CADTH Reimbursement Review

Ravulizumab (Ultomiris)

Sponsor: Alexion Pharma GmbH

Indication: For the treatment of adult patients with anti-acetylcholine receptor antibody-positive generalized Myasthenia Gravis

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Submitted for Review

AChR = acetylcholine receptor; gMG = generalized myasthenia gravis; NOC = Notice of Compliance.

Source: Sponsor’s drug reimbursement review submission for ravulizumab.¹

Introduction

Myasthenia gravis (MG) is an autoimmune disease in which antibodies against acetylcholine receptors (AChRs) or functionally associated molecules in the neuromuscular junction disrupt nerve impulse conduction, resulting in localized or generalized skeletal muscle weakness.² In a minority of patients, symptoms remain restricted exclusively to the eyes (ocular MG), while most patients either are diagnosed with or progress within a few years to generalized myasthenia gravis (gMG), which affects the bulbar and other muscles.^2,3 Symptoms of gMG include eyelid drooping and double vision, altered facial expression, difficulty chewing and swallowing food, difficulty speaking, and in patients with more severe disease, problems with limb movement and breathing;^2,3 collectively, symptoms negatively impact health-related quality of life (HRQoL).⁴ The disease has a fluctuating natural history: MG exacerbation (an increase in symptoms in patients who were previously asymptomatic or minimally symptomatic) and myasthenic crisis (muscle weakness causing life-threatening difficulties with breathing and swallowing and requiring ventilator support) can occur gradually or without warning.⁵ In Canada, the incidence of MG is approximately 23 cases per 1 million population annually and its prevalence is approximately 263 cases to 320 cases per 1 million population.^6-8 According to the clinical experts consulted by CADTH for this review, the prevalence worldwide, based on an average of epidemiological studies, may be slightly lower (approximately 100 cases to 200 cases per 1 million population).

According to the clinical experts consulted by CADTH for this review, gMG is initially treated symptomatically with acetylcholinesterase inhibitors (AChEIs) such as pyridostigmine. If this provides insufficient symptom relief, immunosuppressive therapy (IST) with corticosteroids is administered. Maximal responses typically occur 2 months to 6 months later, after which the slow tapering of corticosteroids is begun. In patients who do not respond to corticosteroids, who have significant comorbidities such that long-term corticosteroid treatment is contraindicated, or in whom doses of corticosteroids cannot be tapered, treatment with a steroid-sparing immunosuppressant and/or immunomodulatory drugs — including rituximab — may be initiated; access to steroid-sparing ISTs and rituximab varies by jurisdiction. Patients with severe gMG are often started on all 3 of pyridostigmine, corticosteroids, and a steroid-sparing drug simultaneously. In patients with moderate to severe gMG, IV immunoglobulin (IVIg), plasma exchange (PE), or plasmapheresis (PP) may be administered, either at the time of IST initiation, or to treat MG exacerbation or myasthenic crisis. Critical care, including intensive care unit (ICU) admission and ventilator support, may also be required for patients experiencing myasthenic crisis. Surgery (thymectomy) may also be considered in a small group of patients. As MG symptoms improve, doses of AChEIs, corticosteroids, and then other ISTs are reduced and the frequency of IVIg, PE, or PP is reduced until the minimal maintenance therapy required for remission is identified. Patients whose symptoms persist despite treatment with adequate doses of corticosteroids, other ISTs, and/or chronic IVIg, PE, or PP and patients for whom the doses or frequencies of these therapies cannot be reduced are considered to have refractory gMG (approximately 10% to 15% of patients). Patients with refractory gMG who are anti-AChR antibody–positive may soon be candidates for the complement inhibitor eculizumab. Eculizumab was recommended for reimbursement with conditions in 2020.⁹ However, funding is not yet in place; negotiation concluded without an agreement in December 2022.¹⁰

According to the clinical experts, the goal of treatment in most patients with gMG is to reduce disease symptoms as well as the adverse effects of MG therapy and to allow the patient to function and work normally with good HRQoL. Other goals of treatment include avoiding MG exacerbations and myasthenic crisis, minimizing hospitalizations and ICU admissions, and reducing the numbers and doses of therapies required for symptom control. The clinical experts consulted by CADTH for this review stated that most patients with gMG (more than 80%) will respond well to currently available treatments; although these cannot cure the disease, excellent symptom control is achieved in most patients and prognosis is generally good in terms of muscle strength and function as well as HRQoL. However, many of the patients with MG who respond well to currently available treatments in terms of their MG symptoms still experience treatment-related side effects, which may be severe.

Ravulizumab is a monoclonal antibody and terminal complement inhibitor that is supplied as a 10 mg/mL or 100 mg/mL concentrate and administered at a maintenance dosage of 3,000 mg to 3,600 mg by IV infusion every 8 weeks. The drug underwent standard review at Health Canada and received a Notice of Compliance on January 6, 2023. The relevant Health Canada indication is “for the treatment of adult patients with anti-AChR antibody–positive generalized Myasthenia Gravis (gMG).” The sponsor’s reimbursement request is the same as the Health Canada indication. The drug was previously reviewed by CADTH “for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH)” and received a positive reimbursement recommendation from the CADTH Canadian Drug Expert Committee (CDEC) on March 2, 2022.¹¹ Ravulizumab was also previously reviewed by CADTH “for the treatment of adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA)” and received a draft recommendation for reimbursement with conditions from CDEC on October 26, 2022.¹²

The objective of this report was to perform a systematic review of the beneficial and harmful effects of ravulizumab for the treatment of adult patients with anti-AChR antibody–positive gMG.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups that responded to CADTH’s call for patient input, by the clinician groups that responded to CADTH’s call for clinician input, and from clinical experts consulted by CADTH for the purpose of this review.

Patient Input

One patient group, Muscular Dystrophy Canada, provided input for this review. Information was collected from 149 individuals impacted by MG through a health care experience survey and semistructured phone or virtual interviews. These individuals consisted of 92 (61.7%) women and 57 (38.3%) men from all provinces of Canada, including 9 respondents from Quebec and 29 patients with a confirmed diagnosis of anti-AChR antibody–positive gMG; ages ranged from 23 years to 75 years. Half of patients (50%) recounted difficulties with MG diagnosis, including delays, misdiagnoses, and costs incurred. The patient group input highlighted the negative impacts of MG on daily activities and HRQoL, including fatigue and sleep disruptions, lack of strength and mobility, decreased independence and social participation, eyesight problems, difficulties with speech and swallowing, loss of employment and financial hardships, and mental health burdens for family members. The input also highlighted the potential benefits and side effects of currently available treatments, including prednisone (depression, weight gain, diabetes), pyridostigmine (diarrhea, nausea, jumpy legs), thymectomy (painful recovery), and IVIg (inconvenience of hospital administration). Respondents indicated that currently available therapies may decrease MG exacerbations but not their overall impact on HRQoL. Only 1 respondent had experience with ravulizumab and felt it had been helpful in improving their symptoms. Respondents identified an unmet need for new treatments that can decrease the intensity of MG exacerbations, allow them to maintain independence, and prevent hospitalization. Patients also desired treatments with minimal side effects and convenient administration (e.g., once daily oral administration, easy to swallow, fast onset, long duration of action, low cost) but indicated they would be willing to accept the side effects of new therapies that better control the consequences of MG.

Clinician Input

Input From Clinical Experts Consulted by CADTH

Input was provided by 2 clinical specialists with expertise in the diagnosis and management of patients with anti-AChR antibody–positive gMG. The clinical experts explained that in some patients with gMG, symptom control can only be achieved by the chronic administration of IVIg every 1 to 4 weeks or cannot be achieved with any standard treatment (refractory gMG). For these patients, there are very few remaining options, including complement inhibitors. Some patients also experience side effects of currently available treatments that necessitate permanent discontinuation of the drug. The clinical experts stated that additional treatments are needed with more rapid onset of action, longer-lasting benefits, improved efficacy in patients with refractory gMG, and fewer side effects. According to the clinical experts, ravulizumab has a similar mechanism of action to eculizumab, which is rarely used and only in patients with refractory gMG; because of their distinct mechanism of action, ravulizumab and eculizumab may be used in combination with standard treatments. The clinical experts felt that there might also be a rationale for the use of either ravulizumab or eculizumab early in the disease course in patients with more severe disease in addition to or instead of other options (e.g., AChEIs, IST, IVIg, PE or PP), but acknowledged that at the moment, there are limited data to justify this approach. The clinical experts stated that because currently available standard treatments are generally effective in most patients, it would be difficult to recommend the early use of ravulizumab unless it was clearly more effective and/or pharmacoeconomically favourable compared with other options.

According to the clinical experts, candidates for ravulizumab (primarily patients with refractory gMG, as well as potentially those with severe but nonrefractory gMG) would be identified through the judgment of an expert neurologist based on clinical evaluation following serologic testing for anti-AChR antibodies and, potentially, following a chest CT to rule out thymoma and thymic carcinoma. The clinical experts stated that although patients with thymoma were excluded from the trials of complement inhibitors, there is no reason to believe that these patients could not benefit from these drugs. Response to ravulizumab would be assessed by monitoring patient symptoms and/or signs on clinical examination (e.g., the Myasthenia Gravis Activities of Daily Living [MG-ADL] assessment and/or Quantitative Myasthenia Gravis [QMG] score every 1 month to 3 months) and via reduction of other MG therapies (especially chronic IVIg). Clinically meaningful responses to ravulizumab would be reflected by improvements in disease symptoms (approximately 2 points for the MG-ADL score and approximately 3 points for the QMG score) as well as by the reduction of other treatments (e.g., chronic IVIg, PE or PP, rituximab) and hospitalizations. The drug would be discontinued in patients who do not achieve clinical improvement or are unable to reduce the numbers and doses of other MG therapies, in patients who experience worsening of MG symptoms requiring additional interventions, in patients who experience serious toxicities such as meningococcal infections, or by patient preference. However, the clinical experts also noted that in some patients, treatment with complement inhibitors, including ravulizumab, could be lifelong if this is required to achieve sustained clinical benefit. Ravulizumab would be prescribed by a neurologist with expertise in managing patients with MG and administered in a hospital setting or at an infusion clinic.

Clinician Group Input

One clinician group, The Neuromuscular Disease Network for Canada (NMD4C), provided input for this review that reflected the views of 4 neurologists with experience in the management of patients with gMG. No major contrary views were presented that diverged from those provided by the clinical experts consulted by CADTH for this review. The clinician group reiterated that standard treatments for gMG are often transiently effective, may require relatively long treatment periods for benefits to be observed, may carry side effects, and may not be effective in all patients. NMD4C indicated that ravulizumab would be unlikely to cause a shift in the standard treatment paradigm for gMG and would be used as an add-on third-line therapy in patients with anti-AChR antibody–positive gMG who are not responsive to AChEIs and IST and require chronic IVIg, or PE or PP. The clinician group noted the more convenient administration of ravulizumab (every 8 weeks) compared with eculizumab (every 2 weeks).

Drug Program Input

The Formulary Working Group identified the following jurisdictional implementation issues that may impact its ability to implement a recommendation: relevant comparators, considerations for the initiation of therapy, considerations for the continuation or renewal of therapy, considerations for the discontinuation of therapy, considerations for the prescribing of therapy, care provision issues, and system and economic issues. The clinical experts consulted by CADTH for this review weighed evidence from the included study and other clinical considerations to provide responses to drug program implementation questions.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

The CHAMPION trial (study identification number ALXN1210-MG-306, N = 175)^13,14 was a phase III, double-blind (DB), multicentre, placebo-controlled randomized controlled trial (RCT) with an open-label (OL) extension period of up to 4 years. The primary objective of the CHAMPION trial was to evaluate the safety and efficacy of ravulizumab compared with placebo in complement inhibitor–naive adult patients with gMG. Following screening, adult patients with anti-AChR antibody–positive gMG (patients had to have a Myasthenia Gravis Foundation of America [MGFA] clinical classification¹⁵ of class II to class IV, an MG-ADL total score of 6 or more, and be nonthymomatous; there were no requirements for prior treatment experience or its outcome) were enrolled at 85 centres in 13 countries (5 sites in Canada) and randomized 1:1 to receive either a weight-based dose of ravulizumab (n = 86) or a matching placebo (n = 89) for 26 weeks. The primary outcome of the study was change from baseline in the MG-ADL total score at week 26 of the randomized controlled period, while secondary outcomes included the change from baseline in the QMG total score at week 26, the proportion of patients with improvements of 5 points or more in the QMG total score at week 26, the change from baseline in the Myasthenia Gravis Quality of Life 15-item scale – Revised (MG-QoL15r) score at week 26, the change from baseline in the Quality of Life in Neurological Disorders (Neuro-QoL) Fatigue score at week 26, and the proportion of patients with improvements of 3 points or more in the MG-ADL total score at week 26.

Patients’ baseline demographic and disease characteristics were generally well balanced across treatment arms; there were minor imbalances by race, age at MG diagnosis, age at first study drug infusion, MG type at diagnosis (ocular versus generalized), time to gMG from diagnosis among patients whose first presentation was ocular MG, MGFA clinical classification, and prior corticosteroid use. The mean age at first infusion in the overall study population was 55.6 (standard deviation [SD] = 15.2) years and most patients were from North America (45.7%) or Europe (36.6%). Prior to screening, 55.7% of patients had experienced moderate to severe MG (MGFA class IIIb, class IV, or class V), 60.0% of patients had experienced MG exacerbations, 21.7% of patients had experienced MG crises, and 17.1% of patients had required ventilator support. At the study baseline, 23.4% of patients had moderate to severe MG; at the first dose of the study drug, 83 (47.4%) patients were receiving 2 or more ISTs, 74 (42.3%) patients were receiving 1 IST, and 18 (10.3%) patients were receiving no IST.

Efficacy Results

Key efficacy results during the randomized controlled period of the CHAMPION trial are summarized in Table 2.

Activities of Daily Living

At week 26, the least squares mean (LSM) change in the MG-ADL total score in the placebo arm was –1.4 (95% confidence interval [CI], –2.1 to –0.7) versus –3.1 (95% CI, –3.8 to –2.3) in the ravulizumab arm. The LSM difference in MG-ADL total score between the ravulizumab and placebo arms was –1.6 (95% CI, –2.6 to –0.7; P = 0.0009). The adjusted percentage of patients with improvements of at least 3 points in MG-ADL total score at week 26 was 56.7% (95% CI, 44.3% to 68.3%) in the ravulizumab arm and 34.1% (95% CI, 23.8% to 46.1%) in the placebo arm (odds ratio [OR] of at least a 3-point improvement = 2.526; 95% CI, 1.330 to 4.799). The adjusted percentage of patients with improvements of at least 2 points in the MG-ADL total score (a recognized response threshold that indicates clinical improvement) at week 26 was 63.9% (95% CI, 51.7% to 74.6%) in the ravulizumab arm and 53.0% (95% CI, 41.1% to 64.6%) in the placebo arm (OR of at least a 2-point improvement = 1.569; 95% CI, 0.833 to 2.955).

Disease Severity

At week 26, the LSM change in the QMG total score in the placebo arm was –0.8 (95% CI, –1.7 to 0.1) versus –2.8 (95% CI, –3.7 to –1.9) in the ravulizumab arm. The LSM difference in QMG total score between the ravulizumab and placebo arms was –2.0 (95% CI, –3.2 to –0.8; P = 0.0009). The adjusted percentage of patients with improvements of at least 5 points in their MG-ADL total score at week 26 was 30.0% (95% CI, 19.2% to 43.5%) in the ravulizumab arm and 11.3% (95% CI, 5.6% to 21.5%) in the placebo arm (OR of at least a 5-point improvement = 3.350; 95% CI, 1.443 to 7.777; P = 0.0052). The adjusted percentage of patients with improvements of at least 3 points in the QMG total score (the estimated minimal important difference [MID]) at week 26 was 44.8% (95% CI, 32.3% to 58.0%) in the ravulizumab arm and 24.2% (95% CI, 15.3% to 36.2%) in the placebo arm (OR of at least a 3-point improvement = 2.544; 95% CI, 1.283 to 5.044).

Hospital Admission

A total of || patients ||||||| in the placebo arm and | |||||||| ||||||| in the ravulizumab arm were hospitalized. Among these, | |||||||| |||||| in the placebo arm and | |||||||| |||||| in the ravulizumab arm were hospitalized due to MG. Only | ||||||| |||||| in the placebo arm and | |||||||| |||||| in the ravulizumab arm required ventilator support.

Number and Dose of Existing Medications

The number and dose of existing medications was not an efficacy outcome in the CHAMPION trial. Patients were to maintain stable doses of concomitant MG medications during the randomized controlled period unless there was a compelling medical need.

Need for Rescue Therapy

In the placebo arm, 14 (15.7%) patients required rescue therapy (IVIg = 12 patients; PE or PP and high dose corticosteroids = 1 patient each). In the ravulizumab arm, 8 (9.3%) patients required rescue therapy (IVIg = 5 patients; PE or PP = 2 patients; high dose corticosteroids = 1 patient).

Table 2: Summary of Key Results From the Randomized Controlled Period of the CHAMPION Trial

AE = adverse event; CI = confidence interval; FAS = full analysis set; GLMM = generalized linear mixed model; LSM = least squares mean; MG-ADL = Myasthenia Gravis Activities of Daily Living; MG-QoL15r = Myasthenia Gravis Quality of Life 15-item scale - Revised; MMRM = mixed model of repeated measures; Neuro-QoL = Quality of Life in Neurological Disorders; OR = odds ratio; QMG = Quantitative Myasthenia Gravis; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

^aThe P value was derived from a MMRM that included change from baseline at postdosing visits as the response variable, fixed categorical effects of treatment, study visit, and treatment-by-study-visit interaction, the randomization stratification variable of geographical region, and the fixed covariate of baseline score.

^bThe P value was derived from a GLMM that included the indicated point responses at postdosing visits as the response variable, fixed categorical effects of treatment, study visit, and treatment-by-study-visit interactions, the randomization stratification variable of geographic region, and a fixed covariate of baseline score as a continuous variable.

^cThe P value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled). These outcomes were tested following a previous nonstatistically significant result in the statistical hierarchy.

Source: CHAMPION Clinical Study Report.¹³

Health-Related Quality of Life

At week 26, the LSM change in MG-QoL15r score in the placebo arm was –1.6 (95% CI, –3.0 to –0.3) versus –3.3 (95% CI, –4.7 to –1.9) in the ravulizumab arm. The LSM difference in MG-QoL15r score between the ravulizumab and placebo arms was –1.7 (95% CI, –3.4 to 0.1; P = 0.0636).

At week 26, the LSM change in Neuro-QoL Fatigue score in the placebo arm was –4.8 (95% CI, –8.1 to –1.1) versus –7.0 (95% CI, –10.7 to –3.2) in the ravulizumab arm. The LSM difference in Neuro-QoL Fatigue score between the ravulizumab and placebo arms was –2.2 (95% CI, –6.9 to 2.6).

Harms Results

Key harms results during the randomized controlled period of the CHAMPION trial are summarized in Table 2. Most patients (90.7% of ravulizumab-treated patients and 86.5% of placebo-treated patients) experienced adverse events (AEs). The most common AEs were headache (ravulizumab arm = 25.8%; placebo arm = 18.6%), diarrhea (ravulizumab arm = 12.4%; placebo arm = 15.1%), and nausea (ravulizumab arm = 10.1%; placebo arm = 10.5%). A total of 23.3% of ravulizumab-treated patients and 15.7% of placebo-treated patients experienced serious adverse events (SAEs). The most common SAEs were COVID-19 pneumonia (ravulizumab arm = 2.3%; placebo arm = 0%), cellulitis (ravulizumab arm = 0%; placebo arm = 2.2%), transient ischemic attack (ravulizumab arm = 2.3%; placebo arm = 0%), and MG (ravulizumab arm = 0%; placebo arm = 3.4%). Only 2.3% of ravulizumab-treated patients and 3.4% of placebo-treated patients experienced withdrawals due to adverse events (WDAEs). Two (2.3%) patients treated with ravulizumab experienced AEs leading to death. These deaths were due to COVID-19 pneumonia and cerebral hemorrhage (||| |||||| || |||||||| |||| |||||| |||||||||||||| |||||| || ||||| || ||||||||||||||||||| |||||||| | ||||| || ||||||||||||||| |||||||| ||||||||||| ||||||||||. No patients experienced meningococcal infections. | ||||| || ||||| || ||||||||||||||||||| |||||||| || ||||| || ||||||||||||||| |||||||| ||||||||||| |||||||| ||||||||||

Critical Appraisal

There were no major internal validity concerns regarding the CHAMPION trial. Minor baseline imbalances between study arms were viewed as unlikely to be prognostic or to significantly affect the study results. Study discontinuations before completing the randomized controlled period were relatively infrequent (6% to 7% of patients) and missing data for reasons other than discontinuation were relatively rare (1 to 5 patients in each arm, depending on outcome). During the study, concomitant MG therapy was generally similar in both study arms, apart from rescue therapy (IVIg), which was administered more frequently in the placebo arm. Important protocol deviations occurred similarly in both arms and were not viewed as likely to impact the study results. The instruments used to evaluate the primary and secondary efficacy outcomes (MG-ADL, QMG, MG-QoL15r, Neuro-QoL Fatigue) were appropriate and their psychometric properties have been investigated in patients with MG, although no MIDs have been estimated for the MG-QoL15r and Neuro-QoL Fatigue scores. Statistical tests were appropriate overall, power was adequate for the primary analysis, and multiplicity was controlled using a hierarchical testing strategy. Statistical testing for a 3-point or greater improvement in the MG-ADL score and change from baseline in the Neuro-QoL Fatigue score at 26 weeks occurred after a prior nonsignificant result in the statistical hierarchy, so there was an increased risk of type I error. Subgroup analyses identified as being of interest in the CADTH review protocol by MGFA clinical classification and IST at baseline were not adjusted for multiplicity, nor were they specifically powered to detect differences among strata; wide CIs and small numbers of patients within strata reflected imprecision in effect estimates.

