Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
- Experimental Therapies
- Experimental Therapies
There are different therapeutic options available for treating myasthenia gravis (MG). The goal in MG treatment is focused on reducing the manifestations of the disease and achieving remission.1 The need for increasing specificity and addressing refractory cases has boosted the development of new therapeutic strategies for MG management. Immunotherapies, including monoclonal antibodies developed against specific B cell molecules or the fragment crystallizable neonatal receptor (FcRn), and inhibitors of the complement system are a few of the new therapies being investigated.2
B Cell-Directed Immunotherapies
Monoclonal Antibodies Targeting CD20
Rituximab, developed by Genentech, is a chimeric murine-human monoclonal antibody against CD20 that induces the depletion of B cells. CD20 is a protein with an important role in the growth and differentiation of B cells. Rituximab can deplete B cells that express CD20 protein in patients with MG; however, it does not interfere with the level of pathogenic autoantibodies produced.3 A phase 3 clinical trial, Rinomax (NCT02950155), is currently ongoing for the evaluation of the safety and efficacy of rituximab in patients with MG.4
Monoclonal Antibodies Targeting CD40
CFZ533, also known as iscalimab, has been used in thyroid disease and evaluated as a potential add-on therapeutic for patients with generalized MG.5 Developed by Novartis, CFZ533 is a fully human, Fc-silenced, immunoglobulin G (IgG) 1 anti-CD40 monoclonal antibody that interferes with the CD40 signaling pathway and the activation of B cells, as well as other CD40-positive cells. The interaction of CD40 with the ligand CD154 plays an important role in the production of antibodies.3 A good safety profile was reported for CFZ533 after a phase 2 clinical trial (NCT02565576).2,6
Monoclonal Antibodies Targeting FcRn
Batoclimab, also known as IMVT-1401, is a fully human monoclonal antibody being developed by Immunovant that targets the FcRn. This investigational product candidate promotes the degradation of IgG by binding to the FcRn and preventing the binding of natural IgG. The increased IgG degradation helps reduce the effects of the autoantibodies produced.7
A phase 1 clinical trial supported the safety and tolerability of batoclimab (NCT03971916) and reported an induced reduction in IgG levels.8 A phase 2 trial, Ascend MG (NCT03863080), further evaluated the safety, pharmacodynamics, and efficacy of batoclimab in adult participants with MG.9 The results of this randomized, placebo-controlled, double-blind trial have been recently published, showing clinical improvements in both MG activities of daily living (MG-ADL) and MG composite scale scores in patients treated with batoclimab.10 A phase 3 trial is expected in the first half of 2022.11
Other monoclonal antibodies targeting the FcRn include rozanolixizumab (also known as UCB7665), developed by UCB, and nipocalimab (also known as M281), from Johnson & Johnson. Rozanolixizumab was shown to decrease the levels of anti-acetylcholine receptor antibodies by at least 68% from baseline in patients with MG in a phase 2 clinical trial.12 Two phase 3 trials evaluating the efficacy, safety, and long-term safety of rozanolixizumab have been completed (NCT03971422 and NCT04124965),13,14 and a third phase 3 trial (NCT04650854) to assess the safety, tolerability, and efficacy of additional 6-week treatment cycles with rozanolixizumab in patients with generalized MG is ongoing.15 Nipocalimab is a human deglycosylated IgG1 anti-FcRn monoclonal antibody that targets FcRn.2 A phase 2 trial (NCT03772587) demonstrated the safety and tolerability of the drug.16 A phase 3 trial (NCT04951622) led by Janssen evaluating the safety of nipocalimab in adults with generalized MG is currently ongoing.17
The activation of the complement system can lead to the damage of specific structures such as the neuromuscular endplate in patients with MG.5 Complement inhibitors, such as the synthetic macrocyclic peptide zilucoplan, can block C5 and C6 cleavage, reducing complement activation.2,5 Additionally, this drug also prevents binding between C5b and C6. Zilucoplan may represent a potential therapeutic alternative for nonresponders to eculizumab due to its different binding site.5
A phase 2 multicenter, randomized, double-blind clinical trial evaluated the safety and efficacy of zilucoplan in 44 patients with MG (NCT03315130), showing an improvement in the quantitative MG and MG-ADL scores.18,19 A phase 3 trial (RAISE, NCT04115293) is currently ongoing to further evaluate the drug’s efficacy in patients with moderate to severe generalized MG, and it includes nonrefractory patients.5,20,21
The use of subcutaneously administered IgGs may provide advantages over intravenous IgGs. Subcutaneous immunoglobulins (SCIG) do not require intravascular access for administration and do not promote a vascular volume load.21 The use of SCIG as a maintenance therapy in patients with MG was studied in a retrospective case series involving 9 patients, and improvements in MG-ADL and quality of life were reported.22 A multicenter and open-label trial was also performed in 22 seropositive MG patients to evaluate the efficacy, safety, and tolerability of this therapy. The results of the study showed clinical improvements in these patients with a high patient satisfaction and good safety profile.23 However, further studies are needed to evaluate the use of SCIG in the management of acute MG.
