Implications of Post Hoc Analyses of N-MOmentum Trial in Inebilizumab and Future Thoughts

Bruce Cree, MD, PhD, MAS, FAAN

Inebilizumab (Uplizna; Horizon) is the first and only B-cell-depleting monotherapy FDA-approved for adults with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 immunoglobulin G seropositive (AQP4-IgG+). Recently, at the 2023 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, February 23-25, in San Diego, California, new data was presented on 2 post-hoc analyses of the N-MOmentum clinical trial of the agent for NMOSD.¹ All told, the data suggested that inebilizumab does not increase susceptibility to COVID infection or deplete childhood vaccine-generated antibodies.

Lead investigator Bruce Cree, MD, PhD, MAS, FAAN, the clinical research director of the UCSF Multiple Sclerosis Center, caught up with NeurologyLive® at ACTRIMS to discuss the analyses, as well as his future thoughts on future subgroup analyses for the trial. Cree additionally talked about the concerns seen through the MS community regarding the potential infection of depletion of childhood vaccine generated antibodies in patients with NMOSD. He also spoke on the B cells and T cells in relation to patient outcomes and treatment optimization. Lastly, Cree noted the current assessment on the state of care for patients with NMOSD and the continued improvements going forward in the field.

NeurologyLive®: What were the findings of the trial, and how did they contribute to our understanding of the relationship between hypogammaglobulinemia and infections in patients treated with inebilizumab?

Bruce Cree, MD, PhD, MAS, FAAN: The N-MOmentum clinical trial was a randomized controlled trial comparing inebilizumab versus placebo in neuromyelitis optica spectrum disorder. The goal of the study was to determine whether inebilizumab could delay the time to a clinical attack and NMO and look at a wide variety of other secondary outcomes. Now, this study was completed some time ago, the primary results have been published and there have been several secondary analyses that have been completed as well since.

There were 2 abstracts being presented at the Forum, 1 exploring the vaccine status in the context of the clinical trial. One of the observations made had to do with patient safety and that hypogammaglobulinemia can occur during the course of treatment with inebilizumab. Now, inebilizumab is a monoclonal antibody directed against CD19, it depletes B cells. These cells are the cells that go on to produce antibodies. It stands to reason that medications like this could result in the lowering of total gamma globulin levels, which was observed during the course of the study. Some of those levels went quite low.

In this abstract, we wanted to determine whether immunizations from childhood, specifically measles, mumps, rubella, and varicella, were affected by inebilizumab. We know that the total gamma globulin levels go down, and we wanted to explore whether that could result in a decline in antibody levels for these important childhood vaccinations. We found that although some of those levels do decline a little bit, in particular for tetanus, they stay stable. When we looked at the index, where we are looking at whether overall these levels are decreasing in proportion to the total gamma globulin level, we found that they are increased; the index values are increased. We're seeing a loss of gamma globulins that are nonspecific gamma globulins, or gamma globulins, perhaps that have not been directed against specific pathogens. Perhaps this is the reason that we're not seeing strong correlations between hypogammaglobulinemia and infections in inebilizumab treated patients.

What is the effectiveness of COVID vaccination in patients treated with B-cell depleting therapies, and what strategies can address the potential lack of humoral immunity in these patients?

There's more to learn, of course. One of the big events that occurred in the last several years was the COVID pandemic and the second poster that's being presented for outcomes of what happened with COVID infections. We identified two individuals in the N-MOmentum study who developed COVID. There were also quite a few other people who were identified, who were treated with inebilizumab post marketing, who developed COVID. The good news there is that by and large, most of those individuals survived COVID, and many recovered. There were 2 deaths. One unvaccinated individual who probably died of severe COVID related infections, in particular pneumonia. Another individual who probably came just a consequence of deep venous thrombosis, a pattern that we are unfortunately all too familiar with in people independent of their immunization or other status. We see these things occur as part of the risk profile associated COVID.

