Authors: Sarah Ndegwa, Monika Mierzwinski-Urban
Horizon Scan reports provide brief summaries of information regarding new and emerging health technologies. These technologies are identified through the CADTH Horizon Scanning Service as topics of potential interest to health care decision-makers in Canada. This Horizon Scan summarizes the available information regarding emerging targeted therapies for the treatment of generalized myasthenia gravis (MG).
MG is a rare and chronic autoimmune disease in which autoantibodies attack specific proteins in the neuromuscular junction, resulting in muscle weakness. Many patients develop generalized MG resulting in severe fatigable muscle weakness with difficulties in facial expression, speech, swallowing, and mobility.
Current treatments for MG include anticholinesterase inhibitors, systemic corticosteroids, and nonsteroidal immunosuppressive drugs. IV immunoglobulins or therapeutic plasma exchange are the current treatment options for patients with severe or acutely worsening generalized MG. Thymectomy is also considered a treatment option for patients with generalized MG who fail to respond to immunotherapy or have intolerable side effects.
In this scan, we have reviewed 6 new treatment strategies that target specific areas of the immune system involved in the pathogenesis of MG: efgartigimod, rozanolixizumab, zilucoplan, ravulizumab, batoclimab, and nipocalimab. Phase II and III clinical trials have shown that these drugs may potentially benefit patients with generalized MG based on improvements in measures of disease severity and functional disability.
The information presented is limited in that most of the available evidence comes from phase II trials that were designed to primarily investigate safety and tolerability based on small sample sizes, short trial duration, and narrow inclusion criteria. Therefore, findings do not reflect current standard of practice for maintenance therapy for generalized MG in the real-world setting.
Considerations for future use include identifying the population that will most likely benefit from therapy and evaluating these drugs for rare and serious adverse events. Factors such as ease of administration, dosing schedule, and cost are all important factors that will help determine uptake and place in therapy for these emerging targeted therapies.
These bulletins are not systematic reviews and do not involve critical appraisal or include a detailed summary of study findings. Rather, they present an overview of the technology and available evidence. They are not intended to provide recommendations for or against a particular technology.
A limited literature search was conducted by an information specialist on key resources including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the international HTA database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were efgartigimod, rozanolixizumab, zilucoplan, batoclimab, and nipocalimab. No filters were applied to limit the retrieval by study type. The search was also limited to English language documents but not limited by publication year.
Regular alerts updated the search until project completion; only citations retrieved before January 10, 2022 were incorporated into the analysis.
One author screened the literature search results and reviewed the full text of all potentially relevant studies. Studies were considered for inclusion if the intervention was an emerging drug under investigation for the treatment of MG with results (published or preliminary) from phase II or III clinical trials. Conference abstracts and grey literature were included when they provided additional information to that available in the published studies.
A draft version of this bulletin was reviewed by 1 clinical expert. The manufacturers were also given the opportunity to comment on an earlier draft.
Myasthenia gravis (MG) is a rare and chronic autoimmune disease in which immunoglobulin G (IgG) autoantibodies attack specific proteins in the neuromuscular junction, disrupting signal transmission.1,2 In approximately 85% of MG patients, these antibodies are targeted against acetylcholine receptors (AChR).3 Some patients have antibodies targeted against muscle-specific kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (LRP4), although as many as 15% of patients with MG are seronegative with no detectable autoantibodies in the blood.3,4 The thymus is thought to be involved in the production of anti-AChR antibodies.5 The age of onset follows a bimodal distribution, peaking at 30 and 50 years of age.6 Estimates of the incidence of MG range from 0.3 to 2.8 per 100,000 worldwide, and the median global estimated prevalence is 10 per 100,000.7 In Canada, the incidence has been stable over the last few decades and is estimated at 23 per 1 million person-years, with a prevalence of 263 per 1 million population.8,9
Symptoms of MG include muscle weakness that often begins in the eyes and eyelids (ocular MG) affecting vision.2 Many patients eventually develop generalized MG characterized by weakness in other areas of the body, including the head, neck, trunk, limbs, and chest. Patients with generalized MG experience fatigable muscle weakness with difficulties in facial expression, speech, swallowing, and mobility. Severity of the disease can vary for each individual patient due to periods of relapse and periods of remission. In extreme cases, MG can affect the muscles involved in breathing and could be life-threatening (known as myasthenic crisis). Currently, the frequency of mortality from the disease is estimated to be between 5% and 9%.10
Current treatments options for MG, including corticosteroids and nonsteroidal immunosuppressive therapies, broadly suppress the immune system and do not selectively target the autoantibodies that play a role in generalized MG pathophysiology.7 Long-term use of these conventional immunotherapies may be associated with the risk of intolerance and systemic toxicity.11 Moreover, at least 15% of patients do not respond to these treatments.12,13
In recent years, promising new treatment strategies that target specific areas of the immune system involved in the pathogenesis of MG have been explored and several clinical trials have recently been completed or are in progress.14 These new drugs aim to provide improved efficacy, less toxicity, a quicker onset of action, and better maintenance of disease remission compared to conventional immunotherapies for MG. Eculizumab (Soliris, Alexion Pharma Canada Corp.), the first of these new targeted therapies, was approved by Health Canada in 2018 for adult patients with refractory generalized MG.15 A CADTH Canadian Drug Expert Committee (CDEC) recommendation is available for the use of Soliris in this patient population.16 Rituximab, a monoclonal antibody directed against the CD-20 receptor on B-lymphocytes, is increasingly used in treating generalized MG. It has not been approved for this indication by Health Canada and as such is currently used off-label.
There are several emerging immunotherapies for the treatment of generalized MG (Table 1). These drugs have been developed to mitigate the effects of the autoantibodies involved in the pathogenesis of MG, resulting in an improvement in signal transmission at the neuromuscular junction.
Zilucoplan and ravulizumab work by blocking the C5 protein in the terminal complement cascade (a pathway in the immune system).17 Blocking the C5 protein reduces the over-activation of the complement cascade which occurs when pathogenic autoantibodies attack structures in the neuromuscular junction. Efgartigimod, rozanolixizumab, batoclimab, and nipocalimab all target the IgG binding site on the endogenous neonatal Fc receptor (FcRn).14 The FcRn plays a central role in rescuing IgG antibodies from degradation.18 IgG that is not bound to FcRn cannot be recycled and thus undergoes lysosomal degradation. These FcRn antagonists are expected to reduce serum levels of total IgG and pathogenic IgG autoantibodies involved in the pathogenesis of MG.
Table 1: Characteristics of Emerging Immunotherapies for the Treatment of Generalized MG
Generic name (development/brand name) | Manufacturer | Route of administrationa |
|---|---|---|
C5 complement inhibitors | ||
Zilucoplan19 (RA101495) | UCB SA | Subcutaneous injection daily (self-administered at home) |
Ravulizumab20 (ALXN-1210/Ultomiris) | Alexion AstraZeneca Rare Disease | IV infusion every 8 weeks |
FcRn inhibitors | ||
Efgartigimod21 (ARGX-113/Vyvgart) | Argenx | IV infusion once a week |
Rozanolixizumab22 (UCB7665) | UCB SA | Subcutaneous infusion once a week |
Batoclimabb23,24 (HBM9161/IMVT-1401/RVT-1401) | Harbour BioMed Immunovant | Subcutaneous injection every one or two weeks |
Nipocalimab25 (M281) | Janssen Research and Development | IV infusion every two or four weeks |
aInvestigated in phase II or III clinical trials.
bBatoclimab is being developed by Harbour Biomed and Immunovant for commercialization in Greater China (Hong Kong, Macau, and Taiwan) and North America (US and Canada), respectively.26
Efgartigimod (Vyvgart, Argenx US Inc.) was approved by the US FDA on December 17, 2021 for use in adults with generalized myasthenia gravis who test positive for the anti-acetylcholine receptor (AChR) antibody.27 Zilucoplan has been granted orphan drug designation by the FDA for the treatment of MG.28 Ravulizumab is approved by the Health Canada for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH).29
Cost information is not currently available given that these drugs are all still in clinical development and have not been approved for use in Canada or the US.
These emerging targeted therapies are anticipated to be used for patients with severe refractory generalized MG as an adjunct to standard-of-care immunotherapies.
