Pozelimab + Cemdisiran for Paroxysmal Nocturnal Hemoglobinuria

(ACCESS-EXT Trial)

Recruiting at 60 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of two drugs, pozelimab and cemdisiran, for individuals with paroxysmal nocturnal hemoglobinuria (PNH), a rare blood disease. The trial aims to determine the safety and effectiveness of these drugs for long-term use. It examines how well the treatment works, potential side effects, and the body's interaction with the drugs. Individuals with PNH, particularly those who completed a related study or have a specific genetic variation that renders other treatments ineffective, might be suitable candidates. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of pozelimab and cemdisiran has been tested for safety in people with paroxysmal nocturnal hemoglobinuria (PNH). One study found that this combination was generally well-tolerated, with most side effects being mild to moderate. Common side effects included headaches and injection site reactions, while serious side effects were rare.

These findings suggest that pozelimab and cemdisiran are likely safe for people with PNH. As this trial is in a late phase, substantial data already supports its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Pozelimab and Cemdisiran for treating Paroxysmal Nocturnal Hemoglobinuria (PNH) because these drugs offer novel approaches compared to standard treatments like eculizumab and ravulizumab. Pozelimab is unique because it targets the complement pathway differently, providing an alternative for patients with specific genetic variations that make them resistant to other treatments. Cemdisiran works by reducing the production of specific proteins involved in the disease's progression, offering a new mechanism of action. These innovative strategies could potentially offer more effective and personalized treatment options for PNH patients.

What evidence suggests that the pozelimab + cemdisiran combination could be an effective treatment for paroxysmal nocturnal hemoglobinuria?

Research has shown that using pozelimab and cemdisiran together can help manage paroxysmal nocturnal hemoglobinuria (PNH). In this trial, some patients will receive this combination treatment. Patients receiving this treatment have shown better disease control, indicated by lower levels of lactate dehydrogenase (LDH), a marker of disease activity. Previous studies found that patients experienced positive results with this treatment. The combination targets proteins involved in the disease, which may explain its effectiveness. These findings suggest that pozelimab and cemdisiran could be promising options for people with PNH. ^{1 6 7 8 9}

Who Is on the Research Team?

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40708708/

Safety, Efficacy, and Patient-Reported Outcomes From a ... We investigated the efficacy, safety, and patient-reported outcomes data of the combination of pozelimab (a fully human monoclonal antibody) and ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05744921

NCT05744921 | A Study in Adult Patients With Paroxysmal ... The aim of this study is to see how safe and effective the pozelimab + cemdisiran combination is for people with PNH in the long term. The pozelimab + ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12288694/

PMC - PubMed Central - NIH Here, we present the efficacy, safety, and patient‐reported outcomes (PROs) data of pozelimab and cemdisiran combination treatment from a Phase ...

4. investor.regeneron.com investor.regeneron.com/news-releases/news-release-details/novel-combination-pozelimab-and-cemdisiran-poze-cemdi-achieved

Novel Combination of Pozelimab and Cemdisiran (Poze- ... First-in-class poze-cemdi combination treatment helped patients achieve and maintain greater disease control, as measured by lactate dehydrogenase (LDH) levels.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04811716

Study Details | NCT04811716 | Pozelimab and Cemdisiran ... The primary objective of the study is to evaluate the safety and tolerability of 2 dosing regimens of pozelimab and cemdisiran combination therapy during ...

6. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/jha2.70095

Safety, Efficacy, and Patient‐Reported Outcomes From a ... Here, we present the efficacy, safety, and patient-reported outcomes (PROs) data of pozelimab and cemdisiran combination treatment from a Phase ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05133531

NCT05133531 | A Study to Evaluate How Safe Pozelimab ... The aim of the study is to see how safe and effective the pozelimab + cemdisiran combination is for people with PNH and how the combination compares with 2 ...

8. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/2716/502943/52-Week-Open-Label-Extension-Data-from-a-Phase-2

52-Week Open-Label Extension Data from a Phase 2 Study ... A Phase 2, Randomized Trial Evaluating the Safety and Efficacy of Pozelimab and Cemdisiran in Patients with Paroxysmal Nocturnal Hemoglobinuria.

9. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper194610.html

306 Efficacy and Safety of Pozelimab Plus Cemdisiran Vs ... Here, we present results from an exploratory arm of a 26-week (wk), phase 3, open-label, active-controlled trial (NCT05133531) along with ...