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Clinical Trial Results:
A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ISIS 721744 in Patients With Hereditary Angioedema (HAE)

Summary
EudraCT number	2021-002571-19
Trial protocol	FR IT ES NL DE BE BG DK PL
Global end of trial date	08 Nov 2023

Results information
Results version number	v1(current)
This version publication date	22 Dec 2024
First version publication date	22 Dec 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ISIS721744-CS5

ISRCTN number

US NCT number

NCT05139810

WHO universal trial number (UTN)

Sponsor organisation name

Ionis Pharmaceuticals, Inc.

Sponsor organisation address

2855 Gazelle Court, Carlsbad, United States, 92010

Public contact

Ionis Clinical Trial Information, Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., 1 760-603-2346, globalregulatoryaffairs@ionis.com

Scientific contact

Ionis Clinical Trial Information, Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., 1 760-603-2346, globalregulatoryaffairs@ionis.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-003112-PIP01-21

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

08 Nov 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Nov 2023

Was the trial ended prematurely?

Main objective of the trial

To evaluate the safety and efficacy of donidalorsen in subjects with Hereditary Angioedema (HAE) and effect of donidalorsen on the quality and pattern of HAE attacks and their impact on quality of life (QoL).

Protection of trial subjects

Each subject, or legally acceptable representative, signed an informed consent form before participating in the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Dec 2021

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 18

Country: Number of subjects enrolled

Türkiye: 20

Country: Number of subjects enrolled

Italy: 9

Country: Number of subjects enrolled

Netherlands: 8

Country: Number of subjects enrolled

Spain: 6

Country: Number of subjects enrolled

Israel: 5

Country: Number of subjects enrolled

Poland: 5

Country: Number of subjects enrolled

United Kingdom: 5

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

Bulgaria: 3

Country: Number of subjects enrolled

Canada: 3

Country: Number of subjects enrolled

France: 3

Country: Number of subjects enrolled

Belgium: 1

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects took part in the study at 39 investigative sites from 03 December 2021 to 09 November 2023.

Screening details

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

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Carer, Investigator, Assessor

Are arms mutually exclusive

Yes

Pooled Placebo

Arm description

Subjects 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).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo was administered SC either every 4 weeks or 8 weeks.

Cohort A: Donidalorsen 80 mg

Arm description

Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.

Arm type

Experimental

Investigational medicinal product name

Donidalorsen 80 mg

Investigational medicinal product code

ISIS 721744

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Donidalorsen, 80 mg, administered SC, every 4 weeks.

Cohort B: Donidalorsen 80 mg

Arm description

Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.

Arm type

Experimental

Investigational medicinal product name

Donidalorsen 80 mg

Investigational medicinal product code

ISIS 721744

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Donidalorsen, 80 mg, administered SC, every 8 weeks.

Number of subjects in period 1	Pooled Placebo	Cohort A: Donidalorsen 80 mg	Cohort B: Donidalorsen 80 mg
Started	22	45	23
Completed	0	1	3
Not completed	22	44	20
Roll Over to CS7	19	44	20
Voluntary Withdrawal	2	-	-
Pregnancy	1	-	-

Baseline characteristics

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Reporting group title

Pooled Placebo

Reporting group description

Subjects 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).

Reporting group title

Cohort A: Donidalorsen 80 mg

Reporting group description

Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.

Reporting group title

Cohort B: Donidalorsen 80 mg

Reporting group description

Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.

Reporting group values	Pooled Placebo	Cohort A: Donidalorsen 80 mg	Cohort B: Donidalorsen 80 mg	Total
Number of subjects	22	45	23
Age Categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	35.4 ( 11.03 )	39.6 ( 15.23 )	34.1 ( 13.22 )	-
Gender categorical
Units: Subjects
Male	14	17	11	42
Female	8	28	12	48
Race
Units: Subjects
American Indian or Alaskan Native	2	0	1	3
Asian	0	1	0	1
Black or African American	1	1	0	2
White	18	42	22	82
Multiple	1	0	0	1
Other	0	1	0	1
Ethnicity
Units: Subjects
Hispanic or Latino	1	2	3	6
Not Hispanic or Latino	21	43	20	84

End points

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Reporting group title

Pooled Placebo

Reporting group description

Subjects 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).