Treatment for MG is individualized and dependent on the rate of progression of symptoms, the presence of respiratory and bulbar involvement, the age of the patient, and the presence of anti-AchR or anti-MuSK antibodies.30,31 The main goal of treatment is to achieve long-term remission and improve functional ability and quality of life by reducing the severity of MG to mild or minimal symptoms. Treatment approaches include increasing the amount of acetylcholine available to bind with receptors and to decrease the binding of antibodies to AchR through immunosuppression.30
The current mainstays of MG treatment include anticholinesterase inhibitors (e.g., pyridostigmine), systemic corticosteroids (e.g., prednisone), and nonsteroidal immunosuppressive agents (e.g., azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus).30 It can take weeks to several months for these treatments to have a beneficial effect.32 Rapid immunomodulatory drugs (such as IV immunoglobulins or therapeutic plasma exchange) are the current treatment options for patients with severe or acutely worsening generalized MG. However, these therapies can be associated with high treatment burden (requiring IV preparations and long administration times), high cost and potential adverse effects.33 Based on the results of an international randomized controlled trial,34 guidelines were recently updated to recommend the consideration of thymectomy (surgical removal of the thymus gland) early in therapy to improve clinical outcomes in patients with generalized MG who are positive for anti-AchR antibodies and have no evidence of a thymoma (Thymoma, a tumour originating from cells in the thymus, is found in about 20% of patients, and is treated by thymectomy and sometimes radiotherapy).30 Thymectomy is also considered a treatment option for patients with generalized MG who fail to respond to immunotherapy or have intolerable side effects, regardless if they are positive for anti-AchR antibodies. The guidelines also recommend that rituximab and eculizumab be considered for patients with disease refractory to conventional treatment.30
This section summarizes the available evidence of efficacy and safety for efgartigimod, rozanolixizumab, zilucoplan, ravulizumab, batoclimab, and nipocalimab in the treatment of generalized MG. The Myasthenia Gravis Foundation of America (MGFA) clinical classification was used in the trials to define disease severity (Appendix 1, Table 3).35 Efficacy outcome measures included changes in the MG Activity of Daily Living (MG-ADL) scale and the Quantitative Myasthenia Gravis (QMG) scale (Appendix 1, Table 3).36 The MG-ADL scale is a patient-reported outcome measure that assesses day-to-day functional disability while the QMG scale is an objective measure of disease severity based on clinical evaluation.36
The characteristics of the published and ongoing trials investigating efgartigimod for generalized MG are depicted in Appendix 1, Table 4. One phase II trial37 and 1 phase III trial (ADAPT)38 evaluating the safety and efficacy of IV efgartigimod in adult patients with generalized MG have been published. The safety and efficacy of a subcutaneous (SC) formulation of efgartigimod is being studied in a phase III trial.39 The long-term safety of the IV and SC formulations of efgartigimod is being evaluated in 2 single-arm, open-label extension studies.40,41 A phase III open-label study42 is investigating the efficacy and safety of a continuous IV regimen of efgartigimod compared with a cyclic IV regimen. In addition, an ongoing phase II/III trial43 is assessing the safety and efficacy of IV efgartigimod in children and adolescents with generalized MG aged between 2 and 18 years.
In a double-blind phase II trial, 24 participants were randomized 1:1 to receive 4 weekly doses over a 3-week period of either 10 mg/kg IV efgartigimod or matched placebo in combination with stable standard-of-care MG treatment.37 This treatment period was followed by an observation period with no infusions up to day 78. The clinical efficacy analysis was performed on the full analysis set which consisted of all randomized patients with 1 or more evaluable efficacy end points (including changes in the MG-ADL and QMG scores). More efgartigimod-treated patients (75%) showed a 2-point or greater improvement in the change from baseline in MG-ADL score for a period of at least 6 consecutive weeks compared to placebo-treated patients (25%). The difference in proportions was 50.34% (95% confidence interval [CI], 15.93 to 84.74; P = 0.0391).
The safety analysis consisted of data of all randomized patients who received at least 1 full or partial infusion of efgartigimod or placebo.37 There were no deaths, serious adverse events (SAEs), severe treatment-emergent adverse events (TEAEs), or TEAEs that led to discontinuation during the study. One patient discontinued efgartigimod treatment because they received rescue therapy due to lack of efficacy. TEAEs occurred with equal frequency in each treatment group (83.3%; 10 of 12 for both groups). The majority of TEAEs were mild. A moderately severe headache was reported by 1 patient in the placebo group and a moderately severe episode of shingles on the arm preceded by infusion site pain was reported by 1 patient in the efgartigimod group who was also on prednisone and mycophenolate mofetil. The most frequently reported TEAE (any grade) in patients who received efgartigimod were headache (33.3%; 4 of 12 in efgartigimod group versus 25.0%; 3 of 12 in placebo group). Abnormal differential white blood cell counts were observed in 3 patients, 2 of which were on chronic cortisone and azathioprine and all cases were mild and asymptomatic.
ADAPT was a randomized, double-blind phase III trial evaluating the safety and efficacy of efgartigimod in 167 adult patients with generalized MG who were on a stable dose of at least 1 treatment for generalized MG.38 Although patients were enrolled regardless of AchR-antibody status, the primary efficacy analysis was conducted on 129 patients positive for anti-AchR antibodies. Patients were randomly assigned 1:1 to efgartigimod 10 mg/kg IV or matching placebo, administered as 4 infusions per cycle (one infusion per week), repeated as needed depending on clinical response but no sooner than 8 weeks after initiation of the previous cycle. Of interest, although patients were required to be on a stable dose of at least 1 treatment for generalized MG, approximately 30% had never been treated with nonsteroidal immunosuppressants.
Results showed that more anti- AchR-antibody positive patients were responders following treatment with efgartigimod (67.7%; 44 of 65) than placebo (29.7%; 19 of 64) during the first treatment cycle (odds ratio [OR] 4.95; 95% CI, 2.21 to 11.53; P < 0.001). Responders were defined as having at least a 2-point improvement sustained for 4 or more consecutive weeks on the MG-ADL score. Additionally, the improvement in MG-ADL score was seen in the majority (84.1%; 37 of 44) of responders within the first 2 weeks of treatment. A subgroup analysis for patients who were anti-AchR-antibody negative showed that patients randomized to efgartigimod were only slightly more likely to respond based on the MG-ADL score (68.4%; 13 of 19 versus 63.3%; 12 of 19).
The percentage of QMG responders (patients with ≥ 3-point improvement for at least 4 consecutive weeks with the first reduction in score occurring no later than 1 week after the last infusion) was greater in AChR-Ab seropositive patients treated with efgartigimod (63.1%; 41 of 65) than in AChR-Ab seropositive patients treated with placebo (14.1%; 9 of 64) during cycle 1 (OR 10.84; 95% CI, 4.18 to 31.20; P < 0.0001).
The safety analysis included all participants who received at least 1 full or partial dose of efgartigimod or placebo.38 No deaths were reported and most TEAEs were mild or moderate in severity. SAEs were reported in 4.8% (4 of 84) of patients randomized to efgartigimod and in 8.4% (7 of 83) of those randomized to placebo. SAEs reported in the efgartigimod treatment group included thrombocytosis, renal adenocarcinoma, MG worsening (each leading to discontinuation) and depression. SAEs reported in the placebo group, included 1 case each of myocardial ischemia, atrial fibrillation, and spinal ligament ossification, which all led to treatment discontinuation. The remaining SAEs reported in the placebo group were upper respiratory infection, spinal compression fracture, MG worsening, and MG crisis.
The percentage of TEAEs reported in the efgartigimod group was 77.4% (65 of 84) compared to 84.3% (70 of 83) in the placebo group. The most common TEAEs were headache, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, and urinary tract infection. Of these, infections were more common in the efgartigimod group compared to the placebo group (46.4%; 39 of 84 versus 37.3%; 31 of 83). However, the infections were mild-to-moderate except for 3 severe events, which were influenza and pharyngitis in efgartigimod-treated patients and upper respiratory tract infections in the placebo group. Three patients in each treatment group (4%) discontinued treatment during the study.
The characteristics of the published, completed, and ongoing trials investigating SC rozanolixizumab for generalized MG are depicted in Appendix 1, Table 5. One phase II trial evaluating the clinical efficacy of rozanolixizumab as a chronic-intermittent treatment for generalized MG has been published.44 A phase III randomized controlled trial (RCT) is further evaluating the efficacy and safety of rozanolixizumab in patients with generalized MG.45 Two phase III single-group, open-label extension studies are evaluating the long-term safety of additional treatment cycles with rozanolixizumab.46,47
The phase II double-blind trial consisted of 2 treatment periods followed by an observation period.44 In period 1 (days 1 to 29), 43 adults with generalized MG were randomized 1:1 to receive 3 once-weekly SC infusions of rozanolixizumab 7 mg/kg or matched placebo. A treatment-free period of 2 weeks occurred between the last dose of period 1 (day 15) and initiation of period 2 (day 29). In period 2 (days 29 to 43) participants were re-randomized to 3 once-weekly SC infusions of rozanolixizumab 7 mg/kg or 4 mg/kg. This was followed by an observation period from days 44 to 99. Improvements from baseline to day 29 in QMG score was obtained for rozanolixizumab compared with placebo (least squares [LS] mean −1.8 versus −1.2; difference −0.7; 95% upper confidence limit [UCL] 0.8; P = 0.221). Improvements from baseline to day 29 in MG-ADL was observed following treatment with rozanolixizumab compared with placebo (LS mean −1.8 versus −0.4; difference −1.4; 95% UCL −0.4). Day 29 responder rates (with at least a 3-point improvement from baseline) were higher in patients receiving rozanolixizumab 7 mg/kg versus placebo for QMG (38% versus 23%) and MG-ADL (48% versus 14%). Efficacy measures continued to improve for patients during period 2 but were greater in patients receiving the 7 mg/kg dose.
