Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.
Currently, more than 50 trials for myasthenia gravis (MG) are active or recruiting. The interventions being evaluated range from surgical procedures to investigational drug therapies.
Several studies are examining the potential effectiveness of monoclonal antibodies as a treatment for MG; these include inebilizumab,1 tocilizumab,2 rozanolixizumab,3 nipocalimab,4 pozelimab, and satralizumab.5 Inhibition of the complement system, interleukin receptors, and the neonatal Fc receptor (FcRn) with various investigational agents is another popular subject of research in the clinical trials arena for MG, as is Janus kinase (JAK) and Bruton tyrosine kinase inhibition.
Inebilizumab is a CD-19-directed cytolytic antibody used to treat patients with neuromyelitis optica spectrum disorder (NOSD).6 Its therapeutic potential is currently being studied in adult patients who have MG with acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) antibodies. The primary outcome of the study is the change from baseline in the Myasthenia Gravis Activities of Daily Living (MG-ADL) Profile score over a 26- or 52-week period in patients with anti-AChR or anti-MuSK antibodies, respectively.1
Tocilizumab and satralizumab are anti-interleukin 6 (IL-6) receptor monoclonal antibodies used to treat selected autoimmune disorders, such as rheumatoid arthritis (tocilizumab) and NOSD (satralizumab).7,8 A randomized, double-blind, placebo-controlled study is underway to investigate the use of tocilizumab in adult patients with MG and anti-AChR antibodies over a 16-week period by measuring change in the Quantitative Myasthenia Gravis (QMG) score.2 The efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab are being evaluated in a randomized, double-blind, placebo-controlled phase 3 trial in patients with generalized MG.5
Rozanolixizumab and nipocalimab are monoclonal antibodies that specifically target FcRn, preventing immunoglobulin G (IgG) recycling by inhibiting the interaction of FcRn with IgG.4,9 The interaction between pathologic IgG and FcRn prevents lysosomal degradation of the abnormal antibody and prolongs its existence in the bloodstream. Inhibiting the interaction results in the elimination of unbound IgG via the natural lysosomal degradation pathway.9 A phase 2 clinical trial has determined that rozanolixizumab is well tolerated over a 29-day period.9 A phase 3 study is being conducted to evaluate the safety, tolerability, and efficacy of additional 6-week cycles of rozanolixizumab treatment in patients with generalized MG.3 Nipocalimab is being investigated in a randomized, double-blind, placebo-controlled phase 3 study to evaluate the average change from baseline in the MG-ADL Profile score over a 24-week period.4
Pozelimab is a fully human monoclonal IgG4 antibody directed against the complement protein C5.10 A clinical trial is being developed to study its use in generalized MG in conjunction with cemdisiran, an N-acetylgalactosamine-conjugated RNA interference (RNAi) therapeutic. The study, which has not yet begun recruiting, is planned to commence in September 2022.11,12
The safety of a novel oral inhibitor of complement factor D, ALXN2050, is being evaluated in a randomized, double-blind, placebo-controlled phase 2 study that is currently in the recruiting phase.13 Factor D is a serine protease involved in activation of the alternative complement pathway.14
Tofacitinib is a JAK inhibitor used to treat rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis.15 It is currently being investigated as a potential therapeutic agent for patients with refractory MG in an early, prospective phase 1 study. The trial will measure any change from baseline in the QMG score over a 6-month period.16
Tolebrutinib is an oral Bruton tyrosine kinase inhibitor that is showing promise for the treatment of relapsing and remitting multiple sclerosis. A randomized, double-blind, placebo-controlled phase 3 trial is evaluating the potential effectiveness of this agent as a treatment option for patients with moderate to severe generalized MG. Change from baseline in MG-ADL Profile total score over a 26-week period is the primary outcome measure of this study. 17
1. Clinical Trials.gov. A Randomized, Double-Blind, Multicenter, Placebo-Controlled Phase 3 Study With Open-Label Period to Evaluate the Efficacy and Safety of Inebilizumab in Adults With Myasthenia Gravis. NCT04524273. https://clinicaltrials.gov/ct2/show/NCT04524273 Accessed February 23, 2022.
2. ClinicalTrials.gov. A Multi-center, Randomized, Double-blind, Placebo-controlled Clinical Trial of the Efficacy and Safety of Tocilizumab in the Treatment of Generalized Myasthenia Gravis. NCT05067348. https://clinicaltrials.gov/ct2/show/NCT05067348 Accessed February 23, 2022.
3. ClinicalTrials.gov. An Open-Label Extension Study to Evaluate Rozanolixizumab in Study Participants With Generalized Myasthenia Gravis. https://clinicaltrials.gov/ct2/show/NCT04650854 Accessed February 23, 2022.
4. ClinicalTrials.gov. Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Nipocalimab Administered to Adults With Generalized Myasthenia Gravis. https://clinicaltrials.gov/ct2/show/NCT04951622 Accessed February 23, 2022.
5. ClinicalTrials.gov. A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study To Evaluate Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics Of Satralizumab In Patients With Generalized Myasthenia Gravis. https://clinicaltrials.gov/ct2/show/NCT04963270 Accessed February 23, 2022.
6. UPLIZNA-inebilizumab injection. DailyMed. Accessed February 23, 2022.
7. ACTEMRA® (tocilizumab). Highlights of prescribing information. Genentech. Revised June 2019. Accessed February 23, 2022.
8. ENSPRYNGTM (satralizumab-mwge) injection, for subcutaneous use. Highlights of prescribing information. Genentech. Revised August 2020. Accessed February 23, 2022.
9. Bril V, Benatar M, Andersen H, et al. 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
10. Jang JH, Weyne J, Chaudhari U, et al. Pozelimab, a human monoclonal antibody against complement factor c5, provided inhibition of intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria [ASH abstract 1128]. Blood. 2021;138(Suppl 1):1128.
11. Badri P, Jiang X, Borodovsky A, et al. Pharmacokinetic and pharmacodynamic properties of cemdisiran, an rnai therapeutic targeting complement component 5, in healthy subjects and patients with paroxysmal nocturnal hemoglobinuria. Clin Pharmacokinet. 2021;60(3):365-378. doi:10.1007/s40262-020-00940-9
12. ClinicalTrials.gov. Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Patients With Symptomatic Generalized Myasthenia Gravis. NCT05070858. https://clinicaltrials.gov/ct2/show/NCT05070858 Accessed February 23, 2022.
13. ClinicalTrials.gov. A Phase 2, Randomized, Double-Blind, Placebo-Controlled Multicenter Study to Evaluate the Efficacy and Safety of ALXN2050 in Adult Participants With Generalized Myasthenia Gravis. https://clinicaltrials.gov/ct2/show/NCT05218096 Accessed February 20, 2022.
14. Complement factor D. ScienceDirect. Accessed February 23, 2022.
15. Tofacitinib. MedlinePlus. Accessed February 23, 2022.
16. ClinicalTrials.gov. A Prospective, Single-center, Single-Arm, Single-Blind Pilot Study To Investigate The Efficacy Of Tofacitinib In Patients With Refractory Myasthenia Gravis. NCT04431895 https://clinicaltrials.gov/ct2/show/NCT04431895 Accessed February 23, 2022.
17. ClinicalTrials.gov. A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of Tolebrutinib (SAR442168) in Adults With Generalized Myasthenia Gravis (MG). NCT05132569. https://clinicaltrials.gov/ct2/show/NCT05132569 Accessed February 21, 2022.
Reviewed by Hasan Avcu, MD, on 2/26/2022.