Reporting group title

Cohort A: Donidalorsen 80 mg

Reporting group description

Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.

Reporting group title

Cohort B: Donidalorsen 80 mg

Reporting group description

Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.

Primary: Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25

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End point title

Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25

End point description

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 subject 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).The full analysis set (FAS) included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). As given in protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.

End point type

Primary

End point timeframe

Week 1 to Week 25

End point values	Pooled Placebo	Cohort A: Donidalorsen 80 mg	Cohort B: Donidalorsen 80 mg
Number of subjects analysed	22	45	23
Units: HAE attacks per month
least squares mean (confidence interval 95%)	2.26 (1.657 to 3.085)	0.44 (0.265 to 0.727)	1.02 (0.651 to 1.594)

Statistical analysis 1

Statistical analysis description

The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 1 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion. Model adjusted rate ratio from Poisson regression model.

Comparison groups

Pooled Placebo v Cohort A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Poisson regression model

Parameter type

IC HAE attack rate ratio

Point estimate

0.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.107

upper limit

0.351

Statistical analysis 2

Statistical analysis description

The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 1 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential overdispersion. Model adjusted rate ratio from Poisson regression model.

Comparison groups

Pooled Placebo v Cohort B: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

Poisson regression model

Parameter type

IC HAE attack rate ratio

Point estimate

0.45

Confidence interval

level

95%

sides

2-sided

lower limit

0.261

upper limit

0.777

Secondary: Percentage of IC HAE Attack-Free Subjects From Week 5 to Week 25

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End point title

Percentage of IC HAE Attack-Free Subjects From Week 5 to Week 25

End point description

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. The FAS included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). As given in protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.

End point type

Secondary

End point timeframe

Week 5 to Week 25

End point values	Pooled Placebo	Cohort A: Donidalorsen 80 mg	Cohort B: Donidalorsen 80 mg
Number of subjects analysed	22	45	23
Units: Percentage of subjects
number (not applicable)	9.1	53.3	34.8

Statistical analysis 2

Comparison groups

Pooled Placebo v Cohort B: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.24 ^[1]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

3.23

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

22.85

Notes
[1] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.

Statistical analysis 1

Comparison groups

Pooled Placebo v Cohort A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[2]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

11.79

Confidence interval

level

95%

sides

2-sided

lower limit

2.34

upper limit

59.36

Notes
[2] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.

Secondary: Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25

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End point title

Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25

End point description

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 subject 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). The FAS included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). As given in protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.

End point type

Secondary

End point timeframe

Week 5 to Week 25

End point values	Pooled Placebo	Cohort A: Donidalorsen 80 mg	Cohort B: Donidalorsen 80 mg
Number of subjects analysed	22	45	23
Units: HAE attacks per month
least squares mean (confidence interval 95%)	2.25 (1.594 to 3.183)	0.30 (0.151 to 0.581)	0.90 (0.529 to 1.520)

Statistical analysis 2

Statistical analysis description

The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion. Model adjusted rate ratio from Poisson regression model.

Comparison groups

Pooled Placebo v Cohort B: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

Poisson regression model

Parameter type

IC HAE attack rate ratio

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.212

upper limit

0.748

Statistical analysis 1

Statistical analysis description

The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion. Model adjusted rate ratio from Poisson regression model.

Comparison groups

Pooled Placebo v Cohort A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Poisson regression model

Parameter type

IC HAE attack rate ratio

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.062

upper limit

0.281

Secondary: Number of Subjects With a Clinical Response From Week 5 to Week 25

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End point title

Number of Subjects With a Clinical Response From Week 5 to Week 25

End point description

Clinical response= ≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline in HAE attack rate from Week 5 to Week 25. HAE attack rate between Week 5 and Week 25 for each subject is calculated as number of HAE attacks (occurring from Week 5 to week 25)/number of days subject contributed to period*28 days. An HAE attack- an event with signs or symptoms consistent with an attack in at least 1 of locations: peripheral angioedema (cutaneous swelling involving an extremity, 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 period from screening to last day prior to Day 1. FAS. As per protocol/SAP, data for placebo subjects from Cohort A&B was pooled for comparison to donidalorsen treated subjects.

