CADTH Reimbursement Review

Avalglucosidase Alfa (Nexviazyme)

Sponsor: Sanofi Genzyme, a division of Sanofi-Aventis Canada Inc.

Therapeutic area: Pompe disease

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.

Introduction

Pompe disease is a rare, autosomal recessive disorder caused by pathogenic variants in the acid alpha-glucosidase (GAA) gene, resulting in dysfunctional GAA enzymes.¹ With Pompe disease, the defect in the enzyme allows glycogen to accumulate in cells, leading to impaired cellular function and tissue damage.^1,2 Patients with late-onset Pompe disease (LOPD) have variable and reduced enzyme function (between 2% and 40% of normal),³ whereas patients with infantile-onset Pompe disease (IOPD) have minimal or no enzyme activity.^1,3 Pompe disease is usually diagnosed with molecular testing or enzymatic analysis of white blood cells or dried blood spots; however, in some cases, a biopsy of skin or muscle tissue can be performed and may show glycogen accumulation, but this method is more invasive. Gene sequencing is the preferred method to confirm a diagnosis and is both noninvasive and routinely available. The presence of 2 pathogenic variants of the GAA gene confirms a diagnosis of Pompe disease.

The rate of disease progression varies among patients, and disease severity is inversely correlated with residual GAA activity.³ Additionally, disease severity is associated with disease duration, and patients who have symptom onset at a younger age have more severe disease.¹ It has been estimated that the 5-year post-diagnosis survival for untreated patients with LOPD is 95%, and 30-year post-diagnosis survival is 40%.¹ It has been reported that patients treated with enzyme-replacement therapy have a mean age at death of less than 60 years,¹ although this varies with rate of progression, extent of muscle involvement, and comorbidities.³ For instance, early involvement of the diaphragm is followed by respiratory failure and death during the second or third decade of life.¹ In general, earlier diagnosis and treatment can improve outcomes. Clinical features vary from a slowly progressive myopathy, which might be preceded by an asymptomatic interval, to a much more rapid and progressive myopathy that results in wheelchair and ventilatory dependence and early death.¹ It is also a common and unique feature of Pompe disease to have early involvement of the diaphragm and respiratory accessory muscles that is not observed with most other myopathies. This can lead to respiratory failure, which is a major cause of morbidity and mortality in patients with LOPD.^1,3,4 The progression of symptoms often leads to new or increased use of respiratory support and mobility aids, and patients with LOPD can also experience respiratory failure while still ambulatory.³

The clinical expert CADTH consulted for this review estimated that a prevalence of 1 in 40,000 for all Pompe disease would be reasonable. For LOPD specifically, a study from the Netherlands estimated a prevalence of 1 in 57,000.⁵ The sponsor indicated that there were |||| patients with LOPD in Canada receiving treatment with alglucosidase alfa (|||| adults and |||| children) as of December 2020.⁶ The incidence of all Pompe disease (both LOPD and IOPD) has been estimated to be between 1 in 14,000 and 1 in 300,000, depending geographic location and ethnicity,³ whereas the incidence of LOPD has been estimated to be 1.75 in 100,000 births.⁷ A study using data from births between 1969 and 1996 in British Columbia estimated the incidence of Pompe disease to be 1 in 115,091.⁸ It is expected that this is an underestimate of the true number of patients with LOPD in Canada because many would be have been undiagnosed at the time of the study. No updated prevalence or incidence data specific to Canada have been identified.

Clinicians consulted by CADTH for the purpose of this review indicated that enzyme-replacement therapy with alglucosidase alfa, a recombinant human GAA (rhGAA), at a dose of 20 mg/kg by IV infusion every 2 weeks, is the standard treatment and the only specific treatment for LOPD, although it is not a cure for Pompe disease. Aside from enzyme-replacement therapy, supportive care includes continued monitoring of pulmonary function and motor performance to assess new or increased need for ventilatory support and mobility aids. Canadian guidelines for the diagnosis and management of Pompe disease state that there is no evidence for the use of enzyme-replacement therapy in patients who have confirmed Pompe disease but are otherwise asymptomatic.⁹

Supportive therapies also include exercise and dietary changes, and new disease-specific therapies include other forms of enzyme-replacement therapy, and gene therapies are in development. Other interventions, such as physical therapy, occupational therapy, speech therapy, and assistive technological devices, can be used to support respiratory and motor function and attempt to improve health-related quality of life (HRQoL).^3,4 Input from the clinical expert indicated that beta-2 agonists have been used off-label to try to increase the efficacy of enzyme-replacement therapy, although this is outside of the indication approved by Health Canada. The clinical expert emphasized that the main goals of currently available forms of treatment are to stabilize and/or improve motor and respiratory function, as well as to prevent further disease progression. New treatments should improve immune tolerance, have a low risk of treatment-related reactions, and be less of a burden on patients; current infusions are frequent and require hours to complete.

Avalglucosidase alfa is a rhGAA that provides an exogenous source of GAA enzyme-replacement therapy with an approximate 15-fold increase in mannose-6-phosphate, compared with alglucosidase alfa.¹⁰ The increased mannose-6-phosphate moieties provide a mechanism to drive uptake of avalglucosidase alfa into the diaphragm and other skeletal muscle through the cation-independent receptor.¹⁰ In Canada, avalglucosidase alfa is indicated for the long-term treatment of patients with LOPD. Avalglucosidase alfa underwent a standard review at Health Canada and reimbursement for the approved Health Canada indication has been requested. Avalglucosidase alfa has not been previously reviewed by CADTH.

The objective of this report is to perform a systematic review of the beneficial and harmful effects of avalglucosidase alfa administered once every other week as an IV infusion of 20 mg/kg of body weight for the treatment of LOPD.

Stakeholder Perspectives

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

Patient Input

Muscular Dystrophy Canada, in partnership with the Canadian Association for Pompe, conducted a survey and semi-structured phone or Zoom teleconference interviews with adults or the parents and caregivers of children living with Pompe disease. In total, 41 individuals affected by Pompe disease provided information for the submission.

Respondents frequently reported that Pompe disease negatively affected motor ability (including mobility, strength, balance, and energy) and breathing. Quality of life was also important to the patient group, and the detrimental effects of the disease on patients’ social health, mental health, and ability to participate in daily activities, and on their families, were identified as key issues related to Pompe disease.

Some respondents reported having no experience with medications for Pompe disease and were focusing on physical therapy, whereas others described being on enzyme-replacement therapy for years. Some patients treated with alglucosidase alfa described minor improvements followed by a plateauing of effect; others reported major improvements. Patients and caregivers said they would like new treatments to improve strength, breathing function, and prevent disease progression. They would also like a better mode of delivery, fewer side effects, a treatment that has a continuous effect in the body, and greater accessibility without the need to travel.

Two adults who reported clinical trial experience with avalglucosidase alfa had been receiving the enzyme-replacement therapy for 2 to 3 years. During this time, they noticed improvements in mobility, balance, and endurance, with the most significant benefits being improvements in daily living and mental health.

All patients from the group submission reported undergoing diagnostic testing with blood tests, and some also underwent confirmatory biopsies. In general, patients did not have to pay for testing, although some did incur costs associated with travelling for appointments. Some respondents experienced no delays in testing, but others faced multiple tests or significant wait times, and many patients recalled the stress of being misdiagnosed.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The clinical expert consulted by CADTH explained that the most important goals of currently available treatments are to stabilize and/or improve motor and respiratory function and to prevent further disease progression. Although reversal of muscle involvement at the time of diagnosis would be ideal, novel tools to target muscle cell growth and regeneration will need to be developed before this goal can be achieved. Therapies should also have a minimal burden on patients and a low risk of infusion-related reactions.

The clinical expert expects that avalglucosidase alfa will replace alglucosidase alfa as first-line treatment for Pompe disease and that all patients who meet the criteria for treatment will receive the new drug. This would include patients who have never received enzyme-replacement therapy; those already being treated with alglucosidase alfa would be switched over to avalglucosidase alfa.

Patients with Pompe disease are identified with enzymatic testing and genetic testing. The clinical expert noted that a free multigene panel provided by the drug manufacturer includes testing for Pompe disease. This has allowed clinicians to screen and identify potential patients before they qualify for genetic testing, which is funded in some jurisdictions.

According to the clinical expert, any patients with symptomatic disease should be treated with enzyme-replacement therapy. The heterogeneity in clinical presentation of LOPD precludes treatment in the primary-prevention setting, and patients without symptoms should be closely monitored to detect early signs of disease progression. Patients with very advanced disease, such as those who are wheelchair-bound and on permanent invasive ventilation, might be least suited for avalglucosidase alfa, although the clinical expert added that clinical context should be considered on a case-by-case basis.

Canadian evidence-based guidelines⁹ for the treatment of LOPD emphasize the importance of having and meeting clearly defined, objective outcomes and tracking progression, the clinical expert reported. Assessments for skeletal muscle function (e.g., 6-minute walk test [6MWT], quantitative muscle strength scoring) and respiratory muscle function (e.g., forced vital capacity [FVC], maximum inspiratory pressure [MIP], maximum expiratory pressure [MEP], change in FVC between upright and supine positions) were noted as relevant outcomes in clinical trials. Testing at individual clinics may vary. It is recommended that patients are followed at least annually by a regional centre of excellence. Patients who begin a new therapy should initially be assessed every 6 months, whereas patients on long-term treatment who remain stable should be assessed at least annually. For patients who live in remote areas, it may be acceptable to have a detailed annual assessment at an expert centre along with visits every 6 months with a local physician.

The clinical expert stated that most patients are treated with enzyme-replacement therapy until they develop end-stage disease, which could include the need for a wheelchair and full-time invasive ventilation. Anaphylactic reactions to the medication that cannot be managed with premedications and comorbidities that significantly reduce lifespan (e.g., cancer) might be reasons to discontinue treatment.

According to the clinical expert, new patients often start their treatment in a hospital clinical setting and, once stable, transition to home infusions. Post-infusion follow-up would always be performed by a centre with expertise in the management of patients with Pompe disease.

Clinician Group Input

Clinician input was provided by the Neuromuscular Disease Network for Canada and 8 clinicians with experience treating Pompe disease.

Input from the clinician group was similar to that given by the clinical expert consulted by CADTH.

Drug Program Input

The drug programs had questions about age eligibility and switching from alglucosidase alfa to avalglucosidase alfa. The drug programs also noted a preference for uniform initiation, renewal, and discontinuation criteria for avalglucosidase alfa among jurisdictions. Responses to the questions are in Table 4.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

One multi-centre, double-blind, active-control, phase III, randomized controlled trial (RCT) was included in the CADTH review for avalglucosidase alfa. The COMET trial was designed to evaluate the efficacy and safety of avalglucosidase alfa 20 mg/kg body weight administered every other week for the treatment of LOPD. The study consisted of a screening period of up to 14 days, a double-blind treatment period of 49 weeks, an open-label extension phase of up to 240 weeks, and follow-up for up to 4 weeks. At the end of the double-blind phase, patients in the alglucosidase alfa arm switched to the avalglucosidase alfa arm for the duration of the open-label treatment phase. The primary outcome of FVC (% predicted) in the upright position was used to test the noninferiority of avalglucosidase alfa to alglucosidase alfa, using a noninferiority margin of –1.1%. Sequential testing continued with superiority testing for FVC (% predicted) followed by the key secondary outcome of distance walked and % predicted on the 6MWT. Patients older than 3 years were eligible to participate in the COMET trial if they had confirmed GAA enzyme deficiency from any tissue source and/or 2 confirmed GAA gene mutations. Patients with known Pompe-specific cardiac hypertrophy or who had severe disease (e.g., wheelchair-dependent, requiring invasive ventilation) were excluded from the study. Previous treatment with alglucosidase alfa or other investigational treatments for Pompe disease were also reasons for exclusion.

In total, 100 patients were randomized in a 1:1 ratio to either avalglucosidase alfa or alglucosidase alfa. The mean age of the patients in the COMET trial was 48 years (standard deviation [SD] = 14), and patients were older in the alglucosidase alfa group. Patients were predominantly White (94%), and there was a similar number of male and female patients within and between treatment groups. The baseline mean distance walked on the 6MWT was numerically higher for the avalglucosidase alfa group (399.3 m; SD = 110.9) than for the alglucosidase alfa group (378.1 m; SD = 116.2). Also, more patients reported using no mobility aids in the avalglucosidase alfa arm. Use of a rolling walker or a single crutch was higher in the comparator arm (6.1% and 4.1%, respectively) than in the avalglucosidase alfa arm (0.0% and 0.0%, respectively). The mean age at diagnosis for Pompe disease was lower for patients in the avalglucosidase alfa group (44.73 years; SD = 14.74) than in the alglucosidase alfa group (48.16 years; SD = 14.64). The time between diagnosis and first infusion of the study drug was shorter in the avalglucosidase alfa group (15.60 months; SD = 32.06) than in the alglucosidase alfa group (26.52 months; SD = 59.86).

Efficacy Results

Patients in the modified intention-to-treat (mITT) population, which was equivalent to the intention-to-treat (ITT) population, demonstrated a least squares (LS) mean change in FVC (% predicted) in the upright position from baseline to week 49 of 2.89% (95% confidence interval [CI] = 1.13 to 4.65) in the avalglucosidase alfa arm and 0.46% (95% CI = –1.39 to 2.31) in the alglucosidase alfa arm. The mean difference of change between treatment groups was 2.43% (95% CI = –0.13 to 4.99), for which the lower bound of the 95% CI did not exceed the noninferiority margin of –1.1%, indicating that the criteria for noninferiority of avalglucosidase alfa to alglucosidase was demonstrated (P = 0.0074). The P value for superiority testing was not statistically significant (P = 0.0626), so statistical testing was stopped for all subsequent efficacy outcomes. Analysis of the per protocol (PP) population had similar results, with a FVC (% predicted) LS mean change from baseline to week 49 of 2.87% (95% CI = 1.02 to 4.73) and 0.19% (95% CI = –1.83 to 2.21) for the avalglucosidase alfa and alglucosidase alfa groups, respectively. The mean difference of change between treatment groups was 2.69% (95% CI = –0.06 to 5.44; P for noninferiority = 0.0076 and P for superiority = 0.0555).

The mean change from baseline to week 49 for the 6MWT distance was 32.21 m (95% CI = 12.47 to 51.94) for the avalglucosidase alfa group and 2.19 m (95% CI = –18.48 to 22.86) for the alglucosidase alfa group. The mean difference of change between treatment groups was 30.01 m (95% CI = 1.33 to 58.69), which was numerically greater for avalglucosidase alfa, with a CI that excluded the null. The mean change from baseline for the 6MWT (% predicted) was 5.02% (95% CI = 1.95 to 8.09) for the avalglucosidase alfa group and 0.31% (95% CI = –2.90 to 3.52) for the alglucosidase alfa group. The mean difference of change was 4.71% (95% CI = 0.25 to 9.17) between treatments.

Harms Results

During the double-blind phase, 44 patients (86.3%) who received avalglucosidase alfa and 45 patients (91.8%) who received alglucosidase alfa experienced an adverse event (AE). The most frequently reported events were nasopharyngitis (12 patients, 23.5%), back pain (12 patients, 23.5%), and headache (11 patients, 21.6%) for the avalglucosidase alfa group, and headache (16 patients, 32.7%), nasopharyngitis (12 patients, 24.5%), and falls (10 patients, 20.4%) for the alglucosidase alfa group. Overall, SAEs were infrequent among either treatment group. Serious AEs (SAE) were reported in 8 (15.7%) patients who received avalglucosidase alfa, compared to 12 (24.5%) patients who received alglucosidase alfa. Four patients (8.2%) in the alglucosidase alfa group withdrew from the study because of the following AEs: acute myocardial infarction, arthritis, dyspnea, and urticaria. No patients withdrew from the avalglucosidase alfa group because of AEs. One death (2%), from acute myocardial infarction, was reported in the alglucosidase alfa group.

Treatment-emergent anaphylactic reactions (pruritus and rash) were reported in 2 patients (approximately 4.0%) in each of the treatment arms during the double-blind phase. Treatment-emergent hypersensitivity reactions occurred in 12 patients (23.5%) and 15 patients (30.6%) in the avalglucosidase alfa and alglucosidase alfa groups, respectively, with pruritus and rash being the most frequently reported. Treatment-emergent infusion-associated reactions occurred in 13 patients (25.5%) in the avalglucosidase alfa and in 16 patients (32.7%) in the alglucosidase alfa group, with pruritus and nausea being the most frequently reported infusion-associated reactions. Treatment-emergent immune-mediated reactions occurred in 12 patients (23.5%) who received avalglucosidase alfa and 15 patients (30.6%) who received alglucosidase alfa, with arthralgia and myalgia being the most common. Nearly all patients were positive for treatment-emergent anti-drug antibodies. Overall, 10 patients (19.6%) in the avalglucosidase alfa group and 16 patients (33.3%) in the alglucosidase alfa group had peak titre levels greater than 12,800. Acute cardiorespiratory failure was not reported in the COMET study.

