CADTH Reimbursement Review

Mepolizumab (Nucala)

Sponsor: GlaxoSmithKline Inc.

Therapeutic area: Severe chronic rhinosinusitis with nasal polyps

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

Chronic rhinosinusitis (CRS) is a chronic inflammatory disease of the nasal passage linings and/or sinuses that may occur with or without nasal polyps. Nasal polyps are outgrowths of sino-nasal tissues, and those that accompany CRS are benign and typically develop bilaterally in the sino-nasal cavity.¹ The prevalence of CRS with nasal polyps (CRSwNP) is estimated to be between 1% and 4% of the US general population and between 25% and 30% of patients with CRS.² Currently, Canadian data on the prevalence and incidence of CRSwNP are not available. CRSwNP is more common in men and older individuals. Nasal obstruction and hyposmia or anosmia,³ as well as rhinorrhea, severe nasal congestion, and loss of smell or taste,^4,5 are key symptoms associated with CRSwNP. The long-term symptoms associated with CRSwNP negatively impact physical and mental health-related quality of life (HRQoL).⁵ Disease burden is particularly high among patients who require repeated treatment with systemic corticosteroids and/or sino-nasal surgeries to alleviate uncontrolled symptoms.⁶

The goal of therapy for CRSwNP is to reduce symptoms and complications by minimizing inflammation and controlling secondary infection if it occurs. In clinical practice in Canada, initial treatment for CRSwNP generally starts with intranasal corticosteroids (INCS) with mometasone furoate (MF) nasal spray (2 sprays each nostril twice daily or an equivalent). Antibiotics are initiated for patients with CRSwNP with a suspected bacterial infection as indicated by pain, documented purulence, or recurrent episodes of sinusitis. Other medical treatments that may be considered are oral corticosteroids (OCS), systemic corticosteroids, leukotriene receptor antagonists (LTRAs), and acetylsalicylic acid (ASA) desensitization. Endoscopic sinus surgery is reserved for patients whose CRSwNP is not responsive to medical treatment.

Mepolizumab is a targeted anti-interleukin-5 immunoglobin (Ig) G1 kappa monoclonal antibody. Mepolizumab binds to soluble interleukin-5 (IL-5) with high affinity, preventing IL-5 from binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface, thereby reducing the production and survival of eosinophils.⁷ On November 5, 2021, mepolizumab received a Notice of Compliance from Health Canada as add-on maintenance treatment with INCS in adult patients with severe CRSwNP inadequately controlled by INCS alone. Mepolizumab is administered as a subcutaneous injection at a dose of 100 mg once every 4 weeks.

The objective of this review is to evaluate the beneficial and harmful effects of mepolizumab 100 mg/mL as add-on maintenance treatment with INCS in adult patients with severe CRSwNP inadequately controlled by INCS alone.

Stakeholder Perspectives

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

Patient Input

Patient input was provided by 2 groups: Asthma Canada and the Patient Lung Groups of the British Columbia Lung Association (BCLA). Survey respondents indicated that CRSwNP symptoms had had a direct negative impact on their daily lives, including decreased quality of life (90%), sleep disturbances (66%), missed time from work or school (30%), financial difficulties (20%), and hospital visits because of CRSwNP (20%). Among the survey respondents who identified as caregivers, 66% reported an impact on sleep related to nighttime symptoms and being burdened by managing frequent appointments (44%) and multiple medications (33%) for the patient they care for. Thirty-nine percent of survey respondents reported using nasal sprays to manage their CRSwNP, while 28% reported having surgery, 17% reported using OCS, and 17% reported using a biologic (e.g., dupilumab or omalizumab) to treat their nasal polyps. The side effects most commonly reported by these patients included altered sense of smell (63%), allergic reactions (36%), mental or mood changes (27%), increased risk of sinus infection (27%), headaches or dizziness (18%), and ineffectiveness (18%). Furthermore, both Asthma Canada and the BCLA expressed concern with the short- and long-term side effects associated with OCS in patients who have not experienced adequate control of their CRSwNP with previous lines of therapy, resulting in symptoms such as weight gain, cataracts, osteoporosis, increased risk of infection, and high blood sugar. Patients and caregivers have deemed the following outcomes as important for new treatment options: easier management of symptoms (63%), decreased anxiety about nasal polyps (45%), decreased reliance on OCS or other steroids (36%), reduced need for surgery (36%), and improved process for taking medication (27%). Sixty-three percent of survey respondents indicated that any potential side effects of mepolizumab would be worth tolerating in exchange for a visible improvement in CRSwNP management.

Clinician Input

Input From Clinical Expert Consulted by CADTH

One clinical expert was consulted for the purpose of this review. According to the clinical expert consulted by CADTH, not all patients are responsive to current treatments for the management of CRSwNP. Due to the chronic and recurring nature of CRSwNP, there is a medical need for targeted treatment of nasal polyps. Recurrence of nasal polyps is most likely in the presence of high levels of local IL-5 and IgE, which drive eosinophilic inflammation. The anti-IL-5 mechanism of mepolizumab would prevent the inflammation most associated with nasal polyp recurrence. The clinical expert noted that mepolizumab would be most appropriate for use in patients who do not experience control of symptoms or cannot tolerate topical steroid treatment. According to the clinical expert consulted, patients with eosinophilic polyps are most likely to respond to anti-IL-5 treatments. Eosinophilic polyps can be identified via pathology at the time of polyp removal. Polyps identified as being neutrophilic are less likely to respond to anti-IL-5 treatments. The clinical expert also noted that biologic treatments would likely be unnecessary among patients who respond to topical steroids. The clinical expert noted that response to treatment is determined by severity of nasal congestion. Response to treatment should typically occur within 6 months of initiating therapy. The clinical expert noted that while use of systemic steroids should be reduced during this time, more than 6 months may be needed in resistant patients to document response. The clinical expert noted that the need for prednisolone or surgery could indicate a loss of response to treatment. For those patients who require surgery, continued treatment with mepolizumab may be considered to prevent recurrence of nasal polyps.

