Trial Outcomes & Findings for OASIS-HAE: A Study to Evaluate the Safety and Efficacy of Donidalorsen (ISIS 721744 or IONIS-PKK-LRx) in Participants With Hereditary Angioedema (HAE) (NCT NCT05139810)

Last Updated: 2025-03-06

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

91 participants

Primary outcome timeframe

Week 1 to Week 25

Results posted on

2025-03-06

Participant Flow

Participants took part in the study at 39 investigative sites from 3 December 2021 to 09 November 2023.

A total of 91 participants were enrolled and randomized in the study. Out of 91, 1 participant withdrew consent prior to receiving the study drug. As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.

Participant milestones

Participant milestones
Measure	Pooled Placebo Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).	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.	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.
Overall Study STARTED	22	46	23
Overall Study Full Analysis Set (FAS)	22	45	23
Overall Study COMPLETED	0	1	3
Overall Study NOT COMPLETED	22	45	20

Reasons for withdrawal

Reasons for withdrawal
Measure	Pooled Placebo Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).	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.	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.
Overall Study Voluntary Withdrawal	2	1	0
Overall Study Pregnancy	1	0	0
Overall Study Roll Over to CS7	19	44	20

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pooled Placebo n=22 Participants Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).	Cohort A: Donidalorsen 80 mg n=45 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.	Cohort B: Donidalorsen 80 mg n=23 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.	Total n=90 Participants Total of all reporting groups
Age, Continuous	35.4 years STANDARD_DEVIATION 11.03 • n=5 Participants	39.6 years STANDARD_DEVIATION 15.23 • n=7 Participants	34.1 years STANDARD_DEVIATION 13.22 • n=5 Participants	37.2 years STANDARD_DEVIATION 13.88 • n=4 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	28 Participants n=7 Participants	12 Participants n=5 Participants	48 Participants n=4 Participants
Sex: Female, Male Male	14 Participants n=5 Participants	17 Participants n=7 Participants	11 Participants n=5 Participants	42 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants	6 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	21 Participants n=5 Participants	43 Participants n=7 Participants	20 Participants n=5 Participants	84 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race/Ethnicity, Customized Race · American Indian or Alaskan Native	2 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Race/Ethnicity, Customized Race · Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Race · Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race/Ethnicity, Customized Race · White	18 Participants n=5 Participants	42 Participants n=7 Participants	22 Participants n=5 Participants	82 Participants n=4 Participants
Race/Ethnicity, Customized Race · Multiple	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Race · Other	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants

PRIMARY outcome

Timeframe: Week 1 to Week 25

Population: The FAS included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.

Outcome measures

Outcome measures
Measure	Pooled Placebo n=22 Participants Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).	Cohort A: Donidalorsen 80 mg n=45 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.	Cohort B: Donidalorsen 80 mg n=23 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.
Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25	2.26 HAE attacks per month Interval 1.657 to 3.085	0.44 HAE attacks per month Interval 0.265 to 0.727	1.02 HAE attacks per month Interval 0.651 to 1.594

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Pooled Placebo n=22 Participants Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).	Cohort A: Donidalorsen 80 mg n=45 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.	Cohort B: Donidalorsen 80 mg n=23 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.
Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25	2.25 HAE attacks per month Interval 1.594 to 3.183	0.30 HAE attacks per month Interval 0.151 to 0.581	0.90 HAE attacks per month Interval 0.529 to 1.52

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Pooled Placebo n=22 Participants Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).	Cohort A: Donidalorsen 80 mg n=45 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.	Cohort B: Donidalorsen 80 mg n=23 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.
Percentage of IC HAE Attack-Free Participants From Week 5 to Week 25	9.1 Percentage of participants	53.3 Percentage of participants	34.8 Percentage of participants

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Pooled Placebo n=22 Participants Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).	Cohort A: Donidalorsen 80 mg n=45 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.	Cohort B: Donidalorsen 80 mg n=23 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.
Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25	1.15 HAE attacks per month Interval 0.718 to 1.831	0.12 HAE attacks per month Interval 0.044 to 0.351	0.68 HAE attacks per month Interval 0.372 to 1.229

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Pooled Placebo n=22 Participants Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).	Cohort A: Donidalorsen 80 mg n=45 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.	Cohort B: Donidalorsen 80 mg n=23 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.
Number of Participants With a Clinical Response From Week 5 to Week 25 ≥ 50% Reduction	6 Participants	42 Participants	19 Participants
Number of Participants With a Clinical Response From Week 5 to Week 25 ≥ 70% Reduction	4 Participants	37 Participants	15 Participants
Number of Participants With a Clinical Response From Week 5 to Week 25 ≥ 90% Reduction	2 Participants	28 Participants	11 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Pooled Placebo n=22 Participants Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).	Cohort A: Donidalorsen 80 mg n=45 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.	Cohort B: Donidalorsen 80 mg n=23 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.
IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25	1.80 HAE attacks per month Interval 1.232 to 2.616	0.15 HAE attacks per month Interval 0.057 to 0.391	0.59 HAE attacks per month Interval 0.308 to 1.146

SECONDARY outcome

Timeframe: Week 25

Population: The FAS included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). Overall number analyzed is the number of participants with data available for analysis at the specified timepoint. As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.

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.

Outcome measures

Outcome measures
Measure	Pooled Placebo n=17 Participants Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).	Cohort A: Donidalorsen 80 mg n=42 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.	Cohort B: Donidalorsen 80 mg n=22 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.
Percentage of Participants Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25	47.1 Percentage of participants	92.9 Percentage of participants	77.3 Percentage of participants

SECONDARY outcome

Timeframe: Week 25

Population: The FAS included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). Overall number of participants analyzed is the number of participants with data available for analysis at the specified time point. As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.

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.

Outcome measures

Outcome measures
Measure	Pooled Placebo n=18 Participants Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).	Cohort A: Donidalorsen 80 mg n=42 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.	Cohort B: Donidalorsen 80 mg n=22 Participants Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.
Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25	-6.19 Score on a scale Interval -13.737 to 1.353	-24.76 Score on a scale Interval -29.86 to -19.652	-19.85 Score on a scale Interval -26.96 to -12.734

Adverse Events

Pooled Placebo

Serious events: 1 serious events

Other events: 15 other events

Deaths: 0 deaths

Cohort A: Donidalorsen 80 mg

Serious events: 0 serious events

Other events: 22 other events

Deaths: 0 deaths

Cohort B: Donidalorsen 80 mg

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Pooled Placebo n=22 participants at risk Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17).	Cohort A: Donidalorsen 80 mg n=45 participants at risk Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.	Cohort B: Donidalorsen 80 mg n=23 participants at risk Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.
Injury, poisoning and procedural complications Limb Injury	4.5% 1/22 • Up to Week 38 The safety set included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.	0.00% 0/45 • Up to Week 38 The safety set included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.	0.00% 0/23 • Up to Week 38 The safety set included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.

Other adverse events

Additional Information

Ionis Pharmaceuticals, Inc.

Phone: 760-603-2346

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Publication restrictions are in place

Restriction type: OTHER