AAN 2026: Rituximab vs Approved NMOSD Therapies, What the SPHERES Registry Reveals About Real-World Treatment Gaps

At the 2026 American Academy of Neurology Annual Meeting, Michael Levy, MD, PhD, an associate professor of neurology at Massachusetts General Hospital, discussed findings from the SPHERES Registry in an interview with Pharmacy Times, noting that most neuromyelitis optica spectrum disorder (NMOSD) patients are still treated with off-label rituximab rather than 1 of 4 FDA-approved biologics. He attributed this trend largely to physician familiarity and patient inertia among those already stable on therapy.

Pharmacy Times: Can you introduce yourself and explain your current role?

Michael Levy, MD, PhD: I’m Michael Levy. I’m an associate professor of neurology at Massachusetts General Hospital at Harvard Medical School in Boston.

Pharmacy Times: What are the most striking treatment pattern shifts the SPHERES Registry has revealed since approved biologics entered the NMOSD space?

Levy: This is a registry of NMOSD patients since the approval of 4 drugs, and what surprised us the most is that the majority of patients are still on older, nonapproved, off-label medications, mostly rituximab. Many of these patients were on rituximab prior to the approval and just never switched over. But some people are still being started on rituximab and prefer it. It is surprising to us because rituximab never went through any of these scientific studies and is not approved for NMO, but it still has such a strong grip on the field. Patients are on it, they’re happy with it, and it just surprises us that they’re not choosing one of these newer, approved medications.

Pharmacy Times: Across rituximab, ravulizumab, inebilizumab, satralizumab, and eculizumab, what does the comparative effectiveness data tell us about relapse prevention, and does any agent stand out?

Levy: When we look at total efficacy, we’re considering not just relapse prevention but also tolerability, cost, and everything combined. So the question is: Can a patient use a medication effectively, given all the logistics and the efficacy combined? When we do that, what emerges is that rituximab is less effective, not because it’s not depleting B cells as well as we would like; that’s not the case. Rather, it has significant tolerability issues. People often have infusion reactions, and the [adverse] effects can last for a week at a time. Patients don’t like it, but they stay on it because they think that is the cost—the burden of the disease—and so they’ll tolerate it because they know it’s protecting them. When we look at the approved drugs, we don’t see those types of [adverse] effects, and they’re much more tolerable. But patients haven’t tried them yet, in part because they’ve been successful on rituximab and don’t necessarily want to fix what isn’t broken.

Pharmacy Times: How should clinicians be thinking about patient selection and sequencing among these biologics, particularly for AQP4-IgG-positive vs seronegative patients?

Levy: For seropositive patients, I think the easiest decision is to use approved medications. You have the scientific backing, you have the FDA regulation, and there is just a lot more evidence that they work. People are still doing what’s familiar to them at the physician level. Some doctors are just used to prescribing rituximab, and so that’s what they do reflexively. But if you look at the data, the data do suggest that the new drugs are superior. For seronegative patients, we don’t have the data that we have for seropositive patients, so we are still using rituximab and other off-label drugs.

Pharmacy Times: What gaps in real-world practice does this registry and trial data expose, and where do you see NMOSD treatment heading next?

Levy: I think the biggest gap is the question of the true relapse efficacy of rituximab, which has never been tested. One of the things that we’re doing now is a study funded by [the Patient-Centered Outcomes Research Institute] to actually test rituximab against the new drugs. The trial is called NMO-BEST. We’re recruiting across about 10 different sites with 160 patients, and we’re testing whether rituximab is either as effective or not as effective as the new drugs. We’re also assessing tolerability. That trial is due to launch next month.