Critical Appraisal

A key limitation to the COMET trial was the difference in baseline characteristics between the treatment arms. The avalglucosidase alfa group had a younger age at baseline, younger age at diagnosis, shorter time between diagnosis and treatment, greater 6MWT mean distance, and fewer patients who used a mobility aid during the 6MWT. Of note, the time between diagnosis and first infusion of the study drug was different between the treatment groups and was not adjusted for in the statistical analysis, which might have confounded the results. The clinical expert consulted for this review stated that the differences may be a result of the small patient numbers, but noted that the differences in baseline characteristics in most cases tend to cause biases in the results in favour of the avalglucosidase alfa group. Patients who present at an early age are likely progressing at an accelerated rate, and earlier treatment is expected to result in better outcomes, but the direction and magnitude of the biases caused by the differences in these factors in the baseline characteristics are unclear. All 5 patients (10.2%) who discontinued treatment during the double-blind phase were from the alglucosidase alfa group, and it is unknown what impact these losses had on the results, considering the small patient numbers. Nearly all outcomes reported in this review had missing data, and methods for handling missing data were lacking, which must be considered when interpreting the results. Missing data were not imputed for the primary outcome, and it was assumed that data were missing at random. This assumption may bias 1 treatment over another, although sensitivity analyses were performed to assess the impact of missing data, which supported the missing-at-random assumption for the primary outcome. To control for multiplicity, a sequential testing strategy was used, and statistical testing was stopped at the first nonsignificant outcome (superiority testing of the primary outcome). As a result, all secondary and tertiary outcomes were not controlled for type I error and should be interpreted as supportive of the primary outcome. Subgroup analyses for the primary outcome were specified a priori; although there was no control for multiplicity, each subgroup had a small number of patients, and the wide 95% CIs indicated imprecision with the estimates.

The noninferiority margin of –1.1% was based on data from the double-blind, placebo-controlled LOTS trial for alglucosidase alfa 20 mg/kg every other week. The noninferiority margin of –1.1% retained approximately half of the lower bound of the 80% CI of the estimated treatment effect of alglucosidase alfa over placebo for FVC (% predicted) in the LOTS trial at 12 months (i.e., 2.14). The clinical expert believes that this is a reasonable approach to estimate the margin, and that it is also a reasonable choice of margin from a clinical perspective. Retention of half the comparator’s treatment effect is consistent with FDA guidance for noninferiority trials.¹² Although FDA guidance¹² indicates that a 95% CI is commonly used, the COMET publication¹³ stated that the CI was lowered to 80% in response to suggestions by regulatory bodies. The rationale for this was not described. The constancy assumption is such that the effect of the active comparator (i.e., alglucosidase alfa) in the current noninferiority trial is the same as the effect observed in past trials and requires the trials be sufficiently similar.¹⁴

The similarities in study design, eligibility criteria, treatment doses, and key outcomes between the COMET and LOTS trials support the constancy assumption. Furthermore, the pre-specified constancy-assumption analysis estimated an effect of 2.87 for alglucosidase alfa, compared with placebo, in the COMET trial, and an effect of 3.02 in the LOTS trial based on the predictive model.¹³ The investigators considered the difference in effect to be small (–0.15) compared with the noninferiority margin (1.1%).¹³ Considering that Pompe disease is rare, the clinical expert noted that the patients who received alglucosidase alfa were mostly similar in the 2 studies. However, key differences in baseline characteristics (e.g., older baseline age, older age at symptom onset, higher FVC, and better 6MWT scores) were noted for patients who received alglucosidase alfa in the COMET trial compared to the LOTS trial. Although these differences should bias the results in favour of alglucosidase alfa in the COMET study, the clinical expert did not feel the differences explained why the patients in the COMET trial did not respond as well as those in the LOTS trial. Consequently, the lower-than-expected improvements in patients in the alglucosidase alfa arm in COMET study could bias the interpretation of results in favour of treatment with avalglucosidase alfa. Although these concerns may have impacted interpretation of the trend toward superiority in the COMET trial, it is the opinion of the clinical expert that the concerns do not affect the statistically significant conclusion of the trial: that avalglucosidase alfa is noninferior to alglucosidase alfa.

In general, the patients in the COMET study resembled those seen in clinical practice in Canada. Despite limited evidence for the treatment of children with LOPD, the clinical expert consulted for this review stated that the results were generalizable to pediatric patients, but not to patients with IOPD, and highlighted the urgent need for additional data in the IOPD population. The clinical expert noted that clinical practice, background care, and reporting of AEs can vary among countries, which may confound results. Canadian guidance⁹ for the management of patients with Pompe disease suggests that assessments be performed at least every 6 months, which is less frequent than in the COMET trial. The greater access to health care resources and attention from clinicians should be considered when the results are generalized to real-world practice.

Given that Pompe disease is a lifelong condition, the 1 year of data for avalglucosidase alfa from the double-blind phase of the COMET trial is somewhat limiting, although the open-label extension phase is ongoing. The literature search conducted to inform the description and appraisal of outcome measures showed there was a lack of evidence supporting the validity, reliability, or responsiveness to change for some of the trial outcomes. Therefore, there is uncertainty around the use of measures such as MEP, SF-12, and GMFM-88 to assess treatment for patients with LOPD. Furthermore, a literature search did not find any minimally important differences (MIDs) for populations with Pompe disease.

Indirect Comparisons

Indirect treatment evidence for avalglucosidase alfa was not identified in this review.

Other Relevant Evidence

Description of Studies

The NEO1 study was a phase I, multi-centre, open-label, ascending-dose study conducted to determine safety and tolerability, pharmacokinetic parameters, and the pharmacodynamic effects of avalglucosidase alfa in patients with LOPD who were treatment-naïve (group 1) and in patients with LOPD who were previously treated with alglucosidase alfa for at least 9 months (group 2). Patients received IV infusions of avalglucosidase alfa every other week, for a total of 13 infusions at 1 of the following doses: 5 mg/kg, 10 mg/kg, or 20 mg/kg. Study participants had to be at least 18 years of age with a confirmed GAA enzyme deficiency and/or a confirmed GAA gene mutation, no known cardiac hypertrophy, FVC in the upright position of 50% predicted or more, and be able to ambulate 50 m without stopping and without an assistive device.

The NEO-EXT study is the long-term extension of NEO1. All patients who completed treatment with the 5 mg/kg or 10 mg/kg dose were invited to enrol in the extension and receive the 20 mg/kg dose for up to 6 years. The results summarized in this review focused on the Health Canada–approved 20 mg/kg dose.

Efficacy Results

All efficacy results in the NEO1 study were considered exploratory in nature.

In the NEO1 study, baseline mean FVC (% predicted) for patients who received avalglucosidase alfa 20 mg/kg were 63.4% (SD = 17.84) and 70.4% (SD = 16.40) in group 1 and group 2, respectively. At week 25, mean FVC (% predicted) changed to 69.5% (SD = 20.63) and 69.9% (SD = 16.92) in group 1 and group 2, respectively, with a mean change from baseline of 6.2% (SD = 3.15) and 1.4% (SD = 5.71) for the respective groups. In the NEO-EXT study, baseline mean FVC (% predicted) were 69.2% (SD = 19.27) and 77.3% (SD = 16.45) in combined (5 mg/kg, 10 mg/kg, or 20 mg/kg doses) group 1 and combined group 2, respectively. At week 286, mean FVC (% predicted) changed to 65.7% (SD = 30.07) and 74.5% (SD = 21.24) in the combined group 1 and combined group 2, respectively. Results beyond week 286 were available, but reduced patient numbers resulted in uninformative data.

In the NEO1 study, baseline mean 6MWT % predicted for patients who received avalglucosidase alfa 20 mg/kg were 75.2% (SD = 9.80) and 72.8% (SD = 20.59) in group 1 and group 2, respectively. At week 25, mean 6MWT % predicted changed to 79.1% (SD = 12.55) and 65.6% (SD = 12.03) in group 1 and group 2, respectively, with mean changes from baseline of 3.9% (SD = 3.45) and –1.3% (SD = 8.94) for the respective groups. In the NEO-EXT study, 6MWT results were 64.9% (SD = 28.05) and 69.1% (SD = 21.37) in group 1 and group 2 at week 286, respectively. Results beyond week 286 were available, but reduced patient numbers resulted in uninformative data.

Harms Results

In the initial NEO1 study period, 1 of the 3 patients in group 1 who received the 20 mg/kg dose experienced an AE: namely, nasopharyngitis and erythema. All 6 patients in group 2 who received the 20 mg/kg dose experienced an AE, but arthralgia and musculoskeletal pain were the only 2 AEs to be reported in multiple patients (33.3%). In the NEO-EXT trial, all 24 patients, including those who switched to 20 mg/kg, experienced an AE. The most commonly reported AEs were nasopharyngitis (15 patients, 62.5%), fall (12 patients, 50.0%), diarrhea (11 patients, 45.8%), headache (10 patients, 41.7%), and muscle spasms (10 patients, 41.7%). None of the patients who received the 20 mg/kg dose reported a SAE in the NEO1 study. In the NEO-EXT study, 9 patients (37.5%) reported a SAE, but no individual SAE was reported in more than 1 patient. In the NEO1 study period, no patients who received the 20 mg/kg dose reported an AE that led to treatment discontinuation. In the NEO-EXT study, 1 patient (4.2%) discontinued treatment due to an AE. No deaths related to AEs were reported in either the NEO1 or NEO-EXT study.

Notable harms — including anaphylactic reactions, hypersensitivity, infusion-associated reactions, and immune-mediated reactions — were less common in the NEO1 study period, but occurrence increased in NEO-EXT. In NEO-EXT, 17 patients (70.8%) experienced a treatment-emergent hypersensitivity reaction, 12 patients (50.0%) experienced a treatment-emergent infusion-associated reaction, 2 patients (8.3%) experienced a treatment-emergent anaphylactic reaction, and no patients experienced a treatment-emergent immune-mediated reaction.

Critical Appraisal

In the NEO1 and NEO-EXT studies, efficacy outcomes were considered strictly exploratory. Inherent in phase I trials are the issues of a low number of patients, the lack of a comparator arm, and the lack of randomization. As a result, it is not possible to determine a causal relationship between the study drug and outcomes observed. The baseline demographics varied between patients receiving different doses, likely because of the low number of patients.

Inclusion of the long-term extension of the phase I NEO1 study in the sponsor’s submission allows for greater generalizability of the safety and tolerability data, beyond the time points presented in the pivotal trials; however, the study design greatly limits the generalizability of any findings.

Conclusions

In the COMET trial, the study’s main objective was achieved, and avalglucosidase alfa met the criteria for noninferiority, compared with alglucosidase alfa. This comparison was made at the noninferiority margin of –1.1%, based on the primary outcome of FVC (% predicted) in the upright position for the first 49 weeks of treatment in patients with LOPD. Based on the evidence from the COMET trial, treatment with avalglucosidase alfa appeared to prevent further respiratory deterioration during the first year, which is 1 of the main goals of currently available forms of treatment, according to the clinical expert. The results from the study were not statistically significant when testing for the superiority of avalglucosidase alfa over alglucosidase alfa for FVC (% predicted). Statistical testing was stopped for secondary outcomes and results should be interpreted as supportive of the primary outcome. Most patients experienced at least 1 AE during the first year of treatment, but fewer experienced a SAE. Notable harms related to anaphylactic reactions occurred with the same frequency among the treatment groups; however, hypersensitivity reactions, infusion-associated reactions, and immune-mediated reactions were numerically lower in patients who received avalglucosidase alfa.

Key limitations include the small number of patients enrolled in the studies and the lack of data available for pediatric patients. The small number of patients limits the ability to accurately quantify the differences in outcomes, beyond the primary outcome, in long-term benefits and in potential harms between the treatments. Moreover, it will be beneficial to have continued long-term efficacy and safety data (including anti-drug antibody assessments) for avalglucosidase alfa, which the extension phase of the COMET study will provide. Last, these results apply only to patients with LOPD; trials evaluating avalglucosidase alfa in patients with IOPD are ongoing.

Introduction

Disease Background

Pompe disease (also known as GAA deficiency, or glycogen storage disease type II) was the first lysosomal storage disease to be identified.¹ It is a rare, autosomal recessive disorder caused by pathogenic variants in the GAA gene, resulting in dysfunctional GAA enzymes. In the low pH of the lysosome, GAA breaks down the alpha-1,4- and the alpha-1,6-glycosidic links of glycogen molecules. With Pompe disease, the defect in the enzyme allows glycogen to accumulate, leading to impaired cellular function and tissue damage.^1,2 Patients with LOPD have variable and reduced enzyme function (between 2% and 40% of normal),³ whereas patients with IOPD have minimal or no enzyme activity.¹

The diagnosis of Pompe disease can be a challenge because symptoms resemble those of other neuromuscular disorders.⁴ Pompe disease might be suspected in children and adults who show progressive proximal limb weakness and significantly reduced FVC.¹ It is diagnosed with molecular testing or enzymatic analysis of white blood cells or dried blood spots, which is typically available in clinical biochemical and genetic diagnostic labs. In some cases, a biopsy of skin or muscle tissue can be performed, and may show glycogen accumulation. Gene sequencing is the preferred method for confirming a diagnosis and is noninvasive and routinely available. Genetic sequencing can also be used to rule out false-positive results that arise from a homozygous pseudodeficiency allele (leading to low GAA activity). The presence of 2 pathogenic variants of the GAA gene confirms a diagnosis of Pompe disease. Newborn screening for GAA deficiency has been implemented in some countries, using a tiered system that consists of an enzymatic assay followed by molecular genetic testing. Differential diagnosis might be necessary to distinguish Pompe disease from other myopathies using age at symptom onset, high creatine kinase levels, and absence of metabolic abnormalities (e.g., hypoglycemia, lactic acidosis, metabolic acidosis). In general, earlier diagnosis and treatment can improve outcomes.

In terms of the natural history of LOPD, the rate of disease progression varies among patients and disease severity is inversely correlated with residual GAA activity.³ Additionally, disease severity is associated with disease duration, and patients who have symptom onset at a younger age have more severe disease.¹ It has been estimated that 5-year post-diagnosis survival for untreated patients with LOPD is 95%, and 30-year post-diagnosis survival is 40%.^1,3 It has been reported that patients treated with enzyme-replacement therapy have a mean age at death of less than 60 years,¹ although this varies with rate of progression, extent of muscle involvement, and comorbidities.³ For instance, early involvement of the diaphragm is followed by respiratory failure and death during the second or third decade of life.¹

Patients with LOPD do not develop hypertrophic cardiomyopathy (a characteristic of IOPD), and clinical presentation can be at any age, even among individuals with the same genetic variant, indicating that there are other factors that influence clinical outcomes.¹ Moreover, clinical features vary from a slowly progressive myopathy, which may be preceded by an asymptomatic interval, to a much more rapid and progressive myopathy that results in wheelchair and ventilatory dependence and early death. Typically, there is greater weakness in the proximal muscles than the distal muscles, and the pelvic girdle is affected more than the shoulder girdle.⁴ Early involvement of the diaphragm and respiratory accessory muscles is a common and unique feature of Pompe disease that is not observed with most other myopathies. This can lead to respiratory failure, which is a major cause of morbidity and mortality in patients with LOPD.^1,3,4 Patients may also have reduced lung volume, impaired ability to cough, and poor breathing during sleep,³ and respiratory dysfunction can be identified through testing that shows reduced FVC in upright and supine positions, as well as lower MIP and MEP measurements.⁴ It has been estimated that 60% of patients have a slight reduction in vital capacity (< 80% predicted), and 30% to 40% have moderate reduction in vital capacity (< 60% predicted).³ The progression of symptoms often leads to new or increased use of respiratory support and mobility aids, and patients with LOPD can experience respiratory failure while still ambulatory. Patients may also have vascular and/or gastrointestinal complications, and muscle weakness can cause difficulties chewing and swallowing foods, leading to poor nutrition.^3,4

The clinical expert CADTH consulted for this review estimated that a prevalence of 1 in 40,000 for all Pompe disease would be reasonable. For LOPD specifically, a study from the Netherlands estimated a prevalence of 1 in 57,000.⁵ The sponsor indicated that there were |||| patients with LOPD in Canada receiving treatment with alglucosidase alfa (|||| adults and |||| children) as of December 2020.⁶ The incidence of all Pompe disease (both LOPD and IOPD) has been estimated to be between 1 in 14,000 and 1 in 300,000, depending on geographic location and ethnicity,³ whereas the incidence of LOPD has been estimated to be 1.75 in 100,000 births.⁷ A study using data from births between 1969 and 1996 in British Columbia estimated the incidence of Pompe disease to be 1 in 115,091.⁸ It is expected that this is an underestimate of the true number of patients with LOPD in Canada because many would be have been undiagnosed at the time of the study. No updated prevalence or incidence data specific to Canada have been identified.