Clinician Group Input

No input was received from any clinician groups for this submission.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for mepolizumab:

• considerations related to initiation of therapy

• considerations related to continuation or renewal of therapy

• considerations related to discontinuation of therapy

• considerations related to prescribing of therapy.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

One sponsor-conducted study that met the CADTH review protocol criteria was included in this systematic review. SYNAPSE was a randomized, double-blind, placebo-controlled, parallel group trial assessing the clinical efficacy and safety of 100 mg mepolizumab as an add-on maintenance treatment in adults with recurrent CRSwNP. A total of 414 adult patients were randomized at 86 sites across 11 countries, including 34 patients (8.2%) across 8 sites in Canada. The study comprised a 4-week run-in period followed by a 52-week treatment period in which patients were randomized to receive either mepolizumab (n = 207) or matching placebo (n = 207). During the treatment period, patients received either mepolizumab 100 mg every 4 weeks (a total of 13 doses) or placebo delivered by subcutaneous injection. The final dose of the study treatment was administered at week 48. The first 200 patients randomized into the study entered a 6-month no-treatment follow-up period following their week 52 visit to assess maintenance of response. All patients remained on standard of care treatment for CRSwNP throughout the study. Standard of care treatment included daily MF nasal spray and, if required, saline nasal douching and/or an occasional short course of high-dose OCS and/or antibiotics. Changes in MF dosing regimen between screening and the end of the study were not permitted.

The co-primary efficacy end points were change from baseline in endoscopic nasal polyp score at week 52 and change from baseline in nasal obstruction visual analogue scale (VAS) symptom score during the 4 weeks before week 52. The key secondary end point was time to first actual surgery for nasal polyps by week 52. Sample size determination was made to ensure sufficient power to detect meaningful changes in this key secondary end point. Other secondary end points included change from baseline in the overall VAS symptom score, change from baseline in the Sino-Nasal Outcome Test 22 (SNOT-22) score, the proportion of patients requiring systemic steroids for nasal polyps, change from baseline in the composite VAS symptom score (combining VAS scores for nasal obstruction, nasal discharge, mucus in the throat, and loss of smell), and change from baseline in the loss of smell VAS score. Multiplicity was controlled using a hierarchical closed testing approach in making inferences for the secondary end points. Analyses were adjusted for the following covariates: country region, blood eosinophil count, baseline endoscopic nasal score, number of previous surgeries, and number of courses of OCS for nasal polyps in the previous 12 months.

Overall, randomized patients were middle aged (mean = 48.8 years; standard deviation [SD] = 13.01) and generally overweight (mean body mass index = 28.16 kg/m²; SD = 5.36). The mean time since onset of nasal polyps at baseline was 11.41 years (SD = 8.39). Patients presented with severe CRSwNP, as indicated by baseline total endoscopic nasal polyp score (centrally read) (mean = 5.5; SD = 1.29), nasal obstruction VAS score (mean 8.97; SD = 0.83), SNOT-22 total score (mean = 64.1; SD = 18.32), and a having had at least 1 surgery for nasal polyps in the past 10 years. While the majority of patients had a history of 1 or 2 surgeries (70%), a greater proportion of patients in the placebo group than in the mepolizumab group had had more than 1 surgery (60% versus 48%).

Efficacy Results

Key efficacy results are presented in Table 2.

Severity of Nasal Polyps

At the end of the 52-week treatment period, the mean change in total endoscopic nasal polyp score from baseline was –0.1 (SD = 1.46) and –0.9 (SD = 1.90) in the placebo and mepolizumab groups, respectively. The median change from baseline in the placebo and mepolizumab groups was 0 (interquartile range [IQR], –1.0 to 1.0) and –1.0 (IQR, –2.0 to 0.0), respectively. The adjusted median difference in change from baseline was statistically significant in favour of mepolizumab compared to placebo (–0.73; 95% confidence interval [CI], –1.11 to –0.34; P < 0.001). In total, 28.4% and 50.5% of patients in the placebo and mepolizumab groups, respectively, demonstrated the minimal important difference (MID) of a 1-point or greater improvement in their total endoscopic nasal polyp score. According to the clinical expert consulted by CADTH for this review, the response to treatment as defined by the total endoscopic nasal polyp score is indicative of a treatment response in the clinical setting.

Exploratory subgroup analyses in patients with or without asthma and in patients with or without prior surgery for nasal polyps were conducted; however, no formal hypothesis testing was done. Therefore, whether the effect of mepolizumab differs between these subgroups is unknown.

Nasal Obstruction

In the 4-week period from week 49 to week 52, the mean change in total nasal obstruction VAS score from baseline was –2.45 (SD = 3.15) and –4.24 (SD = 3.42) in the placebo and mepolizumab groups, respectively. The median change from baseline to week 52 in the placebo and mepolizumab groups was –0.82 (IQR, –4.84 to 0.0) and –4.41 (IQR, –7.27 to –0.36), respectively. The adjusted median difference in change from baseline to week 52 was statistically significant in favour of mepolizumab compared to placebo (–3.14; 95% CI, –4.09 to –2.18; P < 0.001). Twenty-three percent and 44% of patients in the placebo and mepolizumab groups, respectively, demonstrated a more than 5-point improvement (suggested MID) in their nasal obstruction VAS score.

