Donidalorsen for Hereditary Angioedema

Not currently recruiting at 59 trial locations

Overseen By Ionis Pharmaceuticals

Age: Any Age

Sex: Any

Trial Phase: Phase 3

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

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: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests donidalorsen to determine if it can safely and effectively reduce the number of attacks and improve life for people with hereditary angioedema (HAE), a condition causing sudden swelling. Participants will receive donidalorsen through injections over a period to assess its long-term impact. The trial seeks participants diagnosed with HAE type 1 or 2 who have been on stable preventive treatment for at least 12 weeks. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment for HAE.

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.

Is there any evidence suggesting that donidalorsen is likely to be safe for humans?

Research has shown that donidalorsen is generally safe for people with hereditary angioedema (HAE). In an earlier study, donidalorsen effectively reduced the number of HAE attacks without raising safety concerns. A larger study with 171 patients also found no new safety issues, and participants tolerated the treatment well over two years. These findings suggest that donidalorsen is safe for those considering joining a clinical trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for hereditary angioedema, which often include C1 inhibitors and bradykinin receptor antagonists, donidalorsen is unique because it works by targeting the production of kallikrein, a protein involved in the swelling attacks characteristic of this condition. This novel mechanism of action sets it apart from existing therapies that primarily focus on managing symptoms after they occur. Moreover, donidalorsen is administered via subcutaneous injection, potentially offering greater convenience and adherence compared to some intravenous options. Researchers are excited about donidalorsen because it has the potential to provide more consistent and long-term control of symptoms, improving the quality of life for individuals with hereditary angioedema.

What evidence suggests that donidalorsen might be an effective treatment for hereditary angioedema?

Research has shown that donidalorsen, the treatment under study in this trial, can reduce the number of hereditary angioedema (HAE) attacks. One study found that patients taking donidalorsen experienced significantly fewer attacks than those taking a placebo, a harmless pill with no active medicine. Another study revealed that patients who switched from other preventive treatments to donidalorsen had a 62% further reduction in their average monthly attacks. Donidalorsen blocks prekallikrein, a protein involved in triggering these attacks. Overall, these findings suggest that donidalorsen could be a promising option for people with HAE. ^{1 3 5 6 7}

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Donidalorsen

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.

How Is the Trial Designed?

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 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

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

Citations

1. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/10/NCT05139810/Prot_SAP_000.pdf

Donidalorsen for Hereditary Angioedema Clinical data demonstrated a significant degree of efficacy of ISIS 721744 80 mg administered once every-4-weeks for 4 months in reducing the ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2109329

Inhibition of Prekallikrein for Hereditary Angioedema Among patients with hereditary angioedema, donidalorsen treatment resulted in a significantly lower rate of angioedema attacks than placebo in this small, ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38009241/

A phase 2 open-label extension study of prekallikrein ... The 2-year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated.

4. ir.ionis.com ir.ionis.com/news-releases/news-release-details/phase-3-oasisplus-data-demonstrating-benefit-donidalorsen-hae

Phase 3 OASISplus data demonstrating benefit of ... Results indicate that patients who switched to donidalorsen from prior prophylactic treatments showed a 62% further reduction in mean monthly ...

5. clinicaltrials.eu clinicaltrials.eu/inn/donidalorsen/

Donidalorsen – Application in Therapy and Current Clinical ... Donidalorsen is an innovative drug being studied in clinical trials for the treatment of Hereditary Angioedema (HAE). This article explores the ongoing ...

6. medchemexpress.com medchemexpress.com/donidalorsen-sodium.html?srsltid=AfmBOoq3NSc9qn1T5e_VNSJzN0hZUZeiPCSxSCp6-VlTCaiogZ3VU6gj

Donidalorsen sodium (ISIS-721744) | Kallikrein Inhibitor PKK plays an important role in the activation of inflammatory mediators associated with acute attacks of Hereditary angioedema (HAE). Clinical Trial. NCT Number ...

7. ionis.com ionis.com/medicines/DAWNZERA/DAWNZERA-FPI.pdf

DAWNZERA-FPI.pdf The safety of DAWNZERA reflects the exposure in a total of 171 adult and pediatric patients 12 years and older with hereditary angioedema (HAE) from a placebo- ...