Standards of Therapy

Clinicians consulted by CADTH for the purpose of this review indicated that enzyme-replacement therapy with alglucosidase alfa, a rhGAA, at a dose of 20 mg/kg by IV infusion every 2 weeks, is the standard therapy and the only specific treatment for Pompe disease and LOPD, although it is not a cure. The exogenous source of GAA helps to break down glycogen, alleviate symptoms, and slow disease progression. The clinician input describes potential concerns about immune-related intolerance and reduced efficacy related to enzyme-replacement therapy. Aside from enzyme-replacement therapy, supportive care includes continued monitoring of pulmonary function and motor performance to assess new or increased need for ventilatory support and mobility aids. Canadian guidelines for the diagnosis and management of Pompe disease state that there is no evidence for the use of enzyme-replacement therapy in patients who have confirmed Pompe disease but are otherwise asymptomatic.⁹

Supportive therapies also include exercise and dietary changes, and new disease-specific therapies include other forms of enzyme-replacement therapy, and gene therapies are in development. Evidence has indicated that submaximal exercise may be beneficial^3,4 for preserving muscle function, under careful guidance from a patient’s health care team (in particular, a physical therapist and pulmonologist), but strenuous exercise should be avoided.⁴ Although there are no established guidelines, it has been suggested that a high-protein diet and nutritional optimization may also be beneficial. Other interventions, such as physical therapy, occupational therapy, speech therapy, and assistive technological devices, can be used to support respiratory and motor function and attempt to improve HRQoL.^3,4 Input from the clinical expert indicated that beta-2 agonists have been used off-label to try to increase the efficacy of enzyme-replacement therapy, although this is outside of the indication approved by Health Canada.

The clinical expert emphasized that the main goals of currently available forms of treatment are to stabilize and/or improve motor and respiratory function, as well as to prevent further disease progression. New treatments should improve immune tolerance, have a low risk of treatment-related reactions, and be less of a burden on patients; current infusions are frequent and require hours to complete.

As highlighted in the clinician input, a multidisciplinary team of specialists — including neurologists, metabolic geneticists, internists, orthopedists, cardiologists, respirologists, dieticians, and physical therapists — is required for the management of Pompe disease.

Drug

The key characteristics of avalglucosidase alfa and alglucosidase alfa are summarized in Table 3. Avalglucosidase alfa is a rhGAA used to break down lysosomal glycogen.¹⁰ The drug provides an exogenous source of GAA enzyme-replacement therapy with an approximate 15-fold increase in mannose-6-phosphate, compared with alglucosidase alfa. The increased mannose-6-phosphate moieties provide a mechanism to drive uptake of avalglucosidase alfa into the diaphragm and other skeletal muscle through the cation-independent receptor.

Avalglucosidase alfa received a Health Canada Notice of Compliance on November 12, 2021. The drug is intended for long-term, chronic use under the guidance and supervision of a health care professional who is knowledgeable in the treatment of Pompe disease. Avalglucosidase alfa is available as a lyophilized powder in a 100 mg vial that is reconstituted, diluted, and administered via IV infusion by a health care professional in a hospital or an appropriate outpatient-care setting. The recommended dose for patients with LOPD is 20 mg/kg body weight every other week. The product monograph recommends that infusions be administered over approximately 4 to 7 hours at an initial rate of 1 mg/kg per hour, which is increased by 2 mg/kg per hour every 30 minutes to a maximum rate of 7 mg/kg per hour if there are no signs of infusion-associated reactions and the patient responds well and is comfortable. An infusion should be immediately stopped if anaphylaxis, severe hypersensitivity reaction, or severe infusion-associated reaction occurs. The infusion rate may be slowed or temporarily stopped if mild-to-moderate hypersensitivity reactions or infusion-associated reactions occur. Patients may be pre-treated with antihistamines, antipyretics, and/or corticosteroids to prevent or reduce allergic reaction.

Avalglucosidase alfa underwent a standard review at Health Canada, and the manufacturer has requested reimbursement for the approved Health Canada indication. Avalglucosidase alfa has not been previously reviewed by CADTH.

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. Refer to Appendix 1 for the full Patient Group Input.

Muscular Dystrophy Canada, in partnership with the Canadian Association for Pompe, conducted a survey (available in both English and French) and semi-structured phone or Zoom video interviews with adults or the parents or caregivers of children living with Pompe disease. In total, 41 individuals affected by Pompe disease provided information for the submission. Of the respondents, 26 were patients (12 males and 14 females) and 11 identified as parents or caregivers. Patients were 4 to 81 years of age.

The negative impact Pompe disease has on motor ability (including mobility, strength, balance, and energy) and breathing were the issues most frequently reported by respondents. Quality of life was also important to the patient group, and the detrimental effects on patients’ social health, mental health, and ability to participate in daily activities, and on their families, were identified as key issues related to Pompe disease.

Some respondents reported having no experience with medications for Pompe disease (because of allergic reaction to treatment) and focusing on physical therapy, whereas others described being on enzyme-replacement therapy for years. Some patients treated with alglucosidase alfa described minor improvements followed by a plateauing of effect, whereas others reported major improvements. A few respondents also mentioned making high-protein and low-carbohydrate dietary changes.

Patients and caregivers would like new treatments to improve strength and breathing function and prevent disease progression, without the plateauing effect many have described. They would also like a better mode of delivery (e.g., oral medication, shorter infusion time), fewer side effects, a treatment that has a continuous effect in the body, and a reduction in costs associated with treatment and travel.

Two adults who reported clinical trial experience with avalglucosidase alfa had been receiving enzyme-replacement therapy for 2 to 3 years. During this time, they noticed improvements in mobility, balance, and endurance. Neither reported significant breathing issues before treatment. One patient reported no side effects, other than a single allergic reaction after the first few treatments, which was treated with medication and did not recur. The other patient reported no side effects related to treatment, but took medications for nausea and pain and an antihistamine before infusion. The greatest benefits of enzyme-replacement therapy on the patients’ lives were improvements in daily living and mental health. One patient reported having to travel out of province for treatment, which had an impact on their education for a couple of years.

All patients from the group submission reported undergoing diagnostic testing with blood testing, and some also underwent confirmatory biopsies. In general, patients did not have to pay for testing, although some did incur costs associated with having to travel to appointments in different cities. Some respondents described no delays in testing, but others faced multiple tests or significant wait times before receiving a diagnosis, and many patients recalled the stress of being misdiagnosed.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in 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; and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of LOPD.

Unmet Needs

The clinical expert consulted by CADTH stated that, given the biology of the disease, the most important goals of currently available forms of treatment are to stabilize and/or improve motor and respiratory function, as well as to prevent disease progression. Although it would be ideal if muscle functional deficits present at the time of diagnosis could be completely reversed, novel forms of therapy that affect cell growth and regenerative capacity will be required to meet this goal. Therapies should also have minimal burden on patients (e.g., shorter infusion time) and have a low risk of infusion-related reactions, which are unaddressed by alglucosidase alfa, the currently available enzyme-replacement therapy for Pompe disease.

Place in Therapy

The clinical expert expects that avalglucosidase alfa will replace alglucosidase alfa as the first-line treatment for LOPD, and that all patients who meet the criteria for treatment will receive the new drug. This would include patients who have never received enzyme-replacement therapy, and those already being treated with alglucosidase alfa would be switched over to avalglucosidase alfa. The clinical expert agrees that evidence from the COMET trial supports the noninferiority conclusion of avalglucosidase alfa, compared with alglucosidase alfa, and that short-term data show that avalglucosidase alfa has lower levels of immunogenicity.

Patient Population

Patients with Pompe disease are identified with genetic testing and enzymatic testing. The clinical expert noted that enzymatic testing that uses dried blood spots is more accessible than tests using white blood cells, although the former can produce false-positive results, which emphasizes the importance of additional genetic testing for confirmation. The clinical expert also indicated that a free multigene panel provided by the drug manufacturer includes testing for Pompe disease. This has allowed clinicians to screen and identify potential patients before they develop symptoms that are specific to Pompe disease, which may facilitate diagnosis at an earlier stage in the disease. It is hoped that easy access to such multigene panels for the diagnosis of myopathies will allow clinicians to speed up the diagnostic process.

According to the clinical expert, any patients with symptomatic disease should be treated with enzyme-replacement therapy. Although the heterogeneity of LOPD clinical presentation precludes treatment in the primary-prevention setting, patients without symptoms should be closely monitored for early signs of disease progression. This is important because response to treatment is expected to be better in patients who have less-severe disease. Patients with very advanced disease, such as those who are wheelchair-bound and on permanent invasive ventilation, may be least suited for avalglucosidase alfa, although the clinical expert added that clinical context should be considered on a case-by-case basis.

Assessing Response to Treatment

Canadian evidence-based guidelines⁹ for the treatment of LOPD emphasize the importance of having and meeting clearly defined, objective outcomes and tracking progression, the clinical expert reported. Assessments for skeletal muscle function (e.g., 6MWT, quantitative muscle strength scoring) and respiratory muscle function (e.g., FVC, MIP, MEP, change in FVC between upright and supine positions) were noted as relevant outcomes in clinical trials. However, the clinical expert acknowledged that not all tests can be performed in all clinics, particularly if they are smaller clinics or in remote locations. Consequently, it is recommended that patients are followed at least annually at a regional centre of excellence.

The clinical expert emphasized that stabilization of current mobility and pulmonary function is the main goal of currently available forms of therapy. Improved survival, use of mobility aids, ability to perform activities of daily living, frequency of and complications from falls, time lost from work or school, hospitalizations for pulmonary complications, and the need for ventilatory support are considered clinically meaningful measures, if available. Alternatively, surrogate outcomes such as the 6MWT, which can be easily measured, and changes in pulmonary function, which are strongly correlated with pulmonary outcomes, should be tracked.

Patients who begin a new therapy should initially be evaluated every 6 months, whereas patients on long-term treatment who remain stable should be assessed at least annually. For patients who live in remote areas, it may be acceptable to have a detailed annual assessment at an expert centre along with visits every 6 months with a local physician. Additionally, those who switch treatment from alglucosidase alfa to avalglucosidase alfa should be evaluated every 6 months to ensure they are stable on the new medication. Patients who have a high antibody titre or who are dosed based on body mass index (BMI) may require more frequent follow-ups to assess efficacy.

Discontinuing Treatment

Most patients are treated with enzyme-replacement therapy until they develop end-stage disease, which could include wheelchair requirements and full-time invasive ventilation. Anaphylactic reaction to the medication that cannot be managed with premedications, as well as comorbidities that significantly reduce lifespan (e.g., cancer), might be reasons to discontinue treatment.

Prescribing Conditions

According to the clinical expert, new patients often start treatment in a hospital clinical setting and, once stable, transition to home infusions. Patients may also be treated at infusion centres or started immediately with home infusions, depending on patient characteristics, available resources, and the physician’s comfort with the medication. The clinical expert expects that the same approach would be used for avalglucosidase alfa, although some patients who switch from avalglucosidase alfa may be closely monitored and receive infusions in the centres. Post-infusion follow-up would always be performed at a centre with expertise in the management of patients with Pompe disease.

In addition to a patient’s primary care physician, the multidisciplinary team may include neurologists, respirologists, lysosomal disease experts, physiotherapists, relevant specialists for the treatment of related complications, and medical geneticists who can assist with genetic counselling and the screening of family members.

Additional Considerations

The clinical expert highlighted the importance and use of consistent criteria across Canada for the treatment of LOPD, particularly for symptomatic patients, as there is currently a lack of uniformity in this regard.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. Refer to Appendix 2 for the full Clinician Group Input.

CADTH received a submission from the Neuromuscular Disease Network for Canada and from clinicians who treat Pompe disease. The 8 authors consisted of doctors who specialize in neurology, respirology, pediatrics, and clinical biochemical or metabolics genetics who practice in Alberta, British Columbia, Ontario, Québec, and Saskatchewan. The Neuromuscular Disease Network for Canada strives to be a comprehensive, inclusive, and enduring network for Canadian stakeholders working to improve the care, research, and treatment of neuromuscular diseases for all Canadians.

Unmet Needs

Ideally, new treatments would effectively stabilize and/or improve mobility and breathing and stop disease progression. The input highlighted that patients with LOPD have varied responses to enzyme-replacement therapy, and that most show a small improvement, plateau effect of variable duration, and eventual disease progression. The clinician group suggested that although the clinical evidence does not immediately rule out any particular group of patients, those who do not tolerate or progress while on alglucosidase alfa should have priority access to avalglucosidase alfa.

Place in Therapy

The group suggested that avalglucosidase alfa would likely become the first-line standard of care, replacing alglucosidase alfa, for the treatment of all patients with LOPD.

Patient Population

Patients who are best suited for treatment with avalglucosidase alfa can be identified through DNA analysis and GAA enzyme activity. Patients who are least suited to avalglucosidase alfa may be those who experience a new AE or SAE after switching from alglucosidase alfa; a switch back to alglucosidase alfa might be considered for these patients. Furthermore, the clinician input noted that evidence from the NEO1 and NEO-EXT studies showed that patients younger than 50 years with LOPD could have similar or greater improvements with avalglucosidase alfa than with alglucosidase alfa for key outcomes, such as motor and respiratory function, safety, and HRQoL. Although any patient with Pompe disease could benefit from the new therapy, the clinician group drew attention to the need for effective treatment for patients who have progressed on alglucosidase alfa.

Assessing Response to Treatment

The 6MWT, manual muscle testing, and hand-held dynamometry (HHD), and FVC (% predicted) were identified as common outcome measures used in clinical practice to follow patients with Pompe disease. Improvement or stability in 6MWT and FVC measures would be considered clinically meaningful responses to treatment. According to the clinician group, treatment response should be assessed every 6 to 12 months, depending on clinical severity.

Discontinuing Treatment

The clinician group suggested that in the case of clinical decline to the point of severe motor or respiratory disability (e.g., nonambulatory or noninvasive ventilation while awake), when the patient no longer derives benefit from treatment, or severe AE(s), discontinuation of treatment can be considered.

Prescribing Conditions

The clinician group stated that outpatient infusion clinics or home infusion would be appropriate settings for treatment administration. The group also noted that treatment and monitoring should be conducted by a clinical biochemical or metabolics geneticist or a neuromuscular specialist, and acknowledged that patients in remote areas could be monitored by local physicians with regular evaluations by a neuromuscular specialist.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that might 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.

Clinical Evidence

The clinical evidence included in the review of avalglucosidase alfa is presented in 2 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 in accordance with an a priori protocol. The second section includes sponsor-submitted long-term extension studies and additional relevant studies that address important gaps in the evidence included in the systematic review. No indirect evidence was identified from the literature that met the selection criteria specified in the review.

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of avalglucosidase alfa administered once every other week as an IV infusion of 20 mg/kg of body weight for the treatment of LOPD.

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.

The literature search for clinical studies was performed by an information specialist who used a peer-reviewed search strategy in accordance with the PRESS Peer Review of Electronic Search Strategies tool.¹⁶

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 multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Nexviazyme (avalglucosidase alfa). The following clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, 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. See Appendix 3 for the detailed search strategies.

The initial search was completed on October 29, 2021. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on February 23, 2022.

Grey literature (literature that is not commercially published) was identified through searches of relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature tool.¹⁷ Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 3 for more information on the grey literature search strategy.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, in accordance with 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

A total of 6 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

One pivotal study was included in the CADTH review for avalglucosidase alfa. The COMET trial was a multi-centre, double-blind, active-control, phase III RCT designed to evaluate the efficacy and safety of avalglucosidase alfa 20 mg/kg body weight given every other week for the treatment of LOPD. The COMET trial was conducted internationally, with 2 study centres in Canada. The study design is outlined in Figure 2: Diagram of COMET Trial and consisted of a screening period of up to 14 days, a double-blind treatment period of 49 weeks, an open-label extension phase of up to 240 weeks, and follow-up for up to 4 weeks.

In the COMET trial, 100 patients were randomized, using a centralized treatment allocation system in a 1:1 ratio, to either avalglucosidase alfa or alglucosidase alfa. Randomization was stratified based on baseline FVC (% predicted: < 55% versus ≥ 55%), sex, age (< 18 years versus ≥ 18 years), and country (Japan versus not Japan). To control the number of patients with high baseline FVC (% predicted), the number of patients with baseline FVC (% predicted) between 80% and 85% was capped at 15% of the total population. Patients, study investigators, and site personnel were blinded to the treatment assignment until the primary analysis was completed. Independent pharmacists or designees who prepared the study drugs were unblinded. In the event of an AE, the randomization code was broken when knowledge of the study drug was deemed necessary to treat the patient. When the treatment assignment was revealed, the date, time, and reason were documented. Furthermore, the patient was required to withdraw from study drug administration.

The interim clinical study report data cut-off date was March 19, 2020, which included all data from the double-blind phase, followed by a database lock on April 23, 2020. At the end of the double-blind phase, patients in the alglucosidase alfa arm were switched to avalglucosidase alfa for the duration of the open-label treatment phase. There was no washout period for patients who switched treatments.

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Figure 2: Diagram of COMET Trial

D = day; EOS = end-of-study; I = infusion; qow = every other week; W = week.

Source: COMET Clinical Study Report.¹¹

Populations

Inclusion and Exclusion Criteria

Patients older than 3 years were eligible to participate in the COMET trial if they had a confirmed GAA enzyme deficiency from any tissue source and/or 2 confirmed GAA gene mutations. Patients with known Pompe-specific cardiac hypertrophy or with severe disease (wheelchair dependence, unable to ambulate 40 m without stopping and without an assistive device, requiring invasive ventilation, or unable to perform repeated FVC [% predicted] measurements between 30% and 85%) were excluded from the study. Previous treatment with alglucosidase alfa or other investigational treatments for Pompe disease were also reasons for exclusion. Patients were ineligible if they had significant organic disease or had previously used or were currently using immune tolerance induction therapy.

