Myasthenia Gravis Treatment Landscape Rapidly Evolving

Study authors are calling for frequent updating of clinical care treatment guidelines that consider costs vs benefits, risks, patient preferences, and comorbidities in light of the rapidly evolving treatment landscape for patients who have myasthenia gravis (MG), according to new research published in BMJ Medicine.¹

“Research has identified promising new treatments, including targeted treatments with new mechanisms of action that have the potential to improve efficacy and tolerability,” the investigators wrote. “Targeting different pathomechanisms of the disease simultaneously will likely lead to improved outcomes, particularly in the severe cases.”

Approximately 85% of MG cases spring from autoantibodies that target acetylcholine receptors (AChRs) on the postsynaptic membrane of the neuromuscular junction, and 10% from autoantibodies that target muscle specific tyrosine kinase (MuSK) and low density lipoprotein receptor–related protein 4.

The current treatment backbone for MG consists of pyridostigmine, corticosteroids, immunosuppressants (eg, azathioprine and mycophenolate mofetil), and intravenous immunoglobulins or plasmapheresis during an MG crisis or when symptoms become severe. These treatments also are a vital part of the 2020 international consensus guidance for MG management and the Association of British Neurologists’ MG guidelines^2,3; both recommend early thymectomy, although the ages slightly differ: 18 to 50 years with the international consensus guidance and younger than 45 years with the Association of British Neurologists.

Phases of Vaccine Clinical Trials | Image Credit: Olivier Le Moa

The study investigators focused on 5 treatment classes encompassing 12 treatments.

B-cell depletion targets CD20, a protein expressed on B cells. Intravenous (IV) rituximab, a chimeric monoclonal antibody, was investigated in the phase 2 BeatMG trial,⁴ with treatment recommendations being early among patients with muscle-specific tyrosine kinase–positive MG (MuSK+MG) and in the third line for AChR-positive generalized MG (AChR+gMG). The treatment recommendation for IV inebilizumab, a humanized monoclonal antibody, has yet to be determined, as its randomized controlled trial (RCT) in patients with MuSK+MG or AChR+gMG is ongoing.

Complement inhibition blocks cleavage of C5 into C5a and b, thereby preventing a membrane attack complex. IV eculizumab and ravulizumab, humanized monoclonal antibodies, were investigated for use in refractory AChR+gMG and AChR+gMG, respectively, in the phase 3 REGAIN⁵ and CHAMPION⁶ trials. Eculizumab was approved in 2017⁷ and ravulizumabin 2022.⁸ There is not yet an indication for subcutaneous (SC) zilucoplan, a 15 amino acid peptide, which was studied in the phase 3 RAISE trial for AChR+gMG.⁹

Neonatal Fc receptor inhibition helps to reduce immunoglobulin G (IgG) recycling and IgG antibodies by binding to and blocking the Fc receptor. IV efgartigimod alfa, an Fc fragment of human IgG1, was investigated for use in AChR+gMG in the ADAPT trial,¹⁰ with FDA approval in 2021.¹¹ SC rozanolixizumab, humanized IgG4, was studied for use in AChR+gMG and MuSK+MG in the completed phase 3 MycarinG study¹²; the medication has no approved indications but the study’s primary and key secondary end points were met. SC batoclimab, humanized IgG1, and IV nipocalimab, humanized IgG1, are currently being investigated in phase 3 trials of gMG with no treatment recommendations as of yet.

IL-6 inhibition helps to decrease proinflammatory T- and B-cell differentiation through blocking the IL-6 receptor. In this class, SC satralizumab, humanized IgG2, has yet to receive any indications. It is currently under investigation in a phase 3 RCT among patients who have AChR+gMG.

Chimeric antigen receptor (CAR) T-cell treatment modifies T cells and their regulation of B-cell maturation. SC Descartes-08, the first RNA CAR T for autoimmune diseases, is currently in the beginning stages of a phase 2 RCT among patients who have gMG.¹³

The study investigators note that the task to choose optimal treatment for a patient living with MG “might seem daunting,” considering the drugs that are approved and those on the horizon.

“Although drawing comparisons in efficacy across different clinical trials is tempting, especially when the same primary and secondary end points are used, caution is recommended,” they emphasized. “The guidelines that direct the clinical care of our patients with MG will need to be updated frequently to reflect the rapidly changing tools available to treat these patients.”

References

1. DeHart-McCoyle M, Patel S, Du X. New and emerging treatments for myasthenia gravis. BMJ Med. 2023;2(1):e000241. doi:10.1136/bmjmed-2022-000241

2. Sussman J, Farrugia ME, Maddison P, Hill M, Leite MI, Hilton-Jones. The Association of British Neurologists' myasthenia gravis guidelines. Ann N Y Acad Sci. 2018;1412(1):166-169. doi:10.1111/nyas.13503

3. Narayanaswami P, Sanders DB, Wolfe G, et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2021;96(3):114-122. doi:10.1212/WNL.0000000000011124

4. BeatMG: Phase II Trial of Rituximab In Myasthenia Gravis. NCT02110706. Updated March 6, 2020. Accessed September 19, 2023. https://clinicaltrials.gov/study/NCT02110706

5. Safety and Efficacy of Eculizumab in Refractory Generalized Myasthenia Gravis (REGAIN Study). NCT01997229. Updated July 16, 2019. Accessed September 19, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT01997229

6. Safety and Efficacy Study of Ravulizumab in Adults With Generalized Myasthenia Gravis. NCT03920293. Updated August 29, 2023. Accessed September 19, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03920293

7. FDA approves Soliris (eculizumab) for the treatment of patients with generalized myasthenia gravis (gMG). News release. Alexion/Myasthenia Gravis Foundation of America. October 23, 2017. Accessed September 19, 2023. https://myasthenia.org/Portals/0/Press%20Release%20Soliris%20FDA%20Approval.pdf

8. Conquer: emerging therapies for MG. Conquer Myasthenia Gravis. October 2022. Accessed September 19, 2023. https://www.myastheniagravis.org/wp-content/uploads/2022/09/September-2022-newsletter-Conquer-MG-final-proof.pdf

9. Safety, Tolerability, and Efficacy of Zilucoplan in Subjects With Generalized Myasthenia Gravis (RAISE). NCT04115293. Updated May 3, 2023. Accessed September 19, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04115293

10. An Efficacy and Safety Study of ARGX-113 in Patients With Myasthenia Gravis Who Have Generalized Muscle Weakness (ADAPT). NCT03669588. Updated February 8, 2022. Accessed September 19, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03669588

11. Heo YA. Efgartigimod: first approval. Drugs. 2022;82(3):341-348. doi:10.1007/s40265-022-01678-3

12. A Study to Test Efficacy and Safety of Rozanolixizumab in Adult Patients With Generalized Myasthenia Gravis. NCT03971422. Updated September 5, 2023. Accessed September 19, 2023. https://clinicaltrials.gov/study/NCT03971422

13. Pipeline. Cartesian Therapeutics. Accessed September 19, 2023. https://www.cartesiantherapeutics.com/clinical-trials/