Exploratory subgroup analyses in patients with or without concurrent asthma and in patients with or without prior surgery for nasal polyps were conducted; however, no formal hypothesis testing was done. Therefore, whether the effect of mepolizumab differs between these subgroups is unknown.

The magnitude of the treatment effect for nasal obstruction VAS score was modest yet indicative of a treatment response in the clinical setting according to the clinical expert consulted by CADTH for this review. According to the clinical expert, a change in score between 20% and 50% of the baseline VAS score is considered acceptable in clinical practice. In the SYNAPSE trial, the difference in mean change from baseline across the VAS end points fell within this range.

Symptoms

In the 4-week period from week 49 to week 52, the mean change in nasal symptom composite VAS score from baseline was –2.19 (SD = 2.82) and –3.81 (SD = 3.19) in the placebo and mepolizumab groups, respectively. The median change from baseline in the placebo and mepolizumab groups was –0.89 (IQR, –4.06 to 0.0) and –3.96 (IQR, –6.68 to –0.32), respectively. The adjusted median difference in change from baseline was statistically significant in favour of mepolizumab compared to placebo (–2.68; 95% CI, –3.44 to –1.91; P = 0.020). Twenty percent and 37% of patients in the placebo and mepolizumab groups, respectively, demonstrated a more than 5-point improvement in their nasal symptom composite VAS score.

In the 4-week period from week 49 to week 52, the mean change in nasal symptom and facial pain composite VAS score from baseline was –2.24 (SD = 2.88) and –3.80 (SD = 3.18) in the placebo and mepolizumab groups, respectively. The median change from baseline in the placebo and mepolizumab groups was –0.99 (IQR, –4.29 to 0.0) and –3.88 (IQR, –6.45 to –0.25), respectively. The adjusted median difference in change from baseline favoured the mepolizumab group compared to the placebo group (–2.50; 95% CI, –3.33 to –1.67). Twenty-one percent and 38% of patients in the placebo and mepolizumab groups, respectively, demonstrated a more than 5-point improvement in their nasal symptoms and facial pain composite VAS score.

In the 4-week period from week 49 to week 52, the mean change in loss of smell VAS score from baseline was –1.38 (SD = 2.65) and –2.83 (SD = 3.61) in the placebo and mepolizumab groups, respectively. The median change from baseline in the placebo and mepolizumab groups was 0 (IQR, –1.28 to 0.0) and –0.53 (IQR, –5.60 to 0.0), respectively. The adjusted median difference in change from baseline was statistically significant in favour of mepolizumab compared to placebo (–0.37; 95% CI, –0.65 to –0.08; P = 0.020). Thirteen percent and 30% of patients in the placebo and mepolizumab groups, respectively, demonstrated a 5-point or greater improvement in their loss of smell VAS score.

The magnitude of the treatment effect for the compositive VAS scores was indicative of an acceptable treatment response in the clinical setting according to the clinical expert consulted by CADTH for this review. For loss of smell, however, the magnitude of the treatment effect was considered small. According to the clinical expert, it is difficult to regain sense of smell once lost.

Nasal Congestion

At week 52, the mean change from baseline in peak nasal inspiratory flow (PnIF) was greater in the mepolizumab group (32.5; SD = 57.98) than in the placebo group (11.2; SD = 65.78). The median change from baseline in the placebo and mepolizumab groups was 0 (IQR, –20.0 to 50.0) and 30 (IQR, 0.0 to 60.0), respectively. The improvement in the mepolizumab group was in excess of the established 20 L/min MID.

PnIF assesses the objective improvement of nasal congestion since it is affected by both polyp size and nasal mucosa inflammation. Unfortunately, no analysis of treatment difference was conducted between the groups, and the outcome was absent from the statistical testing hierarchy. As a result, conclusions cannot be made on the efficacy of mepolizumab to improve nasal congestion. This represents a missed opportunity to demonstrate an objective treatment effect on an outcome that is considered important in the clinical setting.

Response to Treatment

Twenty-eight percent and 50% of patients in the placebo and mepolizumab groups, respectively, demonstrated a 1-point or greater improvement in their total endoscopic nasal polyp score at the end of the 52-week treatment period. The odds ratio of being a responder in the mepolizumab group compared to the placebo group was 2.74 (95% CI, 1.80 to 4.18).

Fifty-four percent and 73% of patients in the placebo and mepolizumab groups, respectively, demonstrated a 8.9-point or greater improvement in their total SNOT-22 score at the end of the 52-week treatment period. The odds ratio of being a responder in the mepolizumab groups compared to the placebo group was 2.44 (95% CI, 1.60 to 3.73).

The SNOT-22 score is used in the clinical practice setting to determine response to treatment. Just over half the patients in the placebo group demonstrated response to treatment in terms of SNOT-22 score. The observed treatment effect in the placebo group is most likely a result of the effectiveness of MF nasal spray treatment. According to the clinical expert consulted by CADTH for this review, the benefits derived from daily MF treatment may be reflecting improvement in sinusitis, nasal turbinate edema, and secretion, leading to symptomatic and objective improvement despite polyps being resistant to steroids.

Health-Related Quality of Life

At the end of the 52-week treatment period, the mean change in total SNOT-22 score from baseline was –15.7 (SD = 23.93) and –29.4 (SD = 24.67) in the placebo and mepolizumab groups, respectively. The median change from baseline to week 52 in the placebo and mepolizumab groups was –14.0 (IQR, –31.0 to 0.0) and –30.0 (IQR, –46.0 to –4.0), respectively. The adjusted median difference in change from baseline was statistically significant in favour of mepolizumab compared to placebo (–16.49; 95% CI, –23.57 to –9.42; P = 0.003).

