NeuroVoices: Richard Nowak, MD, MS, on the MINT Trial of Inebilizumab in Myasthenia Gravis

Richard Nowak, MD, MS

Traditionally, myasthenia gravis (MG) is managed through a combination of symptomatic treatments, immunosuppressive therapies, and sometimes surgical intervention, depending on the severity and subtype of the disease. In recent years, the number of approved novel treatments for the disease has expanded; however, some patients still struggle to manage their disease. As more is being understood about the underpinnings of neurologic conditions in general, the opportunities for repurposing therapies has only increased.

One agent, inebilizumab (Uplizna; Amgen), an FDA-approved treatment for neuromyelitis optica spectrum disorder (NMOSD), is currently being investigated as a potential therapy for patients with myasthenia gravis (MG). At the 2024 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting, held October 15-18, in Savannah, Georgia, investigators presented data from the phase 3 MINT trial (NCT0452473), a 238-patient cohort study assessing the effects of intravenous inebilizumab in generalized MG for a 12-month period.

The study, which spanned across 103 sites in 18 countries, included 190 patients with acetylcholine receptor (AChR) and 48 muscle-specific kinase receptor (MuSK+) MG. All told, change from baseline in Myasthenia Gravis Activities of Daily Living (MD-ADL), the study’s primary end point, was statistically significant for inebilizumab-treated patients, with scores of –4.2 compared with –1.9 for those on placebo (P <.0001).

To learn more about MINT and the therapeutic potential of inebilizumab in MG, NeurologyLive® sat down with lead investigator Richard Nowak, MD, MS, director of the myasthenia gravis clinic at Yale University. As part of a new iteration of NeuroVoices, Nowak gave additional clinical insight on the notable outcomes of the study, the mechanism of action behind the drug, and how it performed among subtypes of MG. Furthermore, he discussed the long-term plan for the drug, and the significance of MINT being a registrational study.

NeurologyLive: Can you provide an overview of how MINT was conducted?

Richard Nowak, MD, MS: The Myasthenia Gravis Inebilizumab Trial, or MINT, was a placebo-controlled registrational trial aimed at evaluating the safety and efficacy of inebilizumab in individuals with generalized myasthenia gravis. The eligibility criteria included patients who were either acetylcholine receptor or MuSK autoantibody positive. So, it included both of those populations and specifically patients with moderate to severe disease, based on their MGFA Clinical Classification requirement, their MG-ADL score at baseline, and their QMG score at baseline.

What are the greatest takeaways from the results?

Firstly, MINT actually achieved its primary endpoint, showing a statistically significant improvement in the MG-ADL score at week 26 compared to baseline, with a greater reduction in the MG-ADL score in the treated group than in the placebo group. That was really exciting and positive. It's worth noting that this was a combined population; in the primary endpoint, we included both acetylcholine receptor and MuSK autoantibody-positive patients with generalized myasthenia gravis. Our safety analysis showed that the safety and tolerability profile was similar to what has been observed with inebilizumab in NMOSD trials, with no new safety signals or tolerability issues identified in the study. There were also several secondary outcome measures focused on other myasthenia gravis-specific clinical outcomes, including the QMG score, which showed a statistically significant reduction at the end of the study compared to baseline in the combined study population. Additional secondary outcomes looked at the autoantibody subgroups, showing either significant reductions or trends toward reduction. So, the overall data support inebilizumab’s safety and efficacy in an antibody-positive generalized myasthenia gravis population.

Based on its mechanism of action, why do we believe inebilizumab can be an effective therapy for generalized myasthenia gravis?

Inebilizumab is an anti-CD19 positive B-cell depleting biologic, targeting B cells that express the CD19 antigen on their surface. This is important because antibody-secreting cells, including plasmablasts and certain long-lived plasma cells, express that antigen, allowing them to be targeted or depleted by inebilizumab. Myasthenia gravis is a T cell-dependent, B cell-mediated disorder driven by IgG autoantibodies, so targeting B cells makes sense since they produce the pathogenic autoantibodies. The uniqueness of this mechanism is that inebilizumab could be the first-in-class anti-CD19 B-cell depleting agent for generalized myasthenia gravis. There isn't another option like it available for myasthenia gravis right now, which is exciting as it targets some upstream immunopathogenesis of the disease. In short, by targeting antibody-secreting cells, we're essentially addressing the "factories" of antibody production, making it a viable target and mechanism to investigate further, which is what we did in MINT.

Are there any subpopulations of patients who may experience better outcomes with this drug?

We can only comment based on the data we have so far. MINT enrolled patients with either acetylcholine receptor or MuSK autoantibody-positive disease. The acetylcholine receptor group was larger than the MuSK group, but MuSK included 48 participants, which is actually one of the largest—if not the largest—MuSK cohorts in a registrational clinical trial. We haven't done an in-depth comparison of effectiveness between the two groups. However, looking at the acetylcholine receptor population, we saw statistically significant reductions in both ADL and QMG scores at week 26 compared to baseline. In the MuSK group, we saw a significant reduction in ADL scores and a trend toward QMG score reduction, though it didn’t reach statistical significance. This trend isn't too concerning since the MuSK group was smaller, with 48 patients total (24 in each placebo and treatment arm). At this point, there's no striking difference, and we can't predict which patients based on antibody subtype would respond better. But targeting antibody-secreting cells could translate to benefits for both autoantibody subtypes.

What are the next steps for advancing inebilizumab in gMG?

Yes, so these are the top-line study results, focusing on safety and efficacy based on the primary endpoint and some key secondary outcome measures. There’s a lot more additional analysis planned, including looking at different clinical outcome measures, like MG exacerbations, which were pre-specified in the study. So, more details will come. We’re excited about these top-line results demonstrating efficacy and safety. Next steps involve further data analysis and preparing a peer-reviewed publication. This was a top-line results presentation at this year’s AANEM, but we're hopeful to get this published in the medical literature for broader review. For potential regulatory filings, I’d defer to Amgen to comment on the next steps. What we have seen in the data is really promising. I’d also note that this is probably the largest registrational clinical trial for myasthenia gravis, which is quite significant. You asked about next steps, so we also have data collection ongoing from the open-label extension and long-term safety follow-up, which will continue for up to three years or more. So, there’s definitely more to come, and it’s very exciting.

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REFERENCE
1. Amgen Conference Call to Discuss New Topline Data in Inflammation and Rare Disease. News release. Amgen. September 24, 2024. Accessed October 24, 2024. https://amgen2.rev.vbrick.com/#/videos/750c4b9d-5c91-4634-8906-a16b53f346bf.