Understanding Nipocalimab’s Impact on Myasthenia Gravis Using MG-ADL

Constantine Farmakidis, MD

A little over a month ago, Johnson & Johnson announced it was submitting a biologics license application (BLA) to the FDA seeking the initiation approval of nipocalimab for the treatment of patients living with generalized myasthenia gravis (gMG). The therapy, which is designed to exclusive block binding of immunoglobulin G (IgG) to the neonatal fragment crystallizable (Fc) receptor, had its application supported by data from the phase 3 Vivacity-MG3 study (NCT04951622).¹

The trial, which featured 199 adults living with the disease, showed that nipocalimab plus standard of care was superior to placebo on the primary end point of improvement in Myasthenia Gravis-Activities of Daily Living (MG-ADL). In the study, patients who received nipocalimab plus SOC improved by 4.70 points on the MG-ADL, which was significantly more than the 3.25-point improvement from baseline observed in the placebo plus SOC group over weeks 22, 23 and 24 (P = .002).²

At the 2024 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held October 15-18, in Savannah, Georgia, a new analysis focused on specific changes in the MG-ADL total score from the study. Specifically, the results showed that among 153 patients, the odds-ratio of MG-ADL domain responders over 24-weeks were 1.6 (0.9-2.7) for bulbar, 2.0 (1.0-3.6) for respiratory, 1.8 (1.0-3.1) for limb), and 2.9 (1.5-5.4) for ocular, all favoring nipocalimab.³

During the meeting, lead author Constantine Farmakidis, MD, sat down to discuss the data, and the reasons behind observing specific item and domain-level symptoms. Farmakidis, an associate professor of neurology at the University of Kansas Medical Center, provided thoughts on the significance of the data, the clinical relevance of the MG-ADL, and the various ways in which nipocalimab provides clinical benefit.

NeurologyLive®: Why was this an analysis you wanted to pursue?

Constantine Farmakidis, MD: Patients with myasthenia gravis, which is the disease that nipocalimab is being investigated for to see if it is an effective treatment— it can affect the eyes, the mouth, and muscles around the mouth, as well as different muscles around the joints, like around the shoulders and hips, things like that. So, this was an analysis of the data from the study, specifically the efficacy data, looking at how well the drug works and if the improvement from the investigational agent—which was demonstrated in the study—was even across different symptom areas. The analysis looked to see if the improvement was even in the eye symptoms, symptoms around the mouth, and then the rest of the body, like the arms and legs. That was the purpose of it.

Did any of the items on MG-ADL stand out?

What we were looking at were the conclusions of the study. The question was whether the outcome, measured by the scale, was driven by all items or just certain ones. Ideally, the improvement would be driven by many, if not all, items on the scale, rather than being concentrated in one area. Similarly, if you group certain items, you can create domains. For example, there’s a domain for eye symptoms, which includes three items. Then there’s a domain for bulbar symptoms, or mouth symptoms, and another for the arms. The conclusion was that the score changes—the improvement in the nipocalimab trial—were driven by all items and all domains. So, the improvement affected the eyes, mouth, arms, and even breathing—another domain. The results favored the nipocalimab arm of the study versus the placebo arm in a balanced way across these domains.

How does nipocalimab differ from other approved therapies for myasthenia gravis?

Since 2017, after over 60 years without new treatments, we’ve had new treatments approved by the FDA for myasthenia gravis. You can almost think of treatment as “before 2017” and “after 2017.” This doesn’t mean that everything after 2017 is always better than traditional treatments, but these new treatments fall into the biologic category. Nipocalimab is a monoclonal antibody that targets the neonatal Fc receptor. What it does is interfere with the recycling of certain antibodies, including the disease-causing antibodies in myasthenia gravis.

If you think about it, by interfering with the recycling or the keeping of antibodies in circulation, you’re essentially reducing antibody levels, both normal and disease-causing ones. That’s the mechanism through which the drug is hypothesized to work, and there’s strong evidence supporting this. In studies, we’ve seen that after giving the medication, antibody levels drop, and specifically, the disease-causing antibodies also decrease.

Any remaining thoughts regarding the analysis?

When conducting clinical trials to establish whether a proposed treatment works, a lot depends on the quality of the outcome measure. You want an outcome that is meaningful for patients and also clinically significant—where patients feel better and need fewer medications. This was a sub-analysis of the data to examine the quality of the outcome measure and to check for any red flags that the medication might not be working as broadly as desired.

You want the treatment to affect all the major areas where patients have symptoms. This analysis indicates that, while it has limitations (it’s a post-hoc analysis and not intended to meet the most rigorous statistical criteria), there were no red flags. If anything, the evidence suggests that the treatment effect of nipocalimab comes from many different areas of symptoms, which is exactly what we’d prefer to see. That’s a positive takeaway from this analysis.

Transcript edited for clarity.

REFERENCES
1. Johnson & Johnson seeks first approval of nipocalimab to treat broadest population living with antibody positive generalized myasthenia gravis. News Release. Published August 29, 2024. Accessed October 21, 2024. https://www.jnj.com/media-center/press-releases/johnson-johnson-seeks-first-approval-of-nipocalimab-to-treat-broadest-population-living-with-antibody-positive-generalized-myasthenia-gravis
2. Nipocalimab pivotal Phase 3 trial demonstrates longest sustained disease control in FcRn class. News Release. Published June 28, 2024. Accessed October 21, 2024. https://www.jnj.com/media-center/press-releases/nipocalimab-pivotal-phase-3-trial-demonstrates-longest-sustained-disease-control-in-fcrn-class
3. Farmakidis C, Gandhi K, Ait-Tihyaty M, et al. Symptom severity assessment using MG-ADL items and domains in a 24-week, phase 3 study (vivacity) of nipocalimab in generalized myasthenia gravis. Presented at: 2024 AANEM Annual Meeting; October 15-18; Savannah, GA.