NeuroVoices: James Winkley, MD, on Analyzing Phase 3 PREVAIL Trial of Gefurulimab

The treatment landscape for generalized myasthenia gravis (gMG) has expanded considerably since eculizumab became the first targeted biologic approved for the condition in 2017, and new data presented at the 2026 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting and MGFA Scientific Session are adding to that momentum.

Among the abstracts drawing attention are new analyses from the phase 3 PREVAIL trial evaluating gefurulimab (Klygefa; AstraZeneca), an investigational subcutaneous C5 complement inhibitor, in 260 adults with anti-acetylcholine receptor antibody-positive gMG on stable standard of care. The analyses examined clinical deterioration, rescue therapy, and hospitalization rates during the 26-week randomized period, alongside 52-week durability and quality-of-life data from the open-label extension, and were presented as gefurulimab awaits regulatory review in the United States following a positive recommendation from the European Medicines Agency's Committee for Medicinal Products for Human Use.

James Winkley, MD, Chairman of the Neurology Service Line at Baptist Health in Kentucky, served as a lead investigator on the PREVAIL trial and was a presenting author on the clinical deterioration analysis at the meeting. In a new iteration of NeuroVoices, Winkley broke down gefurulimab's mechanism, reviewed the PREVAIL trial design and patient demographics, and walked through the efficacy and safety findings presented at AANEM. Furthermore, he shared his perspective on where the gMG treatment landscape is headed as combination and sequencing approaches come into focus.

NeurologyLive: For our clinical audience, provide a little bit of background on what gefurulimab is, its mechanism of action, and the rationale behind why it could be successful in treating myasthenia gravis.

James Winkley, MD: This medication is a C5 inhibitor, and there are actually three other drugs already on the market that do C5 inhibition. Alexion, who manufactures this medication, already has eculizumab and ravulizumab out on the market. Eculizumab was the first, given as an IV infusion every two weeks. They then came out with ravulizumab, which allowed the antibody to last longer while still targeting C5 complement, and that was given every eight weeks.

This is the next iteration of a C5 monoclonal antibody, but it's a subcutaneous injection given by the patient once a week. The rationale for why this is going to work is all based on complement inhibition being heavily implicated in the pathophysiology of myasthenia gravis. It is a unique, smaller antibody administered in a two-milliliter volume in a self-injecting syringe, which allows patients to be more mobile and not have to have immediate access to an infusion center or a home health nurse to receive their treatment.

Before we talk about the data itself, give a little bit of background on the conduct and design of the PREVIEW trial, as well as the patient demographics.

It was a randomized, double-blind, placebo-controlled, multicenter, 26-week trial of gefurulimab added to standard of care. Whatever patients were on, whether steroids or oral immunosuppressive therapy, they were on a stable dosage of those, and either the investigational agent or placebo was added. They were then followed for over 26 weeks, after which everyone was moved to an open-label extension.

The average age of the patient was about 52.8 years. It was approximately 60% female and 40% male. The MG-ADL, which is a subjective self-reported measure of patients' symptoms, was about a nine at baseline, and you had to have greater than five to be enrolled. Patients had had myasthenia gravis for approximately 9.2 years, and the majority had been on some type of immunosuppressive therapy, either prednisone or an oral IST such as azathioprine or mycophenolate. Some were receiving IVIG, but patients could not be on IVIG and be enrolled in the trial.

Talk through the efficacy findings being presented at the meeting, including the clinical deterioration, rescue therapy, and hospitalization data.

The primary endpoint was a greater than or equal to three-point improvement in the MG-ADL at week 26. What we saw was a 4.2-point decrease in the MG-ADL, which separated from placebo by about 1.6 points. We do traditionally see a placebo response of one to three points on the placebo arm, so this was statistically significant. The secondary endpoint was the Quantitative MG score, defined as a greater than or equal to five-point improvement, and they did reach both endpoints in this trial.

Drilling down further, patients had an MG-ADL score on average of nine. The treatment arm dropped about four points. There is a subgroup of patients who would still have clinical deteriorations, defined as a greater than three-point increase in their MG-ADL significant enough to impact their activities. We saw 18 people in the placebo arm with clinical deterioration versus nine in the treatment arm, which trended toward statistical significance but did not reach it.

Rescue therapy, however, was statistically significant. Of those 18 in the placebo arm who had deteriorated, 16 required rescue therapy, which could be IVIG, plasmapheresis, or high-dose steroids. In the treatment arm, that number decreased to seven. And for hospitalizations, 12 patients required MG-related hospitalization in the placebo arm versus three in the treatment arm, and that measure was also statistically significant.

What did the safety data look like in the PREVIEW trial?

We did see some increase in injection site reactions, which you would expect with a self-administered injection. We also saw a slight uptick in upper respiratory tract infections and some joint and muscle pain. But it was in line with other complement inhibitors already on the market.

If gefurulimab were to reach the market, what could it provide for patients with generalized MG, and what role might it play in an already growing treatment landscape?

The biggest thing is self-administration. The patient will have the medication with them. It's a very quick 15-to-30-second injection, and as long as they can keep the medication refrigerated, they're able to come and go as they please. Whether they're traveling, they don't have to worry about taking time off to go to an infusion center, missing work, or missing other things.

If they want to go on vacation, they can take the medication with them. It gives patients a lot of flexibility in terms of when and where they receive their treatment. Now, there may still be some people who prefer an infusion like ravulizumab every eight weeks because they like being free from doing it themselves, so it just gives patients more options depending on their lifestyle.

As someone who has been involved in multiple MG trials, talk about the evolution of myasthenia gravis trials over the last several years and where you think the field is headed.

It's really been remarkable starting in 2017 when eculizumab was the first targeted biologic released. Then ravulizumab came out making it every eight weeks. We saw the introduction of the FcRn inhibitors, things like rozanolixizumab, efgartigimod, and nipocalimab, each with different routes of administration. And then there's been ublituximab, a B cell depleter given every six months.

What we're seeing is that we are attacking multiple points along the pathway that initiates myasthenia gravis, from the production of autoantibodies from B cells and plasma cells, to decreasing the amount of antibody in the bloodstream, to targeting the very endpoint, which we believe is complement driving the destruction of the neuromuscular junction.

In each of these trials, we see pretty similar efficacy, somewhere between a three and four-point decrease in the MG-ADL, but we see variations. It's not one homogenous group. Some people only have a three-point improvement and others can have an eight, nine, or ten-point improvement.

There is also discussion around whether medicines like gefelorilimab could be combined with IVIG or FcRn inhibitors. Do you start to layer some of these immunosuppressive medications for the more refractory patient? The person who had an MG-ADL of 13 or 15, goes on one of these therapies, and is now at an eight or nine, still has significant disability. Can additional immune-modulating medications be added?

That's really where I think we're going. There are also APRIL-BAF inhibitors being tested right now that are creating a lot of excitement. This is really just the first round of biological agents that are changing people's lives, but the goal is to hit minimum symptom expression for these patients, to really put their disease in remission. That's where we're headed.

Transcript edited for clarity. Click here for more AANEM 2026 coverage.