Pozelimab + Cemdisiran for Paroxysmal Nocturnal Hemoglobinuria

(ACCESS-EXT Trial)

Recruiting at 44 trial locations

Overseen By Clinical Trials Administrator

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Regeneron Pharmaceuticals

Must not be taking: Complement inhibitors

Disqualifiers: Organ transplant, Hepatitis B/C, HIV, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 108 weeks

202 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are taking complement inhibitors, you must stop them at least 5 half-lives before screening, except for eculizumab or ravulizumab, which are allowed.

What data supports the effectiveness of the drug combination Pozelimab + Cemdisiran for treating Paroxysmal Nocturnal Hemoglobinuria?

Research shows that cemdisiran, when used with eculizumab, can help control hemolysis (breakdown of red blood cells) in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) who do not respond well to eculizumab alone. This suggests that cemdisiran may enhance the effectiveness of other treatments in managing PNH. ^{1 2 3 4 5}

Is the combination of Pozelimab and Cemdisiran safe for humans?

Cemdisiran has been generally well tolerated in studies, with most side effects being mild, such as common colds and headaches. No serious safety concerns were reported in the trials involving healthy adults and patients with paroxysmal nocturnal hemoglobinuria (PNH). ^{1 2 4 5 6}

How is the drug Pozelimab + Cemdisiran unique for treating paroxysmal nocturnal hemoglobinuria (PNH)?

Pozelimab + Cemdisiran is unique because it combines two approaches: Pozelimab, a monoclonal antibody, and Cemdisiran, an RNA interference drug, both targeting complement component C5, which is involved in the disease process of PNH. This combination aims to provide a more comprehensive inhibition of the complement system, potentially offering benefits for patients who do not respond adequately to existing treatments like eculizumab alone. ^{1 2 4 5 7}

What is the purpose of this trial?

This study is researching an experimental treatment combination with two experimental drugs called pozelimab and cemdisiran. The study is focused on patients with paroxysmal nocturnal hemoglobinuria (PNH). The aim of this study is to see how safe and effective the pozelimab + cemdisiran combination is for patients with PNH in the long term. The pozelimab + cemdisiran combination may be referred to as "study drugs" in this section. This study is looking at several other research questions, including: * How effective is the pozelimab + cemdisiran combination? * What side effects may happen from taking the study drugs? * How much of each study drug is in the blood at different times? * Whether the body makes antibodies against the study drugs (which could make the drugs less effective or could lead to side effects)

Research Team

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Eligibility Criteria

Adults with a rare blood condition called Paroxysmal Nocturnal Hemoglobinuria (PNH) who have specific genetic variations making them unresponsive to certain other treatments. They should have high levels of an enzyme called LDH, active disease symptoms, and must have completed previous related studies without dropping out.

Inclusion Criteria

I have PNH and a specific genetic variation making me unresponsive to eculizumab or ravulizumab.

My PNH diagnosis was confirmed with a specific blood test.

Patients who have previously participated in related studies.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pozelimab and cemdisiran combination therapy to evaluate long-term safety, tolerability, and efficacy

108 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• Cemdisiran
• Pozelimab

Trial Overview The trial is testing the long-term safety and effectiveness of combining two experimental drugs, Pozelimab and Cemdisiran, for treating PNH. It will also assess how much drug remains in the blood over time and if the body creates antibodies against these drugs.

Participant Groups

Group I: PNH Transition Patients Experimental Treatment 2 Interventions

Patients with PNH who completed treatment/ protocol requirements (as applicable) in the parent study (R3918-PNH-2021 \[NCT05133531\])

Group II: C5 Polymorphism Patients Experimental Treatment 2 Interventions

Patients who have not been treated in either parent study but who have a documented complement component 5 (C5) variation rendering them refractory to eculizumab/ravulizumab. Note: Loading dose of pozelimab administered IV on Day 1.

Who Is Running the Clinical Trial?

Regeneron Pharmaceuticals

Lead Sponsor

Trials

690

Recruited

948,000+

Founded

1988

Headquarters

Tarrytown, USA

Known For

Precision medicine

Top Products

Dupixent, EYLEA, Libtayo, Praluent

Leonard Schleifer

Regeneron Pharmaceuticals

Chief Executive Officer since 1988

MD and PhD in Medicine

George Yancopoulos

Regeneron Pharmaceuticals

Chief Medical Officer since 1997

MD from Harvard Medical School

Findings from Research

In a study of 246 patients with paroxysmal nocturnal hemoglobinuria (PNH) receiving C5 inhibitors eculizumab and ravulizumab, improvements in lactate dehydrogenase (LDH) levels were significantly linked to better patient-reported outcomes related to fatigue and quality of life.

