AAO 2026: New trials target optic neuritis treatment questions

Optic neuritis has evolved from a condition viewed through multiple sclerosis (MS) to one in which antibody biomarkers for neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) affect both prognosis and treatment, according to John J. Chen, MD, PhD, a neuro-ophthalmologist at Mayo Clinic in Rochester, Minnesota. Chen spoke about the topic at a symposium during the American Academy of Ophthalmology (AAO) 2026 Annual Meeting, held October 9-12 in New Orleans.

Chen said aquaporin-4 antibodies, discovered by colleagues at Mayo Clinic in 2004, are a specific biomarker for NMO and a pathogenic cause of it. Patients with NMO optic neuritis have severe disease and poor outcomes, he said. They are treated aggressively with early high-dose corticosteroids and plasma exchange, which removes pathologic antibodies and cytokines, and he said early plasma exchange is thought to lead to better outcomes. Without these treatments, outcomes are incredibly poor, with almost 50% of patients ending up blind, he said.

MOGAD more commonly presents with bilateral optic neuritis and more disc edema at onset, Chen said, with substantial optic nerve inflammation on MRI. Patients are often blind at onset but improve considerably with steroids, and only about 5% end up legally blind.

Because the cause is unknown at presentation, Chen said every patient with severe optic neuritis receives high-dose corticosteroids, followed by plasma exchange if they do not recover. He said the Optic Neuritis Treatment Trial (ONTT), which showed that steroids sped recovery but did not change the ultimate outcome, may have led clinicians to think treatment was not important. Severe cases are now typically sent to the emergency room for an expedited workup, including MRI, IV steroids, and MOG and aquaporin-4 antibody testing. “I think it’s more of a neuro-ophthalmic emergency than it used to be,” he said.

Two randomized trials now enrolling

Chen noted that the ONTT, published in 1992, was the last large optic neuritis trial, and two randomized clinical trials are now ongoing. TIMELY-Plex is testing the timing of plasma exchange in severe optic neuritis, with 32 US sites aiming to enroll 200 patients. Participants are randomized to immediate steroids and plasma exchange or to IV steroids with rescue plasma exchange if they have not recovered at 14 days. Plasma exchange requires a central line and usually five treatments every other day in the hospital, he said, so it is costly and time-intensive. Fifteen patients have been enrolled so far, and Chen anticipates it will take about 3 to 4 years to reach the target.

The second trial, PIONEER 1, is a phase 3 study of a medication for optic neuritis. Chen said a smaller phase 2 trial found significant improvement in low-contrast visual acuity compared with placebo and a significant reduction in the thickness lost with an optic neuritis attack. He asked clinicians to refer patients with acute optic neuritis to the nearest enrolling site for either trial.

Asked what the field is not talking about enough, Chen pointed to regenerating the optic nerve once damage is done. He said there is an ongoing trial of a neuroprotective agent for nonarteritic anterior ischemic optic neuropathy (NAION), but no regeneration solution yet.