Pozelimab + Cemdisiran for Myasthenia Gravis

(NIMBLE Trial)

Recruiting at176 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Regeneron Pharmaceuticals

Must be taking: Acetylcholinesterase inhibitors, Immunosuppressive therapy

Disqualifiers: MuSK antibodies, Recent thymectomy, Cancer, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing two medications, pozelimab and cemdisiran, to help people with generalized myasthenia gravis (gMG), a condition that causes muscle weakness. The study aims to see if these drugs can improve daily functioning and muscle strength by calming down an overactive immune system. The trial will also check the safety of these treatments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications. However, if you are on an immunosuppressive therapy (IST), you should not change the dosage before or during the treatment period.

What data supports the effectiveness of the drug Pozelimab + Cemdisiran for Myasthenia Gravis?

The drug eculizumab, which is similar to Pozelimab, has been shown to help patients with a type of myasthenia gravis that doesn't respond to other treatments. It helps reduce symptoms and improve the condition of these patients. ^{1 2 3 4 5}

How is the drug Pozelimab + Cemdisiran unique for treating myasthenia gravis?

Pozelimab + Cemdisiran is unique because it combines two components that target the complement system, specifically blocking complement factor 5 (C5), which is a different approach compared to traditional treatments that focus on symptomatic relief or general immunosuppression. This combination aims to prevent the destructive effects of autoantibodies at the neuromuscular junction, offering a novel mechanism of action for patients with myasthenia gravis. ^{1 4 6 7 8}

Research Team

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Eligibility Criteria

Adults over 18 with a confirmed diagnosis of myasthenia gravis (MG), specifically those who have MGFA Class II to IVa and an MG-ADL score ≥6. Participants should be on or have a reason for not using acetylcholinesterase inhibitors or immunosuppressive therapy, without plans to change dosages during the trial. Exclusions include MuSK-only positive patients, recent thymectomy, certain cancer histories, HIV infection, no recent meningococcal vaccination unless planned before treatment starts.

Inclusion Criteria

I am on immunosuppressive therapy for myasthenia gravis or have a reason for not taking it.

You have tested positive for certain antibodies related to muscle and nerve function in the past.

I am 18 years old or older.

Exclusion Criteria

I haven't had a meningococcal vaccine in the last 5 years, but I'm willing to get one during screening.

I cannot use certain antibiotics for meningococcal disease prevention due to allergies or side effects.

I had or will have surgery to remove my thymus gland within the last year.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Double Blind Treatment Period (DBTP)

Participants receive either placebo or active treatment in a double-blind manner

24 weeks

Extension Treatment Period (ETP)

Participants are re-randomized to receive combination therapy or cemdisiran

28 weeks

Open Label Treatment Period (OLTP)

Participants receive open-label treatment with combination therapy

68 weeks

Off-treatment Follow-up

Participants are monitored for safety and effectiveness after treatment

52 weeks

Treatment Details

Interventions

• Cemdisiran (siRNA)
• Pozelimab (Monoclonal Antibodies)

Trial Overview The study is testing how well Pozelimab combined with Cemdisiran improves daily functioning affected by MG symptoms compared to each drug alone and placebo. It also looks at muscle strength, quality of life improvements, safety/tolerability of the drugs, their levels in blood/plasma and effects on immune response.

Participant Groups

Group I: Group 4 Experimental Treatment 1 Intervention

Pozelimab monotherapy in DBTP followed by combination in ETP and OLTP

Group II: Group 3 Experimental Treatment 1 Intervention

Cemdisiran throughout the study

Group III: Group 2 Experimental Treatment 1 Intervention

Combination regimen throughout the study

Group IV: Group 1 Experimental Treatment 3 Interventions

Placebo in DBTP; Re-randomized to Combination or Cemdisiran in ETP and OLTP

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

A new sum score has been developed to define treatment-refractory generalized myasthenia gravis (TRgMG), which includes criteria such as disease severity and inefficacy of previous therapies, making it easier for clinicians to make treatment decisions.

This scoring system, created through a consensus of 12 experts and based on a thorough literature review, aims to clarify when eculizumab should be used and can also serve as a basis for inclusion criteria in future clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Sum Score to Define Therapy-Refractory Myasthenia Gravis: A German Consensus. Schroeter, M., Berger, B., Blaes, F., et al.[2022]

The FDA has recently approved new therapies, including complement and Fc receptor inhibitors, for treating generalized myasthenia gravis, highlighting advancements in treatment options for this condition.