According to the clinical experts consulted by CADTH for this review, the demographic and disease characteristics and prior treatment history of patients enrolled in the CHAMPION trial were reflective of the Canadian population of adult patients with anti-AChR antibody–positive gMG that they see in their clinical practice. Although patients with MGFA clinical classifications of class I or class V, patients with MG-ADL scores of less than 6, and patients with thymoma were excluded, the clinical experts stated that a subset of patients with these characteristics could benefit from treatment with ravulizumab, although the results of the trial cannot be generalized to these groups. In addition, changes in concomitant MG therapies would not be generalizable to clinical practice, since changes to these medications were discouraged by the study protocol. However, 2 important external validity issues must be considered in interpreting the results of the CHAMPION study. First, the study enrolled patients with a variety of prior treatment experience and cointerventions at baseline, including patients with no prior IST. There were no specific requirements as to the outcome of prior therapies received and the proportion of the study population with refractory gMG was unknown; however, the clinical experts consulted by CADTH stated that the CHAMPION trial almost certainly would have included some refractory patients, although no subgroup analysis was provided for refractory and nonrefractory patients. According to the clinical experts consulted by CADTH for this review, earlier lines of therapy for nonrefractory MG generally have higher response rates and these patients would be more likely to respond to any therapy compared with patients later in the treatment course (e.g., patients with refractory gMG). Therefore, the results of the CHAMPION trial cannot be directly generalized to any specific line of therapy, including for patients with refractory gMG or patients with severe but nonrefractory gMG. Second, the study was placebo-controlled despite the fact that many of the enrolled patients would have been eligible to receive IST with corticosteroids and steroid-sparing drugs, as well as potentially eculizumab. The study provided no comparative evidence regarding the efficacy of ravulizumab and currently available therapies at various stages of the treatment paradigm for MG, and its results comparing ravulizumab to placebo provided no information regarding the drug’s effectiveness compared with current standard of care.

Indirect Comparisons and Comparative Observational Evidence

Description of Studies

|||||||| |||||||| ||||||||| |||||||| ||||||||| |||||||||| ||||| ||||| |||||| |||| |||||||| |||||||||||| ||||||||||||| ||||| ||||| |||||||||||||||||| ||||||||| ||||| || ||||||| || |||||||||||| || ||||||||| || |||||| || |||||||| || ||||||||||| |||||||| || |||||||||| || |||||||| |||| || || |||| |||| ||||||||||||||||| ||||||||| |||||||||||||| |||||||||| |||||||| |||| |||||||||||||||||| |||||||| |||||||||| |||||| || |||||||||| ||||||||| ||||||||| || |||||||| |||||||| |||| |||| || ||||||| |||||||| |||||||||||| || ||||||||| | |||||| ||||||||||| || |||||||||

Efficacy Results

|||||||| |||||| || |||||||| || |||||||||| |||||||||| ||||||||| ||||||| ||||||||| |||||||||| |||||||| || |||||||||| |||||||| || ||||||||||| |||| ||||||| || |||||| ||||||||||| ||||||||| |||| |||||||||| ||||||||| ||||||| ||||||||||| ||||||||| || |||||| ||||||| || ||||||| |||| || |||||||||| |||||| || ||||||| ||||||||| ||||| | |||||||||||| |||||||| || |||| ||||||||||| ||||||| ||||||||||| || |||||||||| || ||||| |||||||| |||||||| |||||| || ||||||||| || |||| |||||| || |||||| ||||||||| |||| ||||||||| ||||| || ||||| |||||||||| |||||||||| |||||||||||| || |||| |||| ||||||||| || |||||||| ||||||||||| |||||||||| |||||| ||||||||| ||||| |||||| |||||||||| |||||| |||||||||| || ||||||| ||||||||||||||||| |||||| ||||||||||| |||| |||||||||| || |||||||| |||||||||||| |||||| |||||||| || ||||||||| ||||||

Harms Results

No evidence on relative safety or harms were presented for review.

Critical Appraisal

The indirect treatment comparisons (ITCs) and comparative observational study submitted were limited by small effective sample size, selection criteria, and demographic differences between included studies and the absence of adjustment for potentially important clinical covariates. The studies used for comparison were not selected following any systematic process and the risk of bias in the reported results for each study was not assessed. No data were available for hospital admissions, the Myasthenia Gravis Composite (MGC) score, the Myasthenia Gravis Foundation of America Post-intervention Status (MGFA-PIS) score, dose reductions of existing medications, rescue therapy, the MG-QoL15r score, or safety data. Although the appropriateness of each of the selected analysis methods varied depending on the evidence available for comparison, no justifications were provided for the selected methods, nor any direction as to which analysis may have been most valid. The results were inconsistent across the various analyses. As such, there remains uncertainty with respect to the efficacy and safety of ravulizumab relative to eculizumab. These analyses provided no information about the efficacy and safety of ravulizumab relative to other relevant comparators, as identified in the CADTH review protocol.

Other Relevant Evidence

An OL extension study of the CHAMPION trial¹³ is currently ongoing and 60-week data were available at the time this report was prepared. Overall, 91.0% of patients in the placebo arm and 89.5% of patients in the ravulizumab arm of the randomized controlled period received OL ravulizumab in the extension study. Patients randomized to the placebo arm during the randomized controlled period who switched to OL ravulizumab during the extension period experienced numeric improvements in the MG-ADL total score, QMG total score, MG-QoL15r score, and Neuro-QoL Fatigue score that were sustained over the course of the OL extension period. No new safety signals were identified.

Critical Appraisal

Interpretation of the results from the OL extension period was limited by the absence of a randomized comparison group, which precludes causal conclusions. Since patients and study personnel were aware of the treatment received during the extension period, there is a risk of bias in the measurement of subjective outcomes (i.e., MG-ADL, QMG, MG-QoL15r, Neuro-QoL Fatigue, and subjective harms). As long-term efficacy data were summarized descriptively, the absence of formal statistical analysis precluded definitive conclusions. Based on the number of patients in each treatment arm included in the efficacy analysis from the OL extension period baseline to week 60, the data were immature and there is a risk of bias due to missing outcome data at longer follow-up; the magnitude and direction of bias is unknown. However, it should be noted that the missing data are likely due to the fact that not all patients had reached the week-60 visit by the data cut-off.

Conclusions

Evidence from the CHAMPION trial suggested that the administration of ravulizumab in adult patients with anti-AChR antibody–positive gMG (patients had to have an MGFA clinical classification of class II to class IV, an MG-ADL score of 6 or more, and be nonthymomatous) contributed to statistically significant and potentially clinically meaningful improvements compared with placebo in activities of daily living (the MG-ADL total score) and MG disease severity (the QMG total score and the proportion of patients with improvements of at least 5 points in the QMG total score) after 26 weeks of treatment. Results for other outcomes related to disease severity (the MGC score and MGFA-PIS), MG-related hospitalizations, clinical deterioration and the need for rescue therapy, and HRQoL (MG-QoL15r, Neuro-QoL, and 5-Level EQ-5D [EQ-5D-5L]) were supportive of the preceding results, although the lack of formal statistical analysis precluded definitive conclusions. An ongoing OL extension study (60-week data) suggested that patients who switched from placebo to ravulizumab experienced improvements in the aforementioned outcomes that were sustained over the observation period, although the long-term data were descriptive only and the lack of a randomized control group precluded causal conclusions. The safety profile of ravulizumab in the CHAMPION trial was consistent with that reported in the product monograph. Evidence from sponsor-submitted ITCs and an observational study comparing ravulizumab to eculizumab suggested uncertainty in the relative efficacy of these drugs and was limited by small effective sample size, selection criteria, and demographic differences between included studies and the absence of adjustment for potentially important clinical covariates. None of the available evidence provided a clear picture of the efficacy of ravulizumab for any specific place in the MG therapy paradigm (e.g., patients with refractory gMG or severe but nonrefractory gMG) compared with currently available therapies used at various stages of the treatment paradigm. The evidence from the CHAMPION trial was aligned with some outcomes identified as important to patients with MG, who are seeking new therapies that can decrease the intensity of MG exacerbations, allow them to maintain independence, and prevent hospitalization while having acceptable side effects.

Introduction

Disease Background

MG is an autoimmune disease in which antibodies against AChRs or functionally associated molecules in the neuromuscular junction disrupt nerve impulse conduction, resulting in localized or generalized skeletal muscle weakness.² In approximately two-thirds of patients with MG, the disease initially affects the extraocular muscles and in approximately 10% to 20% of these patients, symptoms remain restricted exclusively to the eyes (ocular MG).^2,3 The remainder of patients either are diagnosed with or progress within a few years to gMG, which affects the bulbar and other muscles.^2,3 Symptoms of gMG include eyelid drooping and double vision, altered facial expression, difficulty chewing and swallowing food, difficulty speaking, and, in patients with more severe disease, problems with limb movement and breathing.^2,3 Collectively, symptoms negatively impact HRQoL.⁴ The disease has a fluctuating natural history: MG exacerbation (an increase in symptoms in patients who were previously asymptomatic or minimally symptomatic) and myasthenic crisis (muscle weakness causing life-threatening difficulties with breathing and swallowing, and requiring ventilator support) can occur gradually or without warning.⁵ Autoantibodies against AChR, muscle-specific kinase, and lipoprotein receptor-related protein 4 can be detected in approximately 80% of patients, 1% to 10% of patients, and 1% to 3% of patients with gMG, respectively.¹⁷ Thymoma is present in approximately 10% to 15% of patients with gMG and is associated with more severe disease.¹⁸

Worldwide, the incidence of MG is approximately 4 cases to 30 cases per 1 million population annually and its prevalence is approximately 78 cases to 361 cases per 1 million population.^6-8 In Canada, the incidence of MG is approximately 23 cases per 1 million population annually and its prevalence is approximately 263 cases to 320 cases per 1 million population.^6-8 According to the clinical experts consulted by CADTH for this review, the prevalence worldwide, based on an average of epidemiological studies, may be slightly lower (approximately 100 cases to 200 cases per 1 million population). Diagnosis of MG and gMG is made by a neurologist based on signs and symptoms in conjunction with serological testing (anti-AChR, -muscle-specific kinase, -and lipoprotein receptor-related protein 4 autoantibodies) and electrophysiological testing. In patients with mild symptoms, the disease may be underdiagnosed.

Standards of Therapy

According to the clinical experts consulted by CADTH for this review, mild to moderate gMG (MGFA¹⁵ class II or class IIIa) is initially treated symptomatically with AChEIs (usually pyridostigmine); the onset of benefit occurs in hours to days. If this provides insufficient symptom relief, IST with corticosteroids (usually prednisone) is administered; maximal responses typically occur 2 months to 6 months later, after which the slow tapering of corticosteroids is begun. In patients who do not respond to corticosteroids, who have significant comorbidities such that long-term corticosteroid treatment is contraindicated, or in whom doses of corticosteroids cannot be tapered, treatment with a steroid-sparing immunosuppressant (e.g., azathioprine, mycophenolate mofetil, cyclophosphamide, cyclosporine, tacrolimus, methotrexate) and/or immunomodulatory drugs, including rituximab, may be initiated. The clinical experts explained that the onset of benefit from steroid-sparing drugs occurs in months to years (approximately 9 months to 18 months for azathioprine and mycophenolate). According to the clinical experts, patients with moderate to severe gMG (MGFA class IIIb, class IV, or class V) are often started on all 3 of pyridostigmine, prednisone, and a steroid-sparing drug simultaneously. The clinical experts stated that there is an increasing tendency to use rituximab off label in addition to or in place of steroid-sparing drugs, although access to and reimbursement of rituximab as well as some steroid-sparing drugs varies by jurisdiction. All of the available treatments modify the pathophysiological mechanisms leading to impaired neuromuscular transmission in MG but their relatively nonspecific effects are not restricted to the causative pathogenic autoantibodies. According to the clinical experts, in patients with moderate to severe gMG, especially those who have respiratory or bulbar weakness, IVIg, PE, or PP may be administered in addition to rituximab, either at the time of IST initiation or to treat MG exacerbation or myasthenic crisis. Critical care, including ICU admission and ventilator support, may be required for patients experiencing myasthenic crisis. Surgery (thymectomy) may also be considered in a small group of patients. As MG symptoms improve, doses of AChEIs, corticosteroids, and then other ISTs are reduced and the frequency of IVIg, PE, or PP is reduced until the minimal maintenance therapy required for remission is identified; patients whose symptoms persist despite treatment with adequate doses of corticosteroids, other ISTs, and/or chronic IVIg, PE, or PP or for whom the doses or frequencies of these therapies cannot be reduced are considered to have refractory gMG (approximately 10% to 15% of patients). Patients with refractory gMG who are anti-AChR antibody–positive may soon be candidates for the complement inhibitor eculizumab. A recommendation for reimbursement with conditions was made for eculizumab in 2020,¹⁹ although funding is not yet in place; price negotiations concluded without an agreement in December 2022.¹⁰ Among these drugs, only some (azathioprine, cyclophosphamide, cyclosporine, IVIg, rituximab, and eculizumab) have been rigorously assessed in RCTs while the remainder have been successfully used to treat MG for decades. Some of the drugs prescribed for gMG are prohibitively expensive unless covered by private or public insurance.

According to the clinical experts, the goal of treatment in most patients with gMG is to reduce disease symptoms as well as adverse effects of MG therapy and to allow the patient to function and work normally with good HRQoL. Other goals of treatment include avoiding MG exacerbations and myasthenic crisis, minimizing hospitalizations and ICU admissions, and reducing the numbers and doses of therapies required for symptom control. The clinical experts consulted by CADTH for this review emphasized that MG is not a degenerative disorder and stated that most patients with gMG (more than 80%) will respond well to currently available treatments; although these treatments cannot cure the disease, excellent symptom control is achieved in most patients and prognosis is generally good in terms of muscle strength and function as well as HRQoL. However, many of the patients with MG who respond well to currently available treatments in terms of their MG symptoms still experience treatment-related side effects, which may be severe.

Drug

Key characteristics of ravulizumab and relevant comparators are shown in Table 3. Ravulizumab is a monoclonal antibody that is supplied as a 10 mg/mL or 100 mg/mL concentrate and administered at a maintenance dosage of 3,000 mg to 3,600 mg by IV infusion every 8 weeks.¹⁹ Its mechanism of action involves binding to the complement protein C5, inhibiting C5 cleavage and activation, and thereby disrupting deposition of the membrane attack complex at the neuromuscular junction, preventing damage to the synapse; and impairment of neuromuscular transmission.¹⁹ The drug is an engineered form of eculizumab bearing 4 amino acid substitutions (fragment antigen-binding region: variable heavy chain domain Y27H and variable heavy chain domain S57H; fragment crystallizable region: M428L and N434S) that result in bound C5 being released and degraded in the lysosome as well as extended serum persistence.²⁰

The relevant Health Canada indication for ravulizumab is “for the treatment of adult patients with anti-AChR antibody–positive generalized Myasthenia Gravis (gMG).” The sponsor’s reimbursement request is the same as the Health Canada indication. The drug underwent standard review at Health Canada for this indication and received a Notice of Compliance on January 6, 2023. The drug also has a Health Canada indication “for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH);” it was previously reviewed by CADTH for this indication and received a recommendation for reimbursement with conditions from CDEC on March 2, 2022.¹¹ Ravulizumab was also previously reviewed by CADTH “for the treatment of adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA)” and received a draft recommendation for reimbursement with conditions from CDEC on October 26, 2022.¹²

Table 3: Key Characteristics of Ravulizumab and Other Drugs Used for the Treatment of Generalized Myasthenia Gravis

AChEI = acetylcholinesterase inhibitor; AChR = acetylcholine receptor; gMG = generalized myasthenia gravis; IST = immunosuppressive therapy; IVIg = IV immunoglobulin; NA = not applicable; PE = plasma exchange; PO = per os; PP = plasmapheresis.

^aRelevant Health Canada–approved indications.

^bSupplemental ravulizumab doses of 1,200 mg to 1,800 mg are given following PE or PP and supplemental doses of 600 mg are given following IVIg.

^cSupplemental eculizumab doses of 300 mg to 600 mg are given following PE or PP.

Sources: Sponsor’s drug reimbursement review submission for ravulizumab¹ and product monographs for ravulizumab,¹⁹ eculizumab,²¹ and pyridostigmine.²²

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by a patient group. The original patient group submission can be found at the end of this report.

One patient group, Muscular Dystrophy Canada, provided input for this review. Information was collected from 149 individuals impacted by MG through a health care experience survey and semistructured phone or virtual interviews. These individuals consisted of 92 (61.7%) women and 57 (38.3%) men from all provinces of Canada, including 9 respondents from Quebec and 29 patients with a confirmed diagnosis of anti-AChR antibody–positive gMG; ages ranged from 23 years to 75 years. Half of patients (50%) recounted difficulties with their MG diagnosis, including delays, misdiagnoses, and costs incurred. The patient group input highlighted the negative impacts of MG on daily activities and HRQoL, including fatigue and sleep disruptions, lack of strength and mobility, decreased independence and social participation, eyesight problems, difficulties with speech and swallowing, loss of employment and financial hardships, and mental health burdens for family members. The input also highlighted the potential benefits and side effects of currently available treatments, including prednisone (depression, weight gain, diabetes), pyridostigmine (diarrhea, nausea, jumpy legs), thymectomy (painful recovery), and IVIg (inconvenience of hospital administration). Respondents indicated that currently available therapies may decrease MG exacerbations but not their overall impact on HRQoL. Only 1 respondent had experience with ravulizumab and felt it had been helpful in improving their symptoms. Respondents identified an unmet need for new treatments that can decrease the intensity of MG exacerbations, allow them to maintain independence, and prevent hospitalization. Patients also desired treatments with minimal side effects and convenient administration (e.g., once daily oral administration, easy to swallow, fast onset, long duration of action, low cost) but indicated they would be willing to accept the side effects of new therapies that better control the consequences of MG.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of patients with anti-AChR antibody–positive gMG.

Unmet Needs

According to the clinical experts consulted by CADTH for this review, in some patients with gMG, symptom control can only be achieved by the chronic administration of IVIg every 1 to 4 weeks, which is both inconvenient for patients and a burden to health care systems. For other patients, symptom control cannot be achieved with any standard treatment (refractory gMG). In these patients, there are very few remaining options, including complement inhibitors (eculizumab, ravulizumab) and neonatal fragment crystallizable receptor inhibitors (currently under review by Health Canada). More commonly, patients experience side effects of currently available treatments (especially corticosteroids, but also steroid-sparing drugs) that necessitate permanent discontinuation of the drug; IST also carries some risk of general immunosuppression with the attendant risk of infection. To achieve sustained clinical benefit, many patients need to take these medications (e.g., corticosteroids, steroid-sparing drugs) for years, if not lifelong. The clinical experts stated that additional treatments are needed with more rapid onset of action, longer-lasting benefits, improved efficacy in patients who don’t respond to standard treatments, and fewer side effects.

Place in Therapy

The clinical experts consulted by CADTH for this review stated that ravulizumab is a terminal complement inhibitor with a similar mechanism of action to eculizumab, which is rarely used — in part due to high cost — and only in adult patients with refractory anti-AChR antibody–positive gMG. The clinical experts explained that refractory gMG is typically defined as the failure of AChEIs, corticosteroids, and 2 other ISTs to control symptoms when given at adequate doses and durations, or intolerance to these treatments. In these patients, complement inhibitors (eculizumab or ravulizumab) would be added to standard treatment (AChEIs, IST, IVIg, PE or PP), although if treatment is successful, some of these standard drugs may be reduced or discontinued. The clinical experts noted that ravulizumab has a distinct mechanism of action and thus may be used in combination with standard treatments. The clinical experts felt that there might be a rationale for the use of either ravulizumab or eculizumab early in the disease course in patients with more severe disease (MGFA class IIIb, class IV, or class V) in addition to or instead of other options (e.g., AChEIs, IST, IVIg, PE or PP), given their more rapid onset of benefit compared with steroid-sparing drugs and longer duration of temporary benefit before additional treatments are required compared with IVIg, PE, or PP. However, the clinical experts acknowledged that at the moment, there are limited data to justify this approach. According to the clinical experts, it would be appropriate for patients to try other treatments (AChEIs, IST) before initiating ravulizumab because currently available standard treatments are generally effective in most patients. The clinical experts stated that it would be difficult to recommend the early use of ravulizumab unless it was clearly more effective and/or pharmacoeconomically favourable compared with other treatments (e.g., chronic IVIg, PE or PP, rituximab).

Patient Population

According to the clinical experts consulted by CADTH for this review, the misdiagnosis of patients with anti-AChR antibody–positive gMG is uncommon. However, clinicians with limited experience in managing patients with gMG tend to be quick to label patients as refractory to standard therapy, when in fact these treatments may simply require more time to take effect (sometimes many months or even years). The clinical experts also indicated that in patients with severe gMG at initial presentation (e.g., MGFA class IIIb, MGFA class IV, MGFA class V), some neurologists would wish to use a complement inhibitor early in the treatment course (ravulizumab or eculizumab) due to greater clinical need in these patients, although they acknowledged this use falls outside the Health Canada indication for eculizumab. The clinical experts emphasized that determining whether symptoms are truly secondary to refractory or severe gMG, rather than arising from comorbidities or adverse effects of existing therapy, is very challenging; in their experience, up to half of patients who could be labelled as having refractory disease not responding to treatment or severe disease have reasons other than MG for their symptoms. It is not currently possible to predict which adult patients with anti-AChR antibody–positive gMG would be most likely to respond to ravulizumab. Therefore, clinician judgment would be the principal means by which candidates for ravulizumab (primarily patients with refractory gMG, as well as potentially those with severe gMG) would be identified. The clinical experts noted that serologic testing for anti-AChR antibodies would be required to identify eligible patients; complement inhibitors may not be effective in patients who are seronegative for anti-AChR antibodies (because anti-AChR antibody binding by complement and initiation of the complement cascade is mechanistically involved in the disease). A chest CT may also be required to rule out thymoma and thymic carcinoma. However, the clinical experts emphasized that while patients with thymoma were excluded from the pivotal trial, there is no reason they would not be expected to benefit from ravulizumab.

Assessing Response to Treatment

The clinical experts stated that response to ravulizumab would be assessed by monitoring patient symptoms and/or signs on clinical examination. Some clinicians use a standard bedside assessment while others use instruments such as the MG-ADL and QMG scores. Typically, assessments are performed every 1 month to 3 months. According to the clinical experts, clinically meaningful responses would be reflected by improvements in disease symptoms (approximately 2 points for the MG-ADL score and approximately 3 points for the QMG score). In addition, clinically meaningful responses to ravulizumab may be manifested by the reduction of other treatments (especially chronic IVIg, PE or PP, and rituximab) as well as reduced hospitalizations and health care usage even if the clinical status of the patient remained unchanged.