Baseline Characteristics

Patient baseline characteristics are summarized in Table 7. Overall, the mean age of the patients in the study was 48 years (SD = 14), and patients were older in the alglucosidase alfa group than in the avalglucosidase alfa group. Patients were predominantly White (94 patients [94%]), and there was a similar number of male and female patients within and between treatment arms.

Baseline disease characteristics appeared to be similar among the treatment groups, with a few exceptions. The baseline mean distance walked on the 6MWT was numerically higher for the avalglucosidase alfa group (399.3 m; SD = 110.9) than for the alglucosidase alfa group (378.1 m; SD = 116.2). Also, more patients reported using no mobility aids in the avalglucosidase alfa arm. Use of a rolling walker or a single crutch was higher in the comparator arm (6.1% and 4.1%, respectively) than in the avalglucosidase alfa group (0.0% and 0.0%, respectively). In contrast, other measurements were lower in the avalglucosidase alfa group than in the alglucosidase alfa group for mean MEP % predicted (65.77%; SD = 38.97 versus 74.83%; SD = 35.22) and HHD lower extremity composite scores (1,330.45; SD = 625.44 versus 1,466.16; SD = 604.91).

Patient medical history was similar between the study arms, with a few notable differences. The mean age at diagnosis for Pompe disease was lower for patients in the avalglucosidase alfa group (44.73 years; SD = 14.74) than for those in the alglucosidase alfa group (48.16 years; SD = 14.64). The time between diagnosis and first infusion of the study drug was shorter for the avalglucosidase alfa group (15.60 months; SD = 32.06) than for the alglucosidase alfa group (26.52 months; SD = 59.86).

Interventions

In the COMET trial, patients were randomized to receive either avalglucosidase alfa or alglucosidase alfa. Avalglucosidase alfa was supplied as a sterile, lyophilized product in single-use vial that contained 100 mg of avalglucosidase alfa. Alglucosidase alfa was supplied as a sterile, lyophilized cake or powder in a single-use vial that contained 50 mg of alglucosidase alfa. The number of vials needed depended on the patient’s most recent body weight, if it was measured in the previous 1 month for pediatric patients or in the previous 3 months for adult patients. Both drugs were reconstituted and diluted to a dose of 20 mg/kg body weight and administered by IV infusion every other week during the double-blind phase (up to week 49). The rate of infusion was started at a slow initial rate and gradually increased to a maximum rate if no signs of infusion-associated reactions were observed. The length of infusion depended on the dose of medication administered, and patients remained at the hospital or infusion centre for at least 2 hours after the infusion to monitor AEs. During the open-label extension phase, patients who received alglucosidase alfa were switched to avalglucosidase alfa for the remainder of their treatment (up to 120 doses) or until avalglucosidase alfa was approved in their country.

To maintain blinding of patients and investigators, an independent unblinded pharmacist who was not involved in AE assessments and who did not have access to efficacy data prepared the study drugs on site.

Infusions were scheduled in 14-day increments ± 7 days for infusions and safety assessments and ± 14 days for other assessments, but there had to be at least 7 days between any 2 infusions. Modifications to the dose or frequency of administration were only permitted when resulting from an AE, and doses above 20 mg/kg body weight every other week were not allowed.

Home infusions were permitted during the open-label extension phase, in accordance with local and national regulations, and patients must have met specified eligibility criteria. The investigator had to agree that home infusion was appropriate, the patient had to be willing and able to adhere to home infusion procedures and be trained in the process, and the patient had to be clinically stable on avalglucosidase alfa, with no moderate or severe infusion-associated reactions for at least 12 months on a stable dose. Patients could not have ongoing SAEs, and if a patient experienced a moderate or severe infusion-associated reaction at home, they returned to the study site for infusions until no infusion-associated reactions occurred for at least 3 months. Patients were to be monitored by trained staff for at least 2 hours after infusion.

Concomitant medications, preinfusion medications, and assistive mobility devices were recorded in the electronic case report form (e-CRF). The use of mechanical ventilation was reported on the e-CRF ventilator use form. Although the use of routine pre-treatment with antihistamines, antipyretics, and/or corticosteroids was not recommended, particularly for patients who experienced prior immunoglobulin E-mediated hypersensitivity reactions, pre-treatment was at the discretion of the investigator. It was noted that antihistamines could mask symptoms of hypersensitivity reactions and prevent intervention by infusion staff. Immunomodulating treatments (e.g., methotrexate, rituximab, immunoglobulins, and other immunosuppressants) that would interfere with the evaluation of the immunogenic potential of avalglucosidase alfa were prohibited.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 8. These end points are further summarized in the text that follows the table. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

Efficacy Outcomes

FVC is the total volume of air that can be forcibly exhaled after maximal inspiration.¹¹ Pulmonary function testing (including FVC) was performed locally at the study centre and measured by a central laboratory using a standardized protocol that met American Thoracic Society/European Respiratory Society 2005 quality standards. Patients were required to have at least 3 acceptable FVC manoeuvres with acceptable repeatability. Assessments were made before infusions and performed up to at least week 49. FVC in the upright position was reported in litres, and percent of predicted normal values based on age, sex, race, and height used Global Lung Initiative 2012 reference equations. Normal FVC values range from 80% to 120%;a lower FVC value may indicate abnormal lung function.¹⁸ Acceptable validity has been demonstrated in patients with Pompe disease.¹⁹ Good evidence of reliability and weak evidence of responsiveness were found for patients with pulmonary disorders, although no information was identified for patients with Pompe disease.²⁰ No MID was identified from the literature for patients with Pompe disease.

The 6MWT is the distance a patient can walk on a hard, flat surface in 6 minutes, and was used to assess functional capacity.¹¹ The distance covered was measured in m, and the amount of time walked was recorded (as a measure of endurance) for patients who did not complete the full 6-minute walk. Equipment and administration methods were standardized across study sites and testing was performed before infusions. The percent predicted value was calculated using reference equations applicable to the study population. Patients were permitted to use a walking device, which was recorded in the e-CRF, and any change in the use of mobility devices was also recorded. Validity and reliability of the 6MWT have been established in various patient populations.^21-31 The 6MWT distance showed validity and responsiveness to change, compared with Rotterdam Handicap Scale and Rasch-built Pompe-specific Activity scale instruments, for patients with Pompe disease.¹⁹ No information on reliability and no MIDs were identified from the literature for patients with Pompe disease.

MIP and MEP are measures of the maximum negative or positive pressures from an inspiratory or expiratory effort, respectively. MIP and MEP (% predicted) measurements in the upright position were included with pulmonary function testing (described earlier) for the COMET trial and were performed and assessed in a similar manner. Evidence of validity and reliability for both MIP and MEP was found for patients with pulmonary disorders³² and neuromuscular disorders.^33,34 For patients with Pompe disease, MIP showed acceptable validity and reliability,^35,36 although no information was found that assessed responsiveness to change. No evidence of validity, reliability, or responsiveness was found for MEP for this patient population. No MID was identified from the literature for either MIP or MEP for patients with Pompe disease.

HHD for lower extremity muscle strength was conducted using the make technique.¹¹ Equipment was standardized across sites and testing was performed before infusions. To prevent the use of compensatory muscles, stabilization procedures for all muscle groups were followed. During testing, the examiner holds the dynamometer stationary as the patient exerts a force that gradually increases to a maximal force, which is held for 4 to 5 seconds. Testing was conducted by the same physical therapist or trained assessor each time. The lower extremity muscle groups included hip flexion, hip extension, hip abduction, hip adduction, knee flexion, knee extension, ankle dorsiflexion, and ankle plantar flexion. Limb tests were completed bilaterally to account for differences between dominant and nondominant limbs. Muscle groups were tested twice and the higher value was reported in the e-CRF. Noninvasive ventilation was permitted during testing. Acceptable validity and reliability have been established in other patient populations.^37-41 Scores for the HHD, Rotterdam Handicap Scale, and Rasch-built Pompe-specific Activity scale were significantly correlated among patients with Pompe disease, demonstrating evidence of validity among the outcome measures.¹⁹ Information that assessed reliability and responsiveness was not found for HHD, and no MID was identified from the literature for patients with Pompe disease.

The QMFT was used to evaluate changes in motor function concurrent with the GMFM-88, and testing was performed before infusions.¹¹ The QMFT is an observer-administered assessment that consists of 16 items individually scored on a 5-point ordinal scale (ranging from 0 to 4). The total score for all items ranges from 0 to 64 points, and a higher score indicates greater motor function. Evidence of validity and reliability has been established among patients with Pompe disease,⁴² but no information that evaluated responsiveness was found. No MID was identified from the literature for patients with Pompe disease.

The SF-12, version 2.0, is a questionnaire that consists of 4 2-item health domain scales (physical functioning, role-physical, role-emotional, and mental health) and 4 1-item health domain scales (bodily pain, general health, vitality, and social functioning).¹¹ Similar to the original 36-item Short Form Health Survey (SF-36), the items on the SF-12 are used to reproduce physical component summary and mental component summary scores, which are computed as weighted sums and range from 0 to 100, with higher scores indicating better HRQoL.⁴³ In the COMET trial, the SF-12 was used to assess HRQoL in patients 18 years and older and was measured before infusions, when possible. Validity, reliability, and responsiveness have been demonstrated in various patient populations,^44-46 although no evidence was found for patients with Pompe disease. No MID was identified from the literature for patients with Pompe disease.

The GSGC consists of 4 functional tests — walk 10 m (gait), climb 4 stairs (stair), stand from sitting on the floor (Gower’s maneuver), and stand from sitting position (chair) — used to evaluate functional performance.¹¹ The first 3 tests are scored from 1 to 7, whereas the last test (chair) is scored from 1 to 6. A total score, computed from the sum of the 4 tests, ranges from 4 (normal performance) to 27 (poor functional score). The 4 functional tests were also evaluated for the time required to complete each task. Assessments were performed before infusions. Evidence of validity and correlation with the 6MWT and Walton and Gardner-Medwin scale (a measure of functional status) has been established in patients with LOPD.⁴⁷ No information on reliability or responsiveness and no MID was identified from the literature for patients with Pompe disease.

The GMFM-88 was used to evaluate changes in gross motor function, using 2 of the 5 dimensions: dimension D (standing; 13 items) and dimension E (walking, running, and jumping; 24 items).¹¹ Each item was scored on a 4-point Likert scale (0 = cannot complete, 1 = initiates [< 10% of the task], 2 = partially completes [10% to < 100% of the task], and 3 = task completed). The score for each dimension was expressed as a percentage of the maximum score for the dimension, and a total score was computed from the sum of the percentage scores for each dimension and dividing by the number of dimensions (i.e., each dimension contributes equally to the total score). A higher score indicates greater motor function. Testing was performed before infusions. Validity, reliability, and responsiveness have been established in children with cerebral palsy,⁴⁸ but no evidence was found for patients with Pompe disease. No MID was identified from the literature for patients with Pompe disease.

Because tertiary and exploratory outcomes are descriptive and hypothesis-generating, the Gross Motor Function Classification System (GMFCS), HHD (upper extremity muscle strength), and 5-Level-EuroQoL (EQ-5D-5L) were not reviewed in the CADTH report. A summary of the data for these outcomes has been included in Table 24. Upon review of the limited available data and discussion with the clinical expert CADTH consulted, the description, data, and critical appraisal of the following tertiary and exploratory outcomes have not been included in this report: Pediatric Quality of Life Inventory, Pompe Disease Impact Scale, Pompe Disease Symptom Scale, Rasch-built Pompe-specific Activity scale, and Patient Global Impression of Change.

Harms Outcomes

Incidence and seriousness of AEs, withdrawals due to AEs, and deaths were reported for the double-blind phase for all patients. AEs, SAEs, and AEs related to hypersensitivity and anaphylactic reactions were described based on the preferred term and associated system organ class, using the most recent version of the standardized medical dictionary for regulatory activity (MedDRA) Query (SMQ). Infusion-associated reactions were defined as AEs of special interest that occurred during the infusion or post-infusion observation period that were possibly related to the study drug.

For immunogenicity testing of anti-drug antibodies, samples were taken from patients every month until week 73 and every 3 months thereafter for the duration of the study. Samples were also collected from all patients at week 2 and week 52 when patients switched from alglucosidase alfa to avalglucosidase alfa. Patients were tested for anti-drug antibodies to the study drug they received during the double-blind phase; patients who switched treatment were tested for anti-drug antibodies to both alglucosidase alfa and avalglucosidase alfa during the open-label phase until week 145, after which testing was performed for anti-drug antibodies to avalglucosidase alfa only.

Statistical Analysis

The statistical analysis of efficacy end points conducted in the COMET trial is summarized in Table 9.

Table 9: Statistical Analysis of Efficacy End Points — COMET Trial

6MWT = 6-minute walk test; ANCOVA = analysis of covariance; FVC = forced vital capacity; HHD = hand-held dynamometry; MEP = maximum expiratory pressure; MIP = maximum inspiratory pressure; MMRM = mixed model for repeated measures; QMFT = Quick Motor Function Test; SF-12 = 12-item Short Form Health Survey.

Source: COMET Clinical Study Report.¹¹

Primary Outcome Analysis and Noninferiority Margin

Summary statistics for continuous and categorical variables were presented. Efficacy analyses were performed on the mITT population, and corresponding analysis of the primary outcome was performed for the PP population. A sensitivity analysis was only performed if the ITT population (all randomized patients) was different from the mITT population (randomized patients who received at least 1 infusion).

In the COMET trial, a mixed model repeated measures (MMRM) model assuming data were missing at random was used for the primary outcome. The model included fixed effects of baseline FVC (% predicted) age, sex, treatment group, visit, and treatment-by-visit interaction.

To estimate a noninferiority margin, studies investigating alglucosidase alfa were identified and included. Three studies that enrolled treatment-naïve patients with LOPD were assessed (LOTS, EMBASSY, and TDR12857). The LOTS trial was a placebo-controlled, double-blind RCT that investigated 20 mg/kg alglucosidase alfa every other week (N = 90). Key inclusion criteria for the LOTS study were being 8 years of age or older, being able to walk 40 m or more on the 6MWT, having a FVC (% predicted) upright between 30% and 80%, and having confirmed GAA enzyme deficiency and/or 2 GAA gene mutations. Because of the similar study design and eligibility criteria between the LOTS and COMET studies, the LOTS study was the only 1 used to inform the choice of the noninferiority margin of the COMET trial. Estimated treatment effects of alglucosidase alfa from the single-arm EMBASSY and the open-label TDR12857 multi-dose studies were used for power calculations in the COMET trial.

The estimated treatment effect of alglucosidase alfa, compared with placebo, for FVC (% predicted) in the LOTS trial at 12 months was 3.64% (SD = 4.98; 80% CI = 2.14 to 5.15). A noninferiority margin of 1.1% retained approximately 50% of the treatment effect, based on the lower bound of the 80% CI (i.e., 2.14). The CI was lowered from 95% to 80% in the COMET trial as suggested and agreed upon by regulatory bodies.¹³ Furthermore, the sponsor noted that a recent literature review revealed that 2-thirds of studies using alglucosidase alfa to treat patients with LOPD showed that changes from baseline in FVC (% predicted) were above or within the MID of 2.0% to 6.0% estimated for populations with idiopathic pulmonary fibrosis, and added that 1.1% was less than this range.

Power Calculation and Determination of Sample Size

The sample size calculations were based on noninferiority testing of the primary efficacy end point of change from baseline to week 49 in FVC (% predicted) upright position with the following assumptions:

• The primary end point is normally distributed with a common SD of 5.1% predicted, which was estimated from the phase III, placebo-controlled LOTS trial data.

• A mean difference (avalglucosidase alfa – alglucosidase alfa) of 2.0% predicted was assumed based on a conservative estimate from the LOTS and TDR12857 studies.

• A 2-sided 5% significance level was used.

• Missing data up to 10% was used, based on the LOTS and EMBASSY studies.

• A noninferiority margin of 1.1% predicted was used, which was based on the estimated alglucosidase alfa effect from the LOTS study.

Based on retention rates from the LOTS study (95% of patients remaining at 12 months) and the amount of evaluable data from EMBASSY study (94% of patients with evaluable data at 6 months), the sponsor estimated a 10% dropout rate for the COMET trial and sample size of 96 patients. This sample size provides approximately 80% power to demonstrate noninferiority of avalglucosidase alfa versus avalglucosidase alfa if the true treatment difference was 2.0% predicted. If the noninferiority conclusion was met, a test for superiority was performed. If the true difference was 3.5% predicted, the study would have more than 85% power to demonstrate the superiority of avalglucosidase alfa over alglucosidase alfa.