At the end of the 52-week treatment period, the median change from baseline for both the physical component summary (PCS) and mental component summary (MCS) of the Short Form (36) Health Survey (SF-36) was 0.0 (IQR, –1.75 to 4.61) and 0.0 (IQR, –3.75 to 5.76), respectively, in the placebo group. The median change from baseline to week 52 for the PCS and MCS was 6.75 (IQR, 0.0 to 12.59) and 1.20 (IQR, –2.60 to 10.08), respectively, in the mepolizumab group.

Systemic Steroid Use for Nasal Polyps

Patient groups indicated a need for decreased reliance on OCS and other steroids.

Over the 52-week treatment period, 37% and 25% of patients in the placebo and mepolizumab groups, respectively, required at least 1 course of systemic steroid treatment for nasal polyps. By week 52, the probability of requiring an initial course of systemic steroid use for nasal polyps was 37.5% (95% CI, 31.1% to 44.6%) in the placebo group and 25.4% (95% CI, 20.0% to 32.1%) in the mepolizumab group.

Nasal Inflammation

Nasal inflammation was not assessed in the SYNAPSE trial.

Nasal Polyp Surgery

By week 52, 23% and 9% of patients in the placebo and mepolizumab groups, respectively, had undergone nasal surgery. The estimated risk of having surgery before week 52 was 23.6% (95% CI, 18.3% to 30.3%) in the placebo group and 9.2% (95% CI, 5.9% to 14.2%) for patients in the mepolizumab group. The probability of undergoing nasal surgery at any time before week 52 was statistically significantly lower in the mepolizumab group than in the placebo group (hazard ratio = 0.43; 95% CI, 0.25 to 0.76; P = 0.003).

A reduced need for surgery was deemed to be important by patient groups. However, the durability of the treatment effect could not be assessed due to the short duration of, and the low number of patients entering, the follow-up period.

Work Productivity

At week 52, improvements were observed across all Work Productivity and Activity Impairment — General Health (WPAI-GH) domains, except for work time missed due to health. At week 52, impairment due to health while working was reported by 22.9% and 18.5% of patients in the placebo and mepolizumab groups, respectively. Overall work impairment due to health was reported by 27.0% and 20.6% of patients in the placebo and mepolizumab groups, respectively. Activity impairment due to health was reported by 27.1% and 19.2% of patients in the placebo and mepolizumab groups, respectively. Finally, 6.4% and 4.3% of patients reported work time missed due to health in the placebo and mepolizumab groups, respectively.

Harms Results

Key harm results are summarized in Table 2.

Adverse Events

During the 52-week study period, the proportion of patients who reported at least 1 adverse event (AE) was 84% and 82% in the placebo and mepolizumab groups, respectively. The 3 most common AEs reported in the placebo and mepolizumab groups were nasopharyngitis (23% and 25%, respectively), headache (22% and 18%), and sinusitis (11% and 5%). The following AEs were reported in less than 10% but greater than 5% of patients in either treatment group: epistaxis, asthma, nasal polyps, back pain, upper respiratory tract infection, acute sinusitis, cough, bronchitis, oropharyngeal pain, otitis media, and arthralgia.

Serious AEs

Serious AEs were reported in 7% and 6% of patients in the placebo and mepolizumab groups, respectively. No single serious AEs were reported in more than 1% of patients in either treatment group.

Withdrawals due to AEs

Two percent of patients in each group discontinued treatment due to any AE. The AEs contributing to withdrawal from treatment were not specified.

Mortality

Death occurred in 1 patient in the placebo group. The 1 death was related to a fatal myocardial infarction during the follow-up period after week 52.

Notable Harms

Potential opportunistic infections were reported by 2.48% and 1.46% of patients in the placebo and mepolizumab groups, respectively. Opportunistic infections reported by patients in the placebo group included herpes zoster, oral herpes, candida infection, and oropharyngeal candidiasis. In the mepolizumab group, herpes zoster, oral herpes, and candida infections were reported. Serious infections were reported by 2% and 0.49% of patients in the placebo and mepolizumab groups, respectively. Serious infections reported included acute sinusitis, cellulitis, and influenza in the placebo group and pneumonia in the mepolizumab group. Local injection site reactions were reported by 1.0% of patients in the placebo group and 2.43% of patients in the mepolizumab group. Systemic site reactions were reported in 0.50% and 0.97% of patients in the placebo and mepolizumab groups, respectively. No anaphylaxis events were reported in either group. In the placebo group, serious cardiac, vascular, and thromboembolic events were reported in 1.0% of patients and serious ischemic events in 0.50% of patients. In the mepolizumab group, serious cardiac disorder; serious cardiac, vascular, and thromboembolic events; and serious ischemic events were reported in 1 patient each.

Critical Appraisal

The SYNAPSE trial was limited by between-group imbalances at baseline. First, a greater proportion of patients in the placebo group than in the mepolizumab group initiated therapy with LTRA before treatment with the study drug (17% versus 12%); a potential confounding effect of LTRA cannot be ruled out. Second, a greater proportion of patients in the placebo group than in the mepolizumab group had had 2 or more surgeries (60% versus 48%) at baseline. While it is unclear whether the need for more surgery was a function of disease severity or disease duration, it is a potential marker of treatment resistance. More patients in the mepolizumab group than in the placebo group experienced at least 1 asthma exacerbation in the 12 months before screening (26% versus 15%) and at least 1 asthma exacerbation requiring systemic corticosteroids but not hospitalization or an emergency room visit in the 12 months before screening (20% versus 12%). Overall, these baseline imbalances may have had an impact on the assessment of differences in treatment effects between groups, yet the magnitude and direction of the bias remain uncertain.