Discontinuing Treatment

The clinical experts consulted by CADTH for this review stated that ravulizumab would be discontinued in patients who do not achieve clinical improvement or are unable to reduce the numbers and doses of other MG therapies, in patients who experience worsening of MG symptoms requiring additional interventions, in patients who experience serious toxicities such as meningococcal infections, or by patient preference. The clinical experts noted that the current treatment paradigm for gMG involves initiating treatment until improvement occurs, achieving stability and minimal manifestations, and then slowly withdrawing treatment 1 drug at a time. Some neurologists who manage patients with gMG would follow this approach with complement inhibitors as well, likely 1 year to 2 years after treatment initiation. However, the clinical experts also noted that in some patients, treatment with complement inhibitors, including ravulizumab, could be lifelong if this is required to achieve sustained clinical benefit (refer to “Unmet Needs” earlier in this section).

Prescribing Conditions

The clinical experts consulted by CADTH for this review stated that treatment with ravulizumab would be initiated and supervised by a neurologist with expertise in managing patients with MG. As stated earlier, it would be difficult for nonexpert neurologists to assess patients with gMG to determine whether the main symptoms leading to the request for coverage of a complement inhibitor are actually secondary to MG; if they are not, treatment with ravulizumab will not succeed, resulting in needless exposure to and unnecessary cost of this treatment. The drug would typically be administered in a hospital setting or at an infusion clinic.

Additional Information

The clinical experts consulted by CADTH for this review noted that while the sponsor’s reimbursement request includes all patients with gMG who are anti-AChR antibody–positive, access may be limited to patients with refractory and/or severe disease. Of these 2 patient subpopulations, the clinical experts felt that there is a greater clinical need for ravulizumab in those with refractory gMG (e.g., any severity including milder MGFA class II myasthenia that does not respond to treatment) compared with those with severe gMG that is not refractory (e.g., newly diagnosed MGFA class IIIb, class IV, or class V myasthenia that remains untreated or undertreated).

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by a clinician group. The original clinician group submission can be found at the end of this report.

One clinician group, NMD4C, provided input for this review that reflected the views of 4 neurologists with experience in the management of patients with gMG. No major contrary views were presented that diverged from those provided by the clinical experts consulted by CADTH for this review. The clinician group reiterated that standard treatments for gMG are often transiently effective, may require relatively long treatment periods for benefits to be observed, may carry side effects, and may not be effective in all patients. NMD4C indicated that ravulizumab would be unlikely to cause a shift in the standard treatment paradigm for gMG and would be used as an add-on therapy in patients with anti-AChR antibody–positive gMG who are not responsive to AChEIs and IST, and who require chronic IVIg, PE, or PP. The clinician group noted the more convenient administration of ravulizumab at every 8 weeks compared with eculizumab at every 2 weeks.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

CDEC = CADTH Canadian Drug Expert Committee; FWG = Formulary Working Group; IVIg = IV immunoglobulin; MG = myasthenia gravis.

Clinical Evidence

The clinical evidence included in this review of ravulizumab is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and any indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and any additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of ravulizumab for the treatment of adult patients with anti- AChR antibody–positive gMG.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Of note, the systematic review protocol presented as follows was established before the granting of a Notice of Compliance from Health Canada.

Table 5: Inclusion Criteria for the Systematic Review

AChEI = acetylcholinesterase inhibitor; AChR = acetylcholine receptor; AE = adverse event; EQ-5D-5L = 5-Level EQ-5D; gMG = generalized myasthenia gravis; HRQoL = health-related quality of life; ICU = intensive care unit; IST = immunosuppressive therapy; IVIg = IV immunoglobulin; MG = myasthenia gravis; MG-ADL = Myasthenia Gravis Activities of Daily Living; MG-QoL15r = Myasthenia Gravis Quality of Life 15-item scale - Revised; MGC = Myasthenia Gravis Composite; MGFA-PIS = Myasthenia Gravis Foundation of America Post-intervention Status; Neuro-QoL = Quality of Life in Neurological Disorders; PE = plasma exchange; PP = plasmapheresis; QMG = Quantitative Myasthenia Gravis; RCT = randomized controlled trial; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.²³

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in Endnote. The search strategy consisted of both controlled vocabulary, such as the US National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Ultomiris (ravulizumab). Clinical trials registries were searched: the US National Institutes of Health’s ClinicalTrials.gov, the WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on November 22, 2022. Regular alerts updated the search until the meeting of CDEC on March 22, 2023.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.²⁴ Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

No studies were identified from the literature for inclusion in the systematic review, while 2 reports of a single study were identified from other sources (Figure 1). The included study is summarized in Table 6.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Note: The publication of the CHAMPION trial (Vu et al. [2022])¹⁴ was not identified in the literature search because the journal in which it appeared, NEJM Evidence, was not indexed in MEDLINE or Embase at the time the search was conducted.

Table 6: Details of the Included Study

AChR = acetylcholine receptor; DB = double-blind; EQ-5D-5L = 5-Level EQ-5D; IST = immunosuppressive therapy; IVIg = IV immunoglobulin; MG = myasthenia gravis; MG-ADL = Myasthenia Gravis Activities of Daily Living; MG-QoL15r = Myasthenia Gravis Quality of Life 15-item scale - Revised; MGC = Myasthenia Gravis Composite; MGFA = Myasthenia Gravis Foundation of America; MGFA-PIS = Myasthenia Gravis Foundation of America Post-intervention Status; Neuro-QoL = Quality of Life in Neurological Disorders; OL = open-label; PD = pharmacodynamics; PE = plasma exchange; PK = pharmacokinetics; PP = plasmapheresis; q.8.w. = every 8 weeks; QMG = Quantitative Myasthenia Gravis; RCT = randomized controlled trial.

Note: One additional report was included (CHAMPION Clinical Study Report).

Sources: CHAMPION Clinical Study Report¹³ and Vu et al. (2022).¹⁴

Description of Studies

Key characteristics of the CHAMPION trial are shown in Table 6 and a summary of its design is shown in Figure 2. The CHAMPION trial (study identification number ALXN1210-MG-306, N = 175)^13,14 was a phase III, DB, multicentre, placebo-controlled RCT with an OL extension period of up to 4 years. Note that only results from the randomized controlled period are described in the Systematic Review (Pivotal and Protocol Selected Studies) section of this report, while results from the OL extension period are summarized in the Other Relevant Evidence section. The primary objective of the CHAMPION trial was to evaluate the safety and efficacy of ravulizumab compared with placebo in complement inhibitor–naive adult patients with gMG.

Following screening, adult patients with anti-AChR antibody–positive gMG were enrolled at 85 centres in 13 countries (primarily North America and Europe; there were 5 sites in Canada) and randomized 1:1 to receive either a weight-based dose of ravulizumab or a matching placebo for 26 weeks. Randomization was stratified by region (North America, Europe, Asia-Pacific, and Japan). The randomized controlled portion of the trial is complete (the data cut-off date was May 11, 2021, and the database was locked on June 30, 2021) and the OL extension is ongoing. The study was funded by the sponsor.

Figure 2: Overall Design of the CHAMPION Trial

DB = double-blind; LD = loading dosage; MD = maintenance dosage; OL = open-label; q8w = every 8 weeks.

Note: In the original study protocol, OL treatment with ravulizumab could continue for up to 2 years. In May 2021, a protocol amendment was made to allow for OL treatment for up to 4 years.

Source: CHAMPION Clinical Study Report.¹³

Populations

Inclusion and Exclusion Criteria

The eligibility criteria for the CHAMPION trial are shown in Table 6. Adult patients (aged 18 years or older) with a confirmed diagnosis of anti-AChR antibody–positive MG, an MGFA clinical classification of class II to class IV, and an MG-ADL total score of 6 or more were eligible if they were on stable doses of AChEIs, corticosteroids, and steroid-sparing drugs, and received meningococcal vaccination. Patients with active or untreated thymoma or a history of thymic carcinoma, thymic malignancy, thymectomy, or meningococcal infection were excluded, as were patients previously treated with complement inhibitors. Patients who received IVIg or PE within 4 weeks of randomization or rituximab within 6 months before screening were also excluded. Note that the eligibility criteria did not include any stipulations regarding prior treatment experience or its outcome, in contrast with the REGAIN study of eculizumab, in which only patients with refractory gMG were eligible.

Baseline Characteristics

The baseline demographic characteristics of patients in the CHAMPION trial are shown in Table 7. Approximately half of patients (50.9%) were female. In the ravulizumab arm, approximately three-quarters of patients (77.9%) were white, while 17.4% were Asian and 2.3% were Hispanic or Latino. In the placebo arm, approximately two-thirds of patients (68.5%) were white, while 18.0% were Asian and 5.6% were Hispanic or Latino. The mean age at first infusion was 53.3 (SD = 16.05) years in the placebo arm and 58.0 (SD = 13.82) years in the ravulizumab arm. Most patients were from either North America (45.7%) or Europe (36.6%).

Table 7: Summary of Demographic and Baseline Characteristics in the CHAMPION Trial — Full Analysis Set

SD = standard deviation.

Source: CHAMPION Clinical Study Report.¹³

The baseline disease characteristics of patients in the CHAMPION trial are shown in Table 8. The mean age at diagnosis was 43.7 (SD = 19.04) years in the placebo arm and 48.6 (SD = 18.54) years in the ravulizumab arm, while the mean time elapsed from MG diagnosis to enrolment in the overall study population was 9.9 (SD = 9.27) years. Approximately one-third of patients (32.6%) in the placebo arm and approximately one-quarter of patients (24.4%) in the ravulizumab arm had ocular MG at diagnosis. Among patients whose first presentation was ocular MG, the mean time to gMG was 24.1 (SD = 54.0) months in the placebo arm and 15.2 (SD = 31.2) months in the ravulizumab arm. Prior to screening, approximately half of patients (55.7%) had experienced moderate to severe MG (MGFA class IIIb, class IV, or class V), 60.0% of patients had experienced MG exacerbations, 24.4% of patients had experienced MG crises, and 17.1% of patients had required ventilator support. The total number of prior MG exacerbations was 100 in the placebo arm and 169 in the ravulizumab arm. At the study baseline, 18.0% of patients in the placebo arm and 29.1% of patients in the ravulizumab arm had moderate to severe MG (MGFA class IIIb or class IV). The mean baseline MG-ADL and QMG total scores in the overall study population were 9.0 (SD = 2.46) and 14.7 (SD = 5.22), respectively.

Table 8: Summary of Baseline Disease Characteristics in the CHAMPION Trial — Full Analysis Set

gMG = generalized myasthenia gravis; MG = myasthenia gravis; MG-ADL = Myasthenia Gravis Activities of Daily Living; MGFA = Myasthenia Gravis Foundation of America; QMG = Quantitative Myasthenia Gravis; SD = standard deviation.

^aTotal patient-years was defined as follows: ([informed consent date minus MG diagnosis date] plus 1) divided by 365.25.

^bEvents of MG crisis before screening were documented based on the patient’s medical history.

Source: CHAMPION Clinical Study Report.¹³

Prior MG treatments in the CHAMPION trial are shown in Table 9. All patients had received prior MG therapy, nearly all patients had received pyridostigmine (93.1%), approximately three-quarters of patients (76.6%) had received corticosteroids, and approximately three-quarters of patients (77.1%) had received steroid-sparing ISTs. In the placebo arm, 80.9% of patients had previously received corticosteroids compared to 72.1% of patients in the ravulizumab arm. Nearly half of patients (43.4%) had received IVIg, approximately one-fifth of patients had received PE or PP (19.4%), and only 6.3% of patients had received rituximab.

Within 2 years before screening, 110 (62.9%) patients had received 2 or more ISTs, 56 (32.0%) patients had received 1 IST, and 9 (5.1%) patients had received no IST. At the first dose of study drug, 83 (47.4%) patients were receiving 2 or more ISTs, 74 (42.3%) patients were receiving 1 IST, and 18 (10.3%) patients were receiving no IST.

Table 9: Summary of Prior Myasthenia Gravis Treatments in the CHAMPION Trial — Safety Set

NOS = not otherwise specified; PE = plasma exchange; PP = plasmapheresis.

^aTreatments used in 5% or more of patients in either treatment group are listed.

^bPP or PE within 2 years before screening.

Source: CHAMPION Clinical Study Report.¹³

Interventions

Patients received a body weight-based loading dose of ravulizumab (10 mg/mL concentrate) on day 1 as per the following:

• 40 kg or greater but less than 60 kg — 2,400 mg, with a minimum infusion time of 1.9 hours

• 60 kg or greater but less than 100 kg — 2,700 mg, with a minimum infusion time of 1.7 hours

• 100 kg or greater — 3,000 mg, with a minimum infusion time of 1.8 hours.

Subsequently, patients received body weight-based maintenance doses of ravulizumab on day 15 and every 8 weeks (± 2 days) thereafter during the randomized controlled period (week 10 and week 18) as per the following:

• 40 kg or greater but less than 60 kg — 3,000 mg, with a minimum infusion time of 2.3 hours

• 60 kg or greater but less than 100 kg — 3,300 mg, with a minimum infusion time of 2.0 hours

• 100 kg or greater — 3,600 mg, with a minimum infusion time of 2.2 hours.

Supplemental doses of ravulizumab were administered if IVIg, PE, or PP rescue therapy was provided on nondosing days (no supplemental drug was given if rescue therapy was provided prior to study drug administration on a dosing day). Supplemental ravulizumab was administered within 4 hours of each PE or PP session or within 4 hours of the completion of each IVIg cycle. A fixed dose of 600 mg of ravulizumab was administered following IVIg (minimum infusion time 0.4 hours to 0.5 hours). Patients received a body weight-based supplemental dose of ravulizumab following PE or PP as per the following:

• 40 kg or greater but less than 60 kg — most recent dose being 2,400 mg, therefore supplemental dose of 1,200 mg, with minimum infusion time of 1.0 hour; most recent dose being 3,000 mg, therefore supplemental dose of 1,500 mg, with minimum infusion time of 1.2 hours

• 60 kg or greater but less than 100 kg — most recent dose being 2,700 mg, therefore supplemental dose of 1,500 mg, with minimum infusion time of 1.0 hour; most recent dose being 3,300 mg, therefore supplemental dose of 1,800 mg, with minimum infusion time of 1.1 hours

• 100 kg or greater — most recent dose being 3,000 mg, therefore supplemental dose of 1,500 mg, with minimum infusion time of 1.0 hour; most recent dose being 3,600 mg, therefore supplemental dose of 1,800 mg, with minimum infusion time of 1.1 hours.

The matching placebo, consisting of a sterile clear solution in an identically packaged 30 mL vial, was administered on the same schedule. All investigative site personnel, sponsor staff, designees, staff directly associated with the conduct of the study, and patients were blinded to treatment assignment.

The matching placebo, consisting of a sterile clear solution in an identically packaged 30 mL vial, was administered on the same schedule. All investigative site personnel, sponsor staff, designees, staff directly associated with the conduct of the study, and patients were blinded to treatment assignment.

Allowed concomitant medications included AChEIs, immunosuppressive drugs (corticosteroids, azathioprine, mycophenolate, methotrexate, tacrolimus, cyclosporine, cyclophosphamide), and rescue therapy with IVIg, PE, or PP. Patients who entered the study receiving AChEIs were to maintain the dose and schedule unless there was a compelling medical need; AChEIs were withheld for at least 10 hours prior to QMG and MGC assessments. Patients who entered the study receiving corticosteroids or IST were to maintain the dose and schedule; dose changes needed to be authorized by the sponsor and corticosteroid dose increases could not exceed the dose at baseline. Disallowed concurrent medications included rituximab and eculizumab (or other complement inhibitors).

Rescue therapy with IVIg, PE, or PP could be administered for clinical deterioration, defined per protocol as 1 of the following:

• an MG crisis (respiratory muscle weakness severe enough to necessitate intubation or delay extubation following surgery, often accompanied by severe bulbar muscle weakness)

• a significant symptomatic worsening to a score of 3 points or a 2-point worsening from baseline on any 1 of the individual MG-ADL items other than double vision or eyelid droop

• patient health would be in jeopardy if rescue therapy were not given, in the opinion of the investigator or investigator-designated physician.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the CHAMPION trial is provided in Table 10. These end points are briefly summarized as follows (categorized according to the end points identified in the CADTH review protocol). A detailed discussion and critical appraisal of the outcome measures and their measurement properties is provided in Appendix 2.

Table 10: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

EQ-5D-5L = 5-Level EQ-5D; MG = myasthenia gravis; MG-ADL = Myasthenia Gravis Activities of Daily Living; MG-QoL15r = Myasthenia Gravis Quality of Life 15-item scale - Revised; MGC = Myasthenia Gravis Composite; MGFA-PIS = Myasthenia Gravis Foundation of America Post-intervention Status; Neuro-QoL = Quality of Life in Neurological Disorders; QMG = Quantitative Myasthenia Gravis.

Source: CHAMPION Clinical Study Report.¹³

Activities of Daily Living

The MG-ADL²⁵ is an 8-item patient-reported outcome measure assessing MG symptoms and functional activities related to activities of daily living and produces a total score ranging from 0 to 24, where higher scores indicate greater severity of symptoms and a more significant impact on daily living. Each of the 8 subcomponents is scored from 0 to 3, where higher scores indicate greater severity of symptoms and greater impact on daily living. The recall period is the preceding 7 days. The validity of the MG-ADL instrument in patients with MG was demonstrated by strong correlations with MGC and Myasthenia Gravis Quality of Life 15-item scale (MG-QoL15) scores as well as with physician impression of change. Reliability was demonstrated by high test-retest concordance and responsiveness to change was demonstrated by correlations between improvements in MG-ADL total score, improvements in MG-QoL15 score, and physician impression of change. Although no MID has been estimated, an improvement of approximately 2 points in the total MG-ADL score is a recommended response threshold that indicates clinical improvement at the level of individual patients with MG. No MIDs have been estimated for the subcomponent scores. Change from baseline in MG-ADL total score at week 26 of the randomized controlled period was the primary outcome of the CHAMPION trial, while the proportion of patients experiencing improvements of at least 3 points in MG-ADL total score at week 26 was a secondary outcome. Change from baseline in MG-ADL subcomponent scores (bulbar, limbs, respiratory, and ocular) at week 26 was an exploratory outcome.

Disease Severity

The QMG²⁶ is a 13-item direct physician assessment scoring system that quantifies MG disease severity, based on impairments of body functions and structures; it produces a total QMG score ranging from 0 to 39, where higher scores indicate greater disease severity. Each of the 13 subcomponents is scored from 0 to 3, where higher scores indicate greater disease severity. The validity of the QMG instrument in patients with MG was demonstrated by correlations with the manual muscle test (MMT); reliability was demonstrated by high internal consistency and test-retest concordance, and responsiveness to change was demonstrated by correlations between improvements in QMG total score and physician impression of change, as well as evidence from clinical trials of IVIg and cyclosporine showing greater improvements in the active arms compared with the placebo arms. An MID of approximately 3 points has been estimated at the level of individual patients with MG. No MIDs have been estimated for the subcomponent scores. Change from baseline in QMG total score at week 26 of the randomized controlled period and the proportion of patients with improvements of at least 5 points in QMG total score at week 26 were secondary outcomes of the CHAMPION trial. Change from baseline in QMG subcomponent scores (bulbar, limbs, respiratory, and ocular) at week 26 was an exploratory outcome.

The MGC²⁸ is a 10-item instrument that measures the symptoms and signs of MG based on physician examination and patient history. The total score ranges from 0 to 50, where higher scores indicate more severe impairments. The validity of the MGC instrument in patients with MG was demonstrated by strong correlations with the MG-QoL15 score, MG-ADL total score, and MMT score; reliability was demonstrated by high internal consistency and test-retest concordance. Responsiveness to change of the MGC score has not been assessed in patients with MG. A 3-point improvement in the MGC score reflects a meaningful improvement at the level of individual patients with MG. MGC was an exploratory outcome in the CHAMPION trial.

The MGFA-PIS¹⁵ is designed to assess the clinical state of patients with MG after they have received treatment. It provides the physician’s global assessment of the patient’s clinical status. MGFA-PIS does not have an evaluative purpose and is aimed at stratifying patients based on disease severity and locations of symptoms; therefore, its measurement properties (validity, reliability, responsiveness to change, and MID) are unknown. MGFA-PIS at week 26 was an exploratory outcome in the CHAMPION trial.

Hospital Admission, Intensive Care Unit Admission, and Need for Ventilator Support

The incidence and duration of hospitalizations and MG-related hospitalizations, including requirement for ventilator support, was an exploratory outcome in the CHAMPION trial. Information on ICU admissions was not available.

Number and Dose of Existing Medications

Change in concomitant MG medications was not an efficacy outcome in the CHAMPION trial but this information was collected during the trial.

Need for Rescue Therapy

The frequency of clinical deterioration and need for rescue therapy (IVIg, PE, or PP) was an exploratory outcome in the CHAMPION trial.

Health-Related Quality of Life

The MG-QoL15³⁰ is a 15-item questionnaire that allows clinicians to estimate a patient’s MG-specific HRQoL. The MG-QoL15 score ranges from 0 to 60, with higher scores representing worse HRQoL. MG-QoL15r²⁷ is a revised version of the MG-QoL15, in which 3 items from the original MG-QoL15 scale were reworded to improve the instrument’s clinimetric properties and face and content validity. The validity of the original MG-QoL15 instrument was demonstrated by strong correlations with MGC score and the physical and mental components of the Short Form (36) Health Survey, as well as moderate correlations with the QMG total score, MG-ADL total score, and the MMT. The reliability of the original MG-QoL15 instrument was demonstrated by high internal consistency and test-retest concordance, while responsiveness to change has not been studied. The validity of the revised MG-QoL15r instrument was demonstrated by correlations with the MG-ADL total score, QMG total score, MGC score, and MGFA clinical classification. The reliability of the revised MG-QoL15r instrument was demonstrated by high internal consistency, while responsiveness to change was demonstrated by correlations between changes in the MG-QoL15r score and changes in the QMG total score, MG-ADL total score, and MGC score. The MID has not been estimated for either the original or revised instrument. Change from baseline in the MG-QoL15r score at week 26 of the randomized controlled period was a secondary outcome in the CHAMPION trial.