No deaths were reported during the trial.44 During period 1, SAEs were not reported in any patients receiving rozanolixizumab 7 mg/kg compared with 9% (2 of 22) of patients receiving placebo. By the end of the observation period (day 99), 5 of 43 (12%) reported 1 or more SAE. Headache was the most common TEAE which was reported in 38% (8 of 21) patients receiving rozanolixizumab 7 mg/kg and 9% (2 of 22) of patients receiving placebo. Overall, 4 rozanolixizumab-treated patients withdrew from the trial, 1 due to MG crisis (considered a SAE) and 3 due to headache (2 due to the pre-specified protocol withdrawal criteria of severe headache [1 of which was considered a SAE] and 1 moderately severe headache). Infusion site reactions occurred in 1 patient in each of the following groups: placebo (4.5%, period 1), placebo/rozanolixizumab 4 mg/kg (9.1%, period 2), rozanolixizumab 7 mg/kg/ rozanolixizumab 7 mg/kg (10%, period 2). The incidence of infections between rozanolixizumab and placebo groups were similar.
The characteristics of the published and ongoing trials investigating SC zilucoplan for generalized MG are depicted in Appendix 1, Table 6. A phase II trial evaluating the safety and efficacy of 2 different doses of zilucoplan in patients with generalized MG has been published.48 An ongoing phase III trial is further investigating the efficacy and safety of zilucoplan in patients with generalized MG who are on stable therapy.49 An open-label extension study is evaluating the long-term efficacy and safety of zilucoplan in patients with generalized MG.50
In a phase II double-blind trial, 44 patients were randomized 1:1:1 to receive once daily zilucoplan 0.3 mg/kg SC, zilucoplan 0.1 mg/kg SC, or matched placebo SC.48 Study drug or placebo were self-administered at home. Treatment with zilucoplan 0.3 mg/kg resulted in improvements compared with placebo in QMG score at 12 weeks (LS mean [SEM] difference –2.8 [1.7]; P = 0.05) and MG-ADL score (–2.3 [1.3]; P = 0.04). A total of 10 patients (71.4%) in the zilucoplan 0.3 mg/kg group achieved an improvement in QMG score (at least a 3-point decrease) when compared with the placebo group (53.3%; 8 of 15) (P = 0.27). The zilucoplan 0.1 mg/kg group showed a delayed and less pronounced response than the 0.3 mg/kg group versus placebo at week 12 for the MG-ADL score (SEM difference –2.2 [1.3]; P = 0.05).
No deaths or life-threatening events were reported.48 A total of 8 SAEs were reported, 5 (35.8%) with the higher dose of zilucoplan and 3 (20.0%) for the placebo group. The highest number of TEAEs occurred in the zilucoplan 0.1 mg/kg group (53.3%; 8/15) followed by the zilucoplan 0.3 mg/kg and placebo groups (21.4; 3/14 and 20.0%; 3/15, respectively). The most common TEAE was headache which occurred more frequently in the zilucoplan groups (26.7%; 4 of 15 for 0.1 mg/kg and 14.3%; 2.14 for 0.3 mg/kg) compared with the placebo group (6.7%; 1 of 15). Injection-site reactions occurred in 3 (21.4%) of 14, 4 (26.7%) of 15, and 2 (13.3%) of 15 patients who received zilucoplan 0.3 mg/kg, zilucoplan 0.1 mg/kg, and placebo, respectively. All injection-site reactions in zilucoplan-treated patients were mild. All patients were vaccinated against Neisseria meningitidis, and no meningococcal infections were reported. Two patients discontinued the study before week 12 (1 placebo-treated patient owing to worsening MG and 1 patient receiving 0.3mg/kg zilucoplan due to a prolonged hospital admission for an exacerbation of preexisting diverticulitis with paracolic abscess).
The characteristics of 1 ongoing phase III trial51 investigating IV ravulizumab for generalized MG with preliminary results is depicted in Appendix 1, Table 7. Currently, there are no published or other ongoing trials.
In a phase III double-blind trial, 175 patients were randomized 1:1 to receive ravulizumab 10 mg/mL IV or matched placebo for a total of 26 weeks.51 Patients received a loading dose on day 1, followed by maintenance doses every 8 weeks beginning on day 15. Results from a press release showed that the study met its primary end point, with a change in MG-ADL score from baseline through week 26 for patients receiving ravulizumab compared to those receiving placebo (ravulizumab −3.1 versus placebo −1.4; treatment difference −1.6; P < 0.001).52 A total of 30% of patients receiving ravulizumab experienced an improvement of at least 5 points in their QMG score compared to 11.3% of patients receiving placebo (P value not reported). The improvements in MG-ADL and QMG scores were observed by week 1 and were sustained through to week 26.
No deaths were reported in the preliminary results. Adverse events (AEs) were comparable between the ravulizumab and placebo groups. The most frequently observed SAEs were MG crisis (ravulizumab 1.2%) and MG worsening (placebo 3.4%). The most frequently observed AEs were headache (ravulizumab 18.6% versus placebo 25.8%), diarrhea (ravulizumab 15.1% versus placebo 12.4%) and nausea (ravulizumab 10.5% versus placebo 10.1%).
Patients who completed the randomized controlled period were eligible to continue into an ongoing open-label extension study evaluating the long-term safety of ravulizumab for up to 2 years. At the time of the preliminary analysis, 75 patients had completed 26 weeks of treatment in the extension study for a total of 52 weeks of treatment. Over 52 weeks, there were 4 deaths in the ravulizumab group (three due to COVID-19). No cases of meningococcal infection were observed during the 52-week period.
The characteristics of the completed and ongoing trials investigating SC batoclimab for generalized MG are depicted in Appendix 1, Table 8. One phase II trial in patients with generalized MG has been completed with preliminary results.53 An ongoing phase III is further evaluating the safety and efficacy of batoclimab in patients with generalized MG.
The phase II double-blind trial randomized 30 adult patients with generalized MG 1:1:1 to receive batoclimab 340 mg SC, batoclimab 680 mg SC or matching placebo once weekly for 6 weeks.53 The treatment period was followed by an open-label extension study evaluating batoclimab 340 mg SC every other week for a further 6 weeks. Results obtained from a press release and abstract show that the batoclimab treatment groups demonstrated MG-ADL score improvement on day 43, by −4.7 (standard error [SE] 0.6) for the 340 mg group and −4.4 (SE 1.0) for the 680 mg group, respectively, compared with −2.2 (SE 0.9) for the placebo group (P = 0.043).54,55 A greater proportion of batoclimab-treated patients showed improvements in 2 weeks after first dose in the MG-ADL scale (defined as a score drop of at least 2 points) (57% versus 33% for placebo) and in the QMG scale (defined as a decline in score of 3 or more points) (76% versus 11% for placebo).
In preliminary results from the phase II trial, batoclimab treatment had an incidence of AEs comparable to placebo, with most AEs characterized as mild. No deaths, SAEs and no discontinuation due to AEs were reported.54 Of note, clinical dosing in all clinical trials for batoclimab was voluntarily paused in February 2021 due to elevated low-density lipoprotein cholesterol levels (associated with an increased risk for heart disease) in an ongoing trial for thyroid eye disease.56 Following a review of data from multiple clinical trials, it was determined that the increase was dose-dependent, reversible, and tied to a decrease in albumin (a protein that helps regulate the transport of cholesterol). Clinical testing of batoclimab for generalized MG has since been resumed.
The characteristics of the completed and ongoing trials investigating IV nipocalimab for generalized MG are depicted in Appendix 1, Table 9. One phase II trial (Vivacity-MG) has been completed with preliminary results.57 An open-label extension study of the Vivacity-MG trial originally intended to assess the long-term safety and tolerability of nipocalimab in generalized MG was halted due to the COVID-19 pandemic and later terminated.58 An ongoing phase III double-blind, placebo-controlled RCT is investigating the efficacy and safety of nipocalimab in adult patients with generalized MG.59 This study will consist of a screening phase (up to 4 weeks), treatment phase (a 24-week double-blind placebo-controlled phase) followed by an open-label extension phase of up to 2 years and a follow-up safety visit (up to 8 weeks after last infusion of study intervention). The overall duration of study will be up to 4 years and 8 months.
Vivacity-MG was a phase II double-blind, placebo-controlled RCT that evaluated the safety, tolerability, and efficacy of nipocalimab in 68 adults with generalized MG who did not have a sufficient clinical response to ongoing standard-of-care therapy.57 Patients with anti-AChR or anti-MuSK antibodies were randomized to nipocalimab treatment groups at various doses or a placebo group. All patients received an IV infusion (either nipocalimab or placebo) every other week for a total of 5 infusions during the 8-week treatment period. Preliminary results obtained from a conference abstract show that treatment with nipocalimab resulted in greater mean improvement from baseline in MG-ADL scores across nipocalimab dosing arms compared with placebo at the end of the treatment period (day 57). A greater proportion of patients treated with nipocalimab showed improvement within 2 weeks of treatment in MG-ADL across all 4 dosing arms compared to placebo. A total of 51.9% of patients who received nipocalimab (all doses) were MG-ADL responders (defined as an MG-ADL improvement of 2 points or greater from baseline for at least 4 consecutive weeks during the first 8 weeks of treatment) versus 15.4% of those who received placebo (P = 0.017).