End point type

Secondary

End point timeframe

Week 5 to Week 25

End point values	Pooled Placebo	Cohort A: Donidalorsen 80 mg	Cohort B: Donidalorsen 80 mg
Number of subjects analysed	22	45	23
Units: Subjects
≥ 50% Reduction	6	42	19
≥ 70% Reduction	4	37	15
≥ 90% Reduction	2	28	11

Statistical analysis 1

Statistical analysis description

≥ 50% Reduction: The odds ratio and its 95% confidence interval were calculated based on a logistic regression with baseline (the time-normalized run-in period attack rate) and the treatment-by-baseline interaction as a covariate.

Comparison groups

Pooled Placebo v Cohort A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[3]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

310.35

Confidence interval

level

95%

sides

2-sided

lower limit

11.63

upper limit

8279.94

Notes
[3] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.

Statistical analysis 2

Statistical analysis description

Comparison groups

Pooled Placebo v Cohort B: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[4]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

14.8

Confidence interval

level

95%

sides

2-sided

lower limit

3.15

upper limit

69.41

Notes
[4] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.

Statistical analysis 3

Statistical analysis description

≥ 70% Reduction: The odds ratio and its 95% confidence interval were calculated based on a logistic regression with baseline (the time-normalized run-in period attack rate) and the treatment-by-baseline interaction as a covariate.

Comparison groups

Pooled Placebo v Cohort A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[5]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

34.74

Confidence interval

level

95%

sides

2-sided

lower limit

7.32

upper limit

164.87

Notes
[5] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.

Statistical analysis 4

Statistical analysis description

Comparison groups

Pooled Placebo v Cohort B: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[6]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

9.17

Confidence interval

level

95%

sides

2-sided

lower limit

2.05

upper limit

41.09

Notes
[6] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.

Statistical analysis 5

Statistical analysis description

≥ 90% Reduction: The odds ratio and its 95% confidence interval were calculated based on a logistic regression with baseline (the time-normalized run-in period attack rate) and the treatment-by-baseline interaction as a covariate.

Comparison groups

Pooled Placebo v Cohort B: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[7]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

17.04

Confidence interval

level

95%

sides

2-sided

lower limit

3.36

upper limit

86.42

Notes
[7] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.

Statistical analysis 6

Statistical analysis description

Comparison groups

Pooled Placebo v Cohort B: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.014 ^[8]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

8.7

Confidence interval

level

95%

sides

2-sided

lower limit

1.56

upper limit

48.52

Notes
[8] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate.

Secondary: Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25

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End point title

Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25

End point description

Time-adjusted HAE attack rate was calculated as number of IC moderate or severe HAE attacks occurring from Week 5 to Week 25, divided by the number of days the subject 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 tongue, palate, uvula, or larynx). The FAS included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). As given in protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.

End point type

Secondary

End point timeframe

Week 5 to Week 25

End point values	Pooled Placebo	Cohort A: Donidalorsen 80 mg	Cohort B: Donidalorsen 80 mg
Number of subjects analysed	22	45	23
Units: HAE attacks per month
least squares mean (confidence interval 95%)	1.15 (0.718 to 1.831)	0.12 (0.044 to 0.351)	0.68 (0.372 to 1.229)

Statistical analysis 2

Statistical analysis description

The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion. Model adjusted rate ratio from Poisson regression model.

Comparison groups

Pooled Placebo v Cohort B: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.173

Method

Poisson regression model

Parameter type

IC HAE attack rate ratio

Point estimate

0.59

Confidence interval

level

95%

sides

2-sided

lower limit

0.276

upper limit

1.26

Statistical analysis 1

Statistical analysis description

The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion. Model adjusted rate ratio from Poisson regression model.

Comparison groups

Pooled Placebo v Cohort A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Poisson regression model

Parameter type

IC HAE attack rate ratio

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.035

upper limit

0.339

Secondary: IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25

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End point title

IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25

End point description

Time-adjusted HAE attack rate= number of investigator-confirmed HAE attacks requiring acute therapy occurring from Week 5 to Week 25, divided by number of days subject contributed to period multiplied by 28 days. HAE attack- event with signs or symptoms consistent with an attack in at least 1 of 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. FAS. As per protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled.