The Neuro-QoL¹³ Fatigue score is a patient-reported, generic, 19-item survey of fatigue. Scores range from 19 to 95, where higher scores indicate greater fatigue and greater impact of MG on activities. The measurement properties of the Neuro-QoL Fatigue score have only been studied in patients with refractory gMG participating in the REGAIN trial of eculizumab. The validity of the Neuro-QoL Fatigue score in patients with refractory gMG was demonstrated by strong correlations with MG-QoL15 scores, while variable (strong to weak) correlations were observed between the Neuro-QoL Fatigue score, MG-ADL total score, and QMG total score. The reliability and responsiveness to change in the Neuro-QoL Fatigue assessment in patients with MG have not been investigated. The MID has not been estimated in patients with MG. Change from baseline in the Neuro-QoL Fatigue score at week 26 of the randomized controlled period was a secondary outcome in the CHAMPION trial.

The EQ-5D-5L²⁹ is a generic preference-based HRQoL instrument, consisting of the EQ visual analogue scale (EQ VAS) and a composite index score. EQ VAS scores range from 0 (worst imaginable health) to 100 (best imaginable health), while index scores range from less than 0 (negative values representing worse than dead, which is scored as 0) to 1 (full health), with higher scores representing higher health utility. The measurement properties of the EQ-5D-5L instrument have not been studied in patients with MG and the MID has not been estimated. Change from baseline in EQ-5D-5L at week 26 of the randomized controlled period was an exploratory outcome in the CHAMPION trial.

Harms Outcomes

Harms outcomes included treatment-emergent AEs, SAEs, AEs leading to infusion interruption, WDAEs, and deaths. AEs that began or worsened on or after the start of protocol therapy until the end of the randomized controlled period (week 26, 8 weeks after the last study drug infusion) were captured. The only AE of special interest was meningococcal infection. AEs were defined as any untoward medical occurrence and were coded according to Medical Dictionary for Regulatory Activities version 24.0³¹ and graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 5.0.³²

Statistical Analysis

Statistical analysis of efficacy outcomes in the CHAMPION trial is summarized in Table 11. No interim analyses were planned and the primary analysis was to be conducted once the last patient completed the randomized controlled period, the database was locked, and the study was unblinded.

Table 11: Statistical Analysis of Efficacy End Points in the CHAMPION Trial

CCA = complete case analysis; EQ VAS = EQ visual analogue scale; EQ-5D-5L = 5-Level EQ-5D; FAS = full analysis set; GLMM = generalized linear mixed model; LSM = least squares mean; MAR = missing at random; mFAS = modified full analysis set; MG = myasthenia gravis; MG-ADL = Myasthenia Gravis Activities of Daily Living; MG-QoL15r = Myasthenia Gravis Quality of Life 15-item scale - Revised; MGC = Myasthenia Gravis Composite; MGFA-PIS = Myasthenia Gravis Foundation of America Post-intervention Status; MMRM = mixed model of repeated measures; MNAR = missing not at random; Neuro-QoL = Quality of Life in Neurological Disorders; OR = odds ratio; PPS = per-protocol set; QMG = Quantitative Myasthenia Gravis.

Source: CHAMPION Clinical Study Report.¹³

Power Calculations

The planned sample size of approximately 160 patients (randomized 1:1 to receive ravulizumab or placebo, stratified by region) was selected to ensure at least 90% nominal power to reject the null hypotheses of no treatment difference for the primary and secondary end points at a 2-sided alpha level of 0.05 and based on a t-statistic for 2 independent samples. Power calculations were based on longitudinal change from baseline in the MG-ADL total score observed in the REGAIN trial;³³ the difference between the eculizumab and placebo arms in mean change (95% CI) from baseline to week 26 in the MG-ADL total score was estimated to be –1.9 (–3.27 to 0.55) and the estimated common SD was 3.7. It was assumed that the CHAMPION trial would provide similar results. A simulation-based approach was also used to verify sample size calculations. A large number of virtual datasets were generated in which 160 patients (80 patients in the ravulizumab arm and 80 patients in the placebo arm) each had a baseline MG-ADL total score and longitudinal change in the MG-ADL total score generated according to the treatment-specific variance-covariance structure from the REGAIN study. The empirical power was calculated as the proportion of simulations that rejected the null hypothesis using the analytical techniques described as follows. Power calculations for secondary outcomes were not provided.

Control of Type I Error

Type I error was controlled using a closed-loop hierarchical testing strategy to limit the overall 2-sided type I error rate to alpha being equal to 0.05. Between the primary and secondary efficacy outcomes, and within the secondary outcomes, a sequential hypothesis testing procedure was used for multiplicity adjustment. The primary outcome (change in the MG-ADL total score from baseline to week 26) was tested first, followed by 5 secondary outcomes in the following order: (1) change in QMG total score from baseline to week 26, (2) proportion of patients with improvements of at least 5 points in the QMG total score from baseline to week 26, (3) change in the MG-QoL15r score from baseline to week 26, (4) change in the Neuro-QoL Fatigue score from baseline to week 26, and (5) the proportion of patients with improvements of at least 3 points in the MG-ADL total score from baseline to week 26. All null hypotheses were tested at alpha being equal to 0.05. If statistical significance was not achieved for an end point within the hierarchy, subsequent end points in the prespecified order were not to be considered statistically significant and all P values were considered nominal. Exploratory efficacy outcomes were not included in the hierarchical testing strategy and statistical tests of these outcomes were not adjusted for multiplicity.

Analytical Techniques

For the primary analysis of change from baseline in the MG-ADL total score at week 26, the LSM change in the ravulizumab and placebo arms (full analysis set [FAS]) was compared via the LSM difference using the mixed model of repeated measures (MMRM) method. The model included MG-ADL change from baseline as the response variable, fixed categorical effects of treatment, study visit, and treatment-by-study-visit interaction, the randomization stratification variable of geographical region, and the fixed covariate of baseline MG-ADL total score. An unstructured covariance matrix was used to model correlations among repeated measurements within each patient. If this analysis failed to converge, the following structures were tested and the final covariance structure determined using the Akaike information criterion: first-order autoregressive, compound symmetry, and Toeplitz method. For the primary analysis, missing data were not imputed.

The secondary outcomes of change from baseline in the QMG total score, MG-QoL15r score, and Neuro-QoL Fatigue score at week 26 were analyzed as per the primary analysis (using the baseline values of each score as fixed covariates). For the secondary outcomes of the proportions of patients with improvements from baseline of at least 3 points in the MG-ADL total score and of at least 5 points in the QMG total score at week 26, the proportions of patients with various point reductions were analyzed using the generalized linear mixed model method. The models included the MG-ADL 3-point and QMG 5-point responses at postdosing visits as response variables, fixed categorical effects of treatment, study visit, and treatment-by-study visit interactions, the randomization stratification variable of geographic region, and a fixed covariate of baseline MG-ADL total score or QMG total score as continuous variables. An unstructured covariance matrix was used to model the correlations among repeated measurements within each patient; if the analysis failed to converge, a first-order autoregressive structure in which the highest correlation assumed between visits that were closest in time was used. ORs of treatment effect along with 2-sided 95% CIs and P values were calculated.

The exploratory outcomes of changes from baseline in MG-ADL subcomponent scores, QMG subcomponent scores, the MGC score, and the EQ-5D-5L VAS and index score at week 26 were analyzed as per the primary analysis. For the exploratory outcome of MGFA-PIS at week 26, descriptive and summary statistics were presented; in addition, the proportional OR of the cumulative proportions of patients within ordinal categories was calculated. For the exploratory outcomes of incidence of hospitalization, MG-related hospitalization, clinical deterioration, and MG crisis, descriptive and summary statistics were presented; in addition, ORs were calculated using logistic regression models that included treatment group and geographical region.

For all analyses, baseline was defined as the last available assessment before the first study drug infusion. If the day 1 assessment was missing, the last screening assessment was used.

Sensitivity Analyses

Sensitivity analyses of the primary outcome only included a placebo-based analysis and a tipping point analysis. In the placebo-based analysis, for patients who discontinued treatment, responses after treatment discontinuation in both arms were imputed using multiple imputation, based on the responses observed for the placebo arm. Markov chain Monte Carlo (MCMC) imputation was used to fill in the intermittent missing values; subsequently, multiple imputation was performed at each visit sequentially using a regression method obtained from placebo-treated patients with terms for baseline MG-ADL total score and the randomization stratification variable of geographic region. For the tipping point analysis, a search was conducted for a tipping point that reversed the study conclusion from being favourable to ravulizumab to being unfavourable. MCMC imputation was used to fill in the intermittent missing values; subsequently, imputations were performed for missing change observations at every visit sequentially for ravulizumab-treated patients, assuming that they received the treatment effect minus a shift parameter delta. The adjustment was applied to the first unobserved outcome from ravulizumab. After obtaining complete datasets for multiple shift parameters, the complete datasets were used in MMRM analysis and an overall test statistic was obtained for each shift value. Multiple shift parameters were tested until the inference concluded that statistical significance disappeared.

Sensitivity analyses of both the primary and secondary outcomes included identical MMRM analyses conducted in the per-protocol set (PPS) and the modified full analysis set (mFAS) as well as MMRM analysis excluding randomization stratification region and MMRM analysis including rescue therapy received in the model.

Subgroup Analyses

Subgroup analyses were performed for all secondary outcomes as per the primary analysis using an MMRM, except with an additional subgroup covariate by treatment interaction. The following subgroups were prespecified in the statistical analysis plan: geographic region (Asia-Pacific, Europe, Japan, or North America), sex (male or female), race (Asian, white, or other), age at first study drug infusion (18 years to 65 years or older than 65 years), IST use at baseline (corticosteroids only, corticosteroids and IST, IST only, or none), time from diagnosis to informed consent (median time or less versus greater), baseline MGFA classification (class II, class III, or class IV), and baseline body weight (40 kg or greater but less than 60 kg, 60 kg or greater but less than 100 kg, or 100 kg or greater). Of the prespecified subgroups, IST use at baseline and baseline MGFA classification were identified as being of interest in the CADTH review protocol. The study was not specifically powered to evaluate differences in outcomes among the individual strata.

Analysis Populations

The FAS included all patients who received at least 1 dose of the study drug; patients were analyzed according to the treatment they were randomized to receive, regardless of the treatment received. The PPS included all patients in the FAS without any major protocol deviations during the randomized controlled period and who met the following criteria:

• did not miss any doses of the study drug during the randomized controlled period

• met the following inclusion criteria that might affect efficacy —

  • were diagnosed with MG at least 6 months before screening

  • had a confirmed MG diagnosis

  • were MGFA class II to class IV

  • had stable doses of MG treatments during the time periods specified per protocol

• did not meet the following exclusion criteria that might affect efficacy —

  • had active or untreated thymoma or a history of thymic carcinoma or thymic malignancy

  • had a history of thymectomy, thymectomy, or any thymic surgery within 12 months of screening

  • had clinical features consistent with MG crisis, MG exacerbation, or clinical deterioration during screening

  • had taken prohibited medications during the time periods specified per protocol

  • had previous treatment with a complement inhibitor

  • had participated in another interventional treatment study or used any experimental therapy within the time period specified per protocol

• had no major protocol deviations as described below that might affect efficacy —

  • did not receive incorrect randomized treatment

  • did not take AChEIs within 10 hours before QMG and MGC measurements at baseline and week 26

  • did not receive rescue therapy on day 1

  • did not have changes in background MG medication per protocol

  • did not have unblinding of treatment allocation by the investigator.

The mFAS included all patients in the FAS who were not impacted by COVID-19 during the randomized controlled period. The safety set included all patients who received at least 1 dose of study drug; patients were analyzed according to the treatment they actually received, and must have received that treatment for the entire duration of the randomized controlled period.

Results

Patient Disposition

Patient disposition in the CHAMPION trial is summarized in Table 12. Among 242 patients screened, 175 (72.3%) patients were randomized and 67 (27.7%) patients were screen failures. The most common reasons for screen failure were not having a positive serologic test for anti-AChR antibodies (25 [10.3%] patients) and an MG-ADL score of less than 6 (16 [6.6%] patients). All of the 175 randomized patients were treated with the study drug.

Thirteen of 175 (7.4%) randomized patients withdrew from the study before completing the randomized controlled period (6 patients in the placebo arm and 7 patients in the ravulizumab arm). The most common reasons for discontinuation were patient decision (3 patients), physician decision (3 patients), death (2 patients), and AEs (2 patients). Overall, 158 (90.3%) patients entered the OL extension period.

Table 12: Patient Disposition in the CHAMPION Trial

AE = adverse event; FAS = full analysis set; mFAS = modified full analysis set; OL = open-label; PPS = per-protocol set.

Source: CHAMPION Clinical Study Report.¹³

Important protocol deviations in the CHAMPION trial are summarized in Table 13. Overall, 41 (23.4%) patients had important protocol deviations. The most common important protocol deviations were related to investigational product (12 [6.9%] patients; 11 patients had missed or mistimed doses), study procedures or tests (15 [8.6%] patients; 9 patients received AChEIs within 10 hours of QMG or MGC assessments), and safety reporting (11 [6.3%] patients; all were due to delayed reporting of SAEs).

Table 13: Patients With Important Protocol Deviations During the Randomized Controlled Period in the CHAMPION Trial — Full Analysis Set

Source: CHAMPION Clinical Study Report.¹³

Exposure to Study Treatments

Treatment exposure in the CHAMPION study is summarized in Table 14. Study drug adherence was 100% in 94.4% of patients in the placebo arm and 96.5% of patients in the ravulizumab arm.

Exposure to concomitant MG therapies in the CHAMPION study is summarized in Table 15. Almost all patients (174 of 175 [99.4%] patients) received concomitant MG therapy during the trial. Approximately three-quarters of patients (78.7%) in the placebo arm and approximately five-sixths of patients (83.7%) in the ravulizumab arm received concomitant pyridostigmine. Approximately two-thirds (70.8%) of both patients in the placebo arm and the ravulizumab arm (64.1%) received concomitant ISTs. Approximately three-quarters of patients (74.2%) in the placebo arm and approximately two-thirds of patients (66.3%) in the ravulizumab arm received corticosteroids. In the placebo arm, 13 (14.6%) patients received IVIg and 1 (1.1%) patient received PE or PP rescue therapy. In the ravulizumab arm, 5 (5.8%) patients received IVIg and 2 (2.3%) patients received PE or PP rescue therapy.

Table 14: Exposure to Study Drug During the Randomized Controlled Period of the CHAMPION Trial — Full Analysis Set

SD = standard deviation.

^aStudy duration is the date of completion of the randomized controlled period or discontinuation minus the date of informed consent, plus 1.

^bTreatment duration is the date of completion of randomized controlled period or discontinuation minus the first study drug infusion date, plus 1.

^cOne patient in the placebo group received a dose of ravulizumab on day 15.

^dCalculation of drug compliance was defined to reflect the percentage of time during the randomized controlled period that the patient was considered to have complete terminal complement inhibition. Percentage compliance is equal to 100% minus the sum (percentage of time patients were noncompliant with scheduled doses during the randomized controlled period [excluding day 183 infusion]).

Source: CHAMPION Clinical Study Report.¹³

Table 15: Summary of Concomitant Myasthenia Gravis Treatments During the Randomized Controlled Period in the CHAMPION Trial — Safety Set

NOS = not otherwise specified; PE = plasma exchange; PP = plasmapheresis.

^aTreatments used in 5% or more of patients in either treatment group are listed.

Source: CHAMPION Clinical Study Report.¹³

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported as follows. Refer to Appendix 3 for detailed efficacy data (sensitivity and subgroup analyses of primary and secondary outcomes).

Activities of Daily Living

Change from baseline in the MG-ADL total score at week 26 of the randomized controlled period was the primary outcome of the CHAMPION trial. Change from baseline in the MG-ADL total score during the randomized controlled period and at week 26 is shown in Figure 3 and Table 16. At week 26, the LSM change in the MG-ADL total score in the placebo arm was –1.4 (95% CI, –2.1 to –0.7) versus –3.1 (95% CI, –3.8 to –2.3) in the ravulizumab arm. The LSM difference in the MG-ADL total score between the ravulizumab and placebo arms was –1.6 (95% CI, –2.6 to –0.7; P = 0.0009).

Sensitivity analyses were consistent with the primary analysis (refer to Appendix 3). Subgroup analyses of IST use at baseline and MGFA clinical classification were prespecified in the CHAMPION trial and were identified as being of interest in the CADTH review protocol. The LSM difference in changes from baseline in MG-ADL total score at week 26 were consistent with the main analysis for all subgroups (refer to Appendix 3). The LSM difference in changes from baseline in MG-ADL subcomponent scores at week 26 of the randomized controlled period numerically favoured ravulizumab for respiratory and ocular subcomponents and, to a lesser extent, bulbar and limb subcomponents (refer to Appendix 3).

Figure 3: Change From Baseline in MG-ADL Total Score During the Randomized Controlled Period of the CHAMPION Trial — Full Analysis Set

BL = baseline; MG-ADL = Myasthenia Gravis Activities of Daily Living.

Note: Baseline was defined as the last available assessment value before the first study drug infusion. Nominal P values are indicated as follows: * indicates a P value of less than 0.05, ** indicates a P value of less than 0.01, and *** indicates a P value of less than 0.001. Note that only the test of change from baseline at week 26 was part of the statistical hierarchy; for the other time points, there was an increased risk of type I error.

Source: CHAMPION Clinical Study Report.¹³

Table 16: Change From Baseline to Week 26 of the Randomized Controlled Period in MG-ADL Total Score in the CHAMPION Trial — Full Analysis Set

CI = confidence interval; LSM = least squares mean; MG-ADL = Myasthenia Gravis Activities of Daily Living; SEM = standard error of the mean; vs. = versus.

Source: CHAMPION Clinical Study Report.¹³

The proportion of patients with improvements of at least 3 points in the MG-ADL total score at week 26 of the randomized controlled period was a secondary (hierarchically tested) outcome of the CHAMPION trial. Note that this outcome was tested after a prior nonsignificant result of the hierarchical testing procedure and, thus, P values were considered nominal. The proportion of patients with various point reductions in their MG-ADL total score from baseline to week 26 is shown in Figure 4. The adjusted percentage of patients with improvements of at least 3 points in their MG-ADL total score at week 26 was 56.7% (95% CI, 44.3% to 68.3%) in the ravulizumab arm and 34.1% (95% CI, 23.8% to 46.1%) in the placebo arm (OR of at least a 3-point improvement = 2.526; 95% CI, 1.330 to 4.799).

Sensitivity analyses in the PPS and mFAS were consistent with the main analysis (refer to Appendix 3). Subgroup analyses of IST use at baseline and MGFA clinical classification were prespecified in the CHAMPION trial and were identified as being of interest in the CADTH review protocol. The ORs of at least a 3-point improvement in the MG-ADL total score at week 26 were consistent with the main analysis for all subgroups (refer to Appendix 3).

The proportion of patients with improvements of at least 2 points in their MG-ADL total score (a recognized response threshold that indicates clinical improvement) at week 26 was 63.9% (95% CI, 51.7% to 74.6%) in the ravulizumab arm and 53.0% (95% CI, 41.1% to 64.6%) in the placebo arm (OR of at least a 2-point improvement = 1.569; 95% CI, 0.833 to 2.955).

Figure 4: Proportion of Patients With Various Point Reductions in MG-ADL Total Score at Week 26 — Full Analysis Set

MG-ADL = Myasthenia Gravis Activities of Daily Living.

Note: Baseline was defined as the last available assessment value before the first study drug infusion. Nominal P values shown on the left were from tests either following a nonsignificant result of an earlier test in the sequential testing order of the statistical hierarchy (MG-ADL improvements of 3 points or more) or outside of the statistical hierarchy (other thresholds). As a result, there was an increased risk of type I error.

Source: CHAMPION Clinical Study Report.¹³

Disease Severity

Quantitative Myasthenia Gravis Total Score

Change from baseline in the QMG total score at week 26 of the randomized controlled period was a secondary (hierarchically tested) outcome of the CHAMPION trial. Change from baseline in the QMG total score during the randomized controlled period and at week 26 is shown in Figure 5 and Table 17. At week 26, the LSM change in the QMG total score in the placebo arm was –0.8 (95% CI, –1.7 to 0.1) versus –2.8 (95% CI, –3.7 to –1.9) in the ravulizumab arm. The LSM difference in the QMG total score between the ravulizumab and placebo arms was –2.0 (95% CI, –3.2 to –0.8; P = 0.0009).

Sensitivity analyses were consistent with the primary analysis (refer to Appendix 3). Subgroup analyses of IST use at baseline and MGFA clinical classification were prespecified in the CHAMPION trial and were identified as being of interest in the CADTH review protocol. The LSM differences in changes from baseline in the QMG total score at week 26 were consistent with the main analysis for all subgroups (refer to Appendix 3).

Figure 5: Change From Baseline in QMG Total Score During the Randomized Controlled Period — Full Analysis Set

BL = baseline; QMG = Quantitative Myasthenia Gravis.

Note: Baseline was defined as the last available assessment value before the first study drug infusion. Nominal P values are indicated as follows: * indicates a P value of less than 0.05, ** indicates a P value of less than 0.01, and *** indicates a P value of less than 0.001. Note that only the test of change from baseline at week 26 was part of the statistical hierarchy; for the other time points, there was an increased risk of type I error.

Source: CHAMPION Clinical Study Report.¹³

Table 17: Change From Baseline to Week 26 of the Randomized Controlled Period in QMG Total Score in the CHAMPION Trial — Full Analysis Set

CI = confidence interval; LSM = least squares mean; QMG = Quantitative Myasthenia Gravis; SEM = standard error of the mean; vs. = versus.

Source: CHAMPION Clinical Study Report.¹³

The proportion of patients with improvements of at least 5 points in the QMG total score at week 26 of the randomized controlled period was a secondary (hierarchically tested) outcome of the CHAMPION trial. The proportion of patients with various point reductions in the QMG total score from baseline to week 26 is shown in Figure 6. The adjusted percentage of patients with improvements of at least 5 points in the QMG total score at week 26 was 30.0% (95% CI, 19.2% to 43.5%) in the ravulizumab arm and 11.3% (95% CI, 5.6% to 21.5%) in the placebo arm (OR of at least a 5-point improvement = 3.350; 95% CI, 1.443 to 7.777; P = 0.0052).

Sensitivity analyses in the PPS and mFAS were consistent with the main analysis (refer to Appendix 3). Subgroup analyses of IST use at baseline and MGFA clinical classification were prespecified in the CHAMPION trial and were identified as being of interest in the CADTH review protocol. The ORs of at least a 5-point improvement in the QMG total score at week 26 were consistent with the main analysis for all subgroups (refer to Appendix 3).