Other between-group imbalances — namely, greater use of concomitant medications and greater protocol deviations in the placebo group — may have influenced the treatment effect. During the treatment period, a greater proportion of patients in the placebo group than in the mepolizumab group initiated concomitant treatment with any systemic corticosteroid (46% versus 34%). Likewise, a greater proportion of patients in the placebo group than in the mepolizumab group, albeit a low percentage overall, made use of a rescue short-acting beta2-agonist inhaler (9% versus 1%). According to the clinical expert consulted by CADTH, the use of systemic corticosteroids for any reason or the use of rescue corticosteroid (but not short-acting beta2-agonist) medication for asthma may improve nasal polyp symptoms, thereby potentially introducing bias against mepolizumab into the results. While the impact of these additional interventions could not be assessed due to the small percentage of patients requiring their use during the study period, it is possible that that the placebo group benefited from the additional therapies.

A greater proportion of patients in the placebo group than in the mepolizumab group discontinued treatment (17% versus 11%), and a substantial proportion of patients were documented with an incomplete (42% versus 31%) or missing (6% versus 4%) end point assessment. The majority of missed or incomplete assessments were due to missing clinical chemistry, hematology, and/or urinalysis due to spoiled samples; however, missed visits or phone calls related to patient diary, health-related quality of life (HRQoL), and work productivity occurred in 10% and 5% of patients in the placebo and mepolizumab groups, respectively. To mitigate discontinuation and missed assessments, patients were assigned their worst observed score before withdrawal or missed assessment. However, the high percentage of major protocol violations (65% in the placebo group versus 55% in the mepolizumab group) may have compromised the quality of the data from this trial, which may have had an impact on the assessment of efficacy outcomes.

Overall, the study population represented the patients who were more likely to adhere to the long-term use of the study drug. The 4-week run-in period further excluded those patients who met the study eligibility criteria (severe CRSwNP with at least 1 surgery for recurrent nasal polyps and refractory to standard of care) but who were intolerant or poorly adherent to the study drug or procedures (21% did not meet the continuation criteria). An enrichment design tends to overestimate the treatment effectiveness in the clinical practice setting. Clinical improvements noted in the placebo group during the treatment period raised the question of how much of the maintained treatment effect observed during the follow-up period in the mepolizumab group was due to mepolizumab versus standard of care with INCS, given that full onset of action of intranasal steroids may be delayed for some patients.⁹ As noted by the clinical expert, adherence to persistent daily INCS may have led to the placebo group maintaining the modest improvement experienced during the treatment period. Consequently, uncertainty exists in how much of the treatment effect observed in the mepolizumab group was due to the efficacy of mepolizumab versus the effectiveness of MF therapy, although both groups were on INCS therapy. All these factors contributed to the difficulty in interpreting and assessing the generalizability of the efficacy results.

Indirect Comparisons

No indirect treatment comparisons were included in the sponsor’s submission to CADTH or identified in the literature search.

Other Relevant Evidence

No long-term extension studies or other relevant studies were included in the sponsor’s submission to CADTH or identified in the literature search.

Conclusions

Based on the SYNAPSE trial, mepolizumab as an add-on maintenance therapy in combination with standard of care was efficacious in achieving endoscopic improvement and relief of nasal obstruction as measured by the VAS in patients with severe recurrent CRSwNP inadequately controlled by inhaled nasal corticosteroids alone. Moreover, mepolizumab was found to be efficacious in prolonging time to nasal surgery, reducing the need for systemic corticosteroids for nasal polyps, and improving CRSwNP symptoms. However, the magnitude of the treatment effect was modest. Based on the response observed in the placebo group and on input from the clinical expert consulted by CADTH for this review, the extent to which these improvements were due to treatment with mepolizumab remains uncertain. Mepolizumab appeared to be well tolerated. However, due to the lack of head-to-head trials or availability of indirect treatment comparisons, it remains unknown how mepolizumab compares in efficacy and safety to other similar maintenance therapy for severe recurrent CRSwNP. Despite these limitations, mepolizumab fills an unmet need for more treatment options for patients with severe CRSwNP inadequately controlled with standard of care.

Introduction

Disease Background

CRS is a chronic inflammatory disease of the nasal passage linings and/or sinuses. CRS is defined by the presence of anterior or posterior rhinorrhea, nasal congestion, hyposmia, and/or facial pressure or pain lasting for more than 12 weeks.¹⁰ CRS may be subcategorized as CRSwNP or CRS without nasal polyps.² Nasal polyps are outgrowths of sino-nasal tissues, and those that accompany CRS are benign. These nasal polyps typically develop bilaterally in the sino-nasal cavity.¹ Currently, Canadian data on the prevalence and incidence of CRSwNP are not available. The prevalence of CRSwNP is estimated to be between 1% and 4% of the general US population and between 25% and 30% of patients with CRS.^1,10 CRSwNP is more common in men and older individuals.¹¹ Symptoms of CRSwNP tend to be more severe than those associated with CRS without nasal polyps.^12,13 Key symptoms of CRSwNP include nasal obstruction and hyposmia or anosmia,³ as well as rhinorrhea, severe nasal congestion, and loss of smell or taste.^4,5 The long-term symptoms associated with CRSwNP (i.e., prominent nasal obstruction, postnasal drip, loss of smell, and discharge) negatively impact physical and mental HRQoL.^1,6 Disease burden is particularly high among patients who require repeated treatment with corticosteroids and/or sino-nasal surgeries to alleviate uncontrolled symptoms.¹⁴ Some studies suggest that the impact of CRSwNP on HRQoL is comparable with other chronic diseases such as chronic obstructive pulmonary disease, asthma, and diabetes.^15,16

Symptomatic assessment of CRSwNP, as defined by the European Position Paper on Rhinosinusitis and Nasal Polyps guidelines,¹⁰ is as follows: inflammation of the nose and the paranasal sinuses characterized by 2 or more symptoms, 1 of which should either be nasal blockage, obstruction, or congestion or nasal discharge (anterior or posterior nasal drip) with or without facial pain or pressure and with or without reduction or loss of smell for 12 weeks or more. Diagnosis is confirmed upon evidence of sino-nasal inflammation and nasal polyps on sinus via CT scan and/or nasal endoscopy. Currently, there are no single validated biomarkers to distinguish CRSwNP from CRS without nasal polyps, acute sinusitis, or no sinus disease at all.

