What side effects are associated with this type of intervention?

The most common treatments for Paroxysmal Nocturnal Hemoglobinuria (PNH) include complement inhibitors such as eculizumab and crovalimab. Known side effects of eculizumab include an increased risk of infections, particularly meningococcal infections, as well as headaches, hypertension, and gastrointestinal symptoms. Patients may also experience fatigue, infusion-related reactions, and potential thrombotic events. Crovalimab, being studied for its efficacy and safety, is expected to have a similar side effect profile given its mechanism of action as a complement inhibitor.

What prior FDA approvals exist?

The FDA has approved several complement inhibitors for the treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH). Eculizumab, a monoclonal antibody targeting C5, was the first approved treatment and has been effective in reducing hemolysis and thrombosis in PNH patients. Ravulizumab, a second-generation C5 inhibitor, was later approved and offers a longer dosing interval compared to eculizumab. More recently, pegcetacoplan, which targets C3, was approved and provides an alternative mechanism by inhibiting proximal complement activity, addressing both intravascular and extravascular hemolysis.

What other types of research exist?

Promising novel alternatives to Crovalimab for PNH patients include: 1) Ravulizumab, a second-generation eculizumab engineered for longer-lasting effects. 2) Pegcetacoplan, a pegylated pentadecapeptide targeting C3. 3) Avacopan, an orally administered small molecule C5a receptor antagonist. These alternatives have shown efficacy in clinical trials and offer different mechanisms of action or improved convenience.

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Monoclonal Antibodies

Crovalimab vs Eculizumab for Paroxysmal Nocturnal Hemoglobinuria (COMMODORE 2 Trial)

Phase 3

Waitlist Available

Research Sponsored by Hoffmann-La Roche

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 6.5 years

Awards & highlights

No Placebo-Only Group

Pivotal Trial

Summary

This trial is testing if crovalimab is as effective as eculizumab in treating people with PNH who haven't received similar treatments before. Both medications help prevent the immune system from attacking red blood cells. Eculizumab is a treatment for paroxysmal nocturnal hemoglobinuria (PNH) that decreases intravascular hemolysis and thrombosis and improves survival.

Who is the study for?

This trial is for individuals with Paroxysmal Nocturnal Hemoglobinuria (PNH) who haven't been treated with complement inhibitors before. They must be willing to follow the study's procedures, weigh at least 40 kg, have certain vaccination against meningitis, and not be pregnant or breastfeeding. People previously treated with similar drugs or having certain health conditions are excluded.

What is being tested?

The trial is testing Crovalimab against Eculizumab in about 200 participants to see if it's just as effective for PNH patients who haven't used complement inhibitors. It will compare how well each drug works and monitor safety over time.

What are the potential side effects?

While specific side effects aren't listed here, both Crovalimab and Eculizumab can potentially cause reactions related to the immune system since they work by inhibiting parts of it that could lead to symptoms like fever, headache, nausea or infections.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 6.5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 6.5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 6.5 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Percentage of Participants who achieve Transfusion Avoidance (TA)

Percentage of Participants with hemolysis control

Secondary study objectives

Change in PD biomarkers including complement activity (CH50) over time

Mean Change in Fatigue

Percentage of Participants with Adverse Events (AEs)

+2 more

Side effects data

From 2020 Phase 3 trial • 36 Patients • NCT02013037

19%

Bacterial Infections

17%

Viral infections

Fungal infections

100%

80%

60%

40%

20%

Study treatment Arm

Eculizumab

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

3Treatment groups

Experimental Treatment

Active Control

Group I: Arm C (Crovalimab) (Exploratory)Experimental Treatment1 Intervention

Paediatric participants will receive a loading series of Crovalimab comprised of an IV dose on Week 1 Day 1, followed by weekly crovalimab SC doses for 4 weeks on Week 1 (Day 2) then on Weeks 2, 3, and 4. Maintenance SC dosing will begin at Week 5 and will be administered Q4W thereafter. After 24 weeks of crovalimab treatment, participants who derive benefit from the drug may continue to receive crovalimab.

Group II: Arm A (Crovalimab)Experimental Treatment1 Intervention

Crovalimab will be administered at an initial loading dose of 1000 milligrams (mg) (for participants with body weight between 40 and 100 kg) or 1500 mg (for participants with body weight \>=100kg), as intravenous (IV) injection on Day 1 of Week 1 followed by four weekly subcutaneous (SC) injections of 340 mg starting on Day 2 of Week 1 and then once weekly (QW) at Weeks 2,3 and 4. Thereafter crovalimab will be administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100kg) or 1020 mg (for participants with body weight \>=100kg) once every 4 weeks (Q4W) from Week 5 for a total of 24 weeks of study treatment. Participants may continue to receive crovalimab after 24 weeks of treatment up to maximum of 5 years.

Group III: Arm B (Eculizumab)Active Control2 Interventions

Participants will receive loading dose of eculizumab 600 mg on Days 1, 8, 15, and 22, followed by maintenance dose of 900 mg on Day 29 and every 2 weeks (Q2W) thereafter until 24 weeks. Participants may switch to receive crovalimab after 24 weeks of eculizumab treatment.

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Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Paroxysmal Nocturnal Hemoglobinuria (PNH) are complement inhibitors such as Eculizumab and Crovalimab. These treatments work by inhibiting the terminal complement protein C5, which prevents the activation of the terminal complement pathway. This is crucial for PNH patients because uncontrolled activation of this pathway leads to intravascular hemolysis (IVH), causing red blood cells to be destroyed prematurely. By inhibiting C5, these treatments reduce IVH, lower the risk of thrombosis, and improve overall patient outcomes by decreasing anemia and transfusion dependence. Crovalimab, in particular, offers the advantage of extended self-administered subcutaneous dosing, potentially improving patient adherence and quality of life.

The role of the alternative pathway in paroxysmal nocturnal hemoglobinuria and emerging treatments.The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria.CR2-mediated targeting of complement inhibitors: bench-to-bedside using a novel strategy for site-specific complement modulation.