End point type

Secondary

End point timeframe

Week 5 to Week 25

End point values	Pooled Placebo	Cohort A: Donidalorsen 80 mg	Cohort B: Donidalorsen 80 mg
Number of subjects analysed	22	45	23
Units: HAE attacks per month
least squares mean (confidence interval 95%)	1.80 (1.232 to 2.616)	0.15 (0.057 to 0.391)	0.59 (0.308 to 1.146)

Statistical analysis 1

Statistical analysis description

The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion. Model adjusted rate ratio from Poisson regression model.

Comparison groups

Pooled Placebo v Cohort A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Poisson regression model

Parameter type

IC HAE attack rate ratio

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.03

upper limit

0.234

Statistical analysis 2

Statistical analysis description

The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion. Model adjusted rate ratio from Poisson regression model.

Comparison groups

Pooled Placebo v Cohort B: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

Poisson regression model

Parameter type

IC HAE attack rate ratio

Point estimate

0.33

Confidence interval

level

95%

sides

2-sided

lower limit

0.155

upper limit

0.706

Secondary: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25

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End point title

Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25

End point description

AE-QoL: validated tool to assess symptom-specific health-related QOL impairment in subjects 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. Calculated domain and total scores were not raw scores but linear transformations to a 0 to 100 scale. Baseline= score on Study Day 1. FAS. Subjects analyzed= number of subjects with data available for analysis at specified time point. As per protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled.

End point type

Secondary

End point timeframe

Week 25

End point values	Pooled Placebo	Cohort A: Donidalorsen 80 mg	Cohort B: Donidalorsen 80 mg
Number of subjects analysed	18	42	22
Units: Score on a scale
least squares mean (confidence interval 95%)	-6.19 (-13.737 to 1.353)	-24.76 (-29.860 to -19.652)	-19.85 (-26.960 to -12.734)

Statistical analysis 2

Comparison groups

Pooled Placebo v Cohort B: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01

Method

MMRM

Parameter type

Treatment difference]

Point estimate

-13.65

Confidence interval

level

95%

sides

2-sided

lower limit

-24.024

upper limit

-3.286

Statistical analysis 1

Comparison groups

Pooled Placebo v Cohort A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed model with repeated measures(MMRM)

Parameter type

Treatment difference

Point estimate

-18.56

Confidence interval

level

95%

sides

2-sided

lower limit

-27.673

upper limit

-9.454

Secondary: Percentage of Subjects Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25

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End point title

Percentage of Subjects Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25

End point description

AECT is a validated subject-reported outcome instrument to assess disease activity in subjects with recurrent angioedema. Questionnaire consists of 4 questions asking about the frequency and severity of angioedema experienced in last four weeks. Each question has 5 response choices with total score ranging from 0 to 16. AECT can be used to identify subjects with poorly controlled disease by working with a cutoff value of greater than or equal to 10 points. Subjects who score less than 10 points (0-9) in the AECT have poorly controlled disease whereas subjects with well-controlled disease score 10-16 points. Percentages are rounded off to the nearest decimal. FAS included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). Subjects analyzed indicates the number of subjects with data available for analysis at the specified timepoint. As per protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled.

End point type

Secondary

End point timeframe

Week 25

End point values	Pooled Placebo	Cohort A: Donidalorsen 80 mg	Cohort B: Donidalorsen 80 mg
Number of subjects analysed	17	42	22
Units: Percentage of subjects
number (not applicable)	47.1	92.9	77.3

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to Week 38

Adverse event reporting additional description

The safety set included all randomized subjects 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 subjects from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Pooled Placebo

Reporting group description

Subjects 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).

Reporting group title

Cohort B: Donidalorsen 80 mg

Reporting group description

Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17.

Reporting group title

Cohort A: Donidalorsen 80 mg

Reporting group description

Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21.