There is ongoing uncertainty regarding which patients will benefit most from these expensive therapies, prompting discussions on the need for better clinical trial readiness and biomarker development to guide future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The best and worst of times in therapy development for myasthenia gravis. Benatar, M., Cutter, G., Kaminski, HJ.[2023]

About 10% of myasthenia gravis (MG) patients do not respond well to current treatments and are considered treatment refractory, with certain factors like being anti-MuSK positive or having a history of thymoma increasing this risk.

New therapies, including monoclonal antibodies like rituximab, eculizumab, and belimumab, are being proposed for patients who do not respond to standard treatments, aiming to improve outcomes for those with treatment-refractory MG.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

When myasthenia gravis is deemed refractory: clinical signposts and treatment strategies. Mantegazza, R., Antozzi, C.[2022]

Eculizumab significantly improved outcomes in patients with anti-acetylcholine receptor-positive refractory generalized myasthenia gravis (gMG), with 25.0% achieving minimal manifestations (MM) after 26 weeks compared to 13.3% in the placebo group.

After 130 weeks of treatment, 88.0% of patients on eculizumab reported improved status, and 57.3% achieved MM, demonstrating both rapid and sustained efficacy without new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension. Mantegazza, R., Wolfe, GI., Muppidi, S., et al.[2021]

In a 26-week phase 3 study, eculizumab significantly improved symptoms in patients with refractory generalized myasthenia gravis (gMG), with 21.4% of treated patients achieving 'minimal symptom expression' compared to only 1.7% in the placebo group.

The benefits of eculizumab were sustained over a 130-week open-label extension, showing that patients who initially received placebo also achieved similar symptom relief after starting eculizumab, indicating its long-term efficacy and tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

'Minimal symptom expression' in patients with acetylcholine receptor antibody-positive refractory generalized myasthenia gravis treated with eculizumab. Vissing, J., Jacob, S., Fujita, KP., et al.[2021]

Eculizumab has shown efficacy and safety in treating refractory generalized myasthenia gravis (gMG) in Phase II and III studies, potentially offering a new immunosuppressive approach that could reduce the need for corticosteroids.

The drug works by blocking C5, which protects the neuromuscular junction from damage caused by autoantibodies, suggesting it could modify the disease course and improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eculizumab for the treatment of myasthenia gravis. Mantegazza, R., Cavalcante, P.[2021]

Eculizumab demonstrated significant efficacy in treating two out of three patients with refractory MGFA class V generalized myasthenia gravis (gMG), leading to marked improvements in their clinical scores after treatment.

The two responsive patients achieved minimal manifestation status within 4 to 6 weeks, while the third patient showed only a partial response, indicating that eculizumab may be beneficial but results can vary among individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of eculizumab in ventilator-dependent myasthenia gravis patients. Usman, U., Chrisman, C., Houston, D., et al.[2021]

Pozelimab is a newly approved monoclonal antibody that blocks complement factor 5 (C5) and is the first FDA-approved treatment for CD55-deficient protein-losing enteropathy (PLE), also known as CHAPLE disease, in both adults and children aged 1 year and older.

In addition to its approval for PLE, pozelimab has received orphan drug designations for treating paroxysmal nocturnal hemoglobinuria (PNH) and myasthenia gravis, indicating its potential for broader therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pozelimab: First Approval. Hoy, SM.[2023]

References

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

A Sum Score to Define Therapy-Refractory Myasthenia Gravis: A German Consensus. [2022]

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

The best and worst of times in therapy development for myasthenia gravis. [2023]

3. England pubmed.ncbi.nlm.nih.gov

When myasthenia gravis is deemed refractory: clinical signposts and treatment strategies. [2022]

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

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

'Minimal symptom expression' in patients with acetylcholine receptor antibody-positive refractory generalized myasthenia gravis treated with eculizumab. [2021]

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

Eculizumab for the treatment of myasthenia gravis. [2021]

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

The use of eculizumab in ventilator-dependent myasthenia gravis patients. [2021]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Pozelimab: First Approval. [2023]