Zilucoplan’s Edge in Complement Inhibition in Myasthenia Gravis: Miriam Freimer, MD

Continuing a recent interview with Miriam Freimer, MD, clinical professor of neurology at The Ohio State University Wexner Medical Center, here she delves more into the reasons behind the longer-term efficacy of zilucoplan, which was approved by the FDA on October 17, 2023, to treat AChR antibody–positive generalized myasthenia gravis. She also speaks to the treatment’s safety, noting this profile was common between patients either initiating the macrocyclic peptide or switching to it, in reference to the MG0017 (NCT05514873) and the RAISE-XT (NCT04225871) studies.

Freimer was an author on 5 abstracts presented at the recent 15th MGFA International Conference on Myasthenia and Related Disorders, held in Den Haag, The Netherlands.

Revisit part 1 and her discussion on complement C5 inhibition in AChR antibody–positive generalized myasthenia gravis.

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

Transcript

How does zilucoplan compare with other complement C5 inhibitors?

All of these medications have similar efficacy. You have 2 questions there. What happens to somebody at 2 years out? At least in zilucoplan, there's good data to show that people maintain that benefit for at least that 2-year period. There have been some case reports of some patients who've been on eculizumab who stopped responding to it, and it's not entirely clear why that is. One thought is, in the case of eculizumab, that maybe patients are developing their own antibodies to that medication and it's less efficacious—but those things are not clear yet. The number of patients who've had a loss of response 6 years out is still pretty small with those drugs. I'm not sure there's a difference in long-term efficacy in any of these drugs.

The [second] question is, why is there such a rapid response to zilucoplan? It is a little faster than the other drugs that have been studied in the last few years, both the complement class and the FcRns [Fc receptor blockers], which is another class we're not talking about today. It is a very different type of drug than the other ones. All of these other medications are monoclonal antibodies. Zilucoplan is called a macrocyclic peptide, and it binds a little bit more strongly to different parts of the complement pathway. In addition to binding to what's called the C5a, it's also binding to C5b, and so one of the possibilities is that it's having more efficacy in preventing complement function. The other thing is that it does appear that peptides have better penetration into tissue than monoclonal antibodies—so perhaps it's getting to the muscle more effectively than a monoclonal antibody could. The flip side of that is that peptides tend to have a shorter half-life, which is why this drug needs to be administered on a daily basis.

What were some of the most common adverse effects, and did these differ between patients who were initiating vs switching treatment?

If you look at the 2 studies of the switch and the initiation, there basically were no differences. The common adverse events, which are pretty typical for most drug studies, were a little bit of headache, or a little bit of nausea, or a little bit of stomach pain. This is a drug that's administered subcutaneously, often into the fat tissue in the abdomen, and patients would occasionally bruise from that, or there's a little discomfort associated with it. Those are also included in the adverse events.

There have been some reports of elevation in lipase, and that was felt to be nonsignificant, and [for] most of those patients, their lipases returned to baseline. There have been a few cases of patients with something called morphea, which is a skin change, and the etiology of that is just not understood. The majority of those were mild, but a couple of patients stopped treatment because of that.