No deaths have been reported.57 One SAE was reported in the nipocalimab group (shoulder pain) and 2 SAEs were reported in the placebo group (one case of ischemic stroke and 1 case of MG worsening). There were no discontinuations due to TEAEs in the nipocalimab group. The frequency of infections was higher in the nipocalimab combined dose group compared with the placebo group (33.3% versus 21.4%, respectively), but there were no severe or serious infections. The frequency of headaches in the nipocalimab groups were comparable to placebo.
Most of the available evidence comes from phase II trials that were designed to primarily investigate safety and tolerability based on limited sample sizes, short trial duration, and narrow inclusion criteria. Therefore, findings do not reflect current standard of practice for maintenance therapy for generalized MG in the real-world setting.
Most of the patients in the published clinical trials were White, middle aged individuals with MGFA class II or III disease severity. The generalizability of findings to older patients, other ethnic groups, and those with more severe disease is limited.
Many trials did not evaluate safety and efficacy in certain subpopulations with MG including patients who were positive for anti-LRP4 or anti-MuSK antibodies, were seronegative for autoantibodies, were under the age of 18, were women who were pregnant or breastfeeding, or had comorbid conditions including other autoimmune disorders. Consequently, the utility of these drugs in these populations is not known.
None of the published trials required patients to be refractory to standard-of-care MG treatment or have long-standing disease duration. Furthermore, some of the trials required patients to be on a stable treatment or excluded patients who had recently received rescue therapy for severe or acutely worsening generalized MG.
Due to the short-term treatment period of most trials (up to 26 weeks), there is very limited long-term safety data for rare and serious adverse events (SAEs), given that these drugs are intended for a chronic disease. Long-term safety and efficacy will need to be confirmed in open-label extension trials.
Some of the evidence presented for efficacy and safety was obtained from limited preliminary or unpublished results. Findings will need to be confirmed from peer-reviewed published results.
Several other emerging therapies in phase II or III clinical development for generalized MG are awaiting published results (Appendix 1, Table 10). These include additional FcRn and C5 complement inhibitors, and therapies that target different areas of the immune pathway including B-cells (preventing the development of pathogenic autoantibodies that may be involved in the disease process of MG) and interleukin 6 (a cytokine that promotes the inflammatory response in autoimmune conditions).14 Of note, belimumab (Benlysta, GSK) and iscalimab (Novartis) were 2 other investigational B-cell inhibitors that failed to show benefit in phase II trials and are no longer in development for generalized MG.60,61
Efgartigimod, rozanolixizumab, zilucoplan, batoclimab, and nipocalimab are also being evaluated for the treatment of patients with several other autoimmune or immune-related conditions (Appendix 1, Table 11).
The following are all factors to consider for the place in therapy and future uptake of emerging targeted therapies for generalized MG into clinical practice.
There are many subgroups of interest for which there is no data or very limited data. This includes patients who are elderly, have severe or acutely worsening disease, are positive for anti-LRP4 or anti-MuSK antibodies, are seronegative, are people who identify as other than White, are under the age of 18, are pregnant or breastfeeding women, or have a comorbid condition including another autoimmune disorder. Furthermore, a few trials excluded patients who had undergone thymectomy within a year of trial initiation. This is problematic given that current guidelines recommend considering thymectomy early in therapy to improve clinical outcomes in patients with generalized MG who are positive for anti-AchR antibodies or in those who fail to respond to immunotherapy or have intolerable side effects, regardless if they are positive for anti-AchR antibodies.30 None of the published trials required patients to be refractory to standard-of-care MG treatment or have long-standing disease duration. Furthermore, some of the trials required patients to be on a stable treatment or excluded those who received rescue therapy for severe or acutely worsening MG. This does not reflect current standard of practice for maintenance therapy in the real-world setting.
There is very limited long-term safety data for rare and SAEs, given that it is anticipated that these drugs are intended for a chronic disease. C5 complement inhibitors are known to increase the risk of meningococcal infections.17 For this reason, patients treated with C5 complement inhibitors need to be vaccinated against Neisseria meningitides at least 2 weeks before treatment initiation and vaccination should be repeated after 2 years. There appears to be a signal for severe headache following treatment with rozanolixizumab. In addition, there is a signal for a higher frequency of infections with efgartigimod. Long-term safety and efficacy will need to be confirmed in open-label extension trials.
Given that generalized MG symptoms fluctuate, the need for initiation of therapy, discontinuation, and retreatment will require further investigation.33 At present, there is no suggestion that the underlying generation of pathogenic autoantibodies is altered by targeted therapies.62 Therefore, discontinuation of therapy would be expected to lead to a return of muscle weakness. In addition, how to optimize use of targeted therapies in combination with conventional immunosuppressive therapies remains unknown.
Some of the emerging drugs for generalized MG have certain advantages in terms of dosing schedule and ease of administration. Those that have been formulated for SC injection (including rozanolixizumab, batoclimab, and zilucoplan) have the potential to be self-administered at home. These drugs may provide a more feasible option for some patients due to a lower treatment burden and decrease the use of health care resources required for IV infusion. Ravulizumab is being investigated for IV infusion every 8 weeks, which is currently the longest interval between treatments.
In Canada, the estimated annual cost for treatment with eculizumab for refractory generalized MG is over $700,000.16,61 Cost-effectiveness studies will be required to help health care plans assess the value of new targeted therapies over current standard of care to determine place in generalized MG treatment.
1.Koneczny I, Herbst R. Myasthenia gravis: pathogenic effects of autoantibodies on neuromuscular architecture. Cells. 2019;8(7):671. PubMed
2.Gilhus NE, Tzartos S, Evoli A, Palace J, Burns TM, Verschuuren J. Myasthenia gravis. Nat Rev Dis Primers. 2019;5(1):30. PubMed
3.Lazaridis K, Tzartos SJ. Autoantibody specificities in myasthenia gravis; implications for improved diagnostics and therapeutics. Front Immunol. 2020;11:212. PubMed
4.Meriggioli MN, Sanders DB. Muscle autoantibodies in myasthenia gravis: beyond diagnosis? Expert Rev Clin Immunol. 2012;8(5):427-438. PubMed
5.Marx A, Ströbel P, Weis C-A. The pathology of the thymus in myasthenia gravis. Mediastinum. 2018;2.
6.Bubuioc AM, Kudebayeva A, Turuspekova S, Lisnic V, Leone MA. The epidemiology of myasthenia gravis. J Med Life. 2021;14(1):7-16. PubMed
7.Deenen JC, Horlings CG, Verschuuren JJ, Verbeek AL, van Engelen BG. The epidemiology of neuromuscular disorders: a comprehensive overview of the literature. J Neuromuscul Dis. 2015;2(1):73-85. PubMed
8.Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in myasthenia gravis. BMC Neurol. 2010;10(1):46. PubMed
9.Breiner A, Widdifield J, Katzberg HD, Barnett C, Bril V, Tu K. Epidemiology of myasthenia gravis in Ontario, Canada. Neuromuscul Disord. 2016;26(1):41-46. PubMed
10.Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle Nerve. 2008;37(2):141-149. PubMed
11.Rodolico C, Nicocia G, Damato V, Antonini G, Liguori R, Evoli A. Benefit and danger from immunotherapy in myasthenia gravis. Neurol Sci. 2021;42(4):1367-1375. PubMed
12.Suh J, Goldstein JM, Nowak RJ. Clinical characteristics of refractory myasthenia gravis patients. Yale J Biol Med. 2013;86(2):255-260. PubMed
13.Silvestri NJ, Wolfe GI. Treatment-refractory myasthenia gravis. J Clin Neuromuscul Dis. 2014;15(4):167-178. PubMed
14.Menon D, Urra Pincheira A, Bril V. Emerging drugs for the treatment of myasthenia gravis. Expert Opin Emerg Drugs. 2021;26(3):259-270. PubMed
15.Soliris (eculizumab): 30 mL parenterial solution (10 mg/mL) [product monograph]. Zurich (CH): Alexion Pharma GmbH; 2021 Mar 25: https://pdf.hres.ca/dpd_pm/00060546.PDF. Accessed 2021 Oct 31.
16.CADTH Canadian Drug Expert Committee (CDEC) final recommendation: eculizumab (Soliris - Alexion Pharma Canada Corp.). Ottawa (ON): CADTH; 2020 Aug 24: https://www.cadth.ca/sites/default/files/cdr/complete/SR0640%20Soliris%20-%20CDEC%20Final%20Recommendation%20August%2024%2C%202020%20for%20posting.pdf. Accessed 2021 Nov 1.
17.Albazli K, Kaminski HJ, Howard JF, Jr. Complement inhibitor therapy for myasthenia gravis. Front Immunol. 2020;11:917. PubMed
18.Wolfe GI, Ward ES, de Haard H, et al. IgG regulation through FcRn blocking: a novel mechanism for the treatment of myasthenia gravis. J Neurol Sci. 2021;430:118074. PubMed
19.UCB. Clinical studies: Zilucoplan (RA101495). 2021; https://www.ucb.com/clinical-studies/Clinical-studies-index/Zilucoplan-RA101495. Accessed 2021 Oct 23.