Multiple Testing Procedure and Control for Multiplicity

To control for the type I error rate, a sequential testing strategy was used with all tests performed at a 2-sided 5% significance level. All analyses compared the avalglucosidase alfa treatment group with the alglucosidase alfa treatment group at 49 weeks of treatment. Testing was stopped at the first nonsignificant outcome. Elements of the sequential testing strategy consisted of the following:

• FVC (% predicted) tested for noninferiority at a noninferiority margin of –1.1%

• FVC (% predicted) (superiority test)

• 6MWT total distance walked (superiority test)

• MIP (% predicted) (superiority test)

• MEP (% predicted) (superiority test)

• HHD lower extremity strength summary score (superiority test).

Missing Data and Data Imputation

Missing data for the primary outcome of FVC (% predicted) were not imputed and were assumed to be missing at random.

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Subgroup Analyses

Subgroups in the CADTH systematic review protocol include previous treatment with alglucosidase alfa versus no treatment, age, baseline respiratory function, and baseline motor function.

The COMET trial included pre-specified subgroup analyses for FVC (% predicted) for age (< 18 years, ≥ 18 years and < 45 years, or ≥ 45 years), sex, baseline FVC (< 55% or ≥ 55%), race, and ethnicity. Three MMRM models were used to assess the sex, age, and baseline FVC interactions with treatment. The first MMRM model included baseline FVC (% predicted, as continuous), age (as continuous), sex, treatment group, visit, treatment-by-sex interaction, and treatment-by-visit interaction as fixed effects. The second MMRM model included baseline FVC (% predicted, as continuous), age (< 18 years and ≥ 18 years), sex, treatment group, visit, treatment-by-age interaction, and treatment-by-visit interaction as fixed effects. The last MMRM model included baseline FVC (% predicted, as continuous), age (as continuous), sex, treatment group, visit, treatment-by-FVC (categorical) interaction, and treatment-by-visit interaction as fixed effects. The LS mean difference between treatment groups, 95% CI, and P value for interaction were reported. Multiplicity was not controlled for in the subgroup analyses.

Exploratory subgroup analyses were performed for region (US versus non-US), baseline use of walking device during the 6MWT, baseline 6MWT distance, duration of disease, use of walking device, use of respiratory support, and angiotensin-converting-enzyme genotype; only findings related to the 6MWT were summarized in this report.

Sensitivity Analyses

A tipping-point method was used to test how large a difference from the missing-at-random assumption would need to be to change the conclusions of the primary analysis. If it was implausible that the LS mean difference between avalglucosidase alfa and alglucosidase alfa would change the results from statistically significant to not statistically significant, the results were considered robust.

A second set of sensitivity analyses were performed using alternative models and different distribution assumptions. An ANCOVA with baseline FVC, age, sex, and treatment group as covariates was performed for the primary end point. A Wilcoxon-Mann–Whitney test was used on the primary end point to test the robustness of results when there was a deviation in the normality assumption for the MMRM model. Additional MMRM models were tested with covariates of baseline FVC, age, sex, treatment group, visit, and treatment-by-visit interaction as fixed effects. The primary outcome was also evaluated using a linear mixed effects model with fixed effects for age, sex, treatment, time, and the treatment-by-time interaction.

The constancy assumption that the effect of alglucosidase alfa, compared with placebo, in the COMET trial was consistent with the effect observed in the LOTS trial was tested by comparing the change from baseline FVC (% predicted) at week 49 between the 2 trials. An ANCOVA model was fitted to the LOTS data with covariates of treatment, age, sex, race, disease duration, baseline FVC, baseline 6MWT, respiratory support device use at baseline, and treatment interaction with sex, baseline FVC, and respiratory support device use at baseline to estimate the change in FVC (% predicted) from baseline to week 49. The constancy assumption may have been violated if the difference of the estimate of effect of alglucosidase alfa versus placebo between COMET and LOTS exceeded the noninferiority margin of 1.1%.

Supportive Analyses

Supportive analyses for the primary outcome included a responder analysis (responders were defined as having a relative change from baseline of ≥ 5%, ≥ 10%, or ≥ 15% at week 49), change in use of respiratory device from baseline, and correlation between FVC (% predicted) change; in addition, other efficacy parameters, patient-reported outcomes, and safety end points were explored.

Secondary, Tertiary, and Exploratory Outcome Analyses

Secondary outcomes were analyzed using a MMRM model in a manner similar to the primary outcome for the mITT population.

If superiority of avalglucosidase alfa was established for FVC (% predicted), tests for superiority for the 6MWT distance walked, MIP (% predicted), MEP (% predicted), and HHD lower extremity strength summary score at week 49 were performed at a 2-sided 5% significance level, as previously described.

Supportive analyses were presented for the 6MWT, including % predicted change from baseline, categorical response for relative change from baseline, patients who completed the test (excluding those who did not complete the 6 minutes), responder analysis (based on 3 responder thresholds), and change in use of assistive walking device.

Raw measurements for change from baseline and % predicted MIP, MEP, and HHD were summarized descriptively based on the mITT population. Item scores for QMFT and change from baseline in the SF-12 physical component summary and mental component summary scores for adults were summarized descriptively based on the mITT population. Tertiary and exploratory outcomes were analyzed in a method similar to the primary outcome and were summarized descriptively based on the mITT population.

Open-Label Extension phase

All efficacy data for patients who continued receiving treatment in the open-label phase were summarized descriptively.

The effect of switching from alglucosidase alfa to avalglucosidase alfa was assessed in 2 analyses. First, piecewise linear mixed effect models for FVC (% predicted) and 6MWT were fitted for all patients who switched from alglucosidase alfa and for patients who continued with avalglucosidase alfa after the double-blind phase. Model assumption on the linearity of the treatment effect before and after 49 weeks was assessed. Second, FVC (% predicted) was compared between week 49 and week 97, using a within-patient test for those who switched to avalglucosidase alfa at the end of the double-blind phase. A MMRM model with a fixed term for visit and random term for subject was used to calculate the change in FVC (% predicted) and 95% CI between the time points.

Analysis Populations

The mITT population included randomized patients who received at least 1 infusion and was the main population used for efficacy analyses. Analyses with the mITT population were performed according to the treatment arm assigned at randomization, regardless of the treatment received.

The PP population included mITT patients who met the eligibility criteria, received at least 80% of the planned number of doses, had a valid FVC (% predicted) assessment at week 49, and had no major protocol deviations. Major protocol deviations included receiving a dose 2 times greater than that specified in the protocol, receiving a treatment different from the randomized assignment during the double-blind phase of the study, and having the treatment assignment unblinded for reasons other than safety before completion of the double-blind phase. The PP population was used for sensitivity analyses of the primary efficacy end point during the double-blind phase.

The safety population was analyzed according to treatment received during either the double-blind or open-label phase of the study and included randomized patients who received at least 1 infusion during those phases. The overall safety of avalglucosidase alfa was assessed in patients who received at least 1 infusion during either double-blind or open-label phase.

The anti-drug antibody evaluable population included patients from the safety population who had at least 1 valid anti-drug antibody sample taken after baseline.

Results

Patient Disposition

Patient disposition is summarized in Table 10. Of the 146 patients screened, 100 were randomized to receive either avalglucosidase alfa or alglucosidase alfa. The most frequently reported reasons for screening failures included being unable to perform repeated FVC measurements in an upright position between 30% and 85% predicted (37 patients) or between 40% and 85% predicted (5 patients). Overall, 95% of patients completed the double-blind phase of the COMET trial, and 5 patients discontinued alglucosidase alfa because of an AE (8.2%) or other reason (2.0%). Patients who completed the double-blind phase entered the open-label phase, during which 3 patients discontinued avalglucosidase alfa because of an AE (3.9%) or other reason (2.0%) and 1 patient discontinued alglucosidase alfa due to an AE (2.0%).

Major protocol deviations were reported for 11 patients — 5 from the avalglucosidase alfa arm and 6 from the alglucosidase alfa arm — all of whom were excluded from the PP analysis. Reasons for the protocol deviations included use of protocol prohibited medication (n = 6), pulmonary function test not being performed during the protocol specified time (n = 2), not following the sequence of study procedures (n = 1), patient not meeting inclusion criterion for Pompe disease diagnosis (n = 1), and visit data not being performed during the protocol specified time (n = 1).

Exposure to Study Treatments

In the double-blind phase of the COMET trial, the mean duration of exposure to avalglucosidase alfa was 11.56 months (SD = 0.14; median = 10.58 months [range = 0.5 to 27.6]). Patients in this arm had a mean of 24.8 infusions (SD = 0.5; median = 25.0 infusions [range = 23 to 25]). The mean duration of exposure to alglucosidase alfa was 10.69 months (SD = 2.69). Patients had a mean of 22.8 infusions (SD = 5.8; median = 25.0 infusions (range = 1 to 25).

Four patients (8.2%) in the alglucosidase alfa group missed at least 2 consecutive infusions during the double-blind phase of the study. No patients in the avalglucosidase alfa missed more than 2 consecutive doses.

In the open-label phase of the COMET trial (after week 49), the mean duration of exposure to avalglucosidase alfa was 12.11 months (SD = 8.74; median = 10.58 months [range = 0.5 to 27.6]) for patients who received avalglucosidase alfa in both the double-blind and open-label phases. Patients in this arm had a mean of 26.2 infusions (SD = 19.0; median = 23.0 infusions [range = 1 to 60]). The mean duration of exposure to avalglucosidase alfa was 12.17 months (SD = 9.3; median = 10.46 months [range = 0.5 to 29.0]) for patients who received alglucosidase alfa in double-blind phase and avalglucosidase alfa in the open-label phase. Patients in this arm had a mean of 26.0 infusions (SD = 19.8; median = 22.0 infusions [range = 1 to 63]).

Of the patients who received avalglucosidase alfa for both the double-blind and open-label phases of the COMET trial, 3 (5.9%) missed at least 2 consecutive infusions during the open-label phase. No patients who received alglucosidase alfa during the double-blind phase missed more than 2 consecutive doses.

Efficacy

Only efficacy outcomes and subgroup analyses identified in the CADTH review protocol are reported in the subsequent sections.

Survival-Related Outcomes

The 1 death (2.0%) that occurred during the double-blind phase in the alglucosidase alfa treatment group was caused by an acute myocardial infarction.

Respiratory-Related Outcomes

Forced Vital Capacity

Data for the primary efficacy outcome during the double-blind phase are summarized in Table 11. Overall, patients in the mITT population demonstrated a LS mean change in FVC (% predicted) in the upright position from baseline to week 49 of 2.89% (95% CI = 1.13 to 4.65) for the avalglucosidase alfa arm and 0.46% (95% CI = –1.39 to 2.31) for the alglucosidase alfa arm. The mean difference of change between treatment groups was 2.43% (95% CI = –0.13 to 4.99), for which the lower bound of the 95% CI did not exceed the noninferiority margin of –1.1%, indicating that the criteria for the noninferiority of avalglucosidase alfa to alglucosidase alfa was demonstrated (P = 0.0074). The P value for superiority testing was not statistically significant (P = 0.0626), so statistical testing was stopped for all subsequent efficacy outcomes.

Analysis of the PP population showed similar results, with a FVC (% predicted) LS mean change from baseline to week 49 of 2.87% (95% CI = 1.02 to 4.73) and 0.19% (95% CI = –1.83 to 2.21) for the avalglucosidase alfa and alglucosidase alfa groups, respectively. The mean difference of change between treatment groups was 2.69% (95% CI = –0.06 to 5.44; P for noninferiority = 0.0076 and P for superiority = 0.0555).

Based on the tipping-point method used to assess the data-missing-at-random assumption, a 16% reduction in FVC (% predicted) for the avalglucosidase alfa group and a 2% increase in FVC (% predicted) for the alglucosidase alfa group indicated that the results would remain robust for the primary outcome.

Subgroup analyses for the primary outcome are summarized in Table 23. Since the COMET trial permitted only patients who were treatment-naïve, there were no subgroups of patients previously treated with alglucosidase alfa that could be compared with a no-treatment group. Among adult patients 18 to 45 years of age, there was a mean difference between groups of 2.99% (95% CI = –1.52 to 7.49). The results were similar for adults 45 years and older, with a mean between-group difference of 2.46% (95% CI = –0.84 to 5.77). Analysis by baseline FVC (% predicted) showed that patients with a FVC of less than 55% had a mean between-group difference of –0.76% (95% CI = –5.23 to 3.71), whereas patients with a FVC of at least 55% had a mean between-group difference of 4.10% (95% CI = 0.95 to 7.26) for avalglucosidase alfa. Patients who used a walking device on the 6MWT at baseline had a mean difference of change between treatment groups of 4.44% (95% CI = –1.00 to 9.88), whereas those who did not use a walking device had a mean between-group difference of 2.19% (95% CI = –0.76 to 5.13). For analysis of baseline 6MWT distance, patients who walked less than 403.5 m at baseline had a mean difference of change between treatment groups of 1.27% (95% CI = –3.03 to 5.57), and patients who travelled at least 403.5 m had a mean between-group difference of 3.58% (95% CI = 0.36 to 6.81).

Long-term data (week 97) for the primary and key secondary efficacy outcomes from the open-label phase of the COMET trial are summarized in Table 25, and no statistical testing was conducted for these end points. For FVC (% predicted) at week 97, mean change from study baseline was 1.60% (SD = 7.72) for patients who received only avalglucosidase alfa and 1.64% (SD = 8.97) for those who switched from alglucosidase alfa to avalglucosidase alfa. Note that these results are from a preliminary analysis of patients with data at week 97 and do not represent to entire enrolled population.

Good evidence of reliability and weak evidence of responsiveness for FVC measurements were found for patients with pulmonary disorders, although no information was identified for patients with Pompe disease.²⁰ No MID was identified from the literature for patients with Pompe disease.

Need for Ventilation

Changes in the need for ventilatory support were not included as an outcome in the COMET trial, although new use of ventilatory support was reported. During the double-blind phase of the COMET trial, 3 patients (6%) in the avalglucosidase alfa group and 4 patients (8%) in the alglucosidase alfa group were reported to have started using a new respiratory device.

Maximum Expiratory Pressure

Results for the double-blind phase are summarized in Table 12. For MEP (% predicted), the LS mean changes from baseline were 10.89% (95% CI = 5.24 to 16.54) and 8.38% (95% CI = 2.49 to 14.26) for the avalglucosidase alfa and alglucosidase alfa arms, respectively. The mean difference of change between treatment groups was 2.51% (95% CI = –5.70 to 10.73).

No evidence of validity, reliability, or responsiveness was found for MEP for this patient population. No MID was identified from the literature for MEP for patients with Pompe disease.

Maximum Inspiratory Pressure

Results for the double-blind phase are summarized in Table 12. For MIP (% predicted), the LS mean changes from baseline were 8.70% (95% CI = 4.54 to 12.85) and 4.29% (95% CI = –0.07 to 8.65) for the avalglucosidase alfa and alglucosidase alfa arms, respectively. The mean difference of change between treatment groups was 4.40% (95% CI = –1.63 to 10.44).

For patients with Pompe disease, MIP showed acceptable validity and reliability,^35,36 although no information was found on the assessment of responsiveness to change. No MID was identified from the literature for MIP for patients with Pompe disease.

Motor-Related Outcomes

6-Minute Walk Test

Results for the double-blind phase are summarized in Table 12. The mean change from baseline to week 49 for the 6MWT distance was 32.21 m (95% CI = 12.47 to 51.94) for the avalglucosidase alfa group and 2.19 m (95% CI = –18.48 to 22.86) for the alglucosidase alfa group. The mean difference of change between treatment groups was 30.01 m (95% CI = 1.33 to 58.69). The mean change from baseline for the 6MWT (% predicted) was 5.02% (95% CI = 1.95 to 8.09) for the avalglucosidase alfa group and 0.31% (95% CI = –2.90 to 3.52) for the alglucosidase alfa group. The mean difference of change between treatment groups was 4.71% (95% CI = 0.25 to 9.17).

Long-term data (week 97) for the 6MWT from the open-label phase of the COMET trial are summarized in Table 25. No statistical testing was conducted for these end points. The mean change from baseline for distance travelled during the 6MWT was 37.34 m (SD = 68.41) for the avalglucosidase alfa and 25.71 m (SD = 71.31) for the switch group (i.e., patients previously treated with alglucosidase alfa). At week 97, patients had a mean change from baseline for 6MWT (% predicted) of 6.01% (SD = 10.18) for the avalglucosidase alfa group and 4.23% (SD = 11.17) for the switch group.

Validity and reliability of the 6MWT have been established in various patient populations.^21-31 The 6MWT distance showed validity and responsiveness to change, compared with the Rotterdam Handicap Scale and Rasch-built Pompe-specific instruments for patients with Pompe disease.¹⁹ No information on reliability and no MID were identified from the literature for patients with Pompe disease.

Use of Mobility Aids

Change in the use of mobility aids was not included as a main outcome in the COMET trial, although change in use of mobility aids was reported. During the double-blind phase of the COMET trial, 3 patients (6%) in the avalglucosidase alfa group and 1 patient (2%) in the alglucosidase alfa group reported new or increased use of assistive walking devices. However, 8 patients (16%) in the avalglucosidase alfa group and no patients in the alglucosidase alfa group reported decreased use of assistive walking devices.

