What side effects are associated with this type of intervention?

The most common treatments for Paroxysmal Nocturnal Hemoglobinuria (PNH) that target complement factor C5, such as eculizumab and ravulizumab, are associated with several side effects. These include an increased risk of infections, particularly meningococcal infections, headaches, hypertension, and infusion-related reactions. Other potential side effects can include fatigue, nausea, and upper respiratory tract infections. The study drugs pozelimab and cemdisiran, which also target C5, may have similar side effects, including the possibility of the body developing antibodies against them, which could reduce their effectiveness or lead to additional side effects.

What prior FDA approvals exist?

The FDA has approved several treatments for Paroxysmal Nocturnal Hemoglobinuria (PNH) that target the complement system, specifically C5. Eculizumab (Soliris) was the first C5 inhibitor approved for PNH, followed by ravulizumab (Ultomiris), which is a longer-acting C5 inhibitor. These treatments work by inhibiting the cleavage of C5, thereby preventing the formation of the membrane attack complex that leads to hemolysis in PNH patients. The combination of pozelimab, a monoclonal antibody targeting C5, and cemdisiran, an RNA interference therapeutic targeting C5 synthesis, is being studied to potentially offer a new approach to complement inhibition in PNH.

What other types of research exist?

Promising novel alternatives to the Pozelimab + Cemdisiran combination for PNH patients include: 1. Ravulizumab: A long-acting C5 inhibitor that requires less frequent dosing compared to eculizumab. 2. Eculizumab: A well-established C5 inhibitor used in PNH treatment. 3. Pegcetacoplan: A C3 inhibitor that has shown efficacy in PNH patients, particularly those with suboptimal response to C5 inhibitors. 4. Crovalimab: An investigational anti-C5 monoclonal antibody with potential for less frequent dosing. These alternatives offer different mechanisms of action and dosing schedules, providing options for personalized treatment plans.

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Pozelimab + Cemdisiran for Paroxysmal Nocturnal Hemoglobinuria (ACCESS-1 Trial)

Phase 3

Recruiting

Research Sponsored by Regeneron Pharmaceuticals

Eligibility Criteria Checklist

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

Must have

Active disease, as defined by the presence of 1 or more PNH-related signs or symptoms as described in the protocol

Diagnosis of PNH confirmed by high-sensitivity flow cytometry testing with PNH granulocytes or monocytes as described in the protocol

Must not have

Any active, ongoing infection or a recent infection requiring ongoing systemic treatment with antibiotics, antivirals, or antifungals within 2 weeks of screening or during the screening period

Prior treatment with eculizumab within 3 months prior to screening, ravulizumab within 6 months prior to screening, or other complement inhibitors within 5 half-lives of the respective agent prior to screening

Timeline

Screening 3 weeks

Treatment Varies

Follow Up between week 8 and week 26, inclusive

Awards & highlights

No Placebo-Only Group

Pivotal Trial

Summary

This trial is testing a new combination of two drugs, pozelimab and cemdisiran, for patients with a rare blood disorder called PNH. The goal is to see if this new combination is safe and works better than current treatments. Researchers will also check for side effects and how the body reacts to the drugs. Eculizumab is the first approved treatment for PNH and has significantly changed the treatment landscape by inhibiting terminal complement activation.

Who is the study for?

Adults with confirmed PNH and active disease symptoms, including LDH levels at least twice the upper normal limit. Participants must be new to complement inhibitor treatments or not have received them recently. They should meet vaccination requirements for meningococcal disease, be able to take prophylactic antibiotics if needed, weigh over 40 kg, and have no recent serious infections or history of organ/bone marrow transplants.

What is being tested?

The trial is testing a combination therapy of two experimental drugs (pozelimab + cemdisiran) against existing treatments ravulizumab and eculizumab in patients with PNH. It aims to compare their effectiveness and safety while monitoring drug levels in blood, potential antibody development against the study drugs, and side effects experienced by participants.

What are the potential side effects?

Potential side effects from pozelimab + cemdisiran may include reactions where the medication is given, changes in liver function tests, allergic responses that could affect various organs like kidneys or lungs, fatigue, headache or nausea. The exact profile will be compared to those of ravulizumab and eculizumab.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have symptoms related to PNH as described.

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My PNH diagnosis was confirmed by a specific blood test.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I do not have an active infection or haven't needed treatment for one in the last 2 weeks.

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I haven't taken eculizumab, ravulizumab, or other complement inhibitors recently.

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I have had an organ or bone marrow transplant.

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I plan to only use the study drugs and no other complement inhibitor therapies during the treatment.

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I have an active autoimmune disease that is not under control.

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My body weight is less than 40 kilograms.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ between week 8 and week 26, inclusive

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~between week 8 and week 26, inclusive

This trial's timeline: 3 weeks for screening, Varies for treatment, and between week 8 and week 26, inclusive for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Maintenance of adequate control of hemolysis

Percent change in lactate dehydrogenase (LDH)

Secondary study objectives

Adequate control of hemolysis

Breakthrough hemolysis

Change in fatigue as measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale

+24 more

Side effects data

From 2024 Phase 2 & 3 trial • 10 Patients • NCT04209634

20%

Rhinitis

20%

Iron deficiency

20%

Urticaria

20%

Pyrexia

10%

Vomiting

10%

Dehydration

10%

Acarodermatitis

10%

Nasopharyngitis

10%

Tonsillitis

10%

Hypokalaemia

10%

Metabolic acidosis

10%

Alopecia

10%

Alopecia areata

10%

Dermatitis contact

10%

Abdominal pain

10%

Constipation

10%

Gingival bleeding

10%

Blood glucose increased

10%

Blood uric acid increased

10%

Hepatic enzyme increased

10%

Anaemia folate deficiency

10%

Immunisation reaction

10%

Headache

10%

Haematuria

10%

Proteinuria

100%

80%

60%

40%

20%

Study treatment Arm

Pozelimab

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

2Treatment groups

Experimental Treatment

Group I: Cohort BExperimental Treatment3 Interventions

Randomized 1:1

Group II: Cohort AExperimental Treatment3 Interventions

Randomized 1:1

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Cemdisiran

2020

Completed Phase 2

~80

Eculizumab

2009

Completed Phase 4

~1200

Pozelimab

2020

Completed Phase 3

~130

Ravulizumab

2016

Completed Phase 4

~1090

0 / 8Eligibility criteria met

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) involve complement inhibitors that target the C5 component of the complement system. Pozelimab, a monoclonal antibody, and cemdisiran, an RNA interference therapeutic, both aim to inhibit the activity or synthesis of C5. By blocking C5, these treatments prevent the formation of the membrane attack complex (MAC), which is responsible for the destruction of red blood cells in PNH patients. This inhibition reduces hemolysis, decreases the risk of thrombosis, and improves overall quality of life for PNH patients. Effective C5 inhibition is crucial as it directly addresses the underlying pathophysiology of PNH, which is characterized by uncontrolled complement activation leading to severe hemolysis and associated complications.

Hypertension and mild chronic kidney disease persist following severe haemolytic uraemic syndrome caused by Shiga toxin-producing Escherichia coli O104:H4 in adults.