Understanding the Value of B-Cell Depletion in NMOSD

Jeffrey Bennett, MD, PhD

Inebilizumab (Uplizna; Horizon Therapeutics) is the first and only anti-CD19 B-cell depleting monoclonal antibody FDA-approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. The FDA’s decision to greenlight the therapy was based off results from the pivotal phase 2/3 N-MOmentum trial (NCT02200770), which demonstrated a robust reduced risk for relapse over a 6-month period. At the 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), October 13-15, Jeffrey Bennett, MD, PhD, presented a new analysis from the study.

Among the several key findings, all participants demonstrated B-cell reductions at 1 week from first treatment. Additionally, inebilizumab also provided sustained B-cell depletion after 2.5 years and decreased NMOSD activity in treated patients, with a 97% reduction in annualized relapse rate and a 73% reduction in new/enlarging lesions when compared to the placebo group. Those who had B-cell counts less than 4 cells μL also showed persistently deeper B-cell depletion than those who had counts 4 cells μL or greater.

Bennett, professor of neurology, University of Colorado, sat down with NeurologyLive to provide insight on the clinical significance of the findings and the importance of B-cell depletion in the NMOSD space. He also touched upon the steps needed to improve treatment optimization and which clinical outcomes should be held with higher regard.

NeurologyLive: What is the clinical significance of the data? How can clinicians take what they’re reading and apply it to their practice?

Jeffrey Bennett, MD, PhD: In the N-MOmentum trial, inebilizumab, a novel anti-CD19 agent approved for the treatment of NMOSD, was studied for its efficacy in reducing the risk of relapse in these patients. The medication works by depleting B-cells and the target, CD19, is distinct from the typical CD20 surface marker used for depletion of B-cells in other treatments such as rituximab or ocrelizumab, an agent approved for the treatment of patients with MS. This CD20 marker is also used by ofatumumab.

In this study, what physicians can take home is that in the search for a marker of clinical efficacy for anti-CD19 depletion, we examined how rapidly these B-cells were depleted from the blood and how that depletion related to further levels of B-cells monitored during prolonged treatment in the open-label extension period of the study. The data shows that the early behavior of B-cell depletion in patients with NMOSD was similar to what was observed in the long-term throughout the study. This depletion could be related to clinical metrics of disease activity, as well as MRI metrics of disease activity.

What types of studies need to be conducted to improve treatment optimization?

In a space like NMOSD, relapses are the significant driver of disability. If you’re preventing relapse, you’re preventing neurologic disability accumulation in your patients. Having predictor of therapeutic success is key to not having our traditional mantra of “you’re doing well until you’re not.” Then we must play defense and try to switch things to get you to a newer or improved therapeutic agent. With that in mind, having something that can be predictive of therapeutic efficacy, a biomarker per se, is key to optimizing patient’s therapy with any agent. This study is one of those initial steps for doing such an investigation. You have treated patients who are being looked at for long-term outcomes and trying to take a basic biomarker, in this case B-cell depletion, using a depleting agent to measure efficacy in a manner that could be easily adapted by physicians taking care of patients.

What is important to observe in trials that evaluate NMOSD drugs?

The first thing we learned from this study is that whether you had robust and rapid depletion after the first dose of inebilizumab, or even if the B-cells returned to a modest level because you repleted them quickly or you didn’t end up with the same depth of depletion, patients appeared to do well in the long-term. You win regardless of what group you might fall into based on your response to therapy. The second thing we learned is that those patients who had a characteristic type of depletion appeared to behave similarly with each subsequent dose. Therefore, you didn’t tend to stray out of your character, you tended to respond to the drug in a standardized way with each dose.

But independent of those responses, those who had deeper depletion appeared to get that optimal therapeutic effect quicker than those who had a shallower depletion or a more rapid recovery between doses of medication. That gets us to the idea that we could not necessarily change how someone responds to the medicine, but we could potentially move forward in future investigations to look at dosing the drug in a way that can help all patients reach that optimal rapid depletion. This provides us the first clues to doing this and say, “You might not be getting optimized in the rate you get to your highest form of success, but you’re going to get there no matter what.” We just have to come up with a formula, knowing how you respond initially to the drug, that gets you to your best outcome as fast as possible.

What’s the biggest step forward for MS care this year?

The biggest advance in patients with MS is the introduction of B-cell depleting therapy and our understanding of the role of B-cells in disease activity. It has led to blockbuster new therapies that have significantly suppressed inflammatory activity. In certain cases like ocrelizumab, this has given us not an optimal treatment for progressive disease, but at least our first successful treatments. As we move forward in MS, understanding this clinical success is going to lead to new novel avenues that are available for patients, including understanding how to target b-cells within the central nervous system and how to target other cells once we’ve eliminated the B-cells that may be contributing. In particular, innate immune cells such as microglia within the central nervous system.

Is there anything else you’d like to mention about inebilizumab or your findings?

Inebilizumab and the N-MOmentum study provide the most detailed, scientific look at the treatment and its response in the NMOSD field. At this time, this data set and our inroads to understanding both clinical and MRI activity during the disease, is giving us some unique insights into how to optimize therapy. Additionally, this current study on B-cell depletion is one of the first steps to helping us understand how to best monitor patients for therapeutic efficacy before they show any indication of relapse.

Transcript edited for clarity.

REFERENCE

New data reinforce the relationship between B-cell depletion and improved outcomes in people receiving UPLIZNA (inebilizumab) for neuromyelitis optica spectrum disorder (NMOSD). News release. Horizon Therapeutics. October 13, 2021. Accessed October 21, 2021. https://ir.horizontherapeutics.com/news-releases/news-release-details/new-data-reinforce-relationship-between-b-cell-depletion-and