The proportion of patients with improvements of at least 3 points in the QMG total score (the estimated MID) at week 26 was 44.8% (95% CI, 32.3% to 58.0%) in the ravulizumab arm and 24.2% (95% CI, 15.3% to 36.2%) in the placebo arm (OR = 2.544; 95% CI, 1.283 to 5.044).

Figure 6: Proportion of Patients With Various Point Reductions in QMG Total Score at Week 26 — Full Analysis Set

QMG = Quantitative Myasthenia Gravis.

Note: Baseline was defined as the last available assessment value before the first study drug infusion. Apart from QMG improvements of 5 points or more, nominal P values for other thresholds shown on the left were from tests outside of the statistical hierarchy, so there was an increased risk of type I error.

Source: CHAMPION Clinical Study Report.¹³

||| |||||

|||||| |||| |||||||| || || ||||| || |||| || || || |||||||||| |||||||||| |||||| || || ||||||||||| ||||||| || || |||||||| |||||| |||||| |||| |||||||| || || ||||| |||||| || |||||||||| |||||||||| |||||| || || |||| || || ||||| | Figure 7 ||| Table 18 | || |||| || || || |||||| || || ||||| ||||| || || ||||||| || |||| |||| || |||| || ||||| |||||| |||| |||| || |||| || ||||| || || ||||||||||| |||| || || |||||||||| || ||||| ||||||| || ||||||||||| || ||||||| |||| || |||| |||| || |||| || |||||

Figure 7: Redacted

||| ||||| || |||||| ||||||||||| || |||||| || || || ||||| ||||| ||||||| || || || || |||||| ||||| || || ||||||||||| || |||||| |||||| ||||| || || ||||||| || ||||| | ||||| |||| | |||||||||| |||||||||| |||||| || || |||||||| |||||| || || |||||||||| |||||||||||||| || ||||||||| || || ||||||||| || || ||||| || ||||||||||| ||||||| || | ||||||||||| |||| |||||||| || | ||||||||||| ||||||| |||| |||| || |||||||| ||||||||||||| |||||| |||| |||||||||||| |||||||||||

|||| |||||||||| || ||||| |||||||| |||| || ||||||||||| |||||| |||||||||||||||| |||||||| || ||||||| || || |||| ||||||||| |||||||||| ||||| ||||| || ||||| ||||| |||| ||||||||| ||||||| |||||||| || ||||||||| || |||||||| | | |||||| || || ||||||| |||| |||| ||||| ||||| |||| || |||| || | ||||||||||| ||||||||| || ||||| || || ||||||||| |||| || |||| ||||||||||||||| |||||||| |||||||| ||||| |||||||

Note: This figure has been redacted at the request of the sponsor.

Table 18: Redacted

| ||||||||||| ||||||||| || ||||| |||||||| |||| || |||||| ||||||| ||||| || ||||||||||| |||||| |||||||||| | ||||||||| ||||| || || |||||||||| |||| || || |||| || || ||||||||||| ||||||||| || ||||| || || ||||||||| |||| || |||| ||||||||||||||| |||||||| |||||||| ||||| |||||||^||

Note: This table has been redacted at the request of the sponsor.

||||||||

|||||||| || |||| || || || |||||||||| |||||||||| |||||| || || ||||||||||| ||||||| || || |||||||| |||||| || ||||||||||| || |||||||| ||||||||| || |||||||| |||||||| || |||| || | ||||| | Figure 8 || | ||||||| |||| |||| || |||||||| |||||||| || |||||||| ||||||| ||||||||||||||| ||||| |||||||| || || || ||||||| ||||||| ||||||||||||||| ||||| | ||||||||| ||||||| || |||| || ||||| ||||||| || || ||||||||||| |||| ||||| || |||||||| |||||||| || |||||||| ||||||| ||||||||||||||| ||||| |||||||| || | || ||||||| ||||||| ||||||||||||||| ||||| || ||||||||| ||||||| | |||| | ||||| ||||||| || || || ||||||||| || ||||||||| ||||||||||||||||||||| |||||||||||| | |||||||| | || |||| || || || |||||

Figure 8: Redacted

||| ||||| || |||||| ||||||||||| || ||||||||||| || |||||||| || |||| |||||||| || |||||||| ||||||||| || |||||||| ||||||| ||||||||||||||| |||||||| || || || ||||||| ||||||| ||||||||||||||| |||||||||| || |||||| || |||| || || || |||||||||| |||||||||| |||||| || | |||||||| |||||| || || ||||||| || ||||| |||||| ||||||||||| ||||| |||||||| |||||||| || |||||||| ||||||| |||||||||||||| || ||||||||||| |||| |||||||| |||| |||||| ||||||||| || ||||| |||||||| |||| || ||||||||||| || |||||| ||||||| |||||||| || ||||||||||| || |||||||||| || |||| |||||||| |||| || |||||||| ||||||||||||| |||||| |||| |||||||||||| |||||||||||||||| |||||||||| || ||||| |||||||| |||| |||||||| ||||||||||| |||||| |||||||||| || |||||||| ||||||||||||||||| ||||||||||||| |||||||| || || |||||||||| || ||||||||||||| ||||||||||||||||||| |||||||| |||||||| ||||| |||||||

Note: This figure has been redacted at the request of the sponsor.

Hospital Admission

Hospitalization during the randomized controlled period, including MG-related hospitalization, was an exploratory outcome of the CHAMPION trial. Information on hospitalization during the randomized controlled period is shown in Table 19. | ||||| || || |||||||| ||||||| || || ||||||| || || || |||||||| ||||||| || || ||||||||||| || |||| ||||||||||||| ||||| |||||| ||||| |||||||| |||||| || || ||||||| || || ||||| |||||||| |||||| || || ||||||||||| | |||| |||||||||||| | || || |||| || ||||||| |||||| || || ||||||| || || || |||||||| |||||| || || ||||||||||| || |||||||| |||||||||| ||||||||

Table 19: Redacted

||| ||||| |||||||| |||| || ||||||||||| ||||||||||||||||| || ||||||||||||||| || |||||| |||||||||||| |||||||| |||||||| ||||| |||||||

Note: This table has been redacted at the request of the sponsor.

Number and Dose of Existing Medications

Change in MG medications was not an efficacy outcome in the CHAMPION trial, although this information was collected. Note that patients were to maintain stable doses of concomitant MG medications during the randomized controlled period unless there was a compelling medical need. ||||||||||| || || |||||||||| ||||||| |||||| || |||||||||| |||||||||| |||||| || ||||| | Table 20 | |||||||| || |||||||| ||||||| |||||||| |||||||||| ||||||| |||||| || |||||||||| |||||||||| ||||||| || |||| |||||| |||||||||| |||||| || || ||||||||||||||| |||||| || |||||||| || || ||||||| || || |||| || |||||||| || || ||||||||||| ||||| ||||||| || ||||||| ||||||||||||||| || ||||| |||| |||| ||||||||||| |||| ||||||| ||||||| || |||||||| |||||||||| || ||||||||||||| ||||||| || |||||||||| || |||||||||| |||| || |||| ||||| |||||

Table 20: Redacted

| ||||||||||| ||||||||||||||| |||||||| |||||||| ||||| |||||||

Note: This table has been redacted at the request of the sponsor.

Need for Rescue Therapy

Clinical deterioration and the need for rescue therapy was an exploratory outcome in the CHAMPION trial. Information on clinical deterioration and rescue therapy administered during the randomized controlled period is shown in Table 21. Overall, ||||| of patients in the placebo arm and ||||| of patients in the ravulizumab arm reported clinical deterioration, while 16.9% of patients in the placebo arm and 9.3% of patients in the ravulizumab arm reported clinical deterioration as per protocol criteria. In the placebo arm, 14 (15.7%) patients required rescue therapy |||||| || ||||||||| || || || || |||| |||| |||||||||||||||| |||||||| |||||| In the ravulizumab arm, 8 (9.3%) patients required rescue therapy |||||| |||||||||| || || || ||||||||| |||| |||| |||||||||||||||| ||||||||||

Table 21: Clinical Deteriorations and Rescue Therapies During the Randomized Controlled Period of the CHAMPION Trial — Full Analysis Set

IVIg = IV immunoglobulin; MG = myasthenia gravis; PE = plasma exchange; PP = plasmapheresis.

^aOne patient in the ravulizumab group experienced a clinical deterioration under the per-protocol criteria of significant symptomatic worsening, which was also reported as a serious adverse event of MG crisis.

Source: CHAMPION Clinical Study Report.¹³

Health-Related Quality of Life

MG-QoL15r Score

Change from baseline in the MG-QoL15r score at week 26 of the randomized controlled period was a secondary (hierarchically tested) outcome in the CHAMPION trial. Change from baseline in the MG-QoL15r score during the randomized controlled period and at week 26 is shown in Figure 9 and Table 22. At week 26, the LSM change in the MG-QoL15r score in the placebo arm was –1.6 (95% CI, –3.0 to –0.3) versus –3.3 (95% CI, –4.7 to –1.9) in the ravulizumab arm. The LSM difference in the MG-QoL15r score between the ravulizumab and placebo arms was –1.7 (95% CI, –3.4 to 0.1; P = 0.0636).

||||||||||| |||||||| || | || || |||| |||| |||||||||| |||| || |||| |||||||| || |||||||| || |||||||| |||||||| || | || || |||||||| || |||| |||||||| |||||||||||||| |||| ||||||||||||| || || |||||||| ||||| || |||| |||||||||| || || |||||||| || || ||||| |||||| ||||||||| || || ||||||||||| || ||||||||| ||||| || |||| || |||| |||||||||| |||| || |||| |||||||| || || ||||||||| |||| |||||||| |||

Figure 9: Change From Baseline in the MG-QoL15r Score During the Randomized Controlled Period — Full Analysis Set

BL = baseline; MG-QOL15r = Myasthenia Gravis Quality of Life 15-item scale - Revised.

Note: Baseline was defined as the last available assessment value before the first study drug infusion. Nominal P values are indicated as follows: * indicates a P value of less than 0.05. Note that only the test of change from baseline at week 26 was part of the statistical hierarchy; for the other time points, there was an increased risk of type I error.

Source: CHAMPION Clinical Study Report.¹³

Table 22: Change From Baseline to Week 26 of the Randomized Controlled Period in MG-QoL15r Score in the CHAMPION Trial — Full Analysis Set

CI = confidence interval; LSM = least squares mean; MG-QoL15r = Myasthenia Gravis Quality of Life 15-item scale - Revised; SEM = standard error of the mean; vs. = versus.

Source: CHAMPION Clinical Study Report.¹³

Quality of Life in Neurological Disorders Fatigue Score

Change from baseline in the Neuro-QoL Fatigue score at week 26 of the randomized controlled period was a secondary (hierarchically tested) outcome in the CHAMPION trial. Note that this outcome was tested after a prior nonsignificant result of the hierarchical testing procedure and, thus, P values were considered nominal. Change from baseline in the Neuro-QoL Fatigue score during the randomized controlled period and at week 26 is shown in Figure 10 and Table 23. At week 26, the LSM change in the Neuro-QoL Fatigue score in the placebo arm was –4.8 (95% CI, –8.1 to –1.1) versus –7.0 (95% CI, –10.7 to –3.2) in the ravulizumab arm. The LSM difference in the Neuro-QoL Fatigue score between the ravulizumab and placebo arms was –2.2 (95% CI, –6.9 to 2.6).

||||||||||| |||||||| || || || || |||| |||| |||||||||| |||| || |||| |||||||| |||| |||||||| || |||||||| |||||||| || || || || |||||||| || |||| |||||||| |||||||||||||| |||| ||||||||||||| || || |||||||| ||||| || |||| |||||||||| || || |||||||| || || ||||| |||||| ||||||||| || || |||||||||| || ||||||| |||| |||||||| || ||||||||| ||||||| ||||| || |||| || || |||||||||| |||| || |||| |||||||| | |||||||||| |||| |||||||| |||

5-Level EQ-5D Visual Analogue Scale and Index Score

Change from baseline in EQ VAS at week 26 of the randomized controlled period was an exploratory outcome of the CHAMPION trial. |||||| |||| |||||||| || |||||||| || |||||| | |||||||||| |||||||||| |||||| || || |||| || || ||||| | Figure 11 ||| Table 24 | || |||| || || || |||||| || |||||||| || || || ||||||| || || |||| || |||| || |||| |||||| || |||| | |||| || |||| || || ||||||||||| |||| || || |||||||||| || |||||||| | ||||| ||||||| || ||||||||||| || ||||||| |||| || || |||| | |||| || |||||

Figure 10: Change From Baseline in Neuro-QoL Fatigue Score During the Randomized Controlled Period — Full Analysis Set

BL = baseline; Neuro-QoL = Quality of Life in Neurological Disorders.

Note: Baseline was defined as the last available assessment value before the first study drug infusion. Note that only the test of change from baseline at week 26 was part of the statistical hierarchy, but was tested following subsequent failure of the hierarchy; the other time points were not part of the hierarchy. For all of these tests, there was an increased risk of type I error.

Source: CHAMPION Clinical Study Report.¹³

Table 23: Change From Baseline to Week 26 of the Randomized Controlled Period in Neuro-QoL Fatigue Score in the CHAMPION Trial — Full Analysis Set

CI = confidence interval; LSM = least squares mean; Neuro-QoL = Quality of Life in Neurological Disorders; SEM = standard error of the mean; vs. = versus.

^aThis test was undertaken after a prior nonsignificant result in the statistical hierarchy; there was an increased risk of type I error.

Source: CHAMPION Clinical Study Report.¹³

Figure 11: Redacted

||| ||||| || |||||| ||||||||||| || |||||| || |||||||| || ||||| ||||||| || || || || |||||| ||||| || || ||||||||||| || |||||| | ||||| || || ||||||| || ||||| |||||| ||||| |||| || |||||||||| |||||||||| |||||| || || |||||||| |||||| || || |||||||||| |||||||||||||| || ||||||||| || || ||||||||| || |||||||| || || ||||||||||| ||||||| || || ||||||||||| |||| |||||||| || || ||||||||||| ||||||| |||| |||| || |||||||| ||||||||||||| |||||| |||| |||||||||||| ||||||||||| || || |||| || ||||||||||| |||||||||| ||||||||| ||||||||| |||| ||||||||||||||||| |||||||||| || ||||| |||||||| |||| || ||||||| |||||| |||||||||||| |||||||| || ||||||| || || |||| ||||||||| |||||||||| ||||| ||||| || ||||| ||||| |||| ||||||||| |||| |||| ||||| ||||| |||| || |||| || || ||||||||||| ||||||||| || ||||| || || ||||||||| |||| || |||| ||||||||||||||| |||||||| |||||||| ||||| |||||||

Note: This figure has been redacted at the request of the sponsor.

Table 24: Redacted

| ||||||||||| ||||||||| || ||||| |||||||| |||| | |||||| ||||||| ||||| || ||||||||| ||||| || || ||||| || ||||||| |||||| |||||||||| |||| || || |||| || || ||||||||||| ||||||||| || ||||| || || ||||||||| |||| || |||| ||||||||||||||| |||||||| |||||||| ||||| |||||||^||

Note: This table has been redacted at the request of the sponsor.

Change from baseline in the EQ-5D-5L index score at week 26 of the randomized controlled period was an exploratory outcome of the CHAMPION trial. |||||| |||| |||||||| || |||||||| ||||| ||||| |||||| | |||||||||| |||||||||| |||||| || || |||| || || ||||| Figure 12 ||| Table 25 | || |||| | || || |||||| || |||||||| ||||| ||||| || || ||||||| || ||||| |||| || ||||| || ||||| |||||| |||| |||| || |||| || ||||| || || ||||||||||| |||| || || |||||||||| || |||||||| ||||| ||||| ||||||| || ||||||||||| || ||||||| |||| || |||| |||| | |||| || ||||||

Figure 12: Redacted

||| ||||| || |||||| ||||||||||| || |||||| || |||||||| ||||| ||||| ||||| ||||||| || || || || |||||| ||||| || || ||||||||||| || |||||| || ||||| || || ||||||| || ||||| |||||| ||||| |||| || |||||||||| |||||||||| |||||| || || |||||||| |||||| || || |||||||||| |||||||||||||| || ||||||||| || || ||||||||| || |||||||| ||||| ||||| | ||||||||||| ||||||| || || ||||||||||| |||| |||||||| || || ||||||||||| ||||||| |||| |||| || |||||||| ||||||||||||| |||||| |||| |||||||||||| ||||||||||| || || |||| || ||||||||||| |||||||||| ||||||||| ||||||||| |||| ||||||||||||||||| |||||||||| || |||| |||||||| |||||||||| |||||||| || ||||||| || || |||| ||||||||| |||||||||| ||||| ||||| || ||||| ||||| |||| ||||||||| ||||||| |||||||| || ||||||||| || |||||||| | | ||||||| |||| |||| ||||| ||||| |||| || |||| || || ||||||||||| |||||||||| |||| |||| ||||| ||||| |||| || |||| || || ||||||||||| ||||||||| || ||||| || || ||||||||| |||| || |||| ||||||||||||||| |||||||| |||||||| ||||| ||||||

Note: This figure has been redacted at the request of the sponsor.

Table 25: Redacted

| ||||||||||| ||||||||| || ||||| |||||||| |||| || |||||| ||||||| ||||| || ||||||||| ||||| || || |||||||||| |||| | || |||| || || ||||||||||| ||||||||| || ||||| || || ||||||||| |||| || |||| ||||||||||||||| |||||||| |||||||| ||||| |||||||

Note: This table has been redacted at the request of the sponsor.

Harms

Only those harms identified in the review protocol are reported as follows. Refer to Table 26 for detailed harms data.

Adverse Events

During the randomized controlled period, most patients (78 [90.7%] ravulizumab-treated patients and 77 [86.5%] placebo-treated patients) experienced AEs. The most common AEs were headache (ravulizumab arm = 16 patients, 18.6%; placebo arm = 23 patients, 25.8%), diarrhea (ravulizumab arm = 13 patients, 15.1%; placebo arm = 11 patients, 12.4%), and nausea (ravulizumab arm = 9 patients, 10.5%; placebo arm = 9 patients, 10.1%).

Serious Adverse Events

During the randomized controlled period, 20 (23.3%) ravulizumab-treated patients and 14 (15.7%) placebo-treated patients experienced SAEs. The most common SAEs were COVID-19 pneumonia (ravulizumab arm = 2 patients, 2.3%; placebo arm = 0 patients, 0%), cellulitis (ravulizumab arm = 0 patients, 0%; placebo arm = 2 patients, 2.2%), transient ischemic attack (ravulizumab arm = 2 patients, 2.3%; placebo arm = 0 patients, 0%), and MG (ravulizumab arm = 0 patients, 0%; placebo arm = 3 patients, 3.4%).

Adverse Events Leading to Infusion Interruption

During the randomized controlled period, 5 (5.8%) ravulizumab-treated patients and 3 (3.4%) placebo-treated patients experienced AEs leading to infusion interruption. In the ravulizumab arm, AEs leading to infusion interruption included vascular pain, infusion site extravasation, syncope, abdominal pain, and coccygodynia (1 patient or 1.2% each). In the placebo arm, AEs leading to infusion interruption included infusion reaction (2 patients or 2.2%), anxiety (1 patient or 1.1%), and back pain (1 patient or 1.1%). All infusions were completed.

Withdrawals Due to Adverse Events

During the randomized controlled period, 2 (2.3%) ravulizumab-treated patients and 3 (3.4%) placebo-treated patients experienced WDAEs. In ||| ||||||||||| |||| ||||| |||||||| |||||||| |||| ||||| || |||||||| ||||||||| || ||||||| |||||| || || ||||||| |||| ||||| |||||||| |||||||| |||| ||||| || |||||||| ||||||||| || ||||||| ||||||

Mortality

During the randomized controlled period, 2 (2.3%) patients treated with ravulizumab experienced AEs leading to death. These deaths were due to COVID-19 pneumonia and cerebral hemorrhage (the latter in a patient with atrial fibrillation). There were no AEs leading to death in the placebo arm.

Notable Harms

|||||| || |||||||||| |||||||||| ||||||| ||||| || ||||||||||||||||||| |||||||| || ||||| || ||||||||||||||| |||||||| ||||||||||| ||||||||||| No patients experienced meningococcal infections during the randomized controlled period. |||||| || |||||||||| |||||||||| ||||||| ||||| || ||||||||||||||||||| |||||||| || ||||| || ||||||||||||||| |||||||| ||||||||||| |||||||| ||||||||||

Table 26: Summary of Harms in the CHAMPION Trial — Safety Set

AE = adverse event; MG = myasthenia gravis; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

^aAEs occurring in 10% or more of patients in either treatment group are listed.

^bSAEs occurring in 2 or more patients in either treatment group are listed.

Source: CHAMPION Clinical Study Report.¹³

Critical Appraisal

Internal Validity

The CHAMPION trial was a phase III, DB, placebo-controlled RCT (N = 175) with an OL extension period of up to 4 years conducted in adult patients with anti-AChR antibody–positive gMG (patients had to have an MGFA clinical classification of class II to class IV, an MG-ADL total score of 6 or more, and be nonthymomatous) with no requirements for prior treatment experience or its outcome. The relatively small size of the trial was expected because of the relative rarity of MG. Only the evidence from the randomized controlled period was included in the systematic review section of this report. The basic features of the study design (methods for randomization, allocation concealment, and blinding) were appropriate to minimize bias and confounding.

Randomization in the CHAMPION trial appeared generally successful in balancing baseline demographic and disease characteristics between study arms. Minor baseline imbalances between arms (e.g., by race, age at MG diagnosis, age at first study drug infusion, MG type at diagnosis [ocular versus generalized], time to gMG from diagnosis among patients whose first presentation was ocular MG, MGFA clinical classification, prior corticosteroid use) were viewed by the clinical experts consulted by CADTH for this review as unlikely to be prognostic or to significantly affect the study results. Study discontinuations before completing the randomized controlled period were relatively infrequent (6% to 7% of patients) and both the rate and reasons for discontinuation were similar in both arms. Missing data for reasons other than discontinuation were relatively rare (1 to 5 patients in each arm, depending on outcome) and therefore unlikely to contribute to bias. There was no indication from the efficacy or harms data that the unblinding of patients or study personnel had occurred.