20.Alexion AstraZeneca Rare Disease. Pipeline: advancing our pipeline every day. 2021; https://alexion.com/our-research/pipeline, 2021 Oct 25.
21.Argenx. Pipeline: efgartigimod 2021; https://www.argenx.com/pipeline/efgartigimod. Accessed 2021 Oct 23.
22.UCB. Clinical studies: Rozanolixizumab (UCB7665). 2021; https://www.ucb.com/clinical-studies/Clinical-studies-index/Rozanolixizumab-UCB7665. Accessed 2021 Oct 23.
23.Harbour BioMed. Immunology: batoclimab (HBM9161). 2021; https://www.harbourbiomed.com/therapeutics/2.html. Accessed 2021 Oct 23.
24.Immunovant. Pipeline: IMVT-1401 (“batoclimab”). 2021; https://www.immunovant.com/pipeline. Accessed 2021 Oct 23.
25.Janssen Global. Janssen showcases phase 2 nipocalimab (M281) data in adults with generalized myasthenia gravis (gMG) at the 2021 American Academy of Neurology Virtual Meeting. 2021 Apr 16; https://www.janssen.com/janssen-showcases-phase-2-nipocalimab-m281-data-adults-generalized-myasthenia-gravis-gmg-2021. Accessed 2021 Oct 23.
26.Batoclimab (HBM9161). Myasthenia Gravis News. 2020 Nov 4; https://myastheniagravisnews.com/batoclimab-hbm9161/. Accessed 2021 Nov 1.
27.U.S. Food and Drug Administration. News release, FDA approves new treatment for myasthenia gravis. 2021 Dec 17; https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-myasthenia-gravis. Accessed 2022 Jan 11.
28.Carvalho J. FDA grants orphan drug status to Ra Pharma’s zilucoplan as potential MG treatment. Myasthenia Gravis News. 2019 Sep 5; https://myastheniagravisnews.com/news-posts/2019/09/05/fda-grants-orphan-drug-status-to-ra-pharmas-zilucoplan-for-mg/. Accessed 2021 Nov 1.
29.Ultomiris (ravulizumab): 10 mg/mL concentrate for solution for infusion [product monograph]. Zurich (CH): Alexion Pharma GmbH; 2019 Aug 28: https://pdf.hres.ca/dpd_pm/00052831.PDF. Accessed 2021 Oct 31.
30.Narayanaswami P, Sanders DB, Wolfe G, et al. International consensus guidance for management of myasthenia gravis: 2021 update. Neurology. 2021;96(3):114-122. PubMed
31.Barnett C, Tabasinejad R, Bril V. Current pharmacotherapeutic options for myasthenia gravis. Expert Opin Pharmacother. 2019;20(18):2295-2303. PubMed
32.Habib AA, Ahmadi Jazi G, Mozaffar T. Update on immune-mediated therapies for myasthenia gravis. Muscle Nerve. 2020;62(5):579-592. PubMed
33.Dalakas MC. Immunotherapy in myasthenia gravis in the era of biologics. Nat Rev Neurol. 2019;15(2):113-124. PubMed
34.Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511-522. PubMed
35.Jaretzki A, 3rd, Barohn RJ, Ernstoff RM, et al. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology. 2000;55(1):16-23. PubMed
36.Thomsen JLS, Andersen H. Outcome measures in clinical trials of patients with myasthenia gravis. Front Neurol. 2020;11:596382. PubMed
37.Howard JF, Jr., Bril V, Burns TM, et al. Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis. Neurology. 2019;92(23):e2661-e2673. PubMed
38.Howard JF, Jr., Bril V, Vu T, et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021;20(7):526-536. PubMed
39.Argenx. NCT04735432: Evaluating the pharmacodynamic noninferiority of efgartigimod PH20 SC administered subcutaneously as compared to efgartigimod administered intravenously in patients with generalized myasthenia gravis (ADAPTsc). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04735432. Accessed 2021 Oct 23.
40.Argenx. NCT03770403: A safety and tolerability sudy of ARGX-113 in patients wth masthenia gavis who have generalized muscle weakness. (ADAPT+). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT03770403. Accessed 2021 Oct 23.
41.Argenx. NCT04818671: Evaluating the long-term safety and tolerability of efgartigimod PH20 SC administered subcutaneously in patients with generalized myasthenia gravis (ADAPTSC+). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04818671?recrs=abdfg&cond=Myasthenia+Gravis&phase=12&draw=3&rank=16. Accessed 2021 Oct 23.
42.Argenx. NCT04980495: An open-label study to investigate the clinical efficacy of different dosing regimens of efgartigimod IV in patients with generalized myasthenia gravis (ADAPT NXT). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04980495?recrs=abdfg&cond=Myasthenia+Gravis&phase=12&draw=3&rank=15. Accessed 2021 Oct 23.
43.Argenx. NCT04833894: Evaluating the pharmacokinetics, pharmacodynamics, and safety of efgartigimod administered intravenously in children with generalized myasthenia gravis. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://www.clinicaltrials.gov/ct2/show/NCT04833894?cond=efgartigimod+OR+argx-113+OR+argx113+OR+who+10455+OR+who10455&draw=2. Accessed 2021 Oct 23.
44.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. PubMed
45.UCB Biopharma SRL. NCT03971422: A study to test efficacy and safety of rozanolixizumab in adult patients with generalized myasthenia gravis. ClinicalTrials.gov. . ClinicalTrails.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT03971422?draw=2. Accessed 2021 Oct 23.
46.UCB Biopharma SRL. NCT04650854: A study to evaluate rozanolixizumab in study participants with generalized myasthenia gravis. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04650854?recrs=abdfg&cond=Myasthenia+Gravis&phase=12&draw=2&rank=7. Accessed 2021 Oct 23.
47.UCB Biopharma SRL. NCT04124965: A study to investigate the long-term safety, tolerability, and efficacy of rozanolixizumab in adult patients with generalized myasthenia gravis. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04124965. Accessed 2021 Oct 23.
48.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. PubMed
49.Ra Pharmaceuticals. NCT04115293: Safety, tolerability, and efficacy of zilucoplan in subjects with generalized myasthenia gravis (RAISE). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04115293?recrs=abdfg&cond=Myasthenia+Gravis&phase=12&draw=3. Accessed 2021 Oct 23.
50.Ra Pharmaceuticals. NCT04225871: Open-label extension of zilucoplan in subjects with generalized myasthenia gravis (RAISE-XT). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04225871?recrs=abdfg&cond=Myasthenia+Gravis&phase=12&draw=3. Accessed 2021 Oct 23.
51.Alexion Pharmaceuticals. NCT03920293: Safety and efficacy study of ravulizumab in adults with generalized myasthenia gravis. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT03920293?recrs=abdfg&cond=Myasthenia+Gravis&phase=12&draw=3&rank=18. Accessed 2021 Oct 23.
52.Alexion AstraZeneca Rare Disease. Press release, Alexion announces positive topline results from phase 3 study of Ultomiris (ravulizumab-cwvz) in adults with generalized myasthenia gravis (gMG). 2021 Jul 15: https://ir.alexion.com/news-releases/news-release-details/alexion-announces-positive-topline-results-phase-3-study.
53.Harbour BioMed (Guangzhou) Co. Ltd. NCT04346888: A study to evaluate the efficacy, safety and PD and PK of HBM9161 in MG patients. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04346888. Accessed 2021 Oct 23.
54.Harbour BioMed. Press release, Harbour BioMed reports positive topline results from phase 2 trial of batoclimab (HBM9161) in generalized myasthenia gravis. 2021 Jul 6; https://www.harbourbiomed.com/news/157.html. Accessed 2021 Oct 23.
55.Zhao C, Yan C, Yang H, et al. Double-blinded, randomized, placebo-controlled phase 2 study of FCRN antagonist batoclimab in Chinese generalized myasthenia gravis. J Neurol Sci. 2021;429(Suppl).
56.Wexler M. Immunovant planning pivotal trial of IMVT-1401. Myasthenia Gravis News. 2021 Jun 3; https://myastheniagravisnews.com/news-posts/2021/06/03/immunovant-planning-pivotal-trial-of-imvt-1401-in-myasthenia-gravis/. Accessed 2021 Nov 1.
57.Antozzi C, Guptill J, Bril V, et al. Phase 2 RCT trial evaluating the fcrn antagonist nipocalimab in adults with generalized myasthenia gravis. J Neuromuscul Dis. 2021;8 (Suppl 1):S160-S161.
58.Momenta Pharmaceuticals I. NCT03896295: An extension study of MOM-M281-004 to evaluate the safety, tolerability, and efficacy of M281 administered to patients with generalized myasthenia gravis. U.S. National Library of Medicine. Bethesda (MD): ClinicalTrials.gov; 2021: https://clinicaltrials.gov/ct2/show/NCT03896295. Accessed 2021 Oct 23.
59.Janssen Research & Development LLC. NCT04951622: A study of nipocalimab administered to adults with generalized myasthenia gravis. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04951622. Accessed 2021 Oct 23.
