Interpreting the DAWN Trial: Where Anti-CD38 Therapy May Fit in NMOSD Care

Neuromyelitis optica spectrum disorder (NMOSD) has entered a new therapeutic era over the past decade, with multiple phase 3 trials leading to FDA approved therapies that target distinct immune pathways involved in disease pathogenesis. Despite these advances, unmet needs remain, including treatment failures, long-term safety concerns, and limited options that directly address antibody-producing cells or disability progression.

At the 2026 Americas Committee for Treatment & Research in Multiple Sclerosis (ACTRIMS) Forum, held February 5-7, in San Diego, California, researchers presented late-breaking data from the phase 3 DAWN trial (NCT05403138), a pivotal trial testing daratumumab, an anti-CD38 therapy in patients with NMOSD. Daratumumab, an intravenously delivered treatment, is a CD38-directed cytolytic monoclonal antibody used to treat multiple myeloma and AL amyloidosis by directly killing cancer cells and activating the immune system.

Prior to the presentation, NeurologyLive^® sat down with study authors Michael Levy, MD, PhD, and Fu-Dong Shi, MD, PhD, to gain clinical perspectives on the data and the significance of the results. Levy, an associate professor of neurology at Massachusetts General Hospital, and Shi, a professor of neurology at Beijing Tiantan Hospital, outlined the biological rationale behind targeting CD38 in NMOSD, key aspects of trial design and conduct, as well as early efficacy and safety signals.

NeurologyLive: Provide some background on daratumumab, its mechanism of action, and why it was selected as a potential therapy for NMOSD?

Michael Levy, MD, PhD: I will start by setting the context. At this point, we have four approved therapies for NMOSD that have all gone through phase 3 clinical trials. One of those targets B cells, specifically inebilizumab (Uplizna). We know B cells play a central role in NMOSD pathogenesis, both through antigen presentation and through production of aquaporin-4 antibodies, and B-cell depletion clearly works in many patients.

That said, there are important limitations. You cannot deplete B cells indefinitely without consequences. Over time, patients may develop hypogammaglobulinemia, infections, and other complications. In addition, there are patients who fail B-cell–directed therapies, whether that is an approved agent or off-label rituximab. So the question becomes whether we can target the immune system more selectively and more effectively, particularly further downstream in the antibody-producing pathway.

Daratumumab targets CD38, which is highly expressed on plasmablasts and plasma cells, the cells that are actually producing pathogenic antibodies. By targeting these populations, we aim to reduce aquaporin-4 antibody production more directly, rather than broadly suppressing the entire B-cell compartment.

Fu-Dong Shi, MD, PhD: I agree with Dr. Levy, and I would add that CD38 is also expressed on natural killer cells. These cells participate in antibody-dependent cytotoxicity, which contributes to astrocyte injury in NMOSD. So by targeting CD38-positive cells, daratumumab may reduce antibody production and also reduce immune-mediated tissue damage.

This is not an accidental or off-target effect. Depleting CD38-positive NK cells was an intentional part of the strategy. The idea is to intervene at multiple points in the immune cascade that leads to astrocyte damage.

Can you walk us through the design and conduct of the DAWN trial, including the patient population that was enrolled?

Michael Levy, MD, PhD: The DAWN trial was conducted entirely in China across eight NMOSD centers. One important point is that NMOSD represents a much higher proportion of demyelinating disease in China compared with many Western countries. As a result, recruitment was relatively efficient.

To give some perspective, Dr. Shi’s group alone follows nearly 1,800 NMOSD patients, whereas in my own clinic we are closer to 200. That difference matters when you are trying to conduct a large randomized trial.

The study enrolled approximately 135 patients, all of whom were aquaporin-4 antibody positive. This was intentional. Prior trials that included seronegative patients often saw dilution of treatment effects, so this study focused exclusively on seropositive NMOSD. Patients were required to have experienced a relapse within the prior one to two years, using inclusion criteria similar to those in other pivotal NMOSD trials.

