An Open-Label, Long Term Safety and Efficacy Study of Donidalorsen in the Prophylactic Treatment of Hereditary Angioedema (HAE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ionis Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16], Phenomena and Processes [G] - Genetic Phenomena [G05]

Trial duration

2 Nov 2022 → ongoing

Decision date (initial)

2024-04-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ionis Pharmaceuticals, Inc.

External identifiers

EU CT number

2023-509201-77-00

EudraCT number

2022-000757-93

WHO UTN

U1111-1299-6584

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Prophylaxis, Pharmacodynamic, Safety, Efficacy, Therapy

to evaluate the safety of long-term dosing with donidalorsen in patients with HAE

Secondary objectives 1

1. 1. To evaluate the long-term efficacy and the effects of donidalorsen on the number of HAE attacks and their impact on the quality of life (QoL) of patients with HAE.

Conditions and MedDRA coding

Hereditary Angioedema

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003112-PIP01-21

Plan to share IPD

Yes

IPD plan description

Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 1. Participants and, as applicable, legally authorized representatives (i.e. parent(s)/legal guardian), must provide written and signed informed consent form (ICF).
2. 2. Participants must have access to, and the ability to use, ≥ 1 acute medication(s) (e.g. plasma-derived or recombinant C1-INH concentrate or a bradykinin receptor (BK) 2-receptor antagonist) to treat angioedema attacks Open-Label Extension Participants ONLY.
3. 3. Satisfactory completion of ISIS 721744-CS5 (randomized placebocontrolled index study) through Week 25 or participants who are allowed to exit ISIS 721744-CS5 study per protocol with an acceptable safety and tolerability profile New (not previously on donidalorsen) Participants ONLY.
4. 4. Participants must be aged ≥ 12 years at the time of informed consent and, as applicable, assent.
5. 5. Participants must have a documented diagnosis of HAE-1/HAE-2.
6. 6. Participants must be on a stable dose (≥ 12 weeks) of prophylaxis treatment with lanadelumab or berotralstat or C1-esterase inhibitor prior to the Screening Period.

Exclusion criteria 9

1. 1. Have any new condition or worsening of an existing condition or change or anticipated change in medication De-novo Participants.
2. 2. Concurrent diagnosis of any other type of recurrent angioedema, including acquired, idiopathic angioedema or HAE with normal C1-INH (also known as HAE Type III).
3. 3. Anticipated change in the use of concurrent androgen or tranexamic acid prophylaxis used to prevent angioedema attacks Any clinically-significant abnormalities in screening laboratory values.
4. 4. Malignancy within 5 years of Screening, except for non-melanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma that has been successfully treated.
5. 5. Hypersensitivity to the active substance (donidalorsen) or to any of the excipients.
6. 6. Treatment with another investigational drug (non-oligonucleotide) or biological agent within 1 month of Screening or 5 half-lives of investigational agent, whichever is longer.
7. 7. Recent history of, or current drug or alcohol abuse.
8. 8. Participated in a prior donidalorsen study.
9. 9. Exposure to any of the following medications: Angiotensin-converting enzyme (ACE) inhibitors or any estrogen containing medications with systemic absorption Oligonucleotides (including small interfering ribonucleic acid [siRNA]) within 4 months of Screening if single dose received, or within 12 months of Screening if multiple doses received. This exclusion does not apply to vaccines.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Incidence and severity of treatment-emergent adverse events (TEAEs).

Secondary endpoints 6

1. 1. The time-normalized number of Investigator-confirmed HAE attacks (per month) from Week 1 to Week 53.
2. 2. The time-normalized number of Investigator-confirmed HAE attacks (per month) from Week 5 to Week 53.
3. 3. The percentage of Investigator-confirmed HAE attack-free patients from Week 5 to Week 53.
4. 4. The time-normalized number of moderate or severe Investigator-confirmed HAE attacks (per month) from Week 5 to Week 53.
5. 5. The number of Investigator-confirmed HAE attacks requiring acute therapy from Week 5 to Week 53.
6. 6. Angioedema Quality of Life (AE-QoL) questionnaire total score over 53 weeks.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ionis Pharmaceuticals Inc.

Sponsor organisation

Ionis Pharmaceuticals Inc.

Address

2855 Gazelle Court

City

Carlsbad

Postcode

92010-6670

Country

United States

Scientific contact point

Organisation

Ionis Pharmaceuticals Inc.

Contact name

Global Regulatory Affairs

Public contact point

Organisation

Ionis Pharmaceuticals Inc.

Contact name

Global Regulatory Affairs

Third parties 15

Locations

8 EU/EEA countries · 22 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 169 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications