Donidalorsen for Hereditary Angioedema

Recruiting at 13 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ionis Pharmaceuticals, Inc.

Must be taking: C1-INH, BK-2 antagonist

Disqualifiers: New condition, Worsening condition, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 52 weeks

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial uses donidalorsen, given as an injection under the skin, to help people with hereditary angioedema. The goal is to reduce the frequency and severity of their swelling episodes.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you must have access to at least one acute medication to treat angioedema attacks, and any changes in your medication that could affect your participation might make you unsuitable for the study.

What data supports the effectiveness of the drug Donidalorsen for treating hereditary angioedema?

Research shows that Donidalorsen, an antisense oligonucleotide, reduced the frequency of hereditary angioedema attacks and improved patient quality of life in a phase 2 study. Additionally, a pilot study with a similar drug, IONIS-PKK-LRx, showed a reduction in attack rates, supporting the potential effectiveness of Donidalorsen. ^{1 2 3 4 5}

Is Donidalorsen safe for humans?

Donidalorsen, also known as IONIS-PKK-LRx, has been studied in humans and showed an acceptable safety and tolerability profile in healthy volunteers, with similar findings in patients with hereditary angioedema. ^{1 2 3 6 7}

How is the drug Donidalorsen unique in treating hereditary angioedema?

Donidalorsen is unique because it uses antisense oligonucleotides (short DNA or RNA molecules) to specifically target and reduce the production of prekallikrein, a protein involved in the swelling attacks of hereditary angioedema. This approach is different from other treatments as it directly addresses the underlying cause of the disease by reducing the production of bradykinin, a peptide that causes blood vessels to dilate and leads to swelling. ^{1 2 3 6 7}

Eligibility Criteria

This trial is for individuals who have hereditary angioedema and completed a previous study (ISIS 721744-CS2) without safety concerns. Participants must be able to commit to a 64-week study, use effective contraception if of childbearing potential, and have access to acute medications for angioedema attacks.

Inclusion Criteria

Satisfactory completion of ISIS 721744-CS2 (index study) through Week 17 with an acceptable safety and tolerability profile, per Sponsor and Investigator judgement

Able and willing to participate in a 64-week study

I am a male either surgically sterile, abstinent, or using contraception if my partner can bear children.

Exclusion Criteria

Have any new condition or worsening of an existing condition or change or anticipated change in medication, which in the opinion of the Investigator would make the participant unsuitable for enrollment, or could interfere with the participant participating in or completing the study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

up to 4 weeks

Treatment

Participants receive donidalorsen subcutaneously for 52 weeks

52 weeks

Extended Treatment

Participants receive donidalorsen in an extended treatment period for up to an additional 156 weeks

156 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• Donidalorsen
• IONIS-PKK-LRx

Trial Overview The trial is testing the extended use of donidalorsen administered subcutaneously in various dosing patterns or frequencies. It aims to assess the long-term safety and effectiveness of this treatment approach in people with hereditary angioedema.

Participant Groups

Group I: Donidalorsen Experimental Treatment 1 Intervention

Participants will be administered donidalorsen SC for up to 53 weeks. Participants will also be administered donidalorsen in the extended treatment period for an additional 156 weeks, up to week 209.

Donidalorsen is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Donidalorsen for:

• Hereditary Angioedema (HAE)

Approved in United States as Donidalorsen for:

• Hereditary Angioedema (HAE)

Approved in Canada as Donidalorsen for:

• Hereditary Angioedema (HAE)

Who Is Running the Clinical Trial?

Ionis Pharmaceuticals, Inc.

Lead Sponsor

Trials

151

Recruited

27,800+

Dr. Brett P. Monia

Ionis Pharmaceuticals, Inc.

Chief Executive Officer since 2020

PhD in Pharmacology from the University of Pennsylvania, BSc in Molecular Biology and Analytical Chemistry from Stockton State College

Dr. Eric Bastings

Ionis Pharmaceuticals, Inc.