HHD (Lower Extremity Composite Score)

Results for the double-blind phase are summarized in Table 12. For HHD (composite score), the LS mean change from baseline was 260.69 (95% CI = 169.11 to 352.27) for the avalglucosidase alfa group and 153.72 (95% CI = 57.22 to 250.22) for the alglucosidase alfa group. The mean difference of change between treatment groups was 106.97 (95% CI = –26.56 to 240.50).

Scores for the HHD, Rotterdam Handicap Scale, and Rasch-built Pompe-specific Activity scale instruments were found to be significantly correlated among patients with Pompe disease, demonstrating evidence of validity among the outcome measures.¹⁹ Information assessing reliability and responsiveness was not found for HHD, and no MID was identified from the literature for patients with Pompe disease.

Quick Motor Function Test

Results for the double-blind phase are summarized in Table 12. The LS mean change for QMFT (total score) from baseline was 3.98 (95% CI = 2.72 to 5.23) for the avalglucosidase alfa group and 1.89 (95% CI = 0.52 to 3.26) for the alglucosidase alfa group. The mean difference of change between treatment groups was 2.08 (95% CI = 0.22 to 3.95).

Evidence of validity and reliability has been established for the QMFT among patients with Pompe disease,⁴² but no information was found that evaluated responsiveness. No MID was identified from the literature for patients with Pompe disease.

Gait, Stair, Gower’s Maneuver, and Chair

Results for the double-blind phase are summarized in Table 12. The mean changes from baseline for the GSGC were –1.57 (SD = 2.72) and –0.38 (SD = 1.81) for the avalglucosidase alfa and alglucosidase alfa groups, respectively. The mean difference of change between treatment groups was –1.31 (95% CI = –0.37 to –2.25).

Evidence of validity and correlation of the GSGC with the 6MWT and Walton and Gardner-Medwin scale (a measure of functional status) has been established in patients with LOPD.⁴⁷ No information on reliability or responsiveness and no MID was identified from the literature for patients with Pompe disease.

Gross Motor Function Measure-88

Results for the double-blind phase are summarized in Table 12. The mean changes from baseline for the Gross Motor Function Measure (GMFM)-88 dimension D (standing) were 4.29 (SD = 7.37) and 1.77 (SD = 5.79) for the avalglucosidase alfa and alglucosidase alfa groups, respectively. For dimension E (walking, running, and jumping), the mean changes from baseline were 5.33 (SD = 8.02) and 2.81 (SD = 5.38) for the 2 groups, respectively. The mean difference of change between treatment groups 2.58 (95% CI = –0.02 to 5.18) for dimension D and 2.54 (95% CI = –0.09 to 5.18) for dimension E.

Validity, reliability, and responsiveness have been established for the GMFM-88 in children with cerebral palsy,⁴⁸ but no evidence was found for patients with Pompe disease. No MID was identified from the literature for patients with Pompe disease.

GMFCS and HHD (Upper Extremity Muscle Strength)

Results for the GMFCS and HHD (upper extremity muscle strength) from the COMET trial were not described in the CADTH review of avalglucosidase alfa. Results for the double-blind phase are summarized in Table 24.

Disease-Related Symptoms and Impact Outcomes

Pompe Disease Symptom Scale, Pompe Disease Impact Scale, Rasch-Built Pompe-Specific Activity Scale

Results for the Pompe Disease Symptom Scale, Pompe Disease Impact Scale, and Rasch-built Pompe-specific Activity scale from the COMET trial were not described in the CADTH review of avalglucosidase alfa.

Health-Related Quality of Life

12-item Short Form Health Survey

Results for the double-blind phase are summarized in Table 12. For the SF-12 physical component summary, the LS mean changes from baseline were 2.37 (95% CI = 0.40 to 4.34) and 1.60 (95% CI = –0.52 to 3.72) for the avalglucosidase alfa and alglucosidase alfa arms, respectively. The mean difference of change between treatment groups was 0.77 (95% CI = –2.13 to 3.67). For the SF-12 mental component summary, the mean changes from baseline were 2.88 (95% CI = 0.47 to 5.30) and 0.76 (95% CI = –1.86 to 3.39) for the avalglucosidase alfa and alglucosidase alfa arms, respectively. The mean difference of change between treatment groups was 2.12 (95% CI = –1.46 to 5.69).

Validity, reliability, and responsiveness for the SF-12 have been demonstrated in various patient populations,^44-46 although no evidence was found for patients with Pompe disease. No MID was identified from the literature for patients with Pompe disease.

EQ-5D-5L and Pediatric Quality of Life Inventory

Results for the EQ-5D-5L and Pediatric Quality of Life Inventory from the COMET trial were not described in the CADTH review of avalglucosidase alfa. Results for the double-blind phase are summarized in Table 24.

Other Patient-Reported Outcomes

Patient Global Impression of Change

Results for the Patient Global Impression of Change scale from the COMET trial were not described in the CADTH review of avalglucosidase alfa.

Table 11: Primary Efficacy Outcome During the Double-Blind phase — COMET Trial

CI = confidence interval; FVC = forced vital capacity; LS = least squares; mITT = modified intention-to-treat; NA = not applicable; PP = per protocol; SD = standard deviation; SE = standard error.

^aMMRM model with fixed, continuous effects of baseline FVC (% predicted) and age (in years at baseline), and fixed, categorical effects of sex, treatment group, visit, and interaction term between treatment group and visit.

^bNoninferiority margin is –1.1%. P value has been adjusted for multiple testing (i.e., the type I error rate has been controlled).

Source: COMET Clinical Study Report.¹¹

Table 12: Secondary and Selected Tertiary Efficacy Outcomes During the Double-Blind phase — COMET Trial mITT Population

6MWT = 6-minute walk test; CI = confidence interval; FVC = forced vital capacity; GMFM-88 = Gross Motor Function Measure-88; GSGC = gait, stair, Gower’s maneuver, and chair; HHD = hand-held dynamometry; MEP = maximum expiratory pressure; MIP = maximum inspiratory pressure; mITT = modified intention-to-treat; NA = not applicable; QMFT = Quick Motor Function Test; SD = standard deviation; SE = standard error; SF-12 = 12-item Short Form Health Survey.

^aMMRM model for 6MWT distance with fixed effects of baseline FVC (% predicted), baseline 6MWT (distance walked in m), age (in years at baseline), sex, treatment group, visit, and treatment-by-visit interaction.

^bP value is nominal. P value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

^cValues for change from baseline and group difference were provided by the sponsor based on the Diaz-Manera et al. (2021)¹³ publication (without SE). Baseline and week 49 values reflect the data available from the COMET Clinical Study Report.¹¹

MMRM model for MIP % predicted with fixed effects of MIP (% predicted) at baseline, age (in years, at baseline), sex, treatment group, visit, and treatment-by-visit interaction.

^dMMRM model for MEP % predicted with fixed effects of MEP (% predicted) at baseline, age (in years, at baseline), sex, treatment group, visit, and treatment-by-visit interaction.

^eMMRM model for HHD lower extremity muscle strength composite score with fixed effects for summary HHD lower extremity score at baseline, baseline FVC (% predicted), age (in years, at baseline), sex, treatment group, visit, and treatment-by-visit interaction.

^fMMRM model for QMFT total score with fixed effects for QMFT total score at baseline, baseline FVC (% predicted), age (in years, at baseline), sex, treatment group, visit, and treatment-by-visit interaction.

^gMMRM model for SF-12 (physical component summary and mental component summary) with fixed effects for baseline score (physical component summary or mental component summary), baseline FVC (% predicted), age (in years, at baseline), sex, treatment group, visit, and treatment-by-visit interaction.

^hP values are from the Wilcoxon-Mann–Whitney stratified by stratification factors.

Source: COMET Clinical Study Report,¹¹ Diaz-Manera et al. (2021).¹³

Harms

Only harms identified in the CADTH review protocol are reported below. Harms data are summarized in Table 13 for the double-blind phase and Table 26 for the open-label phase.

Adverse Events

During the double-blind phase of the COMET trial, 44 patients (86.3%) who received avalglucosidase alfa and 45 patients (91.8%) who received alglucosidase alfa experienced an AE. The most frequently reported events were nasopharyngitis (12 patients, 23.5%), back pain (12 patients, 23.5%), and headache (11 patients, 21.6%) for the avalglucosidase alfa group, and headache (16 patients, 32.7%), nasopharyngitis (12 patients, 24.5%), and falls (10 patients, 20.4%) for the alglucosidase alfa group. In general, the events were similar between the treatment groups, although influenza and back pain were numerically higher in the avalglucosidase alfa arm and headache was numerically higher in the alglucosidase alfa arm.

AEs in the open-label phase of the COMET study were similar for patients who received avalglucosidase alfa during the double-blind phase and those who received alglucosidase alfa during the double-blind phase but switched to avalglucosidase alfa, and most patients experienced at least 1 AE. Nasopharyngitis (8 patients, 15.7%) and nausea (7 patients, 13.7%) were the most common AEs among patients who continued receiving avalglucosidase alfa, whereas headache (11 patients, 25.0%), nasopharyngitis (10 patients, 22.7%), and diarrhea (10 patients, 22.7%) were the most common AEs among those who switched from alglucosidase alfa.

Serious Adverse Events

Overall, SAEs were infrequent in the 2 treatment groups, with 8 patients (15.7%) reporting a SAE in the avalglucosidase alfa arm and 12 (24.5%) reporting a SAE in the alglucosidase alfa arm. No SAE occurred in more than 1 patient who received avalglucosidase alfa, and only dyspnea occurred in 2 patients who received alglucosidase alfa during the double-blind phase.

During the open-label phase of the COMET trial, 8 patients (15.7%) who continued receiving avalglucosidase alfa reported a SAE, as did 5 patients (11.4%) who switched from alglucosidase alfa. Similarly, no SAE occurred in more than 1 patient for either treatment group.

Withdrawals Due to Adverse Events

Four patients (8.2%) from the alglucosidase alfa group withdrew from the double-blind phase of the COMET study because of the following AEs: acute myocardial infarction, arthritis, dyspnea, and urticaria. No patients from the avalglucosidase alfa group withdrew during the double-blind phase due to AEs.

During the open-label phase, 2 patients (3.9%) who continued receiving avalglucosidase alfa withdrew due to AEs (ocular hyperemia, acute myocardial infarction, and erythema).

Mortality

One death (2.0%) due to acute myocardial infarction was reported in the alglucosidase alfa group during the double-blind phase.

One death (2.3%) due to adenocarcinoma pancreas was reported during the open-label phase for a patient who had received alglucosidase alfa during the double-blind phase.

Notable Harms

Hypersensitivity Reactions (Including Anaphylaxis)

Treatment-emergent anaphylactic reactions (pruritus and rash) were reported for 2 patients (4%) in each of the treatment arms during the double-blind phase.

Treatment-emergent hypersensitivity reactions were generally balanced between treatments (12 patients [23.5%] in the avalglucosidase alfa and 15 patients [30.6%] in the alglucosidase alfa group). In the avalglucosidase alfa group, 4 patients (7.8%) reported experiencing pruritus, 3 patients (5.9%) reported erythema, and 3 patients (5.9%) reported urticaria. In the alglucosidase alfa group, 4 patients (8.2%) each reported experiencing pruritus or rash, and 3 patients (6.1%) each reported erythema or flushing.

No data on treatment-emergent anaphylactic reactions and hypersensitivity reactions were available for the open-label phase.

Infusion-Associated Reactions

Treatment-emergent infusion-associated reactions were similar in the 2 treatment arms: 13 patients (25.5%) in the avalglucosidase alfa and 16 patients (32.7%) in the alglucosidase alfa group. Among those who received avalglucosidase alfa, pruritus (4 patients, 7.8%) and urticaria (3 patients, 5.9%) were the most frequently reported infusion-associated reactions. Among those who received alglucosidase alfa, pruritus (4 patients, 8.2%), nausea (4 patients, 8.2%), and flushing (3 patients, 6.1%) were the most frequently reported infusion-associated reactions.

For the open-label phase, infusion-associated reactions continued to be less frequently reported in the avalglucosidase alfa group (6 patients; 11.8%) than in the group that switched from alglucosidase alfa (15 patients, 34.1%).

Immunogenicity and Anti-Drug Antibodies

Treatment-emergent immune-mediated reactions occurred in || |||||||| ||||||| who received avalglucosidase alfa and || |||||||| ||||||| who received alglucosidase alfa. Arthralgia (5 patients, 9.8%), myalgia (5 patients, 9.8%), and lymphadenopathy (2 patients, 3.9%) were reported among patients who received avalglucosidase alfa, whereas only arthralgia (8 patients, 16.3%) and myalgia (7 patients, 14.3%) were reported among those who received alglucosidase alfa.

No data for treatment-emergent immune-mediated reactions were available for the open-label phase.

Nearly all patients were positive for treatment-emergent anti-drug antibodies (96.1% and 95.8% in the avalglucosidase alfa and alglucosidase alfa groups, respectively) (Table 14). The peak titre is the highest anti-drug antibody titre after baseline for patients who seroconverted or developed anti-drug antibodies de novo. In the avalglucosidase alfa group, 21.3% of patients had a peak titre greater than 12,800, whereas in the alglucosidase alfa group, 36.4% of patients did.

Acute Cardiorespiratory Failure

Acute cardiorespiratory failure was not reported during the double-blind or open-label phases of the COMET study.

Table 13: Summary of Harms During the Double-Blind phase — COMET Trial, Safety Population

NA = not applicable; NR = not reported; SAE = serious adverse events; SMQ = Standardized MedDRA Queries; TEAE = treatment-emergent adverse events; WDAE = withdrawal due to adverse events.

^aFrequency of AE ≥ 5% per treatment group.

^bFrequency of notable harm ≥ 2 patients total for both treatment groups.

Source: COMET Clinical Study Report.¹¹

Critical Appraisal

Internal Validity

Overall, the COMET study was well designed, with a 95% completion rate for the double-blind phase. Randomization was successful at balancing most prognostic factors at baseline, although it is worth noting a few key differences between the 2 arms. Patients who received avalglucosidase alfa had a younger mean age (46 years versus 50 years), a greater 6MWT mean distance (399 m versus 378 m), a younger mean age at diagnosis (45 years versus 48 years), a shorter mean time from diagnosis to first infusion of the study drug (16 months versus 27 months), and fewer used a mobility aid during the 6MWT (44 patients versus 39 patients). Conversely, those randomized to receive alglucosidase alfa had better baseline MEP (% predicted) (75% versus 66%) and HHD (lower extremity) scores (1,466 versus 1,330). Of note, the time between diagnosis and first infusion of the study drug was different between the treatment groups and was not adjusted for in the statistical analysis, which may confound the results. The clinical expert noted that the differences in baseline characteristics in most cases tended to cause biases in the results in favour of the avalglucosidase alfa group. Patients who have symptom onset at a younger age have more severe disease,¹ and earlier treatment is expected to result in better outcomes, but it is unclear the direction and magnitude of the biases caused by the differences in baseline characteristics. No baseline information was reported on the duration of noninvasive respiratory support (e.g., BiPap at night versus day, and how many hours), which the clinical expert suggested has a large impact on a patient’s quality of life, and can also be used to measure treatment efficacy.

Blinding of patients, investigators, and study personnel to treatment assignment and allocation concealment — through the use of independent pharmacists who prepared the study drugs and a centralized treatment allocation system — appeared to be adequate. Based on the harms profiles of avalglucosidase alfa and alglucosidase alfa, there appeared to be little risk of unblinding on the basis of AEs. All 5 (10.2%) patients who discontinued treatment during the double-blind phase were from the alglucosidase alfa arm, and it is unknown what impact these losses had on the results, considering the small patient numbers at the start of the study.

The ITT population was defined as all randomized patients, and the mITT population was defined as all randomized patients who received at least 1 infusion of the study drug. The 2 populations were the same, and no sensitivity analysis was performed. Although the ITT analysis is considered conservative for superiority trials, this is not the case for noninferiority trials.¹² Thus, the presentation of both mITT and PP analyses for the primary outcome helped to confirm that the analyses produced similar estimates of the treatment effect, which allowed the results to be interpreted with greater confidence.

Sample size and study power calculations were based on 3 previous studies that investigated the use of alglucosidase alfa for treatment-naïve patients with LOPD — a patient population that is generally consistent with the COMET trial, although specific eligibility criteria and study designs differed. A 10% dropout rate was estimated based on 2 of the 3 studies (LOTS and EMBASSY), resulting in a necessary sample size of at least 96 patients for the COMET trial to have approximately 80% power. In total, 100 patients were enrolled in the COMET study, of whom 95 completed the double-blind phase. The MMRM statistical models with fixed effects for baseline FVC, age, sex, treatment group, visit, and treatment-by-visit interaction used were considered acceptable for the primary analysis. Missing data were not imputed for the primary outcome, and it was assumed that data were missing at random. This assumption may bias 1 treatment over another, although sensitivity analyses were performed to assess the impact of missing data, which supported the missing-at-random assumption for the primary outcome. Procedures for handling missing data were described for some secondary (e.g., 6MWT, MEP, MIP, and HHD) and tertiary outcomes. Data were missing for nearly all outcomes; thus, the mITT population was not fully represented, and it is unclear what impact the missing data had on the results and conclusions. As these were secondary outcomes, and statistical testing was stopped, there is a high degree of uncertainty when interpreting these results. Sensitivity analyses (both a priori and post hoc analyses) indicated that patients who were excluded for various reasons (e.g., protocol deviation, implausible MEP or MIP values) did not change the noninferiority conclusion. To control for multiplicity, a sequential testing strategy was used. Avalglucosidase alfa showed noninferiority to alglucosidase alfa at the –1.1% margin for the primary outcome, but failed to show superiority, which stopped all subsequent statistical testing. Because testing stopped at the primary outcome, results for all secondary and tertiary outcomes for efficacy and HRQoL were not controlled for type I errors and should be interpreted as supportive of the primary outcome. Subgroup analyses for the primary outcome were specified a priori; although there was no control for multiplicity, each subgroup had a small number of patients and the wide 95% CIs indicated imprecision with the estimates.