This raises a very important question, is COVID vaccination effective in patients who are treated with B cell depleting therapies? I think this is another area of investigation, which really is very important. We've never seen COVID before. Of course, we’ve seen other coronaviruses but they're very different. Unlike influenza, where we have all these layers of immunity against it, we need those layers of immunity if you're on a B cell depleting therapy. At least the humoral component of immunity, which is the antibody portion of it, is abrogated by treatment with inebilizumab and other B cell depleting antibodies. We need to understand the T cell function there a bit better and we also need to develop strategies for if we want to see a strong and robust humoral response. What do we do with inebilizumab patients or for that matter anti-CD20 treated patients?

Has the potential of childhood vaccine generated antibodies been a concern in the past for patients with NMOSD? No, not so much. But nonetheless, [we wanted to] go ahead and try to understand whether there was going to be such an affect, given the hypogammaglobulinemia that we’re seeing with this particular product.

I should say that even though its a cross trial comparison looking across different products, the degree of hypogammaglobulinemia that we see with anti-CD19 seems to be greater than the hypogammaglobulinemia we typically see with anti-CD20s. It stands to reason that something that hits a broader spectrum of B cells—anti-CD19 hits pre B cells, as well as B cells, as well as plasma blasts, and some plasma cells— you're probably going to get a greater degree of hypogammaglobulinemia.

All that kind of makes sense and so the concern is a higher level of concern, because of the mechanism of action of the drug and because of its molecular target. We haven't seen it but that doesn't mean we shouldn't look for it, that we looked for it, and we found relative retention of these antibodies. I think it is important and also interesting that these antibodies that are being produced specifically by long lived plasma cells seem unaffected, right? It suggests that those cells are not the ones being targeted by the anti-CD19 and that fits in with our understanding of the long term, plasma cells that have probably lost CD19 from their surface.

What are the reasons why highly effective and proven drugs are being underutilized for autoimmune treatment, and what measures can be taken to overcome the treatment gap?

I think there is a tremendous amount of room for improvement. We have 3 drugs that are all proven to be highly effective in NMO. In my personal opinion, they are being underutilized across the board for reasons that have to do with traditional conceptions. Many practitioners continue to use medications like mycophenolate mofetil, azathioprine, daily prednisone, or rituximab, none of which are indicated for NMO treatment. But these are long used popular medications and so people are continuing to use them even on the frontline in newly diagnosed patients. I think this is a mistake. When you have drugs that have gone through the gauntlet of FDA approval, where you're able to peg down and say specifically what the safety and tolerability and efficacy profiles are, we should be reaching for those types of medications frontline, as well as potentially switching patients over who are currently on these other treatments. There is, I think, a misconception that the older treatments are in some way safer. That is not the case. The older treatments if anything are less safe. There's a reason from just a patient safety perspective to move patients from these traditional immune suppressants onto these tried-and-true proven therapies.

I think there is a big treatment gap that we still have to overcome. I think part of it may have to do is sticker shock: when people look at the prices of some of these drugs. They are coming in at very high, costly prices. That is perhaps some short sightedness on behalf of the manufacturers in terms of their pricing. But beyond that, we know that these drugs work. The social issues are important social issues, but those need to be worked out at a meta level, not at the individual patient level. When you've got drugs that are safer, better tolerated, more efficacious, and have proven efficacy, we should be reaching for those frontline. Eventually, we will come to a point where I think we're going to see more and more use of these drugs.

Transcript edited for clarity.

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REFERENCES
1. New Data Suggest UPLIZNA (inebilizumab-cdon) for the Treatment of Neuromyelitis Optica Spectrum Disorder (NMOSD) Did Not Increase the Risk of COVID-19 Infection or Reduce Antibody Levels From Childhood Vaccines. Horizon Therapeutics. Published February 23, 2023. Accessed March 1, 2023. https://www.businesswire.com/news/home/20230223005284/en/New-Data-Suggest-UPLIZNA%C2%AE-inebilizumab-cdon-for-the-Treatment-of-Neuromyelitis-Optica-Spectrum-Disorder-NMOSD-Did-Not-Increase-the-Risk-of-COVID-19-Infection-or-Reduce-Antibody-Levels-From-Childhood-Vaccines