The exact etiology of nasal polyps is unknown, although allergies, asthma,^17-19 and gene polymorphism^20-22 have been implicated in nasal polyp occurrence in adults.¹ Inflammatory mediators may also play a role in the development of nasal polyps, including the cytokines IL-4, IL-5, and IL-13 and the C-C motif chemokines ligands 24 and 26. In Western countries, CRSwNP is often associated with eosinophilic inflammation. Those who show evidence of type 2 airway inflammation also present with comorbid asthma and/or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease. Additional contributors to nasal polyps include microbial colonization such as the Alternaria species and Staphylococcus aureus.²³

Standards of Therapy

The goal of therapy for CRSwNP is to reduce symptoms and complications by minimizing inflammation and controlling secondary infection from CRS. However, treatment options for patients with CRSwNP are limited.⁶ Initial treatment for CRSwNP generally starts with an INCS, such as mometasone. The European Position Paper on Rhinosinusitis and Nasal Polyps reported that there is high-quality evidence indicating that treatment with nasal corticosteroids improves symptomatology, reduces nasal polyp size, and improves PnIF.²⁴ When administered after endoscopic sinus surgery, INCS have shown to prevent polyp recurrence.⁹ Antibiotics are initiated for patients with CRSwNP suspected to have a bacterial infection as indicated by pain, documented purulence, or recurrent episodes of sinusitis. Long-term use of antibiotics, however, is not recommended due to potential increased risk of AEs.

Other medical treatments that may be considered are oral steroids, systemic and topical steroids, LTRAs, and ASA desensitization. Monoclonal antibodies, such as dupilumab, are also approved for the treatment of CRSwNP by Health Canada, but use of dupilumab in clinical practice in Canada is currently limited due to the lack of insurance coverage.

Endoscopic sinus surgery is reserved for patients whose CRSwNP is not responsive to medical treatment. Surgery has been shown to reduce disease burden and prevent or prolong the time to polyp recurrence. However, nasal polyps may still recur post-surgery.²⁵ Indeed, 10% to 30% of patients with CRSwNP require revision surgery within 5 years.²⁶

Drug

Mepolizumab is a targeted anti-IL-5 IgG1 kappa monoclonal antibody.⁷ Mepolizumab binds to soluble IL-5 with high affinity, preventing IL-5 from binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface, thereby reducing the production and survival of eosinophils. Inflammation is an important component in the pathogenesis of asthma, CRSwNP, and eosinophilic granulomatosis with polyangiitis. The reduction of eosinophilic inflammation may play an important role in eliciting a therapeutic effect in the treatment of the aforementioned conditions; however, the precise mechanism of mepolizumab action has not been definitively established.

On November 5, 2021, mepolizumab received a Notice of Compliance from Health Canada as add-on maintenance treatment with INCS in adult patients with severe CRSwNP inadequately controlled by INCS alone.²⁷ Health Canada recommends that mepolizumab be administered as a subcutaneous injection at a dose of 100 mg/mL once every 4 weeks.

Mepolizumab was approved by the European Medicines Agency in December 2021as add-on maintenance therapy with INCS for the treatment of adult patients with severe CRSwNP for whom therapy with systemic corticosteroid and/or surgery do not provide adequate control;²⁸ this indication is the same as approved by Health Canada and the subject of the current CADTH review. Mepolizumab received approval from the FDA in July 2021 as add-on maintenance treatment for CRSwNP in adult patients 18 years and older who experience inadequate response to nasal corticosteroids.²⁹

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full original patient input(s) received by CADTH have been included in the Stakeholder Input section at the end of this report.

Patient input was provided by 2 groups: Asthma Canada and the Patient Lung Groups of the BCLA. Asthma Canada conducted an online survey of patients with severe CRSwNP and caregivers residing across 7 Canadian provinces between April and May 2022 (n = 17). Two survey respondents reported experience with mepolizumab; patients did not specify how they received access to mepolizumab. The BCLA summarized its collective knowledge and experience gained through research, practice guidelines, and the direct care of patients with asthma and other respiratory diseases.

Survey respondents indicated that CRSwNP symptoms had had a direct negative impact on their daily lives, including decreased quality of life (90%), sleep disturbances (66%), missed time from work or school (30%), financial difficulties (20%), and hospital visits because of CRSwNP (20%). Among the survey respondents who identified as caregivers, 66% reported an impact on sleep (related to sleep loss due to nighttime symptoms) and being burdened by managing frequent appointments (44%) and managing multiple medications (33%) for the patient they care for. Thirty-nine percent of survey respondents reported using nasal sprays to manage their CRSwNP, while 28% reported having surgery, 17% reported using OCS, and 17% reported using a biologic (e.g., dupilumab or omalizumab) to treat their nasal polyps. The side effects most reported by these patients included altered sense of smell (63%), allergic reactions (36%), mental or mood changes (27%), increased risk of sinus infection (27%), headaches or dizziness (18%), and ineffectiveness (18%). Of the 2 survey respondents with experience using mepolizumab, 1 reported improvement in quality of life and no side effects and the other reported improvement in nasal polyps and no exacerbations. From the information collected by the BCLA, reaction at injection site was reported as a common but minor side effect of mepolizumab, while some patients experienced blood eosinophilia after use of mepolizumab.