During the study, concomitant MG therapy was generally similar in both study arms, apart from rescue therapy (IVIg), which was administered more frequently in the placebo arm. |||||||| ||||| || |||||||| || ||||||||| |||||||| |||||||||| |||||| || |||||||||| |||||||||| ||||||| ||||| |||||||| |||| ||||||| ||||||||| || |||| |||| || ||||||||| ||||||| || |||||| || |||||||| ||||| || |||| || || || |||||| |||||| || ||||| || ||||||||||| || |||| || |||||| || || |||||||| ||||||| ||||||||| || ||||| || |||| |||||| || |||||| || |||||| || ||||| |||||||. The instruments used for evaluation in the primary and secondary efficacy outcomes of the CHAMPION trial (MG-ADL, QMG, MG-QoL15r, Neuro-QoL Fatigue) were appropriate and their psychometric properties have been investigated in patients with MG, although no MIDs have been estimated for the MG-QoL15r and Neuro-QoL Fatigue scores, or for subcomponents of the MG-ADL and QMG.

Several statistical issues should be considered when interpreting the results of the CHAMPION trial. Statistical tests were appropriate overall, power was adequate for the primary analysis, and multiplicity was controlled using a hierarchical testing strategy. However, statistical hypothesis testing failed at the third test in the hierarchy (MG-QoL15r) and for all other outcomes positioned later in the hierarchy, as well as those not included in the hierarchy, type I error was not controlled. In the primary MMRM analysis, missing data were not imputed and were treated as MAR. However, the placebo-based and tipping point sensitivity analyses of the primary outcome (change in MG-ADL total score at week 26) used MCMC imputation to replace missing data, and were consistent with the main analysis. Of note, although the imbalanced use of rescue therapy (IVIg) was not accounted for in the statistical analyses, this would be expected to bias against ravulizumab since rescue therapy was administered more often in the placebo arm. |||||||| |||||||| || |||| |||||||| |||||||||||||| || || || |||||||| |||| |||||||||||| || || ||||||||||| |||||||| ||||| |||||||| |||| |||| || |||||||| || |||||||||||| || |||| |||| |||||||||||| ||||||| || |||||| ||||||||||| ||||| ||||||| |||| |||||||||| ||||||||| || ||||| ||||||| || |||||||| |||||| |||||| ||||||||| ||||||||||||

External Validity

According to the clinical experts consulted by CADTH for this review, the demographic and disease characteristics and prior treatment history of patients enrolled in the CHAMPION trial were reflective of the Canadian population of adult patients with anti-AChR antibody–positive gMG that they see in their clinical practice. The clinical experts felt that the study eligibility criteria would be expected to result in the recruitment of a study population reflective of Canadian clinical practice for the treatment of MG, and noted that the eligibility criteria for MGFA class (class II to class IV) and MG-ADL total score (6 or more) would select appropriately for patients with symptomatic gMG most in need of intervention. The clinical experts emphasized that although patients with thymoma were excluded from the study, thymomatous MG is often more severe and these patients would be expected to potentially derive benefit from complement inhibitors, including ravulizumab. Similarly, the clinical experts stated that a subset of patients with MGFA class I or class V and MG-ADL scores of less than 6 who were excluded from the trial would be suitable for treatment. Specifically, the clinical experts relayed that patients with ocular MG or mild symptoms can still be refractory to other therapies, and patients with MGFA class V (on a ventilator) who have no contraindications would potentially benefit from ravulizumab. However, the results of the trial cannot be directly generalized to these groups of patients. In addition, changes in concomitant MG therapies would not be generalizable to clinical practice, as changes to these medications were discouraged by the study protocol.

Ravulizumab dosing in the CHAMPION trial was aligned with the Health Canada–approved dosing. The outcomes assessed in the primary and secondary efficacy analyses (activities of daily living, disease severity, HRQoL) were identified as important by patient group input, although the outcomes of MG exacerbation and hospitalization were exploratory and occurred infrequently in the study. Due to the low number of events and lack of formal statistical testing, no definitive conclusions could be reached for these outcomes. The duration of follow-up of the randomized controlled period (26 weeks) was considered sufficient by the clinical experts consulted by CADTH for this review to address the primary and secondary efficacy outcomes. The cointerventions and background care in the study were similar to those received by patients with MG living in Canada according to the clinical experts consulted by CADTH for this review.

Two important external validity issues must be considered when interpreting the results of the CHAMPION study. First, the study enrolled patients with a variety of prior treatment experience and cointerventions at baseline, including patients with no prior IST (no prior IST within 2 years before screening = 5.1%; no IST at baseline = 8.0%; no IST at first dose = 10.3%) and patients who had received or were receiving only 1 IST (within 2 years before screening = 32.0%; at first dose of study = 42.3%). There were no specific requirements as to the outcome of prior therapies received and the proportion of the study population with refractory gMG was unknown. While the clinical experts consulted by CADTH stated that the CHAMPION trial almost certainly would have included some refractory patients, there was no subgroup analysis conducted for these patients. According to the clinical experts consulted by CADTH for this review, earlier lines of therapy for nonrefractory MG generally have higher response rates and these patients would be more likely to respond to any therapy compared with patients later in the treatment course (e.g., refractory gMG). Therefore, the results of the CHAMPION trial cannot be directly generalized to any specific line of therapy, including to patients with refractory gMG who are currently the target population for treatment with complement inhibitors, according to the clinical experts consulted by CADTH for this review. In addition, the results cannot be directly generalized to the treatment of patients with severe but nonrefractory gMG who would be potential candidates for therapy according to the clinical experts consulted by CADTH for this review.

The second important external validity issue relates to relevant comparators. The clinical experts consulted by CADTH relayed that patients with refractory gMG currently have very few treatment options other than chronic IVIg, PE or PP, and potentially rituximab; as such, clinical trials of investigational therapies in this population must be placebo-controlled. By contrast, the CHAMPION trial enrolled a study population of patients with a variety of prior IST experience, as noted earlier — including patients who would be eligible to receive IST with corticosteroids and steroid-sparing drugs, as well as potentially IVIg, PE or PP, rituximab, or eculizumab (assuming some patients had refractory gMG). The study provided no comparative evidence regarding the efficacy of ravulizumab and currently available therapies at various stages of the treatment paradigm for MG, and its results comparing ravulizumab to placebo provided no information regarding ravulizumab’s effectiveness compared with the current standard of care.

Indirect and Comparative Observational Evidence

Objectives and Methods for the Summary of Indirect Evidence

The objective of this section is to summarize and appraise the evidence from ITCs and observational evidence for the relative effects and safety of ravulizumab for the treatment of adult patients with anti-AChR antibody–positive gMG. The aim is to fill a gap created by the absence of clinical trials providing direct head-to-head evidence of ravulizumab versus eculizumab.

A focused literature search for ITCs dealing with MG was run in MEDLINE All (1946‒) on November 22, 2022. No limits were applied to the search. Records identified by the search were screened independently by 2 reviewers for eligibility. No published ITCs were identified in the literature search from CADTH comparing ravulizumab to comparators of interest based on inclusion criteria in this clinical report.

Description of Indirect Comparison

A single sponsor-submitted ITC report¹⁶ was reviewed for this submission. The report included 2 ITCs (a Bucher ITC and a matching-adjusted indirect comparison [MAIC]) and 1 observational study in which propensity score weighting was used to adjust for confounding.

Methods of Sponsor-Submitted Indirect Treatment Comparison Report

Objectives

The purpose of the sponsor-submitted ITCs and observational study was to estimate the comparative efficacy of ravulizumab and eculizumab for the treatment of individuals with anti-AChR antibody–positive gMG.

Study Selection Methods

No systematic literature review was undertaken by the sponsor to identify eligible studies. No formal eligibility criteria were applied with respect to the selection of studies for inclusion within the ITC. No details were provided on the data abstraction process, screening process, or quality assessment of included studies. No date was provided for when trials were assessed.

In total, 2 studies were identified by the sponsor to be included in their analysis. The CHAMPION study¹⁴ compared the relative efficacy and safety of ravulizumab to placebo, and the REGAIN study³³ compared the relative efficacy and safety of eculizumab to placebo. No studies were reported to be identified and subsequently excluded. Patient-level data were available for all patients within the 2 trials. The primary outcomes of interest for the indirect comparisons and observational study were MG-ADL and QMG total scores, while secondary outcomes of interest were MG-ADL ocular, bulbar, respiratory, and limb subdomain scores as well as Neuro-QoL Fatigue scores, EQ-5D-5L index scores, and EQ VAS scores.

||| ||| ||||||||||| ||||||||||||| ||||| |||||||| |||||||||| || |||||| |||||||| ||| |||||||||| ||| ||||||| ||||||||| | |||||||| |||| ||| | ||||||||||||| ||||| ||||| |||||||||| ||||| ||||||||| || |||||| ||| |||||||||||| ||| ||| |||||||| || ||||||||| |||| || ||| | |||||||||| |||||||||| |||| ||||| || ||| ||||||| || || |||||||| |||||||||| || ||||||||||| || ||||||| ||||||| ||| ||||||| |||||||| || |||||||||||| |||||||| ||||||||||| |||||||||| ||||||||| |||| |||| |||| ||||||| ||||||||| ||| |||||| ||||||||| |||| |||||||| || | ||||||||||| |||||||||| || ||||||||||| |||||||| |||||| ||| ||||||| ||||| ||||| | |||||| ||||||||||| || |||||||||| ||| ||||||||||| || ||||||| || ||||| ||||||||||||||| |||| ||||||||| |||| |||| ||||||||||||| ||||||| |||||||| | ||||||||||||||||| |||||||| |||||||||| |||||| ||||| ||||||||| |||| |||| |||||| ||| ||||||||||||| |||| |||| ||||||||| ||||||||| ||||||||||| |||| |||| ||| ||| ||||||||| |||||||||||||||| ||| ||||||||||||| ||| ||||||||||||| ||||| |||||||| |||| ||||| ||||||||||||| |||| |||| ||||| ||||| |||| ||||| ||||||| |||||||| ||||||||||||| |||||| ||||| ||||||||||||| ||| ||||| ||||||||||||| |||||||| |||||||||| |||| ||||||||||||| ||| ||||||| ||||||||| || ||| |||| |||||||| |||||||||||| || |||||||||| ||| ||||||||||||| |||| |||| |||||||| ||||||||||||| ||||||||||||| ||||||||||||| ||||||| ||| ||||||||||||| |||| |||| ||| |||||||| |||||||||||||||| || ||||||||| ||| ||||||||||||| |||| |||| || ||||||| |||| |||||||| || ||| ||||||||||| |||| || |||||||| ||| ||||||||||||||| ||||| || ||||| || |||||||||| || |||||||||| ||||||||||||| |||||||||| ||| |||| ||| ||| |||||||| || ||| |||||||| ||||| ||||||||||||| |||| ||||||||| || ||| |||||||| || ||| |||||| |||||||||||| ||||| |||||| |||| ||| |||||||| |||| ||| ||||| || || ||| || |||||||| || ||| |||||||| ||||| ||||| |||||||| || |||| | ||||||| ||||||| |||||||||| || ||| |||||||| || |||||||| ||| |||||||||| || ||| |||||| | |||||| || ||||||| ||| |||| || |||||||| ||| |||||| || |||||||||||| ||| ||| |||| ||||| ||| |||| |||||| ||| | ||||||||| ||| |||||||||||||| ||||||||| ||||||||| ||||| ||||||| ||||||||| ||| || |||| ||||||| || ||| |||||||||||||||||| ||||| |||| || ||| |||||||| |||||| |||| ||||||| |||| |||||||| || ||||||||||||| ||||| ||||| |||| ||||||||||| ||||||||||||| |||| ||| |||| |||||| ||| || |||||||||||||||||| ||||||||| ||||| ||||| || |||||| ||| |||||||||||| || |||| ||||||||| ||| ||||||| |||||||| ||| |||| ||||||||||||||| |||||||||| ||||| ||| ||| |||| |||||||| || ||||||||||| |||||||| |||||||||| |||||| |||| ||||||| ||| ||| ||||| ||||||||| |||| || ||| ||| |||| ||| || ||| |||||||| ||| |||||| ||||||| |||||||| |||| |||||||| ||||||| || ||||| ||||||| |||||||||| |||||| || ||||| |||||||||| || ||||||||||| ||| |||||||| || ||| ||||||||| |||||||| ||| ||| ||| ||||||||| |||| ||| | ||||||||||| ||| |||||||| |||| ||||||| || | |||||| |||| |||||||| || || |||||| || ||||||||||| ||| |||||||| || |||||||| ||| |||||| || | || |||| ||||||||| ||| ||||||||| ||||||||||| |||||| ||| |||||| ||||||| |||||||||| ||||| |||||| ||||| ||| |||| ||| ||||||||||| || | || ||| || ||||| ||||||||||| || |||| ||| ||| ||| ||| |||||| ||||||| |||||||||| |||| ||| |||| ||| || ||| || ||||| ||||||||||| || |||| ||| ||||||||||||| ||| |||||||| ||| || |||| ||||| ||| ||||| ||||| |||||||| ||||||||| |||| |||||||| || |||| ||| ||||| ||| |||||||||| ||||| ||||||| ||| |||| |||||||| || |||| || ||| |||||| |||| ||| ||| ||||| |||||||||| || ||||||||||||| || ||||| |||||||| |||||||||||| |||||||| |||| |||||||| ||||| || ||||||||| ||||| ||||||||| |||||||| || || ||| ||||||||| ||||||||| || |||| ||||||||| ||| |||||||||| || |||||||| ||||||||| | ||||||| ||||||||||| || ||||| |||||| ||| ||| ||||| ||||||| |||||| ||||||| ||| |||||||||| ||| |||| ||||| ||| || |||| ||| ||| |||||||||| |||||||||| ||| |||||| |||| |||||||| |||||| |||| | || | ||| ||||||| | || || || |||| || ||||||||| ||| ||||| |||||||||| ||| |||||||| || ||| ||||||| |||| |||||||||||| |||| ||||||| ||||||| |||||| ||| |||||||| |||| ||||||| |||||| || |||| ||| |||| |||||||| |||||||||| || |||||||||| ||| ||||||||| ||||| || ||| ||| ||| |||||||| | ||||| |||| ||||||||| |||| ||| ||| ||| |||| ||||||||| ||| ||||||||||| |||| ||| ||||||| ||||||||||| || |||||||| |||| ||||||| |||||| |||||| ||| ||||||| || |||||| ||||||||||||| || |||||||| || |||||||||| ||| |||||| ||||||||||| || ||||||||||| |||||||||||| ||||||| ||| |||||||| ||| |||||| |||||||| ||||||||||||||| ||| ||||||||||| |||||| ||||||||||

Table 27: Redacted

||| ||||||||| ||||||||| ||||||||||| |||||| |||||||||| |||||| |||||||||| || ||||| ||||||| ||||||||| |||||||||||| ||||||| || ||||| || |||| ||||||||| || ||||||||||||| |||||||||| ||||||| || ||||||| |||||||| |||||||||||||| ||||||| ||||||||| || |||||||^||

Note: This table has been redacted at the request of the sponsor.

||||||| || ||||||| ||||||||| |||| || ||||||||||| ||||||||||||| ||||||||||||| || |||||||| |||||||||| |||||| |||||||| |||| |||||||| |||||| || ||||||||| |||||||| || ||||||| |||||||| ||||||||| ||||||||||| |||||||||| |||||||| || |||||| ||||||||| |||||||||| |||||||| || |||||||| || ||||||| || || ||||||| ||||||| || | ||||||||||||||| || |||| |||||||||| ||||| |||||||| |||||| || ||||||||| ||||||||| |||||| ||||||||||| || || ||||||| | ||||||||| |||||||||||| |||| |||| |||||| |||||||| ||||| |||||||| |||| || || |||| |||| ||||||||||||||||| || || |||||||| |||||| |||||| || | ||||| || ||||||| ||||| || |||||||| ||||| |||||||| |||||||| || || || ||||||||||| || ||||| ||||||||| |||||||| ||||||| |||||||| || |||||| |||| |||||||| || |||| |||||| |||| || ||||| |||||| |||| || |||||| ||||||||| |||| || ||||| |||| || ||||||| ||||||| ||||| || ||||| || ||||||||||| || |||||||| |||| ||||||| || || ||||||||| || ||||||||| || |||||||| |||| |||| ||||||| || ||||||| |||||||||| || |||||||| || |||||| || || |||||||| |||||||||| ||||||| || || |||||||||| |||||||||| ||||||||||| ||||||| |||||||| || |||||| || |||||||| | Table 28 | |||||||| |||||||| || |||||||| |||| ||||| ||||||||| |||| || ||||| |||||| |||||| |||| || ||||| ||||||| || ||||| || ||||| |||||| ||||||||| |||| || ||||| ||||| |||||| |||||| |||| || ||||| ||||| ||||||| || ||||| |||||| ||||| |||||| ||||||||| |||| |||||| ||||| ||||| ||||| |||||| |||| |||||| ||||| ||||| ||||||| || ||||| ||||||||||| || |||||||| ||||||||| ||||||||||||| |||||||||||| || ||||||||||||| ||||||| ||||||||| |||||||||| ||||||||| ||||| |||| ||||||| |||||| |||||||||| ||||||||| ||||| |||| ||||||| || |||| ||||||||||| || |||||| |||||||||| || ||||| ||||||||| |||||||||| |||||| |||||| |||||| |||||||||| |||||| |||||| |||||||| || |||||||| || |||||||

Table 28: Redacted

|||| ||||||||||| |||||| |||||||||| || |||||||| |||||| ||||||||||| |||||| |||||||||| || ||||| ||||||| || ||||||||||||| |||||||||| ||||||||||||||| ||||||| ||||||||| || |||||||

Note: This table has been redacted at the request of the sponsor.

||||||||| ||||||||| | || ||||||| ||||||||| ||||| || | |||| ||||||||| ||||||| |||||||| ||||||||||||||| |||| |||||||| || || |||| |||||||||| || Table 28 | || ||||||| || ||||| |||||||| || |||||||| | Table 29 | |||||||| |||||||||| |||| |||| ||||||||| |||||||| |||| |||||||| || || |||||||||| ||||||||| | ||||||||| |||||| |||| ||||| || |||||||| |||| |||||||| || ||||||| |||| || |||||||||||||||| |||||| ||||| || |||||||||||| | ||||||||| |||||| |||| || |||| ||||||||| |||| |||| || ||||||||| || |||||||| || |||||||| |||||||||| || || ||||||| |||| | ||||||||| |||||| |||| | |||| ||||||||| |||| |||| || ||||||||| || ||||||| ||||| |||| |||||||||||||||| || ||||||||| ||||| ||||| || || ||||||||| || || |||||||| || |||||||| |||||||| ||||| ||||||||||| |||||||||||| |||||| || |||||||||| || |||||||||||| |||||| || ||||||||| ||||||||||| ||||| |||| || ||||||||||||||| |||| || |||||||| || |||||| || |||||||||

Table 29: Redacted

||| |||||||||| |||||| ||||| |||| |||||||||||||||||| |||||||| ||||||||||| |||| ||||||||||| |||||| |||||||||| || |||||||| |||||| ||||||||||| |||||| |||||||||| || ||||| ||||||| || |||||||||||| |||||||||| ||||||||||||||| ||||||| ||||||||| || |||||||

Note: This table has been redacted at the request of the sponsor.

|||||||| |||||||| || ||||||| ||||||||||||||| || |||||||| ||||||||| || |||| || || ||||||||| || ||||||| || ||||| |||||||| || ||||||||| | Table 30 | |||||||| ||||||| || ||||| || || |||||||| |||||||||||||||| || |||||||||| |||| || || |||| || |||||||| || |||||||| || | |||||||| |||||| ||||||||||| ||||||||| |||||| |||| || || ||||||||| |||| |||| || ||||||||| || || ||||||| | || |||||||| || || ||||||||| |||||| |||| || |||| ||||||||| |||| |||| || ||||||||| || |||||||| || || |||||| |||||| |||||||||| ||||||||| |||||| |||| || |||| ||||||||| |||| |||| || ||||||||| || || ||||||| || || |||||| || || ||||||||| |||||| |||| || |||| ||||||||| |||| |||| || |||||||||

Table 30: Redacted

||| |||||||| |||||||||| |||||||||| |||| ||||||||||| |||||| |||||||||| || |||||||| |||||| ||||||||||| |||||| |||||||||| || ||||| ||||||| || ||||||||||||| |||||||||| ||||||||||||||| ||||||| ||||||||| || |||||||

Note: This table has been redacted at the request of the sponsor.

|||||||| ||||||| |||||||

||| |||||||||| |||||||||| |||||||||||| |||| || |||| || ||||||||| ||||| Table 31 | || |||||||| || || |||||||||| |||||| |||| |||||||| || || |||||| |||| || ||||||||| || |||||| ||||| |||||| || || ||||| |||||| ||||| |||| | || |||||||| |||| |||||||||||| || ||||||| ||||||||||| || || |||||||| |||||||| ||||||||| |||||| || ||||| |||||| |||||||| |||| |||||||||| |||||||| ||||||||||| || |||||| ||||||||| |||| |||||||||| || |||||||| || |||||||||||| |||||| |||||||| || ||||||||| ||||| |||| || ||||||||| || || ||||||||| ||||||||||||| || |||||| |||||||| |||| ||||||||||

|||||||| || || |||||||| || |||||||| ||||| || |||||||||||| |||||||| || |||| ||||||||||| ||||||| ||||||||||| || ||||||||||| |||||||| |||| || || |||||| ||||||||| |||| || ||||||||| || |||| ||||||||||| |||||| || || || |||||||| || ||||||||||| || |||||||| ||||| || |||||||||||| |||||||||| |||||||| || |||||||||||| || ||||||| ||||| ||||||||||| | |||||||| ||||||| |||| |||||||||| |||| ||||||||||| || |||||| ||||||||||| ||||||||| ||||| |||||| |||| |||||||| |||||| ||||||||||| |||||||||| ||||||||||| |||||||| || ||||||||||| ||||| || | |||| || ||||| | || || ||||||||| || || || || |||| || |||||||||| ||||||||| || ||||||||| ||||||| |||||| || ||||||| ||||| || ||||||||||| || |||||||| ||||||| |||| |||||||||| |||| ||||||||||| ||||| |||||| |||| |||||||| ||||||||| ||||||| |||||| ||||||||||| |||||||| || ||||||||||| ||||| | | |||| || |||||| || || |||||||||| ||||||||| || || || || |||| || || ||||||||| |||||||| || ||||||| || ||||||||||| || ||||| || |||||||||| |||| ||||||||||| ||||| |||||| |||| |||||||| |||||| |||||||||||| |||||||| || ||||||||||| ||||||| || || |||||| || |||||| || || ||||| || || || || |||||||||| || || |||||||| || | ||||| |||||||| ||||||||||| |||||||| ||||||| ||||| |||||| |||||| |||||| ||||||||| |||||| |||||| |||||| ||||||||| |||||| |||||| |||| ||||||||| |||||| || ||||| |||||| || |||||||| ||||| |||||| ||||| || |||||||||||| |||||||| || |||| ||||||||||| ||||||| |||||||||| || |||||||||||| || |||| |||||| || |||||| ||||||||| |||| || ||||||||| || |||| ||||||||||| ||||| || |||||| || ||||||||||| |||||||| || |||||||||||

Table 31: Redacted

| ||||||||||| ||||||||| || |||||||| |||||||||| |||||||||| | ||||||||| ||||||||| ||||||||||| |||| |||||||||||||||||| |||||||| ||||||||||| |||||| ||||||||||| |||||| |||||||||| || ||||| ||||||| || ||||| |||||| | |||||||||||| |||||||||| ||||||| | |||||| |||||||| |||||||||||||| ||||||| ||||||||| || |||||||

Note: This table has been redacted at the request of the sponsor.

