last Update Posted Date: April 3, 2023
• Actual Study Start Date: January 7, 2020
• Actual Primary Completion Date: January 4, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 26, 2022)

Time-normalized Number of HAE Attacks (Per Month) From Week 1 to Week 17 [ Time Frame: 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).

• Original Primary Outcome Measures (submitted: July 22, 2019): Time-normalized Number of HAE Attacks (per Month) from Week 1 to Week 17 [ Time Frame: Week 1 to Week 17 ]

Current Secondary Outcome Measures (submitted: July 26, 2022)

• Time-normalized Number of Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17 [ Time Frame: Week 5 to Week 17 ]
  The Week 5 to end of on-treatment period HAE attack rate was calculated for each participant as number of HAE attacks occurring from Week 5 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).
• Time-normalized Number of Moderate or Severe Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17 [ Time Frame: Week 5 to Week 17 ]
  The Week 5 to end of on-treatment period HAE attack rate was calculated for each participant as number of moderate or severe HAE attacks occurring from Week 5 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). HAE attack severity: Mild: transient or mild discomfort, Moderate: mild to moderate limitation in activity, some assistance needed, and Severe: marked limitation in activity, assistance required.
• Number of Participants With Clinical Response by Week 17 [ Time Frame: Week 5 to Week 17 ]
  Clinical response was defined as a ≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline in HAE attack rate from Week 5 to Week 17. The HAE attack rate was calculated as number of investigator-confirmed HAE attacks occurring from Week 5 to 28 days after last dose administration, 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).
• Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy From Week 5 to Week 17 [ Time Frame: Week 5 to Week 17 ]
  The Week 5 to end of on-treatment period HAE attack rate was calculated for each participant as number of HAE attacks requiring acute therapy occurring from Week 5 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). HAE attacks requiring acute therapy included those attacks with medical intervention or hospitalization marked on the case report form (CRFs).
• Percentage of Cleaved High Molecular Weight Kininogen (cHMWK) Levels at Weeks 9 and 17 [ Time Frame: Weeks 9 and 17 ]
  High-molecular-weight kininogen (HMWK) is an abundant protein found in plasma and it has a critical role in acute attacks of HAE. During HAE attack plasma kallikrein cleaves HMWK producing cleaved HMWK (cHMWK) and bradykinin, the major biologic peptide that promotes the edema, one of the characteristic traits of HAE. Percentage of cHMWK levels were assessed to evaluate pharmacodynamics of donidalorsen.
• Prekallikrein (PKK) Activity Levels at Weeks 9 and 17 [ Time Frame: Weeks 9 and 17 ]
  Prekallikrein (PKK) has a critical role in acute attacks of HAE. During HAE attack PKK is activated to form plasma kallikrein. Plasma kallikrein cleaves HMWK producing cleaved HMWK (cHMWK) and bradykinin, the major biologic peptide that promotes the edema, one of the characteristic traits of HAE. Prekallikrein levels were measured to assess pharmacodynamics of donidalorsen.
• Number of Participants Who Consumed On-demand Medication at Weeks 9 and 17 [ Time Frame: Weeks 9 and 17 ]
  Treatment options for HAE included on-demand treatment of attacks and prophylaxis. On-demand medication options included supplementation of C1-INH (either plasma-derived or recombinant C1-INH concentrate) and inhibition of BK2 receptor activation (BK2-receptor antagonist). The number of participants who used on-demand medication at Week 9 (Day 57) and at Week 17 (end of the on-treatment period) were reported.
• Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Weeks 9 and 17 [ Time Frame: Baseline, Weeks 9 and 17 ]
  The AE-QoL was developed to measure health-related quality of life (HRQoL) impairment in participants with recurrent angioedema. The AE-QoL is a self-administered questionnaire that can be completed in less than 5 minutes. It comprises 17 items across 4 domains: functioning, fatigue/mood, fears/shame, and food. Responses use a 5-point Likert scale ranging from '0 = never' to '4 = very often.' Per-participant scores for each domain were computed using the appropriate scoring algorithm applied to the question response scores for each domain. Per-participant total scores (including all 4 domains) were similarly computed using the question response scores for all 17 questions. The outputs from the scoring algorithm were normalized on a scale ranging from 0 (less adverse impact) to 100 (most adverse impact). Global total score ranges from 0 to 100, with higher scores indicating greater impairment. Mixed model for repeated measures (MMRM) was used for analyses.