Patients and caregivers have deemed the following outcomes as important for new treatment options: easier management of symptoms (63%), decreased anxiety about nasal polyps (45%), decreased reliance on OCS or steroids (36%), reduced need for surgery (36%), and improved process for taking medication (27%). Other unmet needs that should be targeted by any new treatment options, as identified by the BCLA, included reduction or cessation of disease progression, improvement in lung function, reduction in lung attacks, and the prevention of subsequent hospitalizations.

Clinician Input

Input From Clinical Expert Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol; assisting in the critical appraisal of clinical evidence; interpreting the clinical relevance of the results; 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 CRSwNP.

Unmet Needs

According to the clinical expert consulted by CADTH, not all patients are responsive to current treatments for the management of CRSwNP. Patients with severe CRSwNP tend to be particularly resistant to treatment. Due to the chronic and recurring nature of CRSwNP, there is a medical need for targeted treatment of nasal polyps.

Place in Therapy

Recurrence of nasal polyps is most likely in the presence of high local levels of IL-5 and IgE, which drive eosinophilic inflammation. The anti-IL-5 mechanism of mepolizumab is anticipated to prevent the inflammation most associated with nasal polyp persistence and recurrence. According to the clinical expert, mepolizumab would be most appropriate for use in patients who do not experience control of symptoms or cannot tolerate topical steroid treatment.

Patient Population

According to the clinical expert consulted, patients with eosinophilic polyps are most likely to respond to anti-IL-5 treatments. Eosinophilic polyps can be identified via pathology at the time of polyp removal. Neutrophilic polyps are less likely to respond to anti-IL-5 treatments. The clinical expert also noted that biologics would be considered unnecessary among patients who respond to topical steroids.

Assessing Response to Treatment

Based on clinical expert input, response to treatment is based on the severity of nasal congestion, usually with SNOT-22. Response to treatment should typically occur within 6 months of initiating therapy. The clinical expert noted that while use of systemic steroids should be reduced during this time, more than 6 months may be needed in resistant patients to document response.

Discontinuing Treatment

According to the clinical expert consulted, the need for prednisolone or surgery would indicate a loss of response to treatment. For those patients who require surgery, continued treatment with mepolizumab may be considered to prevent recurrence.

Prescribing Conditions

According to the clinical expert consulted, ear, nose, and throat specialists or allergists should diagnose, treat, and monitor patients who may receive mepolizumab.

Clinician Group Input

No input was received from any clinician groups for this submission.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical expert consulted by CADTH are summarized in Table 3.

Table 3: Summary of Drug Plan Input and Clinical Expert Response

CRSwNP = chronic rhinosinusitis with nasal polyps; ENT = ear, nose, and throat specialist; IL = interleukin; LTRA = leukotriene receptor antagonist; MID = minimal important difference; NPS = nasal polyp score; SNOT-22 = Sino-Nasal Outcome Test 22; VAS = visual analogue scale.

Clinical Evidence

The clinical evidence included in the review of mepolizumab is presented in only 1 section. The systemic review section includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The other 2 sections that usually accompany the CADTH review are not applicable to the review of mepolizumab as no indirect evidence was identified from the literature, nor were any sponsor-submitted long-term extension studies or additional relevant studies submitted.

Systematic Review: Pivotal and Protocol-Selected Studies

Objectives

To perform a systematic review of the beneficial and harmful effects of mepolizumab 100 mg/mL as add-on maintenance treatment with INCS for the treatment of severe CRSwNP in adult patients inadequately controlled with INCS alone.

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 4. 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 using a peer-reviewed search strategy according to the PRESS (Peer Review of Electronic Search Strategies) checklist.

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were mepolizumab and chronic rhinosinusitis with nasal polyps. 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. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on June 6, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on May 16, 2020.

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

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

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

A focused literature search for indirect treatment comparisons dealing with CRSwNP was run in MEDLINE All (1946–) via Ovid and Embase (1974‒) via Ovid on June 6, 2022. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results.

Findings From the Literature

One study was identified from the literature for inclusion in the systematic review (Figure 1). The included study is summarized in Table 5. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 5: Details of Included Study

ACQ-5 = Asthma Control Questionnaire 5; AE = adverse event; aka = also known as; CRS = chronic rhinosinusitis; CRSwNP = chronic rhinosinusitis with nasal polyps; ECG = electrocardiogram; IM = intramuscular; INCS = intranasal corticosteroids; MCS = mental component summary; MF = mometasone furoate; NP = nasal polyp; OCS = oral corticosteroids; PCS = physical component summary; PD = pharmacodynamic; PK = pharmacokinetic; PnIF = peak nasal inspiratory flow; RCT = randomized controlled trial; SAE = serious adverse event; SF-36 = Short Form (36) Health Survey; SC = subcutaneous; SoC = standard of care; SNOT-22 = Sino-Nasal Outcome Test 22; UPSIT = University of Pennsylvania Smell Identification Test; VAS = visual analogue scale; WPAI = Work Productivity and Activity Impairment.

