Pozelimab + Cemdisiran for Paroxysmal Nocturnal Hemoglobinuria

(ACCESS-1 Trial)

Recruiting at99 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Regeneron Pharmaceuticals

Must not be taking: Complement inhibitors

Disqualifiers: Organ transplant, Autoimmune diseases, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

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.

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.

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

Research shows that ravulizumab, a component of the treatment, is effective in managing Paroxysmal Nocturnal Hemoglobinuria (PNH) by reducing hemolysis (breakdown of red blood cells) and improving quality of life. Additionally, cemdisiran has shown potential benefits when combined with other treatments like eculizumab, suggesting it may enhance the effectiveness of PNH management. ^{1 2 3 4 5}

Is the combination of Pozelimab and Cemdisiran safe for humans?

Cemdisiran was generally well tolerated in a study with healthy adults and patients with paroxysmal nocturnal hemoglobinuria (PNH), with most adverse events being mild, such as common colds and headaches. Ravulizumab, another related treatment, was also found to be safe, with headaches being the most common side effect, and no serious infections or treatment discontinuations due to adverse events. ^{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. ^{1 2 4 5 7}

Research Team

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Cemdisiran (siRNA)
• Pozelimab (Monoclonal Antibodies)
• Ravulizumab (Monoclonal Antibodies)

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.

Participant Groups

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

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]