Fu-Dong Shi, MD, PhD: Yes, and I want to emphasize that all patients had active disease. These were not stable patients. They had recent relapses and ongoing risk, which is important when evaluating treatment efficacy.

Without getting into embargoed details, can you share some high-level insights on the efficacy findings from the trial?

Michael Levy, MD, PhD: The primary outcome was time to first relapse. The key result was a hazard ratio of approximately 0.26, which translates to about a 76 percent reduction in relapse risk compared with background prednisone therapy.

To put that into context, approved NMOSD therapies have hazard ratios ranging from roughly 0.26 down to around 0.06, depending on the mechanism of action. So daratumumab falls well within the established efficacy range of currently approved treatments.

Fu-Dong Shi, MD, PhD: I would also highlight that beyond relapse prevention, we observed signals related to disability. There appeared to be benefits in slowing disability progression, including measures such as EDSS. This aspect has not been well demonstrated in many prior NMOSD trials.

Michael Levy, MD, PhD: That is an important point. In fact, some patients showed improvement in neurological function rather than simply remaining stable. In contrast, patients in the control group tended to worsen following relapses. Demonstration of EDSS improvement is something we have not clearly seen in prior phase 3 NMOSD studies.

What did the safety profile look like in DAWN?

Fu-Dong Shi, MD, PhD: Overall, daratumumab was well tolerated. The most common issues were mild infusion-related reactions. There were no unexpected safety signals during the study.

Michael Levy, MD, PhD: From a broader perspective, daratumumab has an established safety profile from its use in multiple myeloma, and what we observed in NMOSD was consistent with that experience.

What do you see as the major takeaways from this study, particularly given that it was conducted primarily in China?

Michael Levy, MD, PhD: One key takeaway is that there is still room for innovation in NMOSD. Even with multiple approved therapies, there are patients who do not respond, cannot tolerate treatment, or develop long-term complications. Targeting different immune mechanisms gives us additional options.

Another important point is that drug development often begins in one region and then expands internationally. This investigator-initiated trial demonstrates a promising approach that could potentially be evaluated more broadly, depending on regulatory, scientific, and development considerations.

Fu-Dong Shi, MD, PhD: This study was driven by scientific rationale and unmet clinical need. Daratumumab is already approved for another indication and is less expensive than some currently approved NMOSD therapies. If these results can be validated and partnerships established, this approach may be expanded to benefit more patients.

How has daratumumab been used previously outside of NMOSD?

Fu-Dong Shi, MD, PhD: Daratumumab is approved for multiple myeloma. There have also been smaller studies in systemic lupus erythematosus and other autoimmune diseases. This is the first large trial of daratumumab in an organ-specific neurologic autoimmune condition.

Looking ahead, how do we continue to evolve NMOSD trials and therapeutic strategies?

Michael Levy, MD, PhD: Targeting additional mechanisms is critical. Most current NMOSD therapies require lifelong treatment. Ideally, we would like therapies that patients can eventually discontinue, whether through immune tolerance strategies, cellular therapies, or other durable interventions.

We also need to think beyond relapse prevention. Acute relapse management is still an area of unmet need, and recovery after attacks remains limited. Regeneration and repair strategies will become increasingly important.

Fu-Dong Shi, MD, PhD: Repair will not be easy. In NMOSD, demyelination is secondary to astrocyte injury, and intrinsic repair capacity is limited. We likely need to reduce inflammation first and then create an environment that allows repair to occur. There is still a great deal of work ahead.

Michael Levy, MD, PhD: Patients frequently ask about regeneration. We can suppress inflammation, but if patients remain blind or wheelchair-bound, that is not a complete solution. Early-phase work on remyelination and recovery is ongoing, and although progress has been slow, it remains an important direction for the field.

Transcript was edited for clarity. Click here for 2026 ACTRIMS Forum.