Donidalorsen for Hereditary Angioedema

Recruiting at51 trial locations

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Ionis Pharmaceuticals, Inc.

Must be taking: Lanadelumab, Berotralstat, SC C1-inhibitor

Must not be taking: ACE inhibitors, Estrogen

Disqualifiers: Recurrent angioedema, Malignancy, Drug abuse, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing donidalorsen, a medication for people with Hereditary Angioedema (HAE) Types I and II. The goal is to see if it can reduce the number of swelling attacks and improve quality of life. Donidalorsen works by targeting pathways in the body that cause these attacks. Donidalorsen treatment resulted in a significantly lower rate of angioedema attacks.

Will I have to stop taking my current medications?

The trial requires that participants stay on a stable dose of certain medications for at least 12 weeks before joining. You may need to stop taking ACE inhibitors, estrogen medications, and certain other drugs before the trial. The protocol does not specify a washout period for other medications, so it's best to discuss with the trial team.

What data supports the effectiveness of the drug Donidalorsen for Hereditary Angioedema?

Research shows that Donidalorsen, which works by inhibiting prekallikrein, reduced the frequency of swelling attacks in patients with hereditary angioedema and improved their quality of life. In a study, patients experienced fewer attacks after receiving Donidalorsen, indicating its potential effectiveness. ^{1 2 3 4 5}

Is Donidalorsen safe for humans?

Donidalorsen, also known as IONIS-PKK-LRx, has been studied for safety in humans. In studies, it showed an acceptable safety and tolerability profile, meaning it was generally safe and well-tolerated by participants. ^{1 2 3 4 6}

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 that may not target the underlying cause as directly. ^{1 2 3 6 7}

Research Team

Eligibility Criteria

This trial is for individuals aged 12 or older with a confirmed diagnosis of Hereditary Angioedema (HAE) types 1 or 2. They must have completed a previous study through Week 25, be on stable HAE prophylaxis treatment, and able to manage acute attacks. Excluded are those with recent malignancies, certain medication exposures, hypersensitivity to donidalorsen, other angioedema types, drug/alcohol abuse history.

Inclusion Criteria

I can access and use medication for sudden swelling attacks.

I have been diagnosed with hereditary angioedema type 1 or 2.

Participants and, as applicable, legally authorized representatives (i.e., parent(s)/legal guardian), must provide written and signed informed consent form (ICF).

Exclusion Criteria

You have been in a previous study for donidalorsen.

You have had problems with drugs or alcohol in the recent past or are currently using them.

I have taken ACE inhibitors or estrogen medications.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Extended Treatment

Participants receive donidalorsen by SC injection for up to 157 weeks

157 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Donidalorsen (Monoclonal Antibodies)

Trial Overview The trial studies the long-term safety and effectiveness of donidalorsen in preventing HAE attacks. It aims to understand how this intervention affects the frequency of attacks and quality of life over an extended period for people living with HAE.

Participant Groups

Group I: OLE Participants Experimental Treatment 1 Intervention

Group 1 and Group 2 participants will be administered donidalorsen by SC injection for up to 157 weeks.

Donidalorsen is already approved in Canada for the following indications:

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 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 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 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]

Icatibant is a safe and effective treatment for acute attacks of hereditary angioedema in adults, with clinical evidence supporting its use and only 10% of patients needing a second dose.

The most common side effects are mild and localized, such as pain and swelling at the injection site, and no serious adverse reactions have been reported, making it a favorable option for self-administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evidence-based review of the potential role of icatibant in the treatment of acute attacks in hereditary angioedema type I and II. Floccard, B., Hautin, E., Bouillet, L., et al.[2021]

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]

KVD900 is a novel oral small-molecule inhibitor of plasma kallikrein (PKa) that shows rapid and nearly complete inhibition of PKa activity, making it a promising on-demand treatment for hereditary angioedema (HAE).

In clinical trials, KVD900 demonstrated over 95% inhibition of DXS-stimulated PKa activity in individuals with HAE for at least 4 hours post-dose, potentially halting the generation of bradykinin and reversing HAE attacks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological suppression of the kallikrein kinin system with KVD900: An orally available plasma kallikrein inhibitor for the on-demand treatment of hereditary angioedema. Duckworth, EJ., Murugesan, N., Li, L., et al.[2022]

References

1. Denmark pubmed.ncbi.nlm.nih.gov

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

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

Inhibition of Prekallikrein for Hereditary Angioedema. [2023]

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

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

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

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

5. New Zealand pubmed.ncbi.nlm.nih.gov

An evidence-based review of the potential role of icatibant in the treatment of acute attacks in hereditary angioedema type I and II. [2021]

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

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

7. England pubmed.ncbi.nlm.nih.gov

Pharmacological suppression of the kallikrein kinin system with KVD900: An orally available plasma kallikrein inhibitor for the on-demand treatment of hereditary angioedema. [2022]