SAN DIEGO — Treatment with daratumumab, a monoclonal antibody approved to treat multiple myeloma, was associated with a significant decrease in relapse risk in patients with aquaporin-4 immunoglobulin G (AQP4-IgG) antibody-positive neuromyelitis optica spectrum disorder (NMOSD) compared with placebo, new data showed.

Investigators leading the randomized, double-blind, phase 3 trial found that patients who received daratumumab were 74% less likely to relapse than those who received placebo, with similar adverse events (AEs) between groups.

Although there are a number of FDA-approved treatments for NMOSD, researchers say there is a need for other options for patients who don’t respond to available therapies.

“This provides definitive evidence that treatment does reduce the risk of relapse. It also improves disability if they don’t relapse,” investigator Michael Levy, MD, PhD, associate professor at Harvard Medical School and Massachusetts General Hospital, Boston, said.

“This is a totally different mechanism of action, and it offers new therapy for people with NMO, especially in that group of unmet needs — patients who either don’t have access or failed or can’t tolerate the other therapies,” he continued.

The findings were presented on February 7 at Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2026.

‘Novel Approach’ Targets CD38

NMOSD is a relapsing autoimmune inflammatory disorder that causes recurrent optic neuritis and myelitis. In the US, it affects an estimated 22,000 people, mainly women.

Daratumumab targets CD38, a protein that is highly expressed on plasma cells and plasmablasts, which produce AQP4 antibodies that damage astrocytes. The drug is novel because no existing therapies for NMOSD target CD38, study co-author Fu-Dong Shi, MD, PhD, a neurologist with China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China, told Medscape Medical News.

The DAWN trial enrolled 135 patients between November 2022 and March 2025. The trial population was largely women and older than typical patients with MS. Median Expanded Disability Status Scale (EDSS) scores were 3.77 in the daratumumab group and 3.48 in the placebo group. The most common recent attack types were transverse myelitis and optic neuritis, and participants had at least one relapse in the prior year or two relapses in the prior 2 years.

Patients were randomized 2:1 to daratumumab (84% women; mean age, 51.3 years) or placebo (87% women; mean age, 54.3 years).

Daratumumab was dosed at 8 mg/kg intravenous (IV) every 2 weeks during an induction phase, then 4 mg/kg IV 4 every 4 weeks during maintenance, for at least 52 weeks. All patients received background low-dose prednisone (7.5 mg).

Results Favor Daratumumab

In the per protocol analysis, significantly more patients in the daratumumab group were relapse free at 156 weeks than those in the placebo group (69.1% vs 14.6%).

The overall decrease in relapse risk in the treatment group was 74% (hazard ratio [HR], 0.26; P < .001), which Levy said is similar to some other NMOSD drugs. The overall HR in the intention-to-treat population was 0.255 (P < .001).

Similar results were reported on subgroup analysis by sex, age, disease duration, baseline EDSS score, and concomitant autoimmune disorders.

In patients who relapsed, transverse myelitis (53% daratumumab, 74% placebo) and optic neuritis (24% vs 26%) were most common.

Just 6% of those in the daratumumab group experienced EDSS worsening vs 36% of those in the placebo group. 

AE rates were similar between daratumumab and placebo (88% vs 84%, respectively), and treatment-related AEs occurred in 28% vs 22%. That’s similar to AE rates of other monoclonal antibodies, Shi noted.

“Long-term safety, say 5 years down the line, are unknown,” he said. However, daratumumab is expected to be safer than alternatives because it more selectively depletes immune cells, he added.

Questions of Ethics

During a question-and-answer period, Levy was asked about the ethics of the trial, which required that placebo patients refrain from taking NMO treatments. Two MS specialists contacted for comment for this article expressed concerns about the trial’s ethics but didn’t wish to be quoted.

Levy acknowledged that “the ethics of doing a trial in NMO was problematic even back in 2014 when we launched all of the trials because placebo exposes patients to potentially severe relapses and permanent neurological damage.”

But a head-to-head comparison against an existing therapy would be impractical given the rarity of the disease, Levy said.

“We would have to compare daratumumab against a very, very effective drug, which would require hundreds of thousands of patients. It’s really not feasible.”

To mitigate risk, he said, the trial used a 2:1 randomization and allowed background low-dose prednisone in both groups.

Outside Perspective: Alternatives Needed

Levy added that “approved treatments are lifelong so we need therapies that may have a more durable effect without requiring lifelong immune suppression.”

However, the researchers don’t yet know if daratumumab would provide a shorter-term option as the ideal treatment duration is still to be determined, Shi added.

Neurologist Benjamin M. Greenberg, MD, MHS, vice chair for Clinical and Translational Research, University of Texas Southwestern, Dallas, told Medscape Medical News that there’s a need for new NMO therapies that are less risky and appropriate for patients who either have contraindications to them or a lack of response.

“It is great to see additional studies of drugs for NMO, but with multiple approved therapies, future trials will need to be active comparator studies,” he said.

And what about off-label use of daratumumab?

“Given the multitude of on-label therapies for NMO, we tend to start with FDA-approved therapies before progressing to any off-label prescribing,” he said.

Funding information for the investigator-initiated trial was not disclosed. Levy reported relationships with Alexion, Horizon, Genentech/Roche, UCB, Sanofi, Mitsubishi, Alexion/AstraZeneca Rare Disease, and Horizon/Amgen. Greenberg disclosed relationships with Genentech, Amgen, and Alexion. Shi disclosed relationships with Alexion/AstraZeneca, Novartis, Hansoh Pharmaceutical, Sinomab, Lundbeck, European Charcot Foundation, Chinese Neurological Association, Zai Lab, AstraZeneca, New Terrain, Akrivia, and Biogen.