The noninferiority margin was based on the double-blind, placebo-controlled LOTS trial for alglucosidase alfa 20 mg/kg every other week, with eligibility criteria similar to that of the COMET trial. The noninferiority margin of –1.1% retained approximately half of the lower bound of the 80% CI of the estimated treatment effect of alglucosidase alfa over placebo for FVC (% predicted) in the LOTS trial at 12 months (i.e., 2.14). The clinical expert believed that this was a reasonable approach to estimate the margin and that it was also a reasonable choice of margin from a clinical perspective. Retention of half of the comparator’s treatment effect is consistent with FDA guidance for noninferiority trials.¹² Although FDA guidance¹² indicates that a 95% CI is commonly used, the COMET publication¹³ stated that the CI was lowered to 80% in response to a suggestion from regulatory bodies. The rationale for this was not further described.

The constancy assumption is such that the effect of the active comparator (i.e., alglucosidase alfa) in the current noninferiority trial is the same as the effect observed in past trials and requires the trials to be sufficiently similar.¹⁴ The study designs, eligibility criteria, treatment doses, and key outcomes were similar to or the same as those in the COMET and LOTS trials, which supports the constancy assumption. Furthermore, the pre-specified constancy-assumption analysis estimated an effect of 2.87 for alglucosidase alfa, compared with placebo, in the COMET trial, and an effect of 3.02 in the LOTS trial, based on the predictive model.¹³ The investigators considered the difference in effect to be small (–0.15) compared with the noninferiority margin (1.1%).¹³ Pompe disease is rare, but the clinical expert noted that the patients who received alglucosidase alfa were similar overall in the COMET and LOTS trials. However, there were key differences in baseline characteristics — such as older baseline age, older age at symptom onset, higher FVC, and better 6MWT — for patients who received alglucosidase alfa in the COMET trial and LOTS trial. Although these differences should bias the results in favour of alglucosidase alfa treatment in the COMET study, the clinical expert did not feel they explained why the patients in the COMET trial did not respond as well as those in the LOTS trial. Consequently, the lower-than-expected improvements in the alglucosidase alfa arm in the COMET study could bias interpretation of the results in favour of treatment with avalglucosidase alfa. Although these concerns may affect interpretation of the trend toward superiority noted in the COMET trial, it is the opinion of the clinical expert that the concerns do not affect the statistically significant conclusions of the trial that avalglucosidase alfa is noninferior to alglucosidase alfa.

External Validity

In general, patients in the COMET study resembled those seen in clinical practice in Canada. The eligibility criteria included patients with LOPD as young as 3 years. However, only 1 pediatric patient was enrolled in the COMET study; all the other participants were adult patients. Despite the limited evidence for treatment of pediatric patients with LOPD, the clinical expert consulted on this review was of the opinion that the results are generalizable to pediatric patients, but not to patients with IOPD, and highlighted the urgent need for additional data in the IOPD population.

The multi-centre trial took place in 26 countries and included 2 Canadian sites. The clinical expert noted that clinical practice, background care, and reporting of AEs can vary in different countries, which may confound the results. Canadian guidance for the management of patients with Pompe disease suggests regular assessments at least every 6 months, which is less frequent than the study visits in the COMET trial. The greater access to health care resources and attention from clinicians during clinical trials should be considered when generalizing the results to real-world practice.

The avalglucosidase alfa dose of 20 mg/kg body weight every other week is consistent with both the product monograph and the alglucosidase alfa dose used to treat patients with LOPD. Alglucosidase alfa is the only available enzyme-replacement therapy for Pompe disease and, thus, is an appropriate comparator. Home infusions were allowed during the open-label phase when national regulations permitted, which is consistent with Canadian clinical practice.

Given that LOPD is a lifelong condition, the 1 year of data available from the double-blind phase provides only a short-term look at the efficacy and safety results of treatment with avalglucosidase alfa. Long-term efficacy and safety are still unknown and the extension phase of the COMET trial is ongoing (median time was 11 months as of March 19, 2020, the COMET trial primary completion date). When the open-label extension phase began after week 49, patients who started on avalglucosidase alfa continued to receive the medication and patients who had been receiving alglucosidase alfa switched to avalglucosidase alfa. Although it was not part of the primary analysis, the treatment switch meant a loss of the control arm, and the open-label design meant that patients were aware they were receiving avalglucosidase alfa, which could have affected subjective outcomes (e.g., SF-12). The benefit is that the treatment switch allows for the collection of data from patients who started on alglucosidase alfa and changed to avalglucosidase alfa after 1 year.

The literature search conducted to inform the description and appraisal of outcome measures showed there was a lack of evidence supporting the validity, reliability, or responsiveness to change for some of the trial outcomes. Therefore, there is uncertainty around the use of some measures, such as MEP, SF-12, and GMFM-88, to assess treatment for patients with LOPD. Furthermore, a literature search did not find any MIDs for populations with Pompe disease. The sponsor’s submission compared the noninferiority margin with a MID for FVC (% predicted) between 2% and 6%, based on patients with idiopathic pulmonary fibrosis, although the clinical expert believes that idiopathic pulmonary fibrosis and Pompe disease may not be directly comparable because of different physiologies and disease processes. Upon consultation with the clinical expert, in general, the outcome measures were deemed to be clinically relevant to the assessment of treatment in patients with Pompe disease. Moreover, the trial end points aligned with the most important outcomes identified by the patient group submission (i.e., motor- and respiratory-related and HRQoL outcomes). Patient input highlighted concern with how Pompe disease affected social and mental health, activities of daily living, and families or caregivers, but these factors were not the focus of the COMET study or this review. The clinical expert noted that both the primary outcome of FVC and the key secondary outcome of 6MWT have available data for patients with Pompe disease, although some clinics may be restricted in their ability to conduct the tests. For instance, a clinic must have assessors trained to evaluate the 6MWT, as well as the physical space to perform the test.

Although there may be some limitations to generalizability, as discussed here, the results of the COMET trial appear to be generalizable to Canadian clinical practice for the treatment of patients with LOPD.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

A focused literature search for network meta-analyses dealing with Pompe disease was run in MEDLINE All (1946–) on October 28, 2021. No limits were applied to the search. Indirect treatment evidence for avalglucosidase alfa was not identified in this review.

Other Relevant Evidence

This section includes 1 open-label, dose-escalation study and 1 long-term extension of the same open-label, dose-escalation study included in the sponsor’s submission to CADTH that were considered to address important gaps in the evidence included in the systematic review. Safety and exploratory efficacy were evaluated within the sponsor’s submission. A summary and critical appraisal of the additional evidence are presented in this section.

Dose-Escalation Study and Long-Term Extension

TDR12857 (NEO1) was a phase I, multi-centre, open-label, ascending-dose study to determine safety and tolerability, pharmacokinetic parameters, and pharmacodynamic effects of avalglucosidase alfa in treatment-naïve patients with LOPD and in patients with LOPD previously treated with alglucosidase alfa. Three dosing regimens were analyzed in the study; however, only the 20 mg/kg regimen is approved by Health Canada.

LTS13769 (NEO-EXT) is the long-term extension of NEO1. All patients who completed treatment with the 5 mg/kg dose or 10 mg/kg dose were invited to enrol in the extension, where they would receive 20 mg/kg. Both studies will be presented alongside each other in this section. The results will focus on the Health Canada–approved 20 mg/kg dose.

Methods

Two groups of patients were included in the study. Group 1 included treatment-naïve patients with LOPD and group 2 included patients with LOPD who were previously treated with alglucosidase alfa for a minimum of 9 months. Both groups received IV infusions of avalglucosidase alfa every other week for a total of 13 infusions. Three dosing regimens — 5 mg/kg, 10 mg/kg, and 20 mg/kg — were included. After a 90-day screening period, patients receiving the 5 mg/kg dose began the 24-week treatment period, which was followed by post-treatment evaluation at week 27 and an end-of-study visit at week 29. Successive escalating-dosage groups were initiated 5 weeks after initiation of the previous dose.

After completion of NEO1, patients were invited to enrol in the extension study, where either continued to receive the 20 mg/kg dose or were switched to the 20 mg/kg dose. In the extension study, the planned duration for each patient was 6 years. Patients continued in the study until the patient withdrew, the investigator withdrew the patient, or the sponsor terminated the study.

Populations

Patients enrolled in NEO1 were required to be at least 18 years of age with a confirmed GAA enzyme deficiency and/or confirmed GAA gene mutation, without known cardiac hypertrophy. To be enrolled in group 2, patients must have been treated with alglucosidase alfa for at least 9 months. FVC in the upright position of at least 50% of predicted and the ability to ambulate 50 m without stopping and without an assistive device were also requirements for enrolment. Exclusion criteria for NEO1 included dependence on a wheelchair, a need for invasive ventilation, and the unlikelihood that the patient, in the opinion of the investigator, would adhere to the requirements of the study.

A summary of baseline characteristics is shown in Table 15. Mean age was 49.1 (SD = 25.61) years in group 1 patients who received the 20 mg/kg dose and 43.8 (SD = 17.05) years in group 2 patients who received the 20 mg/kg dose. All patients in group 1 and group 2 who received 20 mg/kg were White, and their mean weight was 67.6 kg (SD = 12.55) and 78.1 kg (SD = 23.91), respectively. One-third of group 1 patients who received the 20 mg/kg dose required an assistive walking device for community ambulation, but no group 2 patients who received the 20 mg/kg dose required such assistance.

The NEO-EXT trial included only patients from the NEO1 trial; therefore, baseline characteristics were identical.

Interventions

In NEO1, avalglucosidase alfa was administered to all patients at a dose of 5 mg/kg, 10 mg/kg, or 20 mg/kg every other week for a total of 13 infusions. Infusion length was dependent on the dose received by the patient. Infusion administration began at a slow initial rate and increased if there were no signs of infusion-associated reactions. In NEO-EXT, all patients received the 20 mg/kg dose.

Outcomes

The primary outcomes of NEO1 were related to pharmacodynamics and were not relevant to this report. Assessment of safety and tolerability was another main objective of the study. An AE was defined as any untoward medical occurrence in a patient that did not necessarily have a causal relationship with the study drug. A SAE was defined as any untoward medical occurrence that resulted in death, was life-threatening, required inpatient hospitalization, resulted in persistent or significant disability, was a congenital anomaly, or was considered medically important. AEs of special interest included infusion-associated reactions, pregnancy, and alanine aminotransferase, aspartate transaminase, and serum creatinine abnormalities. All efficacy outcomes were considered exploratory. These measures included pulmonary function tests, 6MWT, GSGC, GMFM-88, QMFT, HHD, and the Pediatric Quality of Life Inventory; only the pulmonary function tests and 6MWT are presented in detail in this report. Results will only be presented for patients who received the Health Canada–approved 20 mg/kg dose.

Statistical Analysis

There was no comparator arm in this phase I trial and, as such, all outcomes are descriptive in nature; no formal statistical testing was conducted. Treatment-naïve patients are referred to as group 1 and patients previously treated with alglucosidase alfa are referred to as group 2.

Patient Disposition

A summary of patient disposition in NEO1 is shown in Table 16. Nearly all patients who received the 20 mg/kg dose completed the trial, with 1 patient in group 1 discontinuing due to SAE and 2 patients in group 2 choosing to withdraw from the study.

Of the 21 patients who completed NEO1, 19 enrolled in NEO-EXT. At the time of the February 27, 2020, data cut, 2 patients had discontinued from the extension study, so 17 patients remained on the study drug. Reasons cited for discontinuation of the extension study were patient’s wishes to discontinue and other.

Exposure to Study Treatments

A summary of treatment exposure in NEO1 is presented in Table 17. Mean duration on avalglucosidase alfa was 175.3 days (SD = 1.15) in group 1 patients who received the 20 mg/kg dose and 161.5 days (SD = 29.95) in group 2 patients who received the 20 mg/kg dose. All patients in group 1 who received the 20 mg/kg dose received the full 13 infusions, whereas group 2 patients who received the 20 mg/kg dose received a mean of 12.2 (SD = 2.04) infusions. In the extension study, mean duration on the study drug was 221.4 weeks (SD = 136.9) in group 1 and 242.3 weeks (SD = 124.5) in group 2.

Efficacy

A summary of respiratory efficacy outcomes in NEO1 and NEO-EXT are presented in Table 18. All efficacy results in NEO1 were considered exploratory in nature. Only results in patients who received the Health Canada–approved dose of 20 mg/kg have been presented.

Survival-Related Outcomes

Survival-related outcomes were not reported in the NEO1 or NEO-EXT trials.

Respiratory-Related Outcomes

Respiratory-related efficacy measures in the NEO1 trial included FVC, MEP, and MIP. Baseline mean FVC was 63.4% (SD = 17.84) and 70.4% (SD = 16.40) in group 1 and group 2, respectively. At week 25, mean FVC changed to 69.5% (SD = 20.63) and 69.9% (SD = 16.92), in group and group 2, respectively, with a mean change from baseline of 6.2% (SD = 3.15) and 1.4% (SD = 5.71) for the respective groups. Baseline mean MEP was 66.1% (SD = 18.51) and 84.9% (SD = 25.21) in group 1 and group 2, respectively. At week 25, mean MEP changed to 78.1% (SD = 22.26) and 85.6% (SD = 17.71), in group 1 and group 2, respectively. Baseline mean MIP was 50.2% (SD = 19.89) and 74.2% (SD = 17.01) in group 1 and group 2, respectively. At week 25, mean MIP changed to 58.1% (SD = 17.97) and 72.8% (SD = 19.00), in group 1 and group 2, respectively.

In the extension study, baseline mean FVC was 69.2% (SD = 19.27) and 77.3% (SD = 16.45) in combined group 1 and combined group 2, respectively. At week 286, mean FVC changed to 65.7% (SD = 30.07) and 74.5% (SD = 21.24), in the combined group 1 and combined group 2, respectively. Baseline mean MEP was 75.7% (SD = 18.06) and 80.1% (SD = 29.47) in the combined group 1 and combined group 2, respectively. At week 286, mean MEP changed to 80.9% (SD = 33.57) and 82.8% (SD = 35.31), in the combined group 1 and combined group 2, respectively. Baseline mean MIP was 67.9% (SD = 30.52) and 67.2% (SD = 23.29) in the combined group 1 and combined group 2, respectively. At week 286, mean MEP changed to 64.8% (SD = 40.20) and 72.3% (SD = 20.22), in the combined group 1 and combined group 2, respectively. Results beyond week 286 were available; however, reduced patient numbers resulted in uninformative data.

Motor-Related Outcomes

Selected motor-related efficacy outcomes are presented in Table 19. Baseline mean 6MWT % predicted was 75.2% (SD = 9.80) and 72.8% (SD = 20.59) in group 1 and group 2, respectively. At week 25, mean 6MWT % predicted changed to 79.1% (SD = 12.55) and 65.6% (SD = 12.03), in group 1 and group 2, respectively, with a mean change from baseline of 3.9% (SD = 3.45) and –1.3% (SD = 8.94) for the respective groups. In the extension study, 6MWT was 64.9% (SD = 28.05) and 69.1% (SD = 21.37) at week 286, in group 1 and group 2, respectively. Results beyond week 286 were available; however, reduced patient numbers resulted in uninformative data.

GSGC, GMFM, QMFT, and HHD were reported in the NEO1 and NEO-EXT studies but are not described in this report.

Health-Related Quality of Life

The Pediatric Quality of Life Inventory was reported in the NEO1 and NEO-EXT studies but not described in this report.

Harms

A summary of harms is presented in Table 20. In the initial study period of the NEO1 trial, 1 of the 3 patients in group 1 who received the 20 mg/kg dose experienced an AE, namely nasopharyngitis and erythema. All 6 patients in group 2 who received the 20 mg/kg dose experienced an AE; arthralgia and musculoskeletal pain were the only 2 AEs to be reported in multiple patients (33.3%). In NEO-EXT, all 24 patients, including those who switched to 20 mg/kg, experienced an AE. The most commonly reported AEs were nasopharyngitis (15 patients, 62.5%), fall (12 patients, 50.0%), diarrhea (11 patients, 45.8%), headache (10 patients, 41.7%), and muscle spasms (10 patients, 41.7%).