Serious adverse events	Pooled Placebo	Cohort B: Donidalorsen 80 mg	Cohort A: Donidalorsen 80 mg
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 22 (4.55%)	0 / 23 (0.00%)	0 / 45 (0.00%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Injury, poisoning and procedural complications
Limb Injury
subjects affected / exposed	1 / 22 (4.55%)	0 / 23 (0.00%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Pooled Placebo	Cohort B: Donidalorsen 80 mg	Cohort A: Donidalorsen 80 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	15 / 22 (68.18%)	23 / 23 (100.00%)	22 / 45 (48.89%)
Injury, poisoning and procedural complications
Limb Injury
subjects affected / exposed	3 / 22 (13.64%)	1 / 23 (4.35%)	0 / 45 (0.00%)
occurrences all number	3	1	0
Nervous system disorders
Headache
subjects affected / exposed	4 / 22 (18.18%)	2 / 23 (8.70%)	7 / 45 (15.56%)
occurrences all number	6	7	18
General disorders and administration site conditions
Injection Site Discolouration
subjects affected / exposed	0 / 22 (0.00%)	1 / 23 (4.35%)	3 / 45 (6.67%)
occurrences all number	0	1	9
Injection Site Pruritus
subjects affected / exposed	0 / 22 (0.00%)	0 / 23 (0.00%)	3 / 45 (6.67%)
occurrences all number	0	0	9
Injection Site Pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 23 (0.00%)	3 / 45 (6.67%)
occurrences all number	0	0	8
Pyrexia
subjects affected / exposed	1 / 22 (4.55%)	3 / 23 (13.04%)	0 / 45 (0.00%)
occurrences all number	1	3	0
Injection Site Erythema
subjects affected / exposed	0 / 22 (0.00%)	1 / 23 (4.35%)	6 / 45 (13.33%)
occurrences all number	0	1	14
Gastrointestinal disorders
Abdominal Discomfort
subjects affected / exposed	0 / 22 (0.00%)	0 / 23 (0.00%)	3 / 45 (6.67%)
occurrences all number	0	0	4
Abdominal Pain
subjects affected / exposed	2 / 22 (9.09%)	0 / 23 (0.00%)	1 / 45 (2.22%)
occurrences all number	2	0	1
Dyspepsia
subjects affected / exposed	2 / 22 (9.09%)	0 / 23 (0.00%)	0 / 45 (0.00%)
occurrences all number	2	0	0
Vomiting
subjects affected / exposed	1 / 22 (4.55%)	2 / 23 (8.70%)	0 / 45 (0.00%)
occurrences all number	1	2	0
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	1 / 22 (4.55%)	1 / 23 (4.35%)	3 / 45 (6.67%)
occurrences all number	1	1	3
Infections and infestations
Oral Herpes
subjects affected / exposed	0 / 22 (0.00%)	2 / 23 (8.70%)	0 / 45 (0.00%)
occurrences all number	0	2	0
Covid-19
subjects affected / exposed	3 / 22 (13.64%)	1 / 23 (4.35%)	1 / 45 (2.22%)
occurrences all number	3	1	1
Gastroenteritis
subjects affected / exposed	2 / 22 (9.09%)	1 / 23 (4.35%)	1 / 45 (2.22%)
occurrences all number	2	1	1
Sinusitis
subjects affected / exposed	2 / 22 (9.09%)	0 / 23 (0.00%)	0 / 45 (0.00%)
occurrences all number	2	0	0
Upper Respiratory Tract Infection
subjects affected / exposed	1 / 22 (4.55%)	3 / 23 (13.04%)	4 / 45 (8.89%)
occurrences all number	1	3	4
Influenza
subjects affected / exposed	2 / 22 (9.09%)	5 / 23 (21.74%)	4 / 45 (8.89%)
occurrences all number	2	5	4
Nasopharyngitis
subjects affected / exposed	5 / 22 (22.73%)	3 / 23 (13.04%)	6 / 45 (13.33%)
occurrences all number	5	7	9
Urinary Tract Infection
subjects affected / exposed	0 / 22 (0.00%)	2 / 23 (8.70%)	4 / 45 (8.89%)
occurrences all number	0	2	4

More information

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Were there any global substantial amendments to the protocol? Yes