60.Hewett K, Sanders DB, Grove RA, et al. Randomized study of adjunctive belimumab in participants with generalized myasthenia gravis. Neurology. 2018;90(16):e1425-e1434. PubMed
61.Novartis Pharmaceuticals. NCT02565576: Safety, tolerability, pharmacokinetics and efficacy of CFZ533 in patients with moderate to severe myasthenia gravis. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/results/NCT02565576?view=results. Accessed 2021 Oct 25.
62.Alabbad S, AlGaeed M, Sikorski P, Kaminski HJ. Monoclonal antibody-based therapies for myasthenia gravis. Biodrugs. 2020;34(5):557-566. PubMed
63.Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW, Barohn RJ. Myasthenia gravis activities of daily living profile. Neurology. 1999;52(7):1487. PubMed
64.Muppidi S, Wolfe GI, Conaway M, Burns TM. MG-ADL: still a relevant outcome measure. Muscle Nerve. 2011;44(5):727-731. PubMed
65.Barnett C, Herbelin L, Dimachkie MM, Barohn RJ. Measuring clinical treatment response in myasthenia gravis. Neurol Clin. 2018;36(2):339-353. PubMed
66.Barohn RJ, McIntire D, Herbelin L, Wolfe GI, Nations S, Bryan WW. Reliability testing of the quantitative myasthenia gravis scorea. Ann N Y Acad Sci. 1998;841(1):769-772. PubMed
67.Harbour BioMed (Guangzhou) Co. Ltd. NCT05039190: Evaluate the efficacy and safety of HBM9161 (HL161) subcutaneous injection in patients with generalized MG patients (MG). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT05039190. Accessed 2021 Oct 23.
68.Alexion Pharmaceuticals. NCT04982289: Study of ALXN1830 administered subcutaneously in adults with generalized myasthenia gravis. ClinicalTrials.gov. Bethesda (MD): U.S. National Libarry of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04982289?draw=6. Accessed 2021 Oct 23.
69.Yancopoulos GD, Baras A, Zambrowicz B, Kyratsous C. Regeneron genetics medicines: building the pipeline of the future. New York (NY): Regeneron Pharmaceuticals, Inc; 2021 Jun 29: https://investor.regeneron.com/static-files/da4ab25e-4da4-4cf6-a86b-9f26516b24ce. Accessed 2021 Oct 25.
70.Regeneron Pharmaceuticals. NCT05070858: A study to examine the efficacy and safety of pozelimab and cemdisiran combination therapy in adult patients with symptomatic generalized myasthenia gravis. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT05070858?term=Pozelimab+and+Cemdisiran&draw=2. Accessed 2021 Oct 25.
71.Inacio P. Dosing begins in phase 2 trial of mezagitamab, antibody to treat MG. Myasthenia Gravis News 2020 Nov 17; https://myastheniagravisnews.com/news-posts/2020/11/17/dosing-begins-in-phase-2-trial-of-mezagitamab-antibody-to-treat-mg/. Accessed 2021 Oct 25.
72.Takeda. NCT04159805: A study of TAK-079 in people with generalized myasthenia gravis. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04159805. Accessed 2021 Oct 23.
73.Viela Bio. NCT04524273: Myasthenia gravis inebilizumab trial (MINT). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04524273. Accessed 2021 Oct 23.
74.Horizon Therapeutics plc. Uplizna (inebilizumab-cdon). 2021; https://www.uplizna.com/. Accessed 2021 Oct 25.
75.Cartesian Therapeutics. NCT04146051: Descartes-08 CAR-T cells in generalized myasthenia gravis (MG). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04146051. Accessed 2021 Oct 23.
76.Cartesian Therapeutics. Pipeline. Autoimmune: myasthenia gravis. 2021; https://www.cartesiantherapeutics.com/clinical-trials/. Accessed 2021 Oct 25.
77.RemeGen Co. L. NCT04302103: A study of TACI (Transmembrane Activator and Calcium-modulator and Cyclophilin Ligand (CAML) Interactor – antibody fusion protein injection (RC18) in subjects with systemic myasthenia gravis. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04302103?recrs=abdf&type=Intr&cond=Myasthenia+Gravis&sort=nwst&draw=3. Accessed 2021 Oct 25.
78.Dhillon S. Telitacicept: first approval. Drugs. 2021;81(14):1671-1675. PubMed
79.Actemra (tocilizumab): 20 mg/mL injection vials, 162 mg/ 0.9 mL injection pre-filled syringe and autoinjector [product monograph]. Mississauga (ON): Hoffmann-La Roche Limited; 2021 Jan 4: https://pdf.hres.ca/dpd_pm/00059560.PDF. Accessed 2021 Oct 23.
80.Tang-Du Hospital. NCT05067348: Efficacy and safety of tocilizumab in the treatment of generalized myasthenia gravis (tMG). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT05067348?recrs=abdfg&cond=Myasthenia+Gravis&phase=12&draw=2&rank=5. Accessed 2021 Oct 23.
81.Enspryng (satralizumab): 120 mg/mL subcutaneous injection [product monograph]. Mississauga (ON): Hoffman-La Roche Limited; 2020 Jun 1: https://pdf.hres.ca/dpd_pm/00056524.PDF. Accessed 2021 Oct 23.
Note that this appendix has not been copy-edited.
Table 2: Myasthenia Gravis Foundation of America Clinical Classification
Class35 | Symptoms |
|---|---|
Class I | Ocular muscle weakness only |
Class II | Ocular and mild systemic weakness |
Class III | Ocular and moderate systemic weakness |
Class IV | Ocular and severe systemic weakness |
Class V | Myasthenic crisis with respiratory failure requiring intubation |
Subtypesa | • Predominately affecting limb and/or axial muscles (oropharyngeal muscles may be affected to lesser extent). • Predominantly affecting oropharyngeal and/or respiratory muscles (limb and/or axial muscles may be affected to lesser extent. |
aApplies to classes II to IV.
Table 3: Description of Key Outcome Measures
Key features | ||
|---|---|---|
Instrument items | An 8-item patient-reported outcome measure assessing functional disability based on the following symptoms:
| A 13-item physician evaluation that quantifies disease severity based on impairments documented using a spirometer and dynamometer:
|
Score rangea | 0 to 24 | 0 to 39 |
Minimally important difference | 2 points | Mild-to-moderate MG (baseline QMG score ≤ 16): 2 points Severe MG (baseline QMG score ≥ 16): 3 points |
aHigher score indicates greater severity of symptoms and functional disability.
MG-ADL = myasthenia gravis; MG-ADL = Myasthenia Gravis-specific Activities of Daily Living; QMG = Quantitative Myasthenia Gravis.
Table 4: Characteristics of Efgartigimod Trials
Author, year; Study name; (NCT number); Funding | Design, Duration, Sample size | Population | Intervention (s), Comparator(s) | Primary outcome |
|---|---|---|---|---|
Published trials | ||||
Howard et al., 201937 ARGX-113 to 1602 (NCT02965573) Argenx | Phase II, double-blind, RCT 78 days N = 24 | Age ≥ 18 years MGFA class II to IVa AChR-antibody positive MG-ADL score ≥ 5 (≥ 50% total score attributable to nonocular symptoms) Stable dose of standard-of-care MG treatment | Intervention: Efgartigimod 10 mg/kg IV (n = 12) Comparator: Placebo IV (n = 12) Both given QW for 4 doses, followed by an 8-week observation period | Safety and tolerability |
Howard et al., 202138 ADAPT (NCT03669588) Argenx | Phase III, double-blind, RCT 26 weeks N = 167a | Age ≥ 18 years MGFA class II to IV AChR-antibody positive or negative MG-ADL score ≥ 5 (≥ 50% total score attributable to nonocular symptoms) Minimum 1 stable gMG therapy (acetylcholinesterase inhibitor, steroid, and/or nonsteroidal immunosuppressive drug) | Initial treatment cycle Intervention: Efgartigimod 10 mg/kg IV (n = 84) Comparator: Placebo IV (n = 83) Both given QW for 4 weeks, followed by 4 weeks with no infusions Subsequent treatment cycles The time between each treatment was individualized based on the duration of the patient’s clinically meaningful response as measured by the MG-ADL scale (maximum 3 treatment cycles in 26 weeks). Patients were eligible for retreatment if they met the following criteria:
| Proportion of AChR-antibody positive patients with at least 2-point reduction in MG-ADL score for at least 4 consecutive weeks in the initial treatment cycle (8 weeks). |
Ongoing trials | ||||
ADAPT+40 (NCT03770403) Argenx Completion: June 2023 | Phase III, single-arm, open-label, extension study Up to 3 years N = 151 | Age ≥ 18 years Participated in ADAPT trial and are eligible for roll over | Intervention: Efgartigimod IV (dosing and schedule not specified) Comparator: N/A | Incidence of treatment-emergent (serious) adverse events in AchR-positive population. |
ADAPTSC39 (NCT04735432) Argenx Completion: November 2021 | Phase III, open-label, RCT 12 weeks N = 111 | Age ≥ 18 years MGFA class II to IV | Intervention: Efgartigimod PH20 SC (dosing and schedule not specified) Comparator: Efgartigimod IV (dosing and schedule not specified) | Percent change from baseline in total IgG levels at day 29. |
ADAPTSC+41 (NCT04818671) Argenx Completion December 2021 | Phase III, open-label, single-arm, extension study Up to 2 years N = 201 | Age ≥ 18 years Previously enrolled in ADAPT or ADAPT+ and are eligible for rollover | Intervention: Efgartigimod PH20 1000 mg SC 3-week treatment periods, repeated as needed with at least 28 days in between treatment periods Comparator: N/A | Incidence and severity of adverse events, SAEs, and adverse events of special interest. |
ADAPT NXT42 (NCT04980495) Argenx Completion: October 2023 | Phase III, open-label, RCT 128 weeks Part A: Regimen comparison period – 21 weeks. Part B: Extension period – up to 105 weeks. N = 72 | Age ≥ 18 years MGFA class II to IV AChR-antibody positive MG-ADL score ≥ 5 (≤ 50% score due to nonocular symptoms) Stable dose of MG treatment (steroids or nonsteroidal immunosuppressive drugs) | Interventions Continuous regimen: Efgartigimod 10 mg/kg IV Q2W Cyclic regimen: Efgartigimod 10 mg/kg IV QW for 4 infusions per treatment period for 2 treatment periods with a fixed 4-week interval between each treatment period Comparator: N/A | Change in mean MG-ADL score from baseline at 21 weeks. |
ARGX-113 to 200643 (NCT04833894) Argenx Completion: December 2022 | Phase II/III, open-label, single-arm 28 weeks Part A: Treatment duration for dose confirmation – 8 weeks. Part B: Treatment response period – 18 weeks N = 12 | Children ≥ 2 and ≤ 18 years MGFA class II, III, and IVa AChR-antibody positive Unsatisfactory response to stable therapy of immunosuppressants, steroids, or acetylcholinesterase inhibitor | Intervention: Efgartigimod IV (dosing and schedule not specified) Comparator: N/A | Serum efgartigimod concentrations, total IgG levels, AchR-antibodies. |
aPrimary efficacy analysis was conducted on 129 adults with gMG positive for anti-AchR antibodies.
