Pozelimab + Cemdisiran for Paroxysmal Nocturnal Hemoglobinuria

(ACCESS-1 Trial)

Recruiting at 123 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, Autoimmune diseases, 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: 26 weeks

190 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug combination, pozelimab and cemdisiran, for paroxysmal nocturnal hemoglobinuria (PNH), a rare blood disorder that can cause severe fatigue and other complications. Researchers aim to determine if this new combination is safe and more effective than existing treatments, ravulizumab and eculizumab. Participants should have active PNH symptoms and be willing to follow all study procedures. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have used eculizumab within 3 months or ravulizumab within 6 months before the trial. You also cannot use any other complement inhibitor therapy during the trial.

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 was safe in earlier studies. In trials where patients took these drugs, most side effects were mild to moderate, such as headaches or nausea, with only a few serious side effects reported.

The drugs pozelimab and cemdisiran are now undergoing testing in a more advanced trial phase, indicating existing evidence of their safety for humans. Treatments typically reach this stage only after demonstrating safety in earlier tests. While no treatment is without risk, data so far suggests that pozelimab and cemdisiran could be safe options for people with PNH. However, discussing all potential risks with a healthcare provider before joining a trial is important. ^{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 they offer a fresh approach to managing this condition. Most treatments for PNH, like eculizumab and ravulizumab, work by inhibiting the complement protein C5. However, Pozelimab is a monoclonal antibody that blocks C5, while Cemdisiran is an RNA interference therapy targeting the production of complement protein C5 at the genetic level. This dual approach not only tackles the condition from different angles but also has the potential to enhance effectiveness and reduce the frequency of treatments needed.

What evidence suggests that this trial's treatments could be effective for paroxysmal nocturnal hemoglobinuria?

This trial will evaluate the combination of pozelimab and cemdisiran for treating paroxysmal nocturnal hemoglobinuria (PNH), a condition where red blood cells break down too easily. Research has shown that this combination may effectively reduce PNH symptoms. Participants in this trial will be randomized into different cohorts to receive the treatment. Studies have found that patients report overall improvement after using this combination, which works by blocking certain proteins in the body that cause PNH. While more research continues, current data appears promising for those considering this treatment option. ^{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 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.

Inclusion Criteria

I have symptoms related to PNH as described.

Your LDH level is more than twice the normal limit at the screening visit.

My PNH diagnosis was confirmed by a specific blood test.

Exclusion Criteria

I have not been vaccinated for meningococcal disease as required for my treatment.

I cannot take antibiotics for meningococcal disease prevention as required.

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

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 or comparator drugs (ravulizumab or eculizumab) to evaluate efficacy and safety

26 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term follow-up

Participants are monitored for long-term safety and antibody development against the study drugs

Up to 60 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cemdisiran
• Pozelimab
• Ravulizumab

Trial Overview 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.

How Is the Trial Designed?

Group I: Cohort B Experimental Treatment 3 Interventions

Randomized 1:1

Group II: Cohort A Experimental Treatment 3 Interventions

Randomized 1:1

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 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 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 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. 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 ...

5. newsroom.regeneron.com newsroom.regeneron.com/news-releases/news-release-details/regeneron-announces-positive-results-phase-3-trial-generalized

Regeneron Announces Positive Results from Phase 3 Trial ... Cemdisiran monotherapy, dosed subcutaneously every three months, met the primary and key secondary endpoints, showing a 2.3-point ...

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/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 + ...

8. 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 ...

9. 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 ... The efficacy and safety of the combination of pozelimab and cemdisiran was evaluated in an open-label, single-arm study in patients with PNH who ...