Understanding How Complement C5 Inhibitors Work in MG: Miriam Freimer, MD

As a neuromuscular physician for over 35 years and currently clinical professor of neurology at The Ohio State University Wexner Medical Center, Miriam Freimer, MD, spends most of her time treating patients who have myasthenia gravis. An author on 5 abstracts presented at the recent 15th MGFA International Conference on Myasthenia and Related Disorders, held in Den Haag, The Netherlands, here she speaks to research presented from the completed MG0017 study (NCT05514873), which investigated patients who switched from intravenous (IV) eculizumab or ravulizumab to subcutaneous (sub-Q) zilucoplan.

The 3 medications are complement C5 inhibitors, approved in 2017 (eculizumab), 2022 (ravulizumab), and 2023 (zilucoplan). Freimer is also director of the Myasthenia Gravis Clinic and the director of the Electromyography Laboratory at OSU.

This transcript was lightly edited for clarity; captions were auto generated.

Transcript

What mechanistic features of complement C5 inhibition underlie its clinical efficacy in AChR antibody–positive generalized myasthenia gravis?

One of the things that happens in many patients with myasthenia gravis is the immune reaction response involves complement. Complement is a protein, which, when combined with antibodies, can cause localized damage. It creates something called a membrane attack complex, and we know that in myasthenia gravis complement plays a very big role in what happens to the muscle end of the neuromuscular junction. In some patients, there can be significant changes to the muscle end of that area that can make it very hard for patients to recover.

About 8 or 9 years ago, the first complement-inhibiting drug was approved in myasthenia gravis. That drug was eculizumab, and it showed a very important response for patients to the disease, and so now there's been interest in developing additional complement inhibitors that might be a little different from the original one.

What factors likely drove patient preference for sub-Q vs IV zilucoplan, and were there differences between patients previously treated with eculizumab vs ravulizumab?

First take a step back and know how these drugs are all administered. Eculizumab is an every-2-week IV medication. Ravulizumab is an every-8-week medication given by IV. Those medications require patients to have an IV, to have to sit for a while and be observed, usually in an infusion center—although some patients were able to receive those medications at home. Zilucoplan is a sub-Q self-administered medication that has to be administered on a daily basis. What we were interested in was, how do patients respond by switching from one of those IV medications to a sub-Q medication? Did they like that mechanism or mode of administration better or worse? Did they feel better? Did they think there was any difference?

First, you have to think about who wants to be in a study like that. The reasons for patients wanting to do a switch was 1, they were tired of getting IV administration. They didn't want to have to travel to an infusion center. When you get an IV medication, that means an IV needs to be placed, and sometimes after a while, patients’ veins stopped to be as easily accessible the more they've had IVs placed. There are some patients who felt a sense of wearing off of those medications, and they thought, “Well, maybe if I take a medication on a daily basis, I might like it better.” That was the motivation for patients agreeing or being interested in participating in the study.

Were there differences between eculizumab and ravulizumab? One of the things that was noticed in the study was that patients who had been on eculizumab and then did the switch really didn't notice any difference in efficacy of the drugs. However, the patients who had been on ravulizumab noticed an improvement when they were on the zilucoplan. One of the things that was noted was that patients’ myasthenia gravis–ADL [activities of daily living] in patients on ravulizumab had actually dropped a little bit. One of the possibilities is that maybe complement inhibition isn't as effective 8 weeks out from the initial administration of ravulizumab, whereas in eculizumab, every 2 weeks, the complement inhibition stays stable.