Original Secondary Outcome Measures (submitted: July 22, 2019)

• Time-normalized Number of HAE Attacks (per Month) from Week 5 to Week 17 [ Time Frame: Week 5 to Week 17 ]
• Time-normalized Number of HAE Attacks (per Month) from Week 9 to Week 21 [ Time Frame: Week 9 to Week 21 ]
• Time-normalized Number of Moderate or Severe HAE Attacks (per Month) from Week 5 to Week 17 [ Time Frame: Week 5 to Week 17 ]
• Time-normalized Number of Moderate or Severe HAE Attacks (per Month) from Week 9 to Week 21 [ Time Frame: Week 9 to Week 21 ]
• Number of Participants with Clinical Response by Week 17 [ Time Frame: Week 17 ]
  Clinical Response is defined as a ≥ 50%, ≥ 70%, or ≥ 90% reduction from baseline in HAE attack rate.
• Number of HAE Attacks Requiring Acute Therapy from Week 5 to Week 17 [ Time Frame: Week 5 to Week 17 ]
• Cleaved High Molecular Weight Kininogen (cHK) Levels at Weeks 9 and 17 [ Time Frame: Weeks 9 and 17 ]
• Prekallikrein (PKK) Activity at Weeks 9 and 17 [ Time Frame: Weeks 9 and 17 ]
• Consumption of On-demand Medication at Weeks 9 and 17 [ Time Frame: Weeks 9 and 17 ]
• Angioedema Quality of Life (AE-QoL) Questionnaire Score at Weeks 9 and 17 [ Time Frame: Weeks 9 and 17 ]
  The AE-QoL was developed to measure health-related quality of life (HRQoL) impairment in participants with recurrent angioedema. The AE-QoL is a self-administered questionnaire that can be completed in less than 5 minutes. It comprises 17 items across 4 domains: functioning, fatigue/mood, fears/shame, and food. Responses use a 5-point Likert scale ranging from 'never' to 'very often.' Global and domain scores range from 0 to 100, with higher scores indicating greater impairment.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Assess the Clinical Efficacy of Donidalorsen (Also Known as IONIS-PKK-LRx and ISIS 721744) in Participants With Hereditary Angioedema
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the Clinical Efficacy of ISIS 721744, a Second-Generation Ligand-Conjugated Antisense Inhibitor of Prekallikrein, in Patients With Hereditary Angioedema
• 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.
• Detailed Description: This was a randomized, double-blind, placebo-controlled study in 23 participants conducted concurrently in 2 parts (Part A and Part B); participants were allocated into Part A or Part B according to type of HAE (i.e., either HAE-1/HAE-2 in Part A or HAE-nC1-INH in Part B). Part A was randomized, double-blind, and placebo-controlled; and Part B was open-label. The length of participation in the study was approximately 8 months, which included an up to 8-week screening period, a 12-week treatment period, and a 13-week post-treatment period.
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:

Part A was randomized, double-blind; Part B was open-label.

Primary Purpose: Treatment

• Condition: Hereditary Angioedema

Intervention

• Drug: Donidalorsen
  Donidalorsen administered SC
  Other Names:

  • ISIS 721744
  • IONIS-PKK-LRx
• Drug: Placebo
  Placebo matching solution administered SC

Study Arms

• Placebo Comparator: Part A: Placebo
  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.
  Intervention: Drug: Placebo
• Experimental: Part A: Donidalorsen 80 mg
  Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.
  Intervention: Drug: Donidalorsen
• Experimental: Part B: Donidalorsen 80 mg
  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.
  Intervention: Drug: Donidalorsen

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 26, 2022): 23
• Original Estimated Enrollment (submitted: July 22, 2019): 24
• Actual Study Completion Date: March 1, 2021
• Actual Primary Completion Date: January 4, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Documented diagnosis of HAE-1/HAE-2 (for inclusion in Part A) or HAE-nC1-INH (for inclusion in Part B)
• 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

Exclusion Criteria:

• 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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands, United States

Administrative Information

• NCT Number: NCT04030598
• Other Study ID Numbers: ISIS 721744-CS2; 2019-001044-22 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Ionis Pharmaceuticals, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Ionis Pharmaceuticals, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Ionis Pharmaceuticals, Inc.
• Verification Date: March 2023