AchR = acetylcholine receptor; gMg = generalized myasthenia gravis; IgG = immunoglobulin G; MG = myasthenia gravis; MG-ADL = myasthenia gravis activities of daily living; MGFA = Myasthenia Gravis Foundation of America; PH20 = recombinant human hyaluronidase; QW = every week; Q2W = every two weeks; RCT = randomized controlled trial; SAE = serious adverse events; SC = subcutaneous.
Table 5: Characteristics of Rozanolixizumab Trials
Author, year: Name of study; (NCT number); Funding | Design, Duration, Sample size | Population | Intervention (s), Comparator(s) | Primary outcome |
|---|---|---|---|---|
Published trials | ||||
Bril et al., 202044 MG0002 (NCT03052751) UCB Biopharma SRL | Phase II, double blind, RCT Treatment period 1: Days 1 to 29 Treatment period 2: Days 29 to 43 Observation period: Days 44 to 99 N = 43 | Age ≥ 18 years Positive for anti-AchR or anti-MuSK antibodies QMG score ≥ 11 at baseline Total serum IgG concentration > 6 g/L at screening Currently considered for IVIg or PLEX treatment | Treatment period 1 Intervention: Rozanolixizumab 7 mg/kg SC (n = 21) Comparator: Placebo SC (n = 22) Both given as 3 once-weekly infusions. Treatment period 2 Intervention: Rozanolixizumab 4 mg/kg SC (n = 21) Comparator: Rozanolixizumab 7 mg/kg SC (n = 21) Both given as 3 once-weekly infusions. | Change from baseline in QMG score at day 29. |
Completed trials (unpublished) | ||||
MG000447 (NCT04124965) UCB Biopharma SRL Completion: September 2021 | Phase III, open-label, single-group, extension study 60 weeks N = 71 | Age ≥ 18 years Eligible for MG0003 or MGC003 trials at the time of enrolment Completed the observation periods of MG0003 or MGC003 or required rescue therapy during the observation period | Interventions: Rozanolixizumab regimen 1 SC or Rozanolixizumab regimen 2 SC (dosing and schedule not specified) Study participants will receive dosage originally assigned for initial cycle. Dosage regimen may be switched before the start of each subsequent treatment cycle based on investigator discretion. Comparator: N/A | Percentage of participants with TEAEs or TEAEs leading to withdrawal of investigational drug at 60 weeks. |
Ongoing trials | ||||
MG000345 (NCT03971422) UCB Biopharma SRL Completion: October 2021 | Phase III, double-blind, RCT screening period: days 1 to 28 treatment period: 6 weeks observation period: 8 weeks N = 200 | Age ≥ 18 years MGFA class II to IVa Positive for anti-AchR or anti-MuSK antibodies MG-ADL score ≥ 3 (with ≥ 3 points from nonocular symptoms QMG score ≥ 11 Currently considered for IVIg or PLEX treatment | Interventions: Rozanolixizumab regimen 1 SC or Rozanolixizumab regimen 2 SC Comparator: Placebo SC (dosing and schedule not specified) | Change from baseline in MG-ADL score at day 43. |
MG000746 (NCT04650854) UCB Biopharma SRL Completion: August 2023 | Phase III, open-label, single-group, extension study 20 months N = 200 | Age ≥ 18 years Completed MG0003, required rescue therapy during the observation period in MG0003, or completed at least 6 visits in MG0004 | Interventions: Rozanolixizumab regimen 1 SC or Rozanolixizumab regimen 2 SC (dosing and schedule not specified) Study participants will receive dosage originally assigned for initial cycle. Dosage regimen may be switched before the start of each subsequent treatment cycle based on investigator discretion. Comparator: N/A | Percentage of participants with TEAEs Percentage of participants with TEAEs leading to withdrawal of investigational drug at 20 months. |
AchR = acetylcholine receptor; IVIg = IV immunoglobulin; MG-ADL = myasthenia gravis activities of daily living; MGFA = Myasthenia Gravis Foundation of America; MuSK = muscle-specific kinase; PLEX = plasma exchange; QMG = quantitative myasthenia gravis; RCT = randomized controlled trial; SC = subcutaneous; TEAE = treatment-emergent adverse event.
Table 6: Characteristics of Zilucoplan Trials
Author, year; Name of study; (NCT number); Funding | Design, Duration, Sample size | Population | Intervention (s), Comparator(s) | Primary outcome |
|---|---|---|---|---|
Published trials | ||||
Howard et al., 202048 (NCT03315130) Ra Pharmaceuticals | Phase II, double-blind, RCT 12 weeks N = 44 | Age 18 to 85 years MGFA class II to IVa Positive for anti-AchR antibodies QMG score ≥ 12 (with a score of ≥ 2 on at least 4 items) No change in corticosteroid dose or immunosuppressive therapy for 30 days before baseline and during trial treatment period | Interventions: Zilucoplan 0.1 mg/kg SC daily (n = 15) Zilucoplan 0.3 mg/kg SC daily (n = 15) Comparator: Placebo SC daily (n = 15) | Change from baseline in QMG score at 12 weeks. |
Ongoing trials | ||||
RAISE49 (NCT04115293) Ra Pharmaceuticals Completion: December 2021 | Phase III, double-blind, RCT 12 weeks N = 174 | Age ≥ 18 years MGFA class II to IV Positive for anti-AchR antibodies MG-ADL score ≥ 6 QMG score ≥ 12 No change in corticosteroid dose or immunosuppressive therapy for 30 days before baseline and during trial treatment period | Intervention:Zilucoplan 0.3 mg/kg SC daily Comparator: Placebo SC daily | Change from baseline in MG-ADL score at 12 weeks. |
RAISE-XT50 (NCT04225871) Ra Pharmaceuticals Completion: December 2023 | Phase III, open-label, single-arm, extension study 36 months N = 200 | Age ≥ 18 years Completion of a qualifying Ra Pharmaceuticals sponsored zilucoplan study | Interventions: Zilucoplan 0.3 mg/kg SC daily Comparator: N/A | Incidence of TEAEs during follow-up of up to 36 months. |
AchR = acetylcholine receptor; MG = myasthenia gravis; MG-ADL = myasthenia gravis activities of daily living; MGFA = Myasthenia Gravis Foundation of America; QMG = quantitative myasthenia gravis; RCT = randomized controlled trial; SC = subcutaneous; TEAEs = treatment-emergent adverse events.
Table 7: Characteristics of Ravulizumab Trials
Author, year; Name of study; (NCT number); Funding | Design, Duration, Sample size | Population | Intervention (s), Comparator(s) | Primary outcome |
|---|---|---|---|---|
Ongoing trials | ||||
ALXN1210-MG-30651 (NCT03920293) Alexion Pharmaceuticals Completion: December 2021 | Phase III, double-blind, RCT 26 weeks N = 175 | Age ≥ 18 years MG diagnosis at least 6 months before screening MGFA class II to IV MG-ADL score ≥ 6 Vaccinated against meningococcal infections within 3 years before, or at the time of initiating trial | Intervention: Ravulizumab 10 mg/mL IV Comparator: Placebo IV Both given as a single weight-based loading dose on day 1, followed by regular weigh-based maintenance dosing beginning day 15 every 8 weeks. | Change from baseline in MG-ADL score at 26 weeks. |
IgG = immunoglobulin G; MG-ADL = myasthenia gravis activities of daily living; MGFA = Myasthenia Gravis Foundation of America; RCT = randomized controlled trial.