No patients who received the 20 mg/kg dose reported a SAE in the initial NEO1 study. In the NEO-EXT study, 9 patients (37.5%) reported a SAE, and there was no individual SAE that was reported in more than 1 individual patient. In the initial NEO1 study period, no patients who received the 20 mg/kg dose reported an AE that led to treatment discontinuation. In the NEO-EXT study, there was 1 patient (4.2%) who discontinued treatment due to an AE. No deaths due to AE were reported in either the NEO1 or NEO-EXT studies.

Notable harms, including anaphylactic reactions, hypersensitivity, infusion-associated reactions, and immune-mediated reactions, were less common during the initial NEO1 study period, and occurrence increased in the NEO-EXT study. In the NEO-EXT study, 17 patients (70.8%) experienced a treatment-emergent hypersensitivity AE, 12 patients (50.0%) experienced a treatment-emergent infusion-associated reaction, 2 patients (8.3%) experienced a treatment-emergent anaphylactic reaction, and no patients experienced a treatment-emergent immune-mediated reaction.

Critical Appraisal

Internal Validity

The phase I NEO1 dose-escalation study was conducted to assess the safety and tolerability of avalglucosidase alfa in patients with LOPD and to characterize the pharmacodynamic and pharmacokinetic profiles. The long-term extension, NEO-EXT, followed these patients for more than 4 years to assess safety and tolerability over a longer period. Efficacy outcomes were considered strictly exploratory. The number of patients who discontinued the trial was acceptable, and therefore there is little concern that results are biased in favour of avalglucosidase alfa for this reason. Inherent to phase I trials are the issues of a low number of patients enrolled, lack of a comparator arm, and lack of randomization. As a result, it is not possible to determine a causal relationship between the study drug and outcomes observed. The baseline demographics varied between patients receiving different doses, likely due to the low number of patients. Specifically, the mean age of group 1 patients receiving 10 mg/kg was 26 years, which is far younger than the rest of the study population. As the clinical expert explained, patients diagnosed earlier in life tend to progress more rapidly than those who present at a later age, and it would be expected that the age difference between groups 1 and 2 would bias the findings against the younger group 1 patients.

External Validity

The inclusion of the long-term extension of the phase I NEO1 study in the sponsor’s submission allows for greater assessment of the safety and tolerability data beyond the time points presented in the pivotal trials. However, the study design greatly limits the generalizability of any findings.

Discussion

Summary of Available Evidence

One multi-centre, active comparator, double-blind, phase III study was included in the CADTH systematic review. The COMET study was designed to assess the efficacy and safety of avalglucosidase alfa 20 mg/kg administered by IV infusion every other week for the treatment of patients with LOPD. Patients received either avalglucosidase alfa or alglucosidase alfa at a dose of 20 mg/kg body weight. The double-blind phase consisted of 49 weeks of treatment; after that, patients who were receiving alglucosidase alfa were switched to avalglucosidase alfa for the open-label phase, which lasted up to 240 weeks. To be included, patients had to be treatment-naïve, 3 years or older, have confirmed GAA enzyme deficiency from any tissue source and/or 2 confirmed GAA gene mutations, and no known Pompe-specific cardiac hypertrophy. Patients must also have been able to ambulate at least 40 m without stopping and without assistive device, be able to successfully perform repeated FVC measurements in the upright position between 30% and 85% predicted, and not require invasive ventilation. In the COMET study, avalglucosidase alfa was compared against alglucosidase alfa for the primary outcome of change from baseline to week 49 in FVC (% predicted) upright. Secondary outcomes included the 6MWT (total distance and % predicted), MEP, MIP, HHD (lower extremity composite score), QMFT, SF-12, and safety. The study included several tertiary and exploratory outcomes, of which the GSGC and GMFM-88 (dimensions D and E) were included in this report.

In total, 100 patients with LOPD were randomized to either avalglucosidase alfa (n = 51) or alglucosidase alfa (n = 49). Patients were between 16 and 78 years of age (mean = 48 years), 52% were male, 94% were White, and 34% were from North America. The mean age of patients who received avalglucosidase alfa was slightly younger than that of those who received alglucosidase alfa, their age at diagnosis was younger, and they had a shorter time between diagnosis and treatment. The mean baseline FVC for all patients was 62.1% predicted, which was similar among the treatment groups. The mean distance on the 6MWT was 388.9 m and 56.3% predicted, both of which were slightly greater in the avalglucosidase alfa group.

The major limitations of the COMET study were the small number of patients and lack of data for pediatric patients. The small number of patients limits the ability to accurately quantify the differences in outcomes, beyond the primary outcome, in long-term benefits and in potential harms between the treatments. Furthermore, the differences in baseline age and time from diagnosis to treatment may result in bias, although the direction and magnitude are unclear. The 5 patients who discontinued treatment during the double-blind phase were from the alglucosidase alfa group, and it is unknown what impact these losses had on the results. Data for week 49 were missing for primary and secondary outcomes, with a lack of information on how missing values were handled for many of the outcomes, which must be considered when interpreting the results. There was also a lack of evidence to support the validity, reliability, or responsiveness for outcome measures, and no MIDs for populations with Pompe disease were identified. Currently, there are limited long-term data available for the COMET study, as the open-label phase is still ongoing.

Two other relevant studies were summarized for this review that provided long-term data for the use of avalglucosidase alfa for the treatment of patients with LOPD. The studies included the open-label, phase I NEO1 and NEO-EXT studies that evaluated patients (N = 19) who were either treatment-naïve or had previously been treated with alglucosidase alfa. NEO1 consisted of treatment for up to 25 weeks, whereas in NEO-EXT, treatment was for up to 6 years. The major limitations included the small number of patients, lack of comparator arm, and lack of randomization, which hinder interpretation of the results and generalizability to clinical practice. No indirect treatment comparisons were identified for this review.

Interpretation of Results

Efficacy

In general, the results of the COMET study indicated that patients responded to both avalglucosidase alfa and alglucosidase alfa, compared with the natural history of Pompe disease (i.e., without treatment). The clinical expert emphasized that, given the progressive nature of the disease, improvement in a patient’s condition is desirable, but the goal of treatment is to prevent further decline. Furthermore, the clinical expert noted that patients who are diagnosed with Pompe disease at an earlier stage of muscle involvement and treated earlier can be maintained at a higher level of muscle function, which impacts patient morbidity.

The mean difference of change between treatment groups for FVC (% predicted) of both mITT and PP analyses at week 49 favoured avalglucosidase alfa (2.43% and 2.69%, respectively). Moreover, neither of the lower bounds of the 95% CIs (–0.13 and –0.06, respectively) exceeded the noninferiority margin of –1.1%, supporting the noninferiority conclusion (P = 0.0074 and P = 0.0076, respectively). Superiority testing followed, but neither P value from the mITT and PP analyses were statistically significant (P = 0.0626 and P = 0.0555, respectively); thus, superiority of avalglucosidase alfa could not be established and statistical testing stopped for all subsequent outcomes. Because no MID was identified from the literature for populations with Pompe disease, it was difficult to assess how meaningful the changes observed in the study were. Nevertheless, the clinical expert noted that any improvement in FVC was beneficial, compared with the natural and constant decline seen in untreated patients.

Because of inherent limitations in subgroup analyses, the overall design of the study, the small sample size, and the demonstrated wide confidence intervals in the results of the subgroups analyses, there is so much uncertainty in these results that they make the use of this information unhelpful for decision-making.

The results for the secondary and tertiary outcomes were generally as expected, in that treated patients did not show a major decline, compared with what would be expected and observed in untreated patients. Statistical testing was stopped after avalglucosidase alfa failed to show superiority for the primary outcome. The direction of estimates for all secondary and tertiary outcomes included in the results section of the CADTH report are in support of avalglucosidase alfa over alglucosidase alfa, except for MEP (% predicted) and GSGC. The clinical expert noted that changes from baseline in HRQoL, as measured by the SF-12, were small. Despite enzyme-replacement therapy possibly being effective and patients feeling better and responding well to treatment, the burden of treatment administration should not be overlooked because infusions are frequent and require hours to complete, which can have a large impact on patients’ HRQoL. Administration of avalglucosidase alfa is the same as for alglucosidase alfa and may not offer notable benefits to patients in this regard. Because tertiary and exploratory outcomes tend to be descriptive and hypothesis-generating, the outcomes assessed that were deemed not to be pivotal to the review were not included. Moreover, the high proportion of missing data for these outcomes reduced their use for the purposes of the CADTH review.

The long-term effects on FVC (% predicted) and 6MWT (distance and % predicted) appear to be sustained throughout the open-label phase of the COMET trial. The clinical expert expected that the best result of current treatment would be for patients to remain stable over time, rather than show continual improvement in measured outcomes, but reinforced the fact that stability is contrary to the natural history of the disease in untreated patients, so resulting benefits would be in considerable over time. Long-term data are limited to 97 weeks for the COMET trial, and it is difficult to draw any conclusions on treatment efficacy with certainty. Moreover, no statistical testing was conducted for end points during the open-label phase and are strictly supportive in nature.

Although there were few patients in the NEO1 and NEO-EXT studies (9 and 19 patients received avalglucosidase alfa 20 mg/kg, respectively), the baseline characteristics in these studies were similar to those of patients in the COMET study. In general, data for FVC (% predicted) showed slight improvements from baseline to the end of the NEO1 study (week 25). The results at week 286 of the extension study showed small decreases from baseline. Published literature studying the natural history of disease progression in patients with Pompe disease report annual declines in FVC (% predicted) in the sitting position between 1.04%⁵¹ and 4.60%⁵² among adults from the Netherlands and Belgium⁵¹ and patients 8 years and older from the US and Europe.⁵² Results for the 6MWT were similar from baseline to the end of the NEO1 study and week 286 of the NEO-EXT study. Other respiratory outcomes for MEP and MIP showed improvements from baseline to week 25 of the NEO1 study. In the NEO-EXT study, improvements were observed from baseline to week 286 for MEP, whereas baseline MIP values were sustained at week 286.

The differences in baseline characteristics (e.g., younger mean age at baseline and at diagnosis, better 6MWT at baseline, and shorter time between diagnosis and treatment start for patients who received avalglucosidase alfa) may bias and limit interpretations of the study results. Only 1 pediatric patient was included in the COMET trial, which limits the generalizability to patients with LOPD younger than 18 years, although the clinical expert was of the opinion that the results were generalizable to pediatric patients, but not to patients with IOPD. No MIDs were identified in populations with Pompe disease, and evidence of validity, reliability, and responsiveness was limited for this patient population; thus, there is greater uncertainty around the interpretation of the results.

Although the outcomes measured in the COMET trial align with the most important outcomes identified by the patient input submission (i.e., motor, respiratory, and HRQoL), the data do not support statistical superiority of avalglucosidase alfa over alglucosidase alfa for the outcomes assessed in the COMET study.

Harms

Overall, 44 patients (86.3%) in the avalglucosidase alfa group and 45 patients (91.8%) in the alglucosidase alfa group reported at least 1 AE during the COMET trial. SAEs were infrequent (8 patients [15.7%] and 12 patients [24.5%] in the avalglucosidase alfa and alglucosidase alfa arms, respectively. The 4 withdrawals due to AEs (WDAEs) and the 1 death were all in the alglucosidase alfa group. The clinical expert was of the opinion that there were no significant safety concerns associated with avalglucosidase alfa treatment. When there were differences in the incidence of some AEs between the groups, the clinical expert suggested they could be due to the small patient numbers or a result of the study being conducted at various international sites with different reporting procedures for AEs.

Notable harms identified in the CADTH systematic review protocol included anaphylactic reactions, hypersensitivity reactions, infusion-associated reactions, immune-mediated reactions, and acute cardiorespiratory failure. Frequencies of notable harms were the same for anaphylactic reactions between the treatment groups or numerically lower for hypersensitivity reactions, infusion-associated reactions, and immune-mediated reactions among patients who received avalglucosidase alfa. Acute cardiorespiratory failure was not reported during the COMET trial.

According to the clinical expert, the association between anti-drug antibody titres and loss of efficacy in LOPD are not well established. The clinical expert explained that high titres of anti-drug antibodies do not necessarily indicate that a patient will have an infusion-associated reaction, but the treating clinician may use more caution in withdrawing premedication before infusions. In the COMET study, numerically fewer number of patients had a peak titre of at least 12,800 in the avalglucosidase alfa group than the alglucosidase alfa group, which the clinical expert suggested could indicate that the former is less immunogenic than the latter. It will be necessary to collect data from more patients and for a longer time on treatment to confirm whether avalglucosidase alfa is less immunogenic than alglucosidase alfa.

The types of AEs in the NEO-EXT study (median duration on study treatment was around 300 days) were different than those in the COMET study. More than 1-third of patients reported an SAE in the NEO-EXT study, 1 patient withdrew due to an AE, and no deaths were reported.

When only data from the double-blind phase of the COMET study were considered, avalglucosidase alfa and alglucosidase alfa appeared to be similar in terms of type of AE, although, because of the small numbers of patients, it is unclear if the new treatment offers significant benefits in terms of reduced harms or lower immunogenicity.

Conclusions

In the COMET trial, the study’s main objective was achieved and avalglucosidase alfa met the criteria for noninferiority, compared with alglucosidase alfa. This comparison was made at the noninferiority margin of –1.1%, based on the primary outcome of FVC (% predicted) in the upright position for the first 49 weeks of treatment in patients with LOPD. Based on the evidence from the COMET trial, treatment with avalglucosidase alfa appeared to prevent further respiratory deterioration during the first year, which is 1 of the main goals of currently available forms of treatment, according to the clinical expert. The results from the study were not statistically significant for the superiority of avalglucosidase alfa over alglucosidase alfa for FVC (% predicted). Statistical testing was stopped for secondary outcomes and results should be interpreted as supportive of the primary outcome. Most patients experienced at least 1 AE during the first year of treatment, and fewer experienced a SAE. Notable harms for anaphylactic reactions occurred with the same frequency among the treatment groups, whereas hypersensitivity reactions, infusion-associated reactions, and immune-mediated reactions were numerically lower for patients who received avalglucosidase alfa.

Key limitations include the small number of patients enrolled in the studies and the lack of data available for pediatric patients. The small number of patients limits the ability to accurately quantify the differences in outcomes, beyond the primary outcome, in long-term benefits, and in potential harms between the treatments. Moreover, it will be beneficial to have continued long-term efficacy and safety data (including anti-drug antibody assessments) for treatment with avalglucosidase alfa, which is expected from the extension phase of the COMET study. Last, these results apply only to patients with LOPD and do not extend to patients with IOPD, for which there are ongoing trials evaluating avalglucosidase alfa.

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Appendix 1: Literature Search Strategy

Note that this appendix has not been copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases:

• MEDLINE All (1946-present)

• Embase (1974-present)

Note: Subject headings and search fields have been customized for each database. Duplicates between databases were removed in Ovid.

Date of search: October 29, 2021

Alerts: Bi-weekly search updates until project completion

Search filters applied: No filters were applied to limit the retrieval by study type.

Limits:

• No date or language limits were used

• Conference abstracts: excluded

Table 21: Syntax Guide

Multi-Database Strategy

1. (Nexviazyme* or avalglucosidase* or Nexviadyme* or gz 402666 or gz402666 or neoGAA or neo GAA or ATB-200 or ATB200 or EO144CP0X9).ti,ab,kf,ot,hw,rn,nm.

2. 1 use medall

3. avalglucosidase alfa/

4. ((Nexviazyme* or avalglucosidase* or Nexviadyme* or gz 402666 or gz402666 or neoGAA or neo GAA or ATB-200 or ATB200).ti,ab,kf,dq.

5. 3 or 4

6. 5 use oemezd

7. 6 not (conference review or conference abstract).pt.

8. 2 or 7

9. remove duplicates from 8

Clinical Trials Registries

ClinicalTrials.gov

Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.

[Search -- Studies with results | Nexviazyme or avalglucosidase alfa]

WHO ICTRP

International Clinical Trials Registry Platform, produced by the WHO. Targeted search used to capture registered clinical trials.

[Search terms -- Nexviazyme or avalglucosidase alfa]

Health Canada’s Clinical Trials Database

Produced by Health Canada. Targeted search used to capture registered clinical trials.

[Search terms -- Nexviazyme or avalglucosidase alfa]

EU Clinical Trials Register

European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.

[Search terms -- Nexviazyme or avalglucosidase alfa]

Grey Literature

Search dates: October 18, 2021 – October 22, 2021

Keywords: Nexviazyme, avalglucosidase alfa, Pompe disease

Limits: None

Updated: Search updated before the completion of stakeholder feedback period.

Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool for Searching Health-Related Grey Literature were searched:

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Drug and Device Regulatory Approvals

• Advisories and Warnings

• Drug Class Reviews

• Clinical Trials Registries

• Databases (free)

• Health Statistics

• Internet Search

Appendix 2: Excluded Studies

Note that this appendix has not been copy-edited.

Table 22: Excluded Studies

Appendix 3: Detailed Outcome Data

Note that this appendix has not been copy-edited.

Table 23: Subgroup Analyses for the Primary Efficacy Outcome – COMET Trial, mITT Population