Despite no significant increase in hemoglobin levels, reductions in LDH were found to be crucial for enhancing fatigue and overall quality of life, indicating that managing LDH levels may be key in treating PNH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors for improvement in patient-reported outcomes: post hoc analysis of a phase 3 randomized, open-label study of eculizumab and ravulizumab in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria. Schrezenmeier, H., Kulasekararaj, A., Mitchell, L., et al.[2023]

Eculizumab treatment in patients with paroxysmal nocturnal hemoglobinuria (PNH) is associated with a 49% reduction in mortality risk compared to untreated periods, based on data from 4118 patients over a follow-up of more than 14 years.

Patients receiving eculizumab also experienced approximately a 60% reduction in the risk of thromboembolic events and major adverse vascular events (TEs/MAVEs), highlighting its efficacy in improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term effectiveness of eculizumab: Data from the International PNH Registry. Terriou, L., Lee, JW., Forsyth, C., et al.[2023]

In a study involving 23 Japanese adults with paroxysmal nocturnal hemoglobinuria (PNH), 82.6% preferred ravulizumab over eculizumab, highlighting a strong patient preference for the new treatment.

The preference for ravulizumab was primarily due to its longer infusion interval of every 8 weeks compared to eculizumab's 2-week schedule, which enhances treatment convenience and overall quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Japanese patient preferences between ravulizumab and eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria]. Ishiyama, K., Usuki, K., Ikezoe, T., et al.[2023]

In a phase 3 study involving 195 patients with paroxysmal nocturnal hemoglobinuria (PNH), ravulizumab, administered every 8 weeks, was found to be noninferior to eculizumab, which is given every 2 weeks, in terms of key efficacy measures such as lactate dehydrogenase (LDH) levels and breakthrough hemolysis.

The switch from eculizumab to ravulizumab was safe, with no reported meningococcal infections or discontinuations due to adverse events, although headaches were more common in the ravulizumab group (26.8% vs. 17.3% for eculizumab).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Kulasekararaj, AG., Hill, A., Rottinghaus, ST., et al.[2021]

Cemdisiran, an investigational RNA interference treatment, was generally well tolerated in a study involving 62 participants, showing significant reductions in complement activity and C5 levels, which are crucial in managing paroxysmal nocturnal hemoglobinuria (PNH).

While cemdisiran alone did not fully prevent hemolysis in PNH patients, it demonstrated potential benefits when used alongside eculizumab, allowing for a reduced dosage of eculizumab needed to control hemolysis effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a phase 1/2 study of cemdisiran in healthy subjects and patients with paroxysmal nocturnal hemoglobinuria. Gaya, A., Munir, T., Urbano-Ispizua, A., et al.[2023]

Eculizumab treatment led to a significant 50% reduction in transfusions for patients with a history of transfusion, decreasing from an average of 10.6 units per patient-year to 5.4 units after treatment.

The therapy also resulted in a 70% decrease in thrombotic events and major adverse vascular events, indicating its broad efficacy regardless of patients' transfusion or bone marrow disease history.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beneficial effects of eculizumab regardless of prior transfusions or bone marrow disease: Results of the International Paroxysmal Nocturnal Hemoglobinuria Registry. Röth, A., Araten, DJ., Larratt, L., et al.[2021]

In a phase 3 trial involving 87 patients with paroxysmal nocturnal hemoglobinuria (PNH), eculizumab significantly stabilized hemoglobin levels in 49% of patients compared to none in the placebo group, demonstrating its efficacy (P<0.001).

Eculizumab also reduced the need for blood transfusions, with a median of 0 units transfused in the eculizumab group versus 10 units in the placebo group, and it lowered intravascular hemolysis by 85.8%, indicating a strong therapeutic effect with a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. Hillmen, P., Young, NS., Schubert, J., et al.[2022]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Predictors for improvement in patient-reported outcomes: post hoc analysis of a phase 3 randomized, open-label study of eculizumab and ravulizumab in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Long-term effectiveness of eculizumab: Data from the International PNH Registry. [2023]

3. Japan pubmed.ncbi.nlm.nih.gov

[Japanese patient preferences between ravulizumab and eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria]. [2023]

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

Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. [2021]

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

Results of a phase 1/2 study of cemdisiran in healthy subjects and patients with paroxysmal nocturnal hemoglobinuria. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Beneficial effects of eculizumab regardless of prior transfusions or bone marrow disease: Results of the International Paroxysmal Nocturnal Hemoglobinuria Registry. [2021]

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

The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. [2022]