Critical Appraisal of Sponsor-Submitted Indirect Treatment Comparisons and Comparative Observational Study

An important limitation of the submitted ITCs and observational study is that of absence of safety data. Without this, it is not possible to evaluate the combined efficacy and safety of ravulizumab relative to eculizumab. Given the absence of a clear conclusion with respect to efficacy, the influence of safety may become of higher priority to physicians and patients considering treatment with ravulizumab. As demonstrated in the observed differences in patient baseline characteristics, and trial eligibility differences between the CHAMPION and REGAIN trials, a naive (unadjusted) comparison of safety rates between these 2 trials is unlikely to be valid. Accordingly, no assessment can be made on the basis of the presented data with respect to the safety of ravulizumab relative to eculizumab. Notably, no justifications were provided for the selected analysis methods (the Bucher ITC, MAIC, and observational comparison with propensity score adjustment) and the appropriateness of each method varies depending on the evidence available for comparison (the validity of each method relies on different assumptions). The results were sometimes inconsistent across the analyses, and no direction was provided as to which may be most reliable.

A limitation of the submitted analyses is with respect to the observable parameters incorporated into both the MAIC and inverse propensity weighting (IPW) models. As demonstrated, the patient baseline characteristics varied across the 2 included studies. While the presented characteristics were incorporated into both the MAIC and IPW models, these approaches were unable to account for characteristics not included (i.e., known but unmeasured confounders, and unknown confounders), which may lead to residual confounding. The sponsor did not provide justification about the choice of parameters for inclusion within the statistical models chosen. It is important to note that certain parameters that may be important were not included in the model owing to a lack of data. For example, no data were provided with respect to IVIg usage in the REGAIN study. This particular covariate was noted by the clinical experts to be a potentially significant prognostic factor. Accordingly, residual confounding may influence the results for characteristics not incorporated into the adjusted models.

Importantly, the included trials differed with respect to inclusion status based on prior therapy. Patients in the REGAIN study were required to have failed with at least 2 immunosuppressive drugs or failed treatment with at least 1 immunosuppressive drug and have required chronic PE or IVIg. No such restriction was applied to patients in the CHAMPION study. This may in part explain the difference observed in the adjusted baseline use of ISTs, as well as perhaps the difference in baseline MG-ADL total scores and QMG total scores identified by the sponsor. Although the 2 trials were separated by approximately 5 years in enrolment periods, the clinical experts who reviewed the sponsor-submitted analysis did not indicate an expectation of significant changes to the standard of care, diagnostic awareness or capacity, and patient demographics over this time period.

For the covariates included under the adjusted models, there were several differences noted by the sponsor before adjustment. Following adjustment, the effective sample size under both the MAIC and IPW approaches was substantially reduced. This is indicative of a limited number of patients overlapping across the 2 trials based on the observed included covariates. Further, the low effective sample size limits the statistical power of the presented analyses, which may explain the comparatively large associated CIs presented in the main report.

No information was provided with respect to the process of the selection of trials for inclusion in the analyses. Within the CADTH review protocol, and in discussion with clinical experts, CADTH considered several other therapies of potential interest such as PE, PP, IVIg, AChEIs (e.g., pyridostigmine), IST (e.g., corticosteroids, azathioprine, mycophenolate mofetil, tacrolimus, cyclosporine, methotrexate, cyclophosphamide) and rituximab. As these therapies were not included in the analyses of indirect evidence, no assessment can be made regarding the relative efficacy of ravulizumab compared to these treatment options. For outcomes and safety data not included, it is unclear whether this is due to their lack of availability, a lack of feasibility, or other reasons. No conclusions with regard to the risk of bias of the included trials could be drawn, since this was not assessed or reported.

With respect to applicability to the Canadian patient population, data were not presented with respect to the geographic distribution of included patients, and therefore the influence of systematic differences in health care provision between the included geographies of patients among the trial populations and patients living in Canada is unclear. Moreover, the indirect evidence from the MAIC cannot be generalized to any specific subpopulation of patients with MG, as the reweighted data for patients in the ravulizumab arm of the CHAMPION trial were not reflective of any specific patient subgroups. Although the intent of this analysis was to enable comparisons with patients with refractory MG in the REGAIN trial, the degree to which the data accurately reflected the use of ravulizumab in refractory patients was unclear.

For the responder analysis, it is important to note that the last observation carried forward method was used, although no information was provided on the numbers of patients where values were imputed. Accordingly, a potential for bias occurs in these results, with an uncertain influence on the direction and magnitude of any such effect owing to the lack of data presented on the imputation approach.

In the submitted ITC, no formal specification was provided in the methods with respect to the estimand of interest used by the sponsor in its propensity weighting models. As such, it is unclear whether the reported results correspond to the average treatment effect on the treated population or the average treatment effect in this analysis.

For outcomes, all analyses are truncated at 26 weeks. Accordingly, no assessment can be made on the influence of ravulizumab relative to eculizumab beyond 26 weeks of treatment.

Other Relevant Evidence

This section includes a summary of the ongoing OL extension period of the CHAMPION¹³ trial with a 60-week data cut-off date³⁶ included in the sponsor’s submission to CADTH that was considered to provide further information on the long-term efficacy and safety of ravulizumab in adult patients with gMG who are treatment-naive to complement inhibitor.

Ongoing Open-Label Extension of the CHAMPION Trial (60-Week Data)

Description of Study

The ongoing OL extension period of the CHAMPION trial¹³ is being conducted for up to 4 years (a protocol amendment was made on May 21, 2021, to increase the maximum duration of the OL extension period to up to 4 years). The objective of the OL extension is to evaluate the long-term efficacy and safety of ravulizumab in adult patients with anti-AChR antibody–positive gMG who are treatment-naive to complement inhibitors (N = 161).³⁶

Details of the CHAMPION trial are presented in the Description of Studies sub-subsection of the Findings From the Literature subsection, Clinical Evidence section. After completing the 26-week randomized controlled period and assessments on day 183 (week 26), all patients who completed the randomized controlled period were eligible to enter the OL extension period and receive ravulizumab. The OL extension period for each patient started when the patient received a blinded dose of ravulizumab on day 183 (week 26). On day 183 (week 26), patients in the ravulizumab group received a blinded maintenance dose of ravulizumab 900 mg (ravulizumab to ravulizumab group) and patients in the placebo group received a blinded loading dose of ravulizumab (placebo to ravulizumab group). Beginning on day 197 (week 28), all patients received a maintenance dose of OL ravulizumab every 8 weeks.³⁶

A summary of the results from the CHAMPION trial collected up to week 60 in the OL extension period is presented as follows. The data cut-off date was November 9, 2021. Note, for patients who did not reach the week 60 visit by the data cut-off date, all data that were available were included.³⁶

Populations

Details of the inclusion and exclusion criteria in the CHAMPION trial are presented in the Description of Studies subsection in the Clinical Evidence section.

Baseline Characteristics (Open-Label Extension Set)

Approximately half of the patients (50.9%; n = 82) were female and approximately three-quarters of patients (73.3%; n = 118) were white. The mean age at the first OL ravulizumab infusion was 55.9 (SD = 15.24) years, and approximately two-thirds of patients (68.3%; n = 110) were aged between 18 years and 65 years at the first infusion of ravulizumab or placebo during the randomized controlled period. The mean baseline weight was 91.1 (SD = 26.66) kg, with more than half of patients (55.3%; n = 89) in the baseline weight category of 60 kg to 100 kg.³⁶

The most common baseline MGFA clinical classifications were class IIIa (32.9%; n = 53), class IIa (26.1%; n = 42), class IIb (18.0%; n = 29), and class IIIb (16.8%; n = 27). The mean baseline MG-ADL total score was 9.0 (SD = 2.41) and the mean baseline QMG total score was 14.5 (SD = 5.20).³⁶

Prior Myasthenia Gravis Therapy (Ravulizumab-Treated Set)

All patients (n = 169; 100%) had received prior treatment for MG, including symptomatic therapies, before the start of the study treatment (at the beginning of the randomized controlled period). |||||| | |||||||| || ||||| |||||| || |||||||| |||||||||| |||| ||||||||||||||||||||| ||||| || ||||| | |||||||||| |||| |||||||| |||||||||||||||, 78.1% (n = 132) had experience with ISTs, 44.4% (n = 75) had experience with immunoglobulins, 6.5% (n = 11) had experience with rituximab, and 1.2% (n = 2) had experience with cyclophosphamide. ||| |||| |||||||| |||| |||||||| |||| || ||||| || || || || ||||||||| || |||||||||| ||||| || ||||| ||||||||| |||| |||||||||||||| ||||||| ||||||| | | ||||| |||||||||| ||||||| | | |||| ||||||||||||| ||||||| ||||||| | | |||| |||||||||||| ||||||| | | |||| || ||||||||||||||| | ||||||||| ||||||||| ||||||| | | |||| || |||||||||| || |||||||| || |||| ||||||||| ||||| |||| |||||||||| |||| |||||||||||||| ||||||| || ||||||||||||| ||||||| |||| |||||||| |||| |||| ||||| || |||||||| || |||| || || ||||||| ||||| || ||||| || |||||||| || |||| || || ||||||| ||||| || |||||||||| |||| ||||||||||| |||||||||||| ||||||| || |||||||| || |||| || || ||||||| ||||| || ||||| || |||||||| || |||| || || ||||||| ||||| || |||||||||| |||| ||||||||||||| |||||||||| ||||||| || |||||||| || ||| || || ||||||| ||||| || ||||| || |||||||| || ||| || || ||||||| ||||| || |||||||||| |||| ||||||||||||||| || ||||||||| ||||||||||

|||||| |||||| ||||| || ||||||||| || || || || ||||| |||| || | ||||| ||||| || |||||||| ||||||| |||||||| || || || | |||||||| ||||||| || || ||||||| ||||| || || |||||||| ||||||| || || ||||||| |||||| || || |||||||| ||||||| |||||||| |||| || |||||||| ||||||| || | ||||||| ||||| || || |||||||| ||||||| || || ||||||| |||||||

| ||||| || || |||||||| ||||||| |||| ||||| || |||| || || || || ||||| |||| || |||||||||||| || |||||||| ||||||| || || ||||||| ||||| || || |||||||| ||||||| || | ||||||| ||||||

Interventions

Details of the dosing information for ravulizumab used in the CHAMPION trial are presented in the Description of Study sub-subsection in the Other Relevant Evidence section, as well as in the Interventions sub-subsection of the Clinical Evidence section. Note that there were no comparators used in the OL extension period.³⁶

Outcomes

The efficacy and safety data of ravulizumab were presented up to week 60 of the OL extension period. The primary efficacy end point was the MG-ADL total score, and the key secondary end points were the QMG total score, Neuro-QoL Fatigue score, and MG-QoL15r score.³⁶

Statistical Analysis

As per the primary efficacy analysis in the randomized controlled period, the MMRM method was used for analysis of all efficacy end points in the OL extension period, but no formal statistical comparisons were made between treatment groups.³⁶

The OL extension set, a subset of the FAS, consisted of patients who received at least 1 dose of ravulizumab in the OL extension period (N = 161).³⁶ The OL extension set included 93% (n = 83) of patients originally randomized to the placebo arm and 91% (n = 78) of patients originally randomized to the ravulizumab arm.

The ravulizumab-treated set consisted of all patients who received at least 1 dose of ravulizumab in either the randomized controlled period or the OL extension period (N = 169).³⁶ For patients in this set, data were presented from the first dose of ravulizumab during either the randomized controlled period or the OL extension period through the data cut-off date up to week 60. The ravulizumab-treated set included 93% (n = 83) of patients originally randomized to the placebo arm and all patients (n = 86) originally randomized to the ravulizumab arm.

Patient Disposition

Of the 175 patients who made up the FAS during the randomized controlled period, 162 patients completed the randomized controlled period, among whom 161 (99.4%) patients entered the OL extension. A total of 78 (98.7%) patients who were originally randomized to the ravulizumab arm entered the OL extension period; 1 patient completed the randomized controlled period but did not enter the OL extension due to patient decision. All patients (n = 83) who were originally randomized to the placebo arm entered the OL extension period.³⁶ As of the data cut-off date, 150 of 161 patients in the OL extension set were ongoing in the study: 71 of 78 patients in the ravulizumab to ravulizumab group and 79 of 83 patients in the placebo to ravulizumab group.³⁶

A total of 7 (9.0%) patients in the ravulizumab to ravulizumab group discontinued from the study during the OL extension period, of which 3 (3.8%) discontinuations were due to withdrawal by patients, 3 (3.8%) discontinuations were due to physician decision, and 1 (1.3%) discontinuation was due to death. A total of 4 (4.8%) patients in the placebo to ravulizumab group discontinued from the study during the OL extension period, of which 2 (2.4%) discontinuations were due to withdrawal by patient, 1 (1.2%) discontinuation was due to physician decision, and 1 (1.2%) discontinuation was due to death.³⁶

Exposure to Study Treatments

Exposure to Ravulizumab (Ravulizumab-Treated Set)

The |||| ||||||||||| ||||||||| |||||||| || ||||| |||| || |||||| |||||| ||||| |||| || ||||| ||||| || | ||||||| ||||| || ||||| |||| || ||||| ||||| || || ||||||| |||||| There had been 141.6 patient-years of exposure to ravulizumab | |||| ||||||||||||| || || ||||||| ||||| || |||| ||||||||||||| || | ||||||| |||||| || |||| |||||| || ||||||||||| ||||||||| || ||||||| || || ||||||||| || |||| ||||||||||| || ||||||||| || |||| |||||||||| || || ||||||| ||||| || || ||||||||| || |||| |||||||||| || | ||||||| ||||||

| ||||| || || |||||||| ||||||| || |||| ||||||||| ||||||||| |||| || ||||| |||| || ||||||||||| ||||||| || |||| |||||| ||||| || |||||||| ||||||| || || ||||||| ||||| || || |||||||| ||||||| || | ||||||| ||||||

Concomitant Myasthenia Gravis Therapy (Ravulizumab-Treated Set)

||| |||||||| |||||| | | |||| |||| || ||||||||||| || |||||||||| |||||||||| ||||||| || ||||| |||||||| ||||||||||| ||||||||||||||||||||| ||||| || |||| |||||||| ||||||||||| |||||||||||||||| || ||||| || ||||| |||||||| ||||| ||||||||||| ||||| || |||| |||||||| |||| |||||||| |||| || ||||| || || || || ||||||||| ||||||||||| || |||||||||||| ||||| |||| ||||| |||| |||||||||||||| ||||||| ||||||| | | ||||| |||||||||| ||||||| | | |||| || ||||||||||||| ||||||| ||||||| | | |||| || |||||||||| || |||||||| || |||| ||||||||| ||||| |||| ||||||||||| |||||||||||||| ||||||| || ||||||||||||| ||||||| |||| |||||||| ||||| || |||||||| ||||||| || || ||||||| ||||| || || |||||||| ||||||| || || ||||||| ||||| |||| ||||||||||| |||||||||||

| ||||| || || |||||||| |||||| |||| ||||||||||| ||||| |||||||| ||||||| || || ||||||| ||||| || ||||||||| |||||| || || ||||||| |||||| ||||| || ||||||||| |||||| |||| || || || || |||||||| |||||| || | ||||||| ||||| |||||||| |||||| ||| ||||||| ||||||

Efficacy

Only those efficacy outcomes identified in the CADTH review protocol are reported as follows.

Myasthenia Gravis Activities of Daily Living Total Score (Open-Label Extension Set)

The LSM changes from the OL extension period baseline in the MG-ADL total score and corresponding 95% CIs through week 60 are presented in Figure 13. The LSM change from OL extension baseline in the MG-ADL total score was 0.1 (standard error of the mean [SEM] = 0.28; 95% CI, –0.4 to 0.7) at week 28 and was –0.3 (SEM = 0.29; 95% CI, –0.9 to 0.3) at week 60 in the ravulizumab to ravulizumab group. The LSM change from OL extension baseline in the MG-ADL total score was –1.7 (SEM = 0.36; 95% CI, –2.4 to –1.0) at week 28 and was –1.7 (SEM = 0.50; 95% CI, –2.7 to –0.8) at week 60 in the placebo to ravulizumab group.³⁶

Figure 13: Change From Open-Label Extension Baseline to Week 60 of the Open-Label Extension Period in MG-ADL Total Score in the CHAMPION Trial — Open-Label Extension Set

BL = baseline; LSM = least squares mean; MG-ADL = Myasthenia Gravis Activities of Daily Living; MMRM = mixed model of repeated measures; OL = open-label; PBO = placebo; Ravu = ravulizumab.

Notes: Data cut-off date — November 9, 2021.

The OL extension baseline was defined as the last available assessment value collected before the first study drug infusion in the OL extension period. The start of the OL extension period was week 26. The estimates were based on an MMRM for each treatment sequence and included stratification factor region, baseline score, and study visit. Three asterisks indicate the 2-sided nominal P value was less than 0.001 for testing whether the LSM was equal to 0; no adjustments for multiplicity were made and there was an increased risk for type I error.

Source: CHAMPION Clinical Study Report Addendum (60-Week Data).³⁶

Quantitative Myasthenia Gravis Total Score (Open-Label Extension Set)

The LSM changes from the OL extension period baseline in the QMG total score and corresponding 95% CIs through week 60 are presented in Figure 14. The LSM change from OL extension baseline in the QMG total score was 0 (SEM = 0.40; 95% CI, –0.8 to 0.8) at week 28 and was –0.9 (SEM = 0.48; 95% CI, –1.9 to 0) at week 60 in the ravulizumab to ravulizumab group. The LSM change from OL extension baseline in the QMG total score was –2.1 (SEM = 0.49; 95% CI, –3.0 to –1.1) at week 28 and was –3.1 (SEM = 0.57; 95% CI, –4.2 to –1.9) at week 60 in the placebo to ravulizumab group.³⁶

Number and Dose of Existing Medications (Open-Label Extension Set)

Change in MG medications was not an efficacy outcome in the CHAMPION trial, although this information was collected. |||||||| || |||||||| ||||||| |||||||| || |||||||||| ||||||| |||||| || || ||||||||| |||||| || || || |||| |||||| ||||| The most common MG medication change was decreased systemic corticosteroids reported in 28.0% of patients (n = 45): 24.4% of patients (n = 19) in the ravulizumab to ravulizumab group and 31.3% of patients (n = 26) in the placebo to ravulizumab group. ||| |||||| |||| |||||| || |||||||||| |||||| ||||||||| |||||||||||||||||||| |||||||| || ||||| || |||||||| || ||||| ||||| || |||||||| || |||| || || ||||||| ||||| || ||||| || |||||||| || |||| || || ||||||| |||||| || ||||| |||| |||||| || |||||||||| |||||| || || |||||||||||||| |||||||| || |||| || |||||||| ||||||| ||||| || |||||||| || || || || ||||||| ||||| || |||| || |||||||| || || || || ||||||| ||||||||| ||||| ||||||| || |||||||| |||||||||||||||| |||||||||||||||| ||||| ||||| || |||||||||||||||||||| |||||||| |||||||||||| |||||| || || |||| || || ||||||||||

Figure 14: Change From Open-Label Extension Baseline to Week 60 of the Open-Label Extension Period in QMG Total Score in the CHAMPION Trial — Open-Label Extension Set

BL = baseline; LSM = least squares mean; MMRM = mixed model of repeated measures; OL = open-label; PBO = placebo; QMG = Quantitative Myasthenia Gravis; Ravu = ravulizumab.

Notes: Data cut-off date — November 9, 2021.

The OL extension baseline was defined as the last available assessment value collected before the first study drug infusion in the OL extension period. The start of the OL extension period was week 26. The estimates were based on an MMRM for each treatment sequence and included stratification factor region, baseline score, and study visit. Three asterisks indicate the 2-sided nominal P value was less than 0.001 for testing whether the LSM was equal to 0; no adjustments for multiplicity were made and there was an increased risk of type I error.

Source: CHAMPION Clinical Study Report Addendum (60-Week Data).³⁶

Need for Rescue Therapy (Open-Label Extension Set)

During the OL extension period, | ||||| || || |||||||| |||||| |||||||| |||||||| ||||||||||||| |||| || |||||||| |||||||| || |||||||| |||||| |||||||| ||||||||| ||||||| || || ||||||| ||||| || |||||| |||||| || || ||||||| ||||||| || |||| |||||| |||||| ||||||||| |||||||||||| |||| |||| |||||| | | |||| || || ||||||||| | | || || |||| |||| ||||||||||||||| |||||| | | |||

MG-QoL15r Total Score (Open-Label Extension Set)

The LSM changes from the OL extension period baseline in the MG-QoL15r score and corresponding 95% CIs through week 60 are presented in Figure 15. The LSM change from OL extension baseline in the MG-QoL15r score was –1.1 (SEM = 0.45; 95% CI, –2.0 to –0.2) at week 30 and was –0.8 (SEM = 0.53; 95% CI, –1.8 to 0.3) at week 60 in the ravulizumab to ravulizumab group. The LSM change from OL extension baseline in the MG-QoL15r score was –3.5 (SEM = 0.79; 95% CI, –5.1 to –1.9) at week 30 and was –3.1 (SEM = 0.87; 95% CI, –4.8 to –1.4) at week 60 in the placebo to ravulizumab group.³⁶

Figure 15: Change From Open-Label Extension Baseline to Week 60 of the Open-Label Extension Period in MG-QoL15r Score in the CHAMPION Trial — Open-Label Extension Set

BL = baseline; LSM = least squares mean; MG-QoL15r = Myasthenia Gravis Quality of Life 15-item scale - Revised; MMRM = mixed model of repeated measures; OL = open-label; PBO = placebo; Ravu = ravulizumab.

