Building the Myasthenia Gravis Armamentarium

Yuebing Li, MD, PhD

Myasthenia Gravis (MG) is a chronic autoimmune neuromuscular disease that affects at least 60,000 people in the United States. This is likely an underestimated prevalence based on recent data, and MG can afflict people of any age, gender or race. The first description of (MG), attributed to Thomas Willis, dates back to 1672, and the first treatment physostigmine was identified in 1934 by the Scottish doctor Mary Walker. However, it was not until 1955, that the U.S. Food and Drug Administration (FDA) approved pyridostigmine (Mestinon) as the first treatment for MG.

During the next 60 years, a long drought in MG-specific drug development ensued, but critical advancement was made in two important areas. One was the breakthrough in recognizing the immunological nature of pathogenesis (involvement of lymphocytes, antibodies, complements, and cytokines etc) in MG. The other was the use of many non-specific immunotherapies such as prednisone, azathioprine, mycophenylate mofetil, cyclosporine, tacrolimus, intravenous immunoglobulin, and plasmapheresis that truly improved the outcome in the majority of MG patients.

Despite the use of these treatments, a small proportion of patients remain treatment-refractory. Non-specific immune targeting by these agents often results in long-term adverse effects such as opportunistic infections, malignancies and systemic organ dysfunction. Finally, many of the corticosteroid-sparing agents have a delayed onset of action that often only become evident after up to 1-2 years of usage, leaving patients on high-dose corticosteroids for long durations.

In the last few years, we have entered an exciting golden age in the history of therapeutic invention for MG. Since 2017, new classes of revolutionary immune target-specific therapies have demonstrated clear efficacy in pivotal clinical trials. Eculizumab, a complement inhibitor, was the first such therapy approved by the FDA in 2017. This paved the way for various agents with distinct immune mechanisms and therapeutic targets. To date, the FDA has approved five different agents or formulations, and it is expected that more are coming in the next few years. Suddenly, neuromuscular providers have a much larger MG treatment repertoire from which to choose.

Different from traditional therapies, these newer medications target specific steps in the immunopathogenic cascade. Eculizumab and ravulizumab, both intravenously (IV) administered, block the terminal complement pathway, which involves the binding of specific antibodies and downstream destruction of the neuromuscular junction. The IV and subcutaneously (SQ) administered forms of efgartigimod, and SQ administered rozanolixizumab reduce the recycling of immunoglobulin G (being neonatal Fc receptor or “FcRn” antagonists), including the autoantibodies that cause MG. Their effect resembles that of plasma exchange, thus can perhaps be regarded as “medical plasmapheresis”.

Many other prospective agents are being investigated and are in the pipeline at an astonishingly rapid pace. These include other complement inhibitors, other FcRN antagonists, B-cell and plasma cell targeting therapies, agents acting on chemokine and cytokine pathways, chimeric antigen receptor (CAR) T cell therapy and autologous hematopoietic stem cell treatment. While none of these are yet FDA-approved for MG, most of them have produced excitingly positive results in preclinical and clinical trial stages.

The newer-generation therapies have also brought with them some formidable challenges. Firstly, their exorbitantly high cost restricts usage to a limited subset of MG patients. They are maximally useful in patients with refractory MG, patients with a rapidly progressive course or patients with a severe disease status in whom the aim is to minimize the dose/duration of corticosteroid and allow time for other more slowly acting nonsteroidal agents to become effective. The high cost also hinders combined usage of these immune specific agents, a strategy that may be useful as more than one pertinent immunological mechanism often account for symptoms in a particular MG patient.

Secondly, most trials have included patients in a short study period such as 26 weeks. The emergence of medication tolerance (due to potential development of anti-drug antibodies) in the long-term needs to be better delineated. Risks of long-term toxicities have not been adequately quantified for some of these newer therapies. These may include opportunistic infections and potentially neoplasms which may emerge with extended use of therapies that alter immune system. Accumulation of real-world data over longer time periods will surely help clarify long-term efficacy and risks of these agents.

Thirdly, most of the new formulas are given via parenteral (IV or SQ) administration. As most MG patients are elderly, access and logistics for long-term medication administration, and associated complications can become obstacles for long-term usage. It is therefore crucial to develop formulations that are easier to use such as oral agents. Finally, many of the new agents (complement inhibitors and FcRn antagonists in particular) do not inhibit the de novo production of antibody, thus their usage is unlikely to lead to disease remission when used as monotherapy. Therefore, a combination with traditional non-specific immunotherapy may still be needed to confer this important advantage.

The clinical severity of MG can range from mild ocular symptoms to respiratory crisis. The traditional view used to be that only one-sixth of patients with the condition manifest only ocular weakness (ocular MG) whereas those with a more diffuse weakness, are referred to as generalized MG. Most often however, patients starting with primarily ocular symptoms develop a generalized phenotype within 2 years. All newer generation treatments have focused on patients with generalized MG in terms of clinical trial populations, and all FDA-approved new therapies have stipulated indication only for patients with generalized MG. However, with the advances in diagnostic methods and improved awareness, many patients are diagnosed earlier than in the past. More recent data suggest that ocular MG may account for up to half of the total MG cases. It is a pivotal time to begin studying the efficacy of the novel therapies in patients with the ocular form of the disease, given that such an early intervention will likely reduce disease burden by curbing secondary generalization.

In summary, the immediate future is promising for MG patients and MG patient care specialists. Recent innovations have made it the most treatable neuromuscular disorder, and with more therapies on the horizon the outlook is bright for the many people living with this condition.