Donidalorsen for Hereditary Angioedema

Recruiting at 67 trial locations

Overseen By Ionis Pharmaceuticals

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Ionis Pharmaceuticals, Inc.

Must not be taking: ACE inhibitors, Estrogen, Oligonucleotides

Disqualifiers: Other angioedema, Abnormal labs, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 24 weeks

91 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing donidalorsen, a medication, to see if it can help people with Hereditary Angioedema (HAE) by reducing the frequency and severity of their swelling attacks. The study aims to improve their quality of life. Donidalorsen has shown a significantly lower rate of angioedema attacks in earlier tests.

Will I have to stop taking my current medications?

You may need to stop taking certain medications like ACE inhibitors, estrogen-containing medications, and some chronic prophylaxis drugs before joining the trial. The protocol mentions specific timeframes for stopping these medications before screening.

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

Research shows that Donidalorsen, which works by inhibiting prekallikrein (a protein involved in swelling), reduced the frequency of swelling attacks in patients with hereditary angioedema and improved their quality of life. ^{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 and patients with hereditary angioedema. It was generally well-tolerated in studies, with no major safety concerns reported. ^{1 2 3 4 6}

How is the drug Donidalorsen unique in treating hereditary angioedema?

Donidalorsen is unique because it is an antisense oligonucleotide that specifically targets and reduces prekallikrein production in the liver, which helps decrease the frequency of swelling attacks in hereditary angioedema. It is administered as a subcutaneous injection every 3 to 4 weeks, offering a novel approach compared to other treatments that may require more frequent dosing or different mechanisms of action. ^{1 2 3 6 7}

Eligibility Criteria

This trial is for people aged 12 or older with a confirmed diagnosis of hereditary angioedema types 1 or 2, who have had at least two attacks during the screening period. They must be able to provide consent and manage their acute attack medications. Exclusions include prior participation in related studies, recent use of certain prophylactic drugs, drug/alcohol abuse, other angioedema diagnoses, significant lab abnormalities, and recent investigational drug treatment.

Inclusion Criteria

Participants, or their legally appointed and authorized representatives, must provide written and signed informed consent form (ICF)/assent

Participants must be aged ≥ 12 years at the time of informed consent and, as applicable, assent

Be willing to complete the participant reported outcomes (PRO) assessments throughout the study

Exclusion Criteria

Participated in a prior ISIS 721744 study

You have been taking certain medications for a long time before the screening.

You have received oligonucleotide medications within the specified time frame, except for vaccines.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

Up to 8 weeks

Treatment

Participants receive donidalorsen or placebo subcutaneously every 4 or 8 weeks

24 weeks

6 visits (in-person) for every 4 weeks group, 3 visits (in-person) for every 8 weeks group

Post-treatment

Participants are monitored for safety and effectiveness after treatment

Up to 13 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Donidalorsen
• Placebo

Trial Overview The OASIS-HAE study is testing the safety and effectiveness of Donidalorsen compared to a placebo in individuals with Hereditary Angioedema (HAE). It aims to see how well Donidalorsen can reduce HAE attacks and improve quality of life for patients.

Participant Groups

Group I: Cohort B: Donidalorsen 80 mg Experimental Treatment 1 Intervention

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

Group II: Cohort A: Donidalorsen 80 mg Experimental Treatment 1 Intervention

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

Group III: Pooled Placebo Placebo Group 1 Intervention

Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Weeks 1, 5, 9, 13, 17, and 21) or 8 weeks (Weeks 1, 9, and 17)

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 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]