01 Oct 2021

Secondary and exploratory objectives were summarized into more cohesive objectives because details were already provided in the endpoints. Added the inclusion and rationale for of a second dosing Cohort with a dose frequency of per 8 weeks (donidalorsen 80 mg once per 8 weeks). Additional subjects were added to the study with a new dosing cohort (donidalorsen 80 mg every 8 weeks). A clarification was added to the collection of HAE attack details that confirmed HAE attacks were based on symptoms and Investigator diagnosis, not on presence of symptoms alone. Safety stopping rules for platelet count and actions in subjects with confirmed low platelet count were updated to increase monitoring frequency for platelets for counts between 100,000 /mm^3 and 125,000/mm^3 and added requirement for Sponsor approval for continued dosing when platelets were ≥ 75,000/mm^3 to ≤ 100,000/mm^3. Added a safety monitoring plan. The definition of clinically relevant non-major bleeding events was updated to the most current version. Updated the Safety and PK population definitions to include randomized subjects. The primary efficacy analysis was updated to reflect that the primary analysis was to compare between the 80 mg donidalorsen-4 group versus placebo group. The recall period for the work productivity and impairment (WPAI) questionnaire was 7 days. Therefore, this assessment was completed by the subject weekly throughout the entire study rather than intermittently as specified in the original protocol. Added directions to follow if urine pregnancy test was positive in Schedule of Procedures. Electrocardiogram (ECG)-related assessment changes were added to the Schedule of Procedures including predose and 2 hours after dose. Updated Schedule of Procedures by adding a physical exam at every visit to examine for reactions due to study drug administration. Updated Schedule of Procedures and PK Sampling Schedule to reflect the new dosing groups.

01 Oct 2021

The time points for PK sampling were accidentally inverted in the original protocol. Study Drug administration did not occur at Week 25 and therefore, the time points for PK sampling at Weeks 21 and 25 were switched. Also added 2-hours post-dosing at Week 21 only for Cohort A and at Week 17 only for Cohort B. Added the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, Sept. 2007 to indicate how Adverse Events (AE) were graded. Exclusion criteria's were updated.

12 Jul 2022

Added a clarification on how many attacks were required for a subject to be randomized i.e., ≥ 2 HAE attacks. Changed inclusion criteria 6 and 7 and contraception requirements to include the use of acceptable instead of highly effective contraceptive methods. Added a clarification to the exclusion criteria to exclude subjects with alcohol or drug abuse. Added a clarification to contraception requirements to note that the exclusion of combined estrogen and progesterone hormonal contraception was intended for oral hormonal therapy, and not for intrauterine or intravaginal estrogens. Updated the urine protein-creatinine ratio (UPCR) to a more accurate lab measure: UPCR > 1000 mg/g confirmed a quantitative total urine protein measurement of >1.0 g/24 hours. Added a clarification that the final analysis was to be performed before the follow-up period was completed. Deleted reference that dose reductions were allowed from the protocol.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ISIS 721744 in Patients With Hereditary Angioedema (HAE)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25

Primary: Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25

Secondary: Percentage of IC HAE Attack-Free Subjects From Week 5 to Week 25

Secondary: Percentage of IC HAE Attack-Free Subjects From Week 5 to Week 25

Secondary: Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25

Secondary: Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25

Secondary: Number of Subjects With a Clinical Response From Week 5 to Week 25

Secondary: Number of Subjects With a Clinical Response From Week 5 to Week 25

Secondary: Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25

Secondary: Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25

Secondary: IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25

Secondary: IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25

Secondary: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25

Secondary: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25

Secondary: Percentage of Subjects Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25

Secondary: Percentage of Subjects Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Cyprus
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Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
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Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ISIS 721744 in Patients With Hereditary Angioedema (HAE)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25

Primary: Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25

Secondary: Percentage of IC HAE Attack-Free Subjects From Week 5 to Week 25

Secondary: Percentage of IC HAE Attack-Free Subjects From Week 5 to Week 25

Secondary: Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25

Secondary: Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25

Secondary: Number of Subjects With a Clinical Response From Week 5 to Week 25

Secondary: Number of Subjects With a Clinical Response From Week 5 to Week 25

Secondary: Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25

Secondary: Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25

Secondary: IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25

Secondary: IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25

Secondary: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25

Secondary: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25

Secondary: Percentage of Subjects Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25

Secondary: Percentage of Subjects Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ISIS 721744 in Patients With Hereditary Angioedema (HAE)