Notes: Data cut-off date — November 9, 2021.

The OL extension baseline was defined as the last available assessment value collected before the first study drug infusion in the OL extension period. The start of the OL extension period was week 26. The estimates were based on an MMRM for each treatment sequence and included stratification factor region, baseline score, and study visit. Three asterisks indicate the 2-sided nominal P value was less than 0.001 for testing whether the LSM was equal to 0; no adjustments for multiplicity were made and there was an increased risk of type I error.

Source: CHAMPION Clinical Study Report Addendum (60-Week Data).³⁶

Quality of Life in Neurological Disorders Fatigue Score (Open-Label Extension Set)

The LSM changes from the OL extension baseline period in the Neuro-QoL Fatigue score and corresponding 95% CIs through week 60 are presented in Figure 16. The LSM change from OL extension baseline in the Neuro-QoL Fatigue score was –4.3 (SEM = 1.63; 95% CI, –7.6 to –1.1) at week 30 and was –1.5 (SEM = 1.74; 95% CI, –5.0 to 1.9) at week 60 in the ravulizumab to ravulizumab group. The LSM change from OL extension baseline in the Neuro-QoL Fatigue score was –9.3 (SEM = 2.18; 95% CI, –13.7 to –5.0) at week 30 and was –8.0 (SEM = 2.19; 95% CI, –12.3 to –3.6) at week 60 in the placebo to ravulizumab group.³⁶

Figure 16: Change From Open-Label Extension Baseline to Week 60 of the Open-Label Extension Period in Neuro-QoL Fatigue Score in the CHAMPION Trial — Open-Label Extension Set

BL = baseline; LSM = least squares mean; MMRM = mixed model of repeated measures; Neuro-QoL = Quality of Life in Neurological Disorders; OL = open-label; PBO = placebo; Ravu = ravulizumab.

Notes: Data cut-off date — November 9, 2021.

The OL extension baseline was defined as the last available assessment value collected before the first study drug infusion in the OL extension period. The start of the OL extension period was week 26. The estimates were based on an MMRM for each treatment sequence and included stratification factor region, baseline score, and study visit. Two asterisks and 3 asterisks indicate the 2-sided nominal P value was less than 0.01 and 0.001, respectively, for testing whether the LSM was equal to 0; no adjustments for multiplicity were made, and there was an increased risk of type I error.

Source: CHAMPION Clinical Study Report Addendum (60-Week Data).³⁶

Harms

A summary of harms in the ravulizumab-treated set (n = 169) is presented in Table 32. Only those safety outcomes identified in the CADTH review protocol are reported as follows. Data were available for harms for ||| |||||||| || || ||||||| || |||||||||| || |||||||| | || || || |||||| || |||||||||| || || |||||||| || || || || |||||| || ||||||||||

During the total treatment duration with ravulizumab through week 60 as of the data cut-off date, a total of 150 (88.8%) patients experienced at least 1 AE. The most common AEs (occurring in 10% or more of patients) were headache in 28 (16.6%) patients, followed by diarrhea in 23 (13.6%) patients. ||| |||||||| ||||||| | | |||| || |||||||| ||||||||||| || || || || |||||||| ||||||| ||||| || |||| || ||||| || |||| ||||||||||| || || || || || || |||||| || | || || ||||||| |||||||||||||

A total of 41 (24.3%) patients had at least 1 SAE. ||| |||| |||||| |||| |||||||||| || || |||| ||||||||| |||| |||||||||| |||||| || ||||||||| ||||||| |||||||| || ||||||||| ||||||| || |||||||| |||||||||| ||||||||||| |||||||||| ||||||||| ||||||||| ||||||| |||||||| ||||||||| || ||||||||| || ||||||||| |||||| ||||| |||||||| |||| |||||||| ||||||||||| |||| || || ||||||| ||||||| | | || || || || |||||| ||||||| | | ||||| |||||||| |||||| | | || ||||||||||| |||| || || || || ||||||||| ||||| || ||||||||| |||||| |||||||| |||| | ||||| |||| || || || || ||||||| || || ||||||| |||||||| |||||||||| |||||||| |||| |||||| || |||||||||| |||||| || |||||||| || |||||||| |||||| ||||| ||||| |||| || ||||||||||| |||| || ||||| |||| ||||| || |||||||

A total of 4 (2.4%) deaths were reported ||||||| || || ||||||: 2 (1.2%) deaths were due to COVID-19 and 1 (0.6%) death each was due to COVID-19 pneumonia and to cerebral hemorrhage. | ||||| || ||||||||||| |||||| |||| |||||||| ||||| || |||| |||||| ||||| |||||| || || || ||||||||| |||||||| || |||||||||||| || ||||||| |||||| |||||| |||||||||| ||||||||||| | |||||||||||| ||||||| ||||| ||||| ||||| || || || |||||||| |||||| | || |||||||| ||||||||||||| |||| ||||||||||| || || || || || || |||||||| |||||| || || ||||||| ||||| | || || |||||||| |||||| || || ||||||| ||||||

| ||||| || || |||||||| ||||||| || |||||||||| || ||||||||||||| |||| |||||||| || || ||||| || || ||||||| ||||||| | | || || || || |||||| ||||||| | | |||| No meningococcal infections were reported; however, 1 event of meningitis of unknown etiology was noted | |||||| || || |||||||| ||||||| ||||||||||| |||||||| |||||||||| |||| |||||||| || || ||||| || || ||||||| ||||||| | | || | || || |||||| ||||||| | | ||||

Table 32: Summary of Harms in the CHAMPION Trial — Ravulizumab-Treated Set

AE = adverse event; |||||||| |||||||||||| ||||||| ||||| || ||||| |||||| SAE = serious adverse event; |||| ||||||||||| || ||||| |||| || || ||||||| ||||||

Notes: Data cut-off date — November 9, 2021.

||||| ||||||| || ||||| ||||||| || ||||| ||||||||| |||||||| |||| ||||||||||| ||||||| |||| || || || || |||| |||||| |||| |||||| || || |||| ||||||| |||||| || ||||| || ||||| |||||||| || ||||||||||| || || ||||||||||||||||||||| |||||| || |||||||| |||||||||| || ||||||||||| || || || || ||||||||| ||||||||

^aAEs occurring in 10% or more of patients are listed.

| |||| ||||||||| || || |||| |||||||||

Source: CHAMPION Clinical Study Report Addendum (60-Week Data).³⁶

Critical Appraisal

Internal Validity

Interpretation of the results from the OL extension period was limited by the absence of a randomized comparison group, which precluded causal conclusions. Since patients and study personnel were aware of the treatment received during the OL extension period, there was a risk of bias in the measurement of subjective outcomes (MG-ADL, QMG, MG-QoL15r, Neuro-QoL Fatigue, and subjective harms). As long-term efficacy data were summarized descriptively, the absence of formal statistical analysis precluded definitive conclusions. Based on the number of patients in each treatment arm included in the efficacy analysis from the OL extension period baseline to week 60, there was a risk of bias due to missing outcome data at longer follow-up; the magnitude and direction of bias was unknown. However, it should be noted that the missing data were likely due to the fact that not all patients had reached the week-60 visit by the data cut-off date.

External Validity

The appraisal of the external validity of the randomized controlled period, presented in the Critical Appraisal subsection regarding the CHAMPION study in the Clinical Evidence section, is also applicable to the OL extension period.

Discussion

Summary of Available Evidence

One phase III, DB, placebo-controlled RCT (CHAMPION, N = 175)^13,14 with an OL extension period of up to 4 years³⁶ designed to evaluate the efficacy and safety of ravulizumab versus placebo in patients with gMG contributed evidence to this report. The study enrolled adult patients with anti-AChR antibody–positive gMG (patients had to have an MGFA clinical classification of class II to class IV, an MG-ADL total score 6 or more, and be nonthymomatous) with no requirements for prior treatment experience or its outcome. Participants were randomized 1:1 to receive ravulizumab or a matching placebo every 8 weeks over a 26-week randomized controlled period. The primary outcome of the study was change from baseline in the MG-ADL total score at week 26 of the randomized controlled period, while secondary outcomes included change from baseline in the QMG total score at week 26, the proportion of patients with improvements of 5 points or more in the QMG total score at week 26, change from baseline in the MG-QoL15r score at week 26, change from baseline in the Neuro-QoL Fatigue score at week 26, and the proportion of patients with improvements of 3 points or more in the MG-ADL total score at week 26. According to the clinical experts consulted by CADTH for the review, the baseline characteristics of the CHAMPION study population were broadly representative of patients with gMG living in Canada at various stages of the treatment paradigm (including a small number of IST-naive patients). However, it was noted that patients with thymoma would likely not be excluded in a clinical setting and that the study population may have been more likely to respond to ravulizumab since some were IST-naive and some may have already responded to prior ISTs. The mean age was 55.6 years and most patients were from North America (45.7%) or Europe (36.6%). Prior to screening, 55.7% of patients had experienced moderate to severe MG (MGFA class IIIb, class IV, or class V), 60.0% of patients had experienced MG exacerbations, 24.4% of patients had experienced MG crises, and 17.1% of patients had required ventilator support. At the study baseline, 23.4% of patients had moderate to severe MG; nearly half of patients (43.4%) were receiving both corticosteroids and other IST, 36 (20.6%) patients were receiving other IST but not corticosteroids, 34 (19.4%) patients were receiving corticosteroids but not other IST, and 14 (8.0%) patients were receiving neither corticosteroids or other IST.

One sponsor-submitted ITC report¹⁶ (which also included comparative observational evidence) compared the efficacy of ravulizumab relative to eculizumab. In this ITC report, 3 different approaches to analysis were performed. No data were available for hospital admissions, the MGC score, MGFA-PIS, dose reductions of existing MG medications, rescue therapy, the MG-QoL15r score, or safety issues.

Interpretation of Results

Efficacy

The LSM change in the total MG-ADL score at week 26 of the randomized controlled period of the CHAMPION trial was –3.1 (95% CI, –3.8 to –2.3) in the ravulizumab arm and –1.4 (95% CI, –2.1 to –0.7) in the placebo arm. According to the clinical experts consulted by CADTH for this review, the LSM difference (–1.6; 95% CI, –2.6 to –0.7) was a statistically significant (P = 0.0009) and potentially clinically significant finding. The clinical experts stated that the LSM change exceeded the recognized response threshold of approximately 2 points in the ravulizumab arm, indicating clinical improvement, but did not do the same in the placebo arm. The clinical experts also noted that this threshold (an improvement of at least 2 points) was achieved by more than half of the patients in the placebo arm (53.0%) versus 63.9% of patients in the ravulizumab arm; the between-group estimate was too imprecise to draw a conclusion regarding the odds of at least a 2-point improvement for patients in the ravulizumab arm relative to those in the placebo arm. Based on the responder analysis at various point thresholds, the clinical experts stated that the overall data appeared to be driven by a relatively small subgroup of patients in the ravulizumab arm who experienced large improvements in their MG-ADL total score; this did not occur in the placebo arm. As the responder analyses at various thresholds for the MG-ADL total score improvement were not adjusted for multiplicity, there was an increased risk of type I error.

Similarly, the clinical experts viewed the LSM change in the total QMG score at week 26 of the randomized controlled period in the ravulizumab arm (–2.8; 95% CI, –3.7 to –1.9) and the placebo arm (–0.8; 95% CI, –1.7 to 0.1), and the LSM difference in the change in total QMG score at week 26 (–2.0; 95% CI, –3.2 to 0.8) as statistically significant (P = 0.009) and potentially clinically significant. Although the LSM change in the ravulizumab arm did not exceed the MID of approximately 3 points, this threshold was achieved by 44.8% of patients in the ravulizumab arm compared with 24.2% of patients in the placebo arm. The P value for the responder analysis at a threshold of at least a 3-point improvement in the total QMG score was not adjusted for multiplicity, so there was an increased risk of type I error. Moreover, the difference in the proportion of patients with improvement of at least 5 points in the total QMG score (ravulizumab arm = 30.0% of patients; placebo arm = 11.3% of patients; P = 0.0052) was viewed by the clinical experts as both statistically and potentially clinically significant. Again, the experts stated that the data appeared to be driven by a relatively small subgroup of patients who experienced large improvements, with some patients deriving less or minimal benefit.

Consistent numeric improvements in other outcomes in the ravulizumab arm versus the placebo arm (the MG-QoL15r score, MGC score, MGFA-PIS, Neuro-QoL Fatigue score, EQ VAS and index score, and most MG-ADL and QMG subscale scores) were viewed as supportive of the statistically tested primary and secondary analyses. Since many of these outcomes were not included in the statistical hierarchy or were tested after a prior nonsignificant result in the statistical hierarchy, there was an increased risk of type I error. Similarly, there were numerically fewer MG-related hospitalizations, patients reporting clinical deterioration, and patients requiring rescue therapy in the ravulizumab arm, supporting the primary and secondary efficacy analyses; however, these differences were not tested statistically. The impact of ravulizumab on changes in MG medications could not be evaluated because this was not allowed per the study protocol.

Efficacy data from the OL extension period were consistent with those from the randomized controlled period: patients who switched from placebo to ravulizumab experienced numeric improvements in a variety of outcomes that were sustained over the observation period. Further interpretation of these data was limited by the OL and descriptive nature of the extension study.

Because of the broad population of patients enrolled in the CHAMPION trial, encompassing both IST-naive patients and patients who had received 3 ISTs as well as patients along a continuum of MG severity, it was unclear how the results of the study would relate to any individual place in MG therapy. Subgroup analyses by prior IST and by MGFA clinical classification were uninformative; despite generally consistent findings across subgroups, the study was not specifically powered to assess differences among strata, sample sizes were small, and wide CIs reflected uncertainty. Furthermore, as the study was placebo-controlled, it was unclear how the drug would compare with standard MG therapies at any individual place in therapy. The submitted ITCs and comparative observational study attempted to compare the efficacy of ravulizumab and eculizumab in the CHAMPION and REGAIN³³ trials and their associated but distinct populations, but substantial uncertainty remained regarding potentially important differences, or lack thereof, in the efficacy of these drugs for various subpopulations of patients with MG. Given the similar mechanism of action between these 2 drugs, the clinical experts stated that the most obvious place in therapy for ravulizumab would be in patients with refractory gMG, although they acknowledged they have yet to be directly compared in this population.

The ITCs indicated favourable results for eculizumab relative to ravulizumab with respect to the MG-ADL respiratory subdomain (IPW analysis), Neuro-QoL Fatigue score (unadjusted analysis), and EQ VAS (MAIC analysis); however, these findings were not consistent across the various analyses. The analyses submitted were limited by small effective sample size, selection criteria, and demographic differences between included studies and the absence of adjustment for potentially important clinical covariates. The risk of bias of the trials used for comparison was not assessed or reported. As such, there remains uncertainty with respect to the efficacy and safety of ravulizumab relative to eculizumab.

Harms

Decreased side effects were identified in the patient input for this review as being of interest for patients with MG. The CHAMPION trial, including its randomized controlled period and OL extension, provided some relevant information regarding the safety profile of ravulizumab. Notably, however, it did not provide direct comparative evidence regarding the side effects of ravulizumab versus other MG therapies.

During the randomized controlled period, AEs, AEs leading to infusion interruption, and WDAEs occurred in similar proportions of ravulizumab-treated and placebo-treated patients in the CHAMPION trial. While SAEs were slightly more common in ravulizumab-treated patients (23.3%) compared with placebo-treated patients (15.7%), the only SAEs that occurred in more than 1 patient were COVID-19 pneumonia and transient ischemic attack. While 2 patients in the ravulizumab arm died during the randomized controlled period, the cause of death was clear in both cases (COVID-19 pneumonia and cerebral hemorrhage). ||||| |||||||||| |||| |||| |||||| || ||||||||||||||||||| |||||||| ||||||| |||||| ||||||||||||||| |||||||| |||||||| these were generally minor (e.g., pharyngitis, sinusitis, gastroenteritis) according to the clinical experts consulted by CADTH for this review. No meningococcal infections were reported. Infusion reactions occurred at similar frequency in ravulizumab-treated and placebo-treated patients.

Safety data from the OL extension, capturing a mean treatment exposure duration of 306.1 days, were consistent with the randomized controlled period. ||||| ||||| || |||||||| |||||||||| ||||||||||, no meningococcal infections were reported (although 1 event of meningitis of unknown etiology was noted). The safety profile of ravulizumab in the CHAMPION trial was considered manageable by the clinical experts consulted by CADTH for this review, especially given the well acknowledged adverse effects of standard MG therapies. However, the clinical experts also acknowledged that the adverse effects associated with the long-term administration of complement inhibitors such as ravulizumab are not yet known with the same certainty given their relatively recent development.

Conclusions

Evidence from the CHAMPION trial suggested that the administration of ravulizumab in adult patients with anti-AChR antibody–positive gMG (patients had to have an MGFA clinical classification of class II to class IV, an MG-ADL score of 6 or more, and be nonthymomatous) contributed to statistically significant and potentially clinically meaningful improvement compared with placebo in activities of daily living (the MG-ADL total score) and MG disease severity (the QMG total score, the proportion of patients with improvements of at least 5 points in the QMG total score) after 26 weeks of treatment. Results for other outcomes related to disease severity (the MGC score, MGFA-PIS), MG-related hospitalizations, clinical deterioration and the need for rescue therapy, and HRQoL (MG-QoL15r, Neuro-QoL, EQ-5D-5L) were supportive of the preceding results, although a lack of formal statistical analysis precluded definitive conclusions. An ongoing OL extension study (60-week data) suggested that patients who switched from placebo to ravulizumab experienced improvements in the aforementioned outcomes that were sustained over the observation period, although the long-term data were descriptive only and the lack of a randomized control group precluded causal conclusions. The safety profile of ravulizumab in the CHAMPION trial was consistent with that reported in the product monograph. Evidence from sponsor-submitted ITCs and an observational study comparing ravulizumab to eculizumab suggested uncertainty in the relative efficacy of these drugs and was limited by small effective sample size, selection criteria, and demographic differences between included studies and the absence of adjustment for potentially important clinical covariates. None of the available evidence provided a clear picture of the efficacy of ravulizumab for any specific place in the MG therapy paradigm (e.g., patients with refractory gMG or severe but nonrefractory gMG) compared with currently available therapies used at various stages of the treatment paradigm. The evidence from the CHAMPION trial was aligned with some outcomes identified as important to patients with MG who are seeking new therapies that can decrease the intensity of MG exacerbations, allow them to maintain independence, and prevent hospitalization while having acceptable side effects.

References

1.Drug Reimbursement Review sponsor submission: Ultomiris (ravulizumab), 10 mg/mL concentrate for solution for infusion [internal sponsor's package]. Zurich (CH): Alexion Pharma GmBH; 2022 Oct 25.

2.Gilhus NE. Myasthenia gravis. N Engl J Med. 2016;375(26):2570-2581. PubMed

3.Jayam Trouth A, Dabi A, Solieman N, Kurukumbi M, Kalyanam J. Myasthenia gravis: a review. Autoimmune Dis. 2012;2012:874680. PubMed

4.Paul RH, Nash JM, Cohen RA, Gilchrist JM, Goldstein JM. Quality of life and well-being of patients with myasthenia gravis. Muscle Nerve. 2001;24(4):512-516. PubMed

5.Wendell LC, Levine JM. Myasthenic crisis. Neurohospitalist. 2011;1(1):16-22. PubMed

6.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

7.Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in Myasthenia Gravis. BMC Neurol. 2010;10:46. PubMed

8.McGrogan A, Sneddon S, de Vries CS. The incidence of myasthenia gravis: a systematic literature review. Neuroepidemiology. 2010;34(3):171-183. PubMed

9.CADTH Canadian Drug Expert Committee recommendation: eculizumab (Soliris). Common Drug Review. Ottawa (ON): CADTH; 2020: https://www.cadth.ca/eculizumab-2. Accessed 2023 Jan 15.

10.Soliris (eculizumab) negotiation status. Toronto (ON): Pan-Canadian Pharmaceutical Alliance (pCPA); 2023: https://www.pcpacanada.ca/negotiation/21306. Accessed 2023 Jan 15.

11.CADTH reimbursement recommendation: ravulizumab (Ultomiris) for treatment of TMA. Can J Health Technol. 2022;2(3). https://www.cadth.ca/ravulizumab-0. Accessed 2023 Jan 15.

12.CADTH Drug Reimbursement Expert Review Committee final recommendation: ravulizumab (ultomiris) for treatment of aHUS. Ottawa (ON): CADTH; 2022: https://www.cadth.ca/ravulizumab-1. Accessed 2023 Jan 15.

13.Clinical Study Report: ALXN1210-MG-306. A phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety and efficacy of ravulizumab in complement-inhibitor-naïve adult patients with generalized myasthenia gravis [internal sponsor's report]. Bosston (MA): Alexion Pharmaceuticals, Inc; 2021 Oct 5.

14.Vu T, Miesel A, Mantegazza R, et al. Terminal complement inhibitor ravulizumab in generalized myasthenia gravis. NEJM Evidence. 2022;1(5).

15.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

16.ITC report: Efficacy of ravulizumab relative to eculizumab for the treatment of generalized myasthenia gravis [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: Ultomiris (ravulizumab), 10 mg/mL concentrate for solution for infusion. Zurich (CH): Alexion Pharma GmBH; 2022 Oct 25.

17.Zhang B, Tzartos JS, Belimezi M, et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol. 2012;69(4):445-451. PubMed

18.Romi F. Thymoma in myasthenia gravis: from diagnosis to treatment. Autoimmune Dis. 2011;2011:474512. PubMed

19.PrUltomiris® (ravulizumab): 10 mg/mL concentrate for solution for infusion [draft product monograph]. Zurich (CH): Alexion Pharma GmbH; 2022 Feb 24.

20.Liu R, Oldham RJ, Teal E, Beers SA, Cragg MS. Fc-engineering for modulated effector functions-improving antibodies for cancer treatment. Antibodies (Basel). 2020;9(4). PubMed