Table 8: Characteristics of Batoclimab Trials
Author, year; Name of study; (NCT number); Funding | Design, Duration, Sample size | Population | Intervention (s), Comparator(s) | Primary outcome |
|---|---|---|---|---|
Completed trials (unpublished) | ||||
NCT0434688853 Harbour BioMed | Phase II, double-blind, RCT Double-blind period: 6 weeks Open-label Extension period: 6 weeks N = 30 | Age 18 to 99 years Moderate to severe gMG Positive for anti-AChR or anti-MuSK antibodies | Double-Blind Period Interventions: Batoclimab 340 mg SC QW (n = 10) Batoclimab 680 mg SC QW (n = 11) Comparator: Placebo SC QW (n = 9) Open-label Extension Period Batoclimab 340 mg SC Q2W | MG-ADL score at day 43 compared to baseline. |
Ongoing trials | ||||
NCT0503919067 Harbour BioMed Completion: March 2023 | Phase II/III, double-blind, RCT Double-blind period: 6 weeks Open-label Extension period: 6 weeks followed by 4-week observation period N = 144 | Age 18 to 99 years MGFA class IIa to IVa Positive (n = 120) or negative (n = 24) for anti-AChR or anti-MuSK antibodies | Double-Blind Period Interventions: Batoclimab 680 mg SC QW Comparator: Placebo SC QW Open-label Extension Perioda Batoclimab 680 mg SC QW | Percentage of patients positive for anti-AChR or anti-MuSK antibodies with MG-ADL score reduction ≥ 3 points from baseline that persists for at least 64 days. |
aParticipants who completed the double-blind period started the open-label extension if they met dosing criteria at week 9.
AchR = acetylcholine receptor; MG-ADL = myasthenia gravis activities of daily living; MGFA = Myasthenia Gravis Foundation of America; MuSK = muscle-specific kinase; QW = every week Q2W = every 2 weeks; RCT = randomized controlled trial; SC = subcutaneous.
Table 9: Characteristics of Nipocalimab Trials
Author, year; Name of study; (NCT number); Funding | Design, Duration, Sample size | Population | Intervention (s), Comparator(s) | Primary outcome |
|---|---|---|---|---|
Completed trials (unpublished) | ||||
Antozzi et al., 202157 (conference abstract) Vivacity-MG (NCT03772587) Momenta Pharmaceuticals, Inc. | Phase II, double-blind, RCT 8 weeks N = 68 | Age ≥ 18 years Moderate to severe gMG Positive for anti-AChR or anti-MuSK antibodies | Interventions: Nipocalimab 5 mg/kg IV Q4W Nipocalimab 30 mg/kg IV Q4W Nipocalimab 60 mg/kg IV Q2W Nipocalimab 60 mg/kg IV single dose Comparator: Placebo IV Q2W | Number of participants with adverse events (up to day 113) Change in MG-ADL score from baseline to day 57. |
Ongoing trials | ||||
CR10904659 (NCT04951622) Janssen Research and Development, LLC Completion: February 2024 | Phase III, double-blind, RCT Double-blind phase: 24 weeks Open-label extension: Up to 2 years N = 180 | Age ≥ 18 years MGFA class II to IV MG-ADL score ≥ 6 | Double-blind phase: Intervention: Nipocalimab IV Q2W (dose not specified) Comparator: Placebo IV Q2W Open-label extension: Intervention: Nipocalimab IV Q2W (dose not specified) (participants who are stable on Q2W dosing regimen may be transitioned to dosing Q4W) Comparator: N/A | Average change from baseline in MG-ADL score over weeks 22, 23 and 24. |
AchR = acetylcholine receptor; gMg = generalized myasthenia gravis; MG = myasthenia gravis; MG-ADL = myasthenia gravis activities of daily living; MGFA = Myasthenia Gravis Foundation of America; MuSK = muscle-specific kinase; Q2W = every two weeks; Q4W = every four weeks; RCT = randomized controlled trial.
Table 10: Immunotherapies in Clinical Development for Generalized Myasthenia Gravis
Generic name (development or brand name), Manufacturer | Clinical development phase | Population | Trial completion | Regulatory status |
|---|---|---|---|---|
FcRn inhibitors | ||||
(ALXN1830) Alexion AstraZeneca Rare Disease | Phase II | Adults with generalized myasthenia gravis with who are positive for anti-AChR antibodies | January 2023 | NR |
Complement C5 inhibitors | ||||
Pozelimab (REGN3918) plus emdisiran Regeneron | Phase III | Adults with generalized myasthenia gravis who are positive for anti-AchR or anti-LRP4 antibodies | February 2024 | NR |
B-cell inhibitors | ||||
(TAK-079) Takeda | Phase II | Adults with generalized myasthenia gravis who are positive for anti-AchR or anti-MuSK antibodies | April 2022 | NR |
(MEDI-551) Horizon Therapeutics | Phase III | Adult with generalized myasthenia gravis who are positive for anti-AChR or anti-MuSK antibodies | June 2023 | Approved by the US FDA for the treatment of adults with NMOSD.74 |
Cartesian Therapeutics | Phase I/II | Adults with generalized myasthenia gravis | November 2021 | NR |
(Telitacicept) RemeGen | Phase II | Adults with generalized myasthenia gravis who are positive for anti-AchR or anti-MuSK antibodies | December 2021 | Approved in China for patients with SLE.78 |
IL-6 inhibitors | ||||
(Actemra) Hoffmann-La Roche | Phase II | Adult with generalized myasthenia gravis who are positive for anti-AChR antibodies | March 2024 | Approved by Health Canada for the treatment of adult patients with moderately to severe active rheumatoid arthritis, adults with giant cell arteritis, children older than 2 years with certain types of arthritis, and patients with CAR T-cell induced cytokine release syndrome.34 |
(Enspryng) Hoffmann-La Roche | Phase III | Patients over the age of 12 with generalized myasthenia gravis who are positive for anti-AchR, anti-MuSK, or anti-LRP4 antibodies | July 2023 | Approved by Health Canada for the treatment of patients over the age of 12 with NMOSD.81 |
AchR = acetylcholine receptor; CAR = chimeric antigen receptor; IL-6 = interleukin 6; LRP = lipoprotein receptor-related protein 4; NMOSD = neuromyelitis optica spectrum disorder; NR = not reported; MuSK = muscle-specific kinase; SLE = systemic lupus erythematosus.
Table 11: Developmental Phase for Additional Indications
Indication | Efgartigimod21 | Rozanolixizumab22 | Zilucoplan19 | Ravulizumab20 | Nipocalimab25 | |
|---|---|---|---|---|---|---|
Primary immune thrombocytopenia | Phase III | Phase III | NR | NR | Phase II/III | NR |
Warm autoimmune hemolytic anemia | NR | NR | NR | NR | Phase II | Phase II/III |
Hemolytic disease of the fetus and newborn | NR | NR | NR | NR | NR | Phase II |
Pemphigus vulgaris and Foliaceus | Phase III | NR | NR | NR | NR | NR |
Chronic inflammatory demyelinating polyneuropathy | Phase II | Phase II | NR | NR | NR | NR |
LGI1 autoimmune encephalitis | NR | Phase II | NR | NR | NR | NR |
PNH | NR | NR | Phase II | Phase III | NR | NR |
ALS | NR | NR | Phase II/III | Phase III | NR | NR |
COVID-19 | NR | NR | Phase III | Phase III | NR | NR |
Graves’ ophthalmopathy | NR | NR | NR | NR | Phase II/III | NR |
NMOSD | NR | NR | NR | Phase III | Phase I | NR |
Rheumatoid arthritis | NR | NR | NR | NR | NR | Phase II |
Sjogren syndrome | NR | NR | NR | NR | NR | Phase II |
SLE | NR | NR | NR | NR | NR | Phase II |
Lupus nephritis | NR | NR | NR | Phase II | NR | Phase II |
IgA nephropathy | NR | NR | NR | Phase II | NR | NR |
Dermatomyositis | NR | NR | NR | Phase II/III | NR | NR |
Atypical hemolytic uremic syndrome | NR | NR | NR | Phase III | NR | NR |
Thrombotic microangiopathy following HSCT | NR | NR | NR | Phase III | NR | NR |
ALS = amyotrophic lateral sclerosis HSCT = hematopoietic stem cell transplantation; IgA = immunoglobulin A; LGI1 = leucine-rich glioma inactivated 1; NMOSD = neuromyelitis optica spectrum disorder; NR = not reported; PNH = paroxysmal nocturnal hemoglobinuria; SLE = systemic lupus erythematosus.
Acknowledgement: Christine Perras; Matthew McDonald; Colin Chalk, MD, CM. FRCPC, Professor, Department of Neurology and Neurosurgery, McGill University.
ISSN: 2563-6596
Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.
While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up to date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.
CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials.
This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners’ own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites.
Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal, provincial, or territorial governments or any third-party supplier of information.
This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user’s own risk.
This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.
The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.
About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.
Questions or requests for information about this report can be directed to Requests@CADTH.ca