Chief Medical Officer

MD

Findings from Research

In a compassionate-use pilot study involving two patients with severe hereditary angioedema, treatment with IONIS-PKK-LRx led to a reduction in the frequency of angioedema attacks after switching from the unconjugated drug IONIS-PKKRx.

The study suggests that IONIS-PKK-LRx, an antisense oligonucleotide designed for targeted delivery to liver cells, may be an effective treatment option for managing severe bradykinin-mediated angioedema.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antisense Inhibition of Prekallikrein to Control Hereditary Angioedema. Cohn, DM., Viney, NJ., Fijen, LM., et al.[2021]

In a 2-year interim analysis of a phase 2 open-label extension study involving 17 patients, donidalorsen demonstrated a remarkable 96% reduction in the frequency of hereditary angioedema (HAE) attacks compared to baseline, indicating strong efficacy.

The treatment was well tolerated with no serious adverse events reported, suggesting that donidalorsen is a safe option for managing HAE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 open-label extension study of prekallikrein inhibition with donidalorsen for hereditary angioedema. Petersen, RS., Bordone, L., Riedl, MA., et al.[2023]

In a phase 2 trial involving 20 patients with hereditary angioedema, treatment with donidalorsen significantly reduced the mean monthly rate of angioedema attacks by 90% compared to placebo, demonstrating its efficacy in managing this condition.

Patients receiving donidalorsen also reported a greater improvement in quality of life, with a mean change of -26.8 points on the Angioedema Quality of Life Questionnaire, compared to -6.2 points in the placebo group, indicating a meaningful impact on their daily lives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of Prekallikrein for Hereditary Angioedema. Fijen, LM., Riedl, MA., Bordone, L., et al.[2023]

In a phase III study involving 54 patients and 374 hereditary angioedema (HAE) attacks, icatibant was shown to provide significant symptom relief, with 89.8% of attacks resolving after a single injection.

The median time to onset of symptom relief was approximately 2.0 hours for cutaneous and abdominal attacks, and even faster for laryngeal attacks, demonstrating both efficacy and a favorable safety profile with no serious drug-related adverse events reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repeat treatment with icatibant for multiple hereditary angioedema attacks: FAST-2 open-label study. Baş, M., Greve, J., Hoffmann, TK., et al.[2016]

IONIS-PKKRx effectively reduces prekallikrein (PKK) levels in both animal models and healthy human volunteers, demonstrating its potential as a targeted treatment for hereditary angioedema (HAE).

The treatment not only lowers PKK mRNA and plasma protein levels but also decreases the capacity to generate bradykinin, with a favorable safety and tolerability profile, indicating its promise for managing conditions related to excessive bradykinin production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IONIS-PKKRx a Novel Antisense Inhibitor of Prekallikrein and Bradykinin Production. Ferrone, JD., Bhattacharjee, G., Revenko, AS., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

Antisense Inhibition of Prekallikrein to Control Hereditary Angioedema. [2021]

2. Denmark pubmed.ncbi.nlm.nih.gov

A phase 2 open-label extension study of prekallikrein inhibition with donidalorsen for hereditary angioedema. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Inhibition of Prekallikrein for Hereditary Angioedema. [2023]

4. Denmark pubmed.ncbi.nlm.nih.gov

Repeat treatment with icatibant for multiple hereditary angioedema attacks: FAST-2 open-label study. [2016]

5. England pubmed.ncbi.nlm.nih.gov

Prophylactic use of an anti-activated factor XII monoclonal antibody, garadacimab, for patients with C1-esterase inhibitor-deficient hereditary angioedema: a randomised, double-blind, placebo-controlled, phase 2 trial. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

IONIS-PKKRx a Novel Antisense Inhibitor of Prekallikrein and Bradykinin Production. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Evaluation of a novel kallikrein inhibitor on hemostatic activation in vitro. [2014]