Reviewing Phase 3 Data on a Subcutaneous C5 Inhibitor for Myasthenia Gravis

Omar Sinno, MD, MBA, medical lead, rare disease, UCB, walks through the findings and implications of the phase 3 RAISE study which evaluated zilucoplan for the treatment of patients with myasthenia gravis.

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Welcome back to PopHealth Perspectives, a conversation with the Population Health Learning Network where we combine expert commentary and exclusive insight into key issues in population health management and more.

In this episode, Dr Omar Sinno shares findings from the phase 3 RAISE trial conducted among patients with myasthenia gravis.

My name is Omar Sinno. I'm a physician by training and the US medical lead for rare disease at UCB. That includes myasthenia gravis and our other indications in neuroinflammation.

Thank you, Omar. Can you comment on the prevalence and burden of myasthenia gravis?

Myasthenia gravis is a rare disease, and it impacts about 200,000 people, not only in the United States but the EU and Japan as well. In the United States, there are about 34,000 to 60,000 individuals with myasthenia gravis, and the prevalence is around 14 to 24 per 100,000.

Can you talk a little bit about the RAISE trial, including its design and what inspired the research?

RAISE is a phase 3 multicenter, randomized, double-blind, placebo-controlled trial. The goal was to evaluate the efficacy, safety, and tolerability of zilucoplan. Zilucoplan is a subcutaneous daily injection, and it's a peptide that inhibits the complement cascade in 2 ways. One is that it prevents the cleavage from C5 into C5a and C5b. But it also prevents the binding of C5b to C6.

The complement cascade, especially when you're talking about the neuromuscular junction in myasthenia gravis, is significant, because the downstream part of the complement cascade when it gets fully formed is something called the membrane attack complex. This membrane attack complex, or MAC, literally punches holes in the postsynaptic membrane. As a result, the muscle reduces its ability to contract, and that precipitates a lot of the weakness that we see in myasthenia gravis.

There were a total of 174 participants, and patients were randomized in a 1:1 ratio to either receive zilucoplan subcutaneously or placebo, for a total of 12 weeks. The study was designed to determine if complete complement inhibition could bring clinical benefit to those individuals with generalized myasthenia gravis, specifically in the patients with acetylcholine receptor antibody positive myasthenia gravis.

What were the key findings from the study?

The primary endpoint for RAISE, which was the change from baseline at week 12 in the Myasthenia Gravis Activities of Daily Living (ADL) score, was met with statistical and clinical significance. Secondary endpoints, including the change in the quantitative myasthenia gravis score (QMG) and the myasthenia gravis composite score (MGC), were also met with clinical and statistical significance.

The MG QoL, measuring patients’ quality of life, was also met with statistical significance. Lastly, the study also met the time to rescue therapy, specifically intravenous immunoglobulin from baseline, and the achievement of minimal symptom expression which is an ADL of 0 of 1.

How do you think these results will impact future clinical practice and outcomes?

The results highlight the importance of complement inhibition in the care of myasthenia gravis. It's been known for a while that complement destruction is one of the main factors that causes the neuromuscular junction to get injured. I think this provides a nice, targeted therapy to add to the care regimen in myasthenia gravis right now. The current care regimen has been used for a long period of time and has been successful in some patients, but, for the most part, is symptomatic therapy, and doesn't get at the foundation as what's driving the disease.

And is there anything else you'd like to add today?

UCB's also investigating the safety and efficacy of rozanolixizumab, which is subcutaneously infused humanized monoclonal antibody. This is important, because this antibody targets the FcRn receptor. The FcRn receptor is an important part of making sure antibodies get back into the bloodstream, but in autoimmune diseases such as myasthenia gravis, when these pathogenic autoantibodies get circulated back into the bloodstream, it increases their potential to cause damage. Last December, specific to rozanolixizumab, UCB announced positive top line results for the phase 3 study in myasthenia gravis.

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This transcript has been edited for clarity.