1. Farrugia ME, Goodfellow JA. A practical approach to managing patients with myasthenia gravis–opinions and a review of the literature. Front Neurol. 2020;11:604. doi:10.3389/fneur.2020.00604
2. Schneider-Gold C, Gilhus NE. Advances and challenges in the treatment of myasthenia gravis. Ther Adv Neurol Disord. 2021;14:17562864211065406. doi:10.1177/17562864211065406
3. Huda R. New approaches to targeting B cells for myasthenia gravis therapy. Front Immunol. 2020;11:240. doi:10.3389/fimmu.2020.00240
4. A study evaluating the safety and efficacy of rituximab in patients with myasthenia gravis (Rinomax). ClinicalTrials.gov. October 31, 2016. Updated March 13, 2020. Accessed February 23, 2022.
5. Lascano AM, Lalive PH. Update in immunosuppressive therapy of myasthenia gravis. Autoimmun Rev. 2021;20(1):102712. doi:10.1016/j.autrev.2020.102712
6. Safety, tolerability, pharmacokinetics and efficacy of CFZ533 in moderate to severe myasthenia gravis. ClinicalTrials.gov. October 1, 2015. Updated January 5, 2021. Accessed February 23, 2022.
7. IMVT-1401 (“batoclimab”). Immunovant, Inc. Accessed February 23, 2022.
8. A phase I study evaluating the safety, tolerability, PK and PD in healthy Chinese volunteers. ClinicalTrials.gov. June 3, 2019. Updated March 10, 2021. Accessed February 23, 2022.
9. A study of RVT-1401 in myasthenia gravis (MG) patients. ClinicalTrials.gov. March 5, 2019. Updated October 8, 2021. Accessed February 23, 2022.
10. Benatar M, Breiner A, Bril V, Nowak R, Dunn I, Jacobs A. Topline results of a phase 2 study of subcutaneous IMVT-1401 in patients with generalized myasthenia gravis (1417). Neurology. 2021;96(S15):1417.
11. Immunovant provides regulatory update regarding initiation of phase 3 trial for batoclimab in myasthenia gravis in the first half of 2022. News release. Immunovant; December 30, 2021.
12. Bril V, Benatar M, Andersen H, et al; MG0002 Investigators. Efficacy and safety of rozanolixizumab in moderate to severe generalized myasthenia gravis: a phase 2 randomized control trial. Neurology. 2021;96(6):e853-e865. doi:10.1212/WNL.0000000000011108
13. A study to test efficacy and safety of rozanolixizumab in adult patients with generalized myasthenia gravis. ClinicalTrials.gov. June 3, 2019. Updated November 29, 2021. Accessed February 23, 2022.
14. A study to investigate the long-term safety, tolerability, and efficacy of rozanolixizumab in adult patients with generalized myasthenia gravis. ClinicalTrials.gov. October 14, 2019. Updated September 28, 2021. Accessed February 23, 2022.
15. A study to evaluate rozanolixizumab in study participants with generalized myasthenia gravis. ClinicalTrials.gov. December 3, 2020. Updated February 11, 2022. Accessed February 23, 2022.
16. A study to evaluate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of M281 administered to adults with generalized myasthenia gravis. ClinicalTrials.gov. December 11, 2018. Updated October 27, 2021. Accessed February 23, 2022.
17. A study of nipocalimab administered to adults with generalized myasthenia gravis. ClinicalTrials.gov. July 7, 2021. Updated February 17, 2022. Accessed February 23, 2022.
18. Safety and efficacy study of RA101495 in subjects with generalized myasthenia gravis. ClinicalTrials.gov. October 19, 2017. Updated April 1, 2021. Accessed February 23, 2022.
19. Howard JF Jr, Nowak RJ, Wolfe GI, et al. Clinical effects of the self-administered subcutaneous complement inhibitor zilucoplan in patients with moderate to severe generalized myasthenia gravis: results of a phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial. JAMA Neurol. 2020;77(5):582-592. doi:10.1001/jamaneurol.2019.5125
20. Safety, tolerability, and efficacy of zilucoplan in subjects with generalized myasthenia gravis (RAISE). ClinicalTrials.gov. October 4, 2019. Updated January 28, 2022. Accessed February 23, 2022.
21. Menon D, Barnett C, Bril V. Novel treatments in myasthenia gravis. Front Neurol. 2020;11:538. doi:10.3389/fneur.2020.00538
22. Bourque PR, Pringle CE, Cameron W, Cowan J, Chardon JW. Subcutaneous immunoglobulin therapy in the chronic management of myasthenia gravis: a retrospective cohort study. PLoS One. 2016;11(8):e0159993. doi:10.1371/journal.pone.0159993
23. Beecher G, Anderson D, Siddiqi ZA. Subcutaneous immunoglobulin in myasthenia gravis exacerbation: a prospective, open-label trial. Neurology. 2017;89(11):1135-1141. doi:10.1212/WNL.0000000000004365
Reviewed by Hasan Avcu, MD, on 2/26/2022.