Pozelimab and cemdisiran for myasthenia gravis

Last updated Oct. 10, 2024, by Joana Carvalho, PhD
Fact-checked by Inês Martins, PhD

What are pozelimab and cemdisiran for myasthenia gravis?

Pozelimab is an antibody therapy that’s being tested in combination with the RNA-based therapy cemdisiran as a potential treatment for myasthenia gravis (MG).

The therapies in combination aim to ease disease severity by completely blocking the activation of the complement system, a part of the immune system thought to be involved in MG-driving autoimmune attacks. The treatment combo is being explored by Regeneron Pharmaceuticals, to be given as once-monthly subcutaneous, or under-the-skin, injections.

The U.S. Food and Drug Administration has granted the combination therapy orphan drug status for the treatment of MG. That designation is awarded to therapies intended to treat rare diseases to hasten their development and regulatory review.

The combination of pozelimab and cemdisiran, which is now in Phase 3 clinical testing for MG, is also being explored as a potential treatment for paroxysmal nocturnal hemoglobinuria (PNH), another rare disease driven by complement activation.

Both Pozelimab and cemdisiran are also in development as stand-alone therapies. Pozelimab, also developed by Regeneron, is already approved under the brand name Veopoz for an ultra-rare immune disease. Cemdisiran is being developed by Alnylam Pharmaceuticals, but the company entered an agreement with Regeneron to explore combinations of complement-blocking agents as potential treatments for a number of conditions.

Therapy snapshot

How do pozelimab and cemdisiran work in myasthenia gravis?

MG is caused by the production of self-reactive antibodies that erroneously target proteins at the nerve-muscle junction, impairing the communication between nerves and muscle cells and leading to severe muscle weakness and fatigue.

When MG-causing antibodies bind to their target, they can trigger the activation of the complement cascade — a group of proteins that normally are found in the bloodstream in an inactive state, but that can be activated by certain stimuli, such as an infection. Complement activation is believed to contribute to the damaging autoimmune response that drives MG.

One of the key steps in complement activation is the cleavage of a protein called C5 into two subunits, C5a and C5b, which each go on to promote further inflammation.

Pozelimab is a monoclonal antibody that’s designed to bind to C5 and prevent it from being cleaved, thereby inhibiting complement activation. This mechanism of action is identical to that of Soliris (eculizumab) and Ultomiris (ravulizumab-cwvz), two complement inhibitor therapies that have been previously approved for generalized myasthenia gravis, or gMG.

Cemdisiran, meanwhile, is a small interfering RNA, or siRNA, that also blocks complement activation by suppressing the production of C5. It works by binding to C5’s messenger RNAs — mRNA is a template molecule produced from DNA that holds instructions for the production of the C5 protein — and targeting it for degradation, thus reducing C5 levels in the body.

That therapy is designed to specifically target liver cells, which are the main producers of complement proteins in the body. This is achieved with the addition of a sugar molecule called N-acetylgalactosamine (GalNAc) to the siRNA molecule. That sugar molecule binds to certain receptors on liver cells that are responsible for internalizing some proteins into the cells, so its addition enables the modified molecule to be taken up by liver cells as intended.

Preclinical studies in monkeys have shown that the combination of pozelimab and cemdisiran is more efficient at blocking complement activation than either therapy alone. Those observations formed the basis for the development of the combination therapy for MG and other complement-mediated diseases.

How will pozelimab and cemdisiran be administered in myasthenia gravis?

Pozelimab and cemdisiran are both designed to be administered through subcutaneous injections. In an ongoing Phase 3 clinical trial involving people with gMG, the combination is being given as monthly injections, although the exact doses tested have not yet been disclosed.

It is still too early to know how the combination of pozelimab and cemdisiran will be administered should the treatment receive approval by regulatory agencies.

Pozelimab and cemdisiran in myasthenia gravis clinical trials

The safety, tolerability, and pharmacological properties of pozelimab and cemdisiran were first evaluated in a series of Phase 1 clinical trials involving healthy volunteers and people with conditions other than MG.

One Phase 1 trial (NCT03115996) sponsored by Regeneron tested multiple dosing regimens of pozelimab in healthy individuals. Data showed that the treatment was safe and well tolerated when administered as single intravenous (into-the-vein) infusions at doses up to 30 mg/kg, and as single subcutaneous injections at doses up to 600 mg. It also was safe and well tolerated when given as an initial intravenous loading dose of 15 mg/kg, followed by four subcutaneous weekly doses of 400 mg. This final dosing regimen also strongly and sustainably inhibited complement activation.

In an Alnylam-sponsored Phase 1/2 trial (NCT02352493), single and multiple ascending doses of cemdisiran were tested in healthy volunteers and PNH patients. The therapy was given subcutaneously at different schedules. In that study, treatment resulted in a rapid suppression of complement activation, which was sustained with repeat dosing.

Models based on the pharmacological properties of the two therapies seen in these studies indicated that the doses of pozelimab and cemdisiran can be significantly reduced by combining the two therapies. These models also showed the dosing interval of pozelimab can be substantially increased when the therapy is given alongside cemdisiran.

Another Phase 1 clinical trial (NCT04601844) assessed the safety and tolerability of increasing subcutaneous doses of pozelimab and cemdisiran when given together on the same day, or sequentially 28 days apart. An interim analysis showed that the combined administration was safe and well tolerated. Pharmacological data was also consistent with previous model-based predictions, supporting the advancement of the combination therapy into more advanced stages of clinical testing.

Ongoing trials

Regeneron now is conducting a Phase 3 clinical trial called NIMBLE (NCT05070858) to evaluate the pozelimab-cemdisiran combination, as well as each component alone, in adults with gMG. The trial will enroll about 235 patients who are positive for self-reactive antibodies against the acetylcholine receptor (AChR) or low-density lipoprotein receptor-related protein 4 (LRP4).

NIMBLE comprises four main parts: a double-blind treatment period lasting 24 weeks, or about six months; an extension treatment period lasting 28 weeks; an open-label extension period lasting 68 weeks, or about 16 months; and an off-treatment follow-up period lasting 52 weeks, or one year.

In the initial double-blind treatment period, participants will be randomly assigned to receive either the combination of pozelimab and cemdisiran, either one of the therapies individually, or a placebo, all given via subcutaneous injections. Double-blind means that neither patients nor doctors will know who is receiving each study drug.

In the following extension periods, patients originally assigned to the combination therapy or cemdisiran alone will continue on the same regimen. Those who received pozelimab alone in the double-blind treatment period will switch to the combination therapy, while those who were initially given a placebo will receive either the combination therapy or cemdisiran alone in the extension parts.

The trial’s main goal is to compare changes in the MG Activities of Daily Living (MG-ADL), a patient-reported measure of MG severity and impact on daily life activities, over the course of the 24-week double-blind treatment period. Changes in other measures of MG severity, including the Quantitative MG and the MG Composite scales, will also be evaluated as secondary goals. Top-line data is planned for 2025 and the trial is expected to conclude in 2028.

Common side effects of pozelimab and cemdisiran

Clinical trials testing the combination of pozelimab and cemdisiran in people with gMG are ongoing and no results have been reported to date. Thus, the therapy’s side effect profile in this patient population is still unknown.

Myasthenia Gravis News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.