On 1 July, at the tenth Congress of the European Academy of Neurology (EAN), during an e-presentation session on generalised myasthenia gravis (gMG), a session sponsored by Amgen outlined an analysis of the role of B cells in gMG and what this entails for the future treatment landscape.
The session, hosted by Maria Isabel Leite and Nils Erik Gilhus, presented clinical data on the BeatMG study, a Phase II randomised, double-blind, placebo-controlled study assessing the efficacy of rituximab in treating gMG with anti-acetylcholine receptor (AChR) antibodies.
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The production of antibodies that target AChRs, or muscle-specific kinase (MuSK), a protein at the neuromuscular junction, is a key mechanism in the underlying pathophysiology of gMG.
Key opinion leaders (KOLs) previously interviewed by leading data and analytics company GlobalData have highlighted the success of antibody therapies in the treatment of gMG.
MG is an autoimmune disease that affects the nerves and muscles and is characterised by muscle weakness and fatigue, especially weakness of the muscles controlling eye and eyelid movement, facial expressions, chewing, and talking.
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The muscle weakness seen in gMG is most often caused by the immune system, namely B cells, producing autoantibodies against AChRs or other components at the neuromuscular junction such as MuSK.
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By GlobalDataPatients are grouped by the presence or absence of anti-AChR or anti-MuSK antibodies.
When treating MG, physicians often prescribe acetylcholinesterase inhibitors (AChEIs), including Mestinon.
However, the majority of patients do not see an improvement in their symptoms when using AChEIs alone.
KOLs previously interviewed by GlobalData have said that AChEIs are typically inadequate in eliminating symptoms and do not affect the underlying pathophysiology involving the immune system.
As a result, patients are often given nonsteroidal immunosuppressants such as azathioprine and tacrolimus, as well as corticosteroids such as prednisone, in order to manage their symptoms.
Corticosteroids also reduce immune system activity, but long-term steroid use is associated with several serious side effects.
Given the negative side-effect profiles of the aforementioned therapies and the fact that they do not adequately address the underlying pathophysiology of B-cell antibody production, there is an unmet need for monoclonal antibody (mAb) therapies.
As a result, mAbs such as rituximab and eculizumab have also been prescribed to gMG patients.
MAbs have a favourable side-effect profile in comparison to steroids.
Rituximab targets B-cell surface markers CD19 and CD19-positive B cells, which have been implicated in antibody production, which leads to gMG.
The session at EAN 2024 on the current treatment landscape and unmet needs of gMG sponsored by Amgen presented topline data from the BeatMG study, which involved 52 patients who have been receiving a daily dose of 15mg or more of prednisone.
A total of 25 patients were treated with rituximab, and 27 patients were treated with placebo.
The primary outcome measure was a steroid-reducing effect, which was defined as the proportion of patients achieving a 75% or more reduction in mean daily prednisone dose.
A total of 60% of patients treated with rituximab and 55.5% of placebo patients saw a more than 75% reduction in steroid use at week 52.
The results indicate that rituximab is not more effective than placebo and is unlikely to reduce steroid use for gMG patients with anti-AChR antibodies.
The results of the BeatMG study contrast with rituximab’s potential in treating refractory MG and the success of rituximab in treating gMG patients with anti-MuSK antibodies.
According to GlobalData’s Pharma Intelligence Center (PIC), there is an ongoing Phase III trial being conducted in China, sponsored by Sun Yat-Sen University, which aims to assess rituximab monotherapy in the treatment of refractory MG.
This highlights that rituximab’s potential in treating gMG is being recognised.
Moreover, KOLs previously interviewed by GlobalData have also noted the success of rituximab in treating gMG patients with MuSK antibodies.
A KOL based in the US stated that they believed that MuSK antibody-positive patients should be treated first-line with rituximab, as in their clinical experience, they had not encountered a single MuSK antibody-positive patient who had not responded to rituximab.
This signifies that although existing B-cell-targeting mAbs have a role to play in the treatment landscape for gMG, it is not clearly defined at this time.
According to GlobalData’s PIC, Amgen is currently sponsoring a clinical trial into its own B-cell-targeting mAb therapy, Uplizna (inebilizumab).
The MINT trial, as it is known, is an ongoing, global Phase III study with an open-label period to assess the safety and efficacy of inebilizumab in treating MG.
Inebilizumab is also a CD19-targeting mAb, and this indicates Amgen’s intent to develop novel therapies that are all-encompassing in their treatment of gMG.
Should inebilizumab be successful in displaying efficacy over several types of gMG, then it would certainly give it a competitive advantage over existing mAb treatments such as rituximab, which are limited in their treatment of gMG.
Considering the understanding surrounding the disease pathophysiology of gMG, a future filled with novel mAbs therapies that target underlying disease mechanisms is not difficult to envision.
These would replace treatments that are only able to suppress the disease as it manifests.
Rituximab has displayed proficiency as an antibody therapy for the treatment of certain types of gMG.
However, novel B-cell-targeting mAbs will need to be developed to be of therapeutic benefit for all gMG patient groups.
The emergence of inebilizumab is a welcome development in the evolving treatment landscape of gMG, and should the MINT trial be successful, it would pave the way for a treatment with a more expansive label for gMG.
Further research is warranted to better understand the role that both rituximab and inebilizumab will play in the future treatment landscape for gMG.
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