Note: Two additional reports were included.^27,29

Source: SYNAPSE Clinical Study Report.⁸

Description of Studies

One sponsor-conducted study that met the CADTH review protocol criteria was included in this systematic review. SYNAPSE was a randomized, double-blind, placebo-controlled, parallel group trial assessing the clinical efficacy and safety of 100 mg/mL mepolizumab as an add-on maintenance treatment in adults with recurrent CRSwNP that was not adequately controlled with optimized medical treatment. A total of 414 adult patients were randomized at 86 sites across 11 countries, including 34 (8.2%) patients across 8 sites in Canada. The study comprised a 4-week run-in period to allow assessment for tolerability of INCS at its maximum dose, followed by a 52-week treatment period in which patients were randomized to receive either mepolizumab or matching placebo in addition to standard of care with INCS. During the treatment period, patients who completed the full treatment regimen received a total of 13 doses of mepolizumab 100 mg/mL or placebo delivered by subcutaneous injection using a prefilled safety syringe. The final dose of the study treatment was administered at week 48. Patients who withdrew from the study treatment prematurely were encouraged to remain in the study per protocol until week 52. Patients who completed the week 52 assessment were considered to have completed the study. The first 200 patients randomized into the study also entered a 6-month no-treatment follow-up period following their week 52 visit to assess maintenance of response. The final visit for the no-treatment follow-up period occurred on week 76. All patients remained on standard of care treatment for CRSwNP throughout the study. Standard of care treatment included daily MF and, if required, saline nasal douching and/or an occasional short course of high-dose OCS and/or antibiotics. A schematic of the SYNAPSE trial is presented in Figure 2.

The randomization schedule was generated using the validated randomization software RandAll NG and was stratified by country. Countries were grouped into regions with consideration for standard of care, medical practice, number of patients enrolled, and regulatory considerations. Treatment allocation was done via an interactive response technology, the Registration and Medication Ordering System Next Generation, per the randomization schedule. Treatment assignment was kept blind to all persons (i.e., physician, nurse, and patients) involved in the study. Post-randomization, the site staff and central study team were blinded to patients’ eosinophil count, including white blood count differential. Treatment codes could be unblinded by the investigator or treating physician only in the case of a medical emergency or in the event of a serious medical condition in which knowledge of the investigational product was essential for clinical management or patient welfare.

The co-primary efficacy end points were change from baseline in endoscopic nasal polyp score at week 52 and change from baseline in nasal obstruction VAS symptom score during the 4 weeks before week 52. The key secondary end point was time to first actual surgery for nasal polyps by week 52. Other secondary end points included change from baseline in the overall VAS symptom score, change from baseline in SNOT-22 score, the proportion of patients requiring systemic steroids for nasal polyps, change from baseline composite VAS symptom score (combining VAS scores for nasal obstruction, nasal discharge, mucus in the throat, and loss of smell), and change from baseline in loss of smell VAS score.

Figure 2: Study Schema for the SYNAPSE Trial

SC = subcutaneous.

Source: SYNAPSE Clinical Study Report.⁸

Protocol Amendments

The original study protocol (dated December 8, 2016) was amended 4 times. Protocol amendment 1 (May 15, 2017) was made before the first patient final visit (May 25, 2017) and applied only to study sites in the Republic of Korea to support country-specific requirements. Protocol amendments 2 (July 14, 2017) and 3 (February 20, 2018) were made after the first patient final visit and applied to all sites. Protocol amendment 2 reflected comments from the investigator to clarify protocol points and reflected the removal of CT scan and exit interviews as well as simplifying the end point related to reduction of endoscopic nasal polyp score. Protocol amendment 3 clarified that screen failures could also be re-screened. Protocol amendment 4 (February 13, 2020) was made after the last patient’s last visit (December 11, 2019) but before unblinding and was related to the data analysis. Protocol amendment 4 reflected regulatory authority feedback to update the analysis methodology for the co-primary end points, including imputation rules; limit the definition of surgery for the key secondary end point to include only events involving polypectomy in the nasal cavity; update the OCS end point; and include 2 additional secondary end points of composite nasal symptom score and loss of smell VAS score, which were previously included as “other” end points.

Populations

Inclusion and Exclusion Criteria

The key inclusion and exclusion criteria for the SYNAPSE trial are summarized in Table 5. Patients eligible for inclusion were male and non-pregnant female adults 18 years or older with bilateral nasal polyps and recurrent CRSwNP that was not adequately controlled with optimized medical treatment. Eligible patients were required to have had at least 1 surgery for the removal of nasal polyps within the previous 10 years and treatment with INCS for at least 8 weeks before screening. Patients were also required to show symptoms of CRS. At screening, participants were required to have severe nasal polyp symptoms, defined as an obstruction VAS symptom score of greater than 5 out of a maximum of 10 and severity consistent with need for surgery as described by an overall VAS symptom score greater than 7 out of a maximum of 10, and an endoscopic bilateral nasal polyp score of 5 or greater out of a maximum of 8.

Patients were excluded from the trial if they had antrochoanal polyps, nasal septal deviation occluding 1 nostril, or rhinitis medicamentosa; had undergone any intranasal and/or sinus surgery within the 6 months before visit 1; or had a confounding medical condition. They were also excluded if nasal polyp surgery was contraindicated for them in the opinion of the investigator. Patients with asthma who had an asthma exacerbation requiring admission to hospital within 4 weeks of screening, had used systemic corticosteroid within 4 weeks before screening, or were planning to use such medications during trials were excluded from the trial.

Baseline Characteristics

Baseline characteristics, demographics, and disease history are summarized in Table 6.

Overall, randomized patients had a mean age of 48.8 years (SD = 13.01) and a mean body mass index of 28.16 kg/m² (SD = 5.36). The majority of patients were between 40 and 64 years old (58%), male (65%), and white (93%). The mean time since onset of nasal polyps at baseline was 11.41 years (SD = 8.39). All patients had had at least 1 surgery for nasal polyps in the past 10 years. While the majority of patients had a history of 1 or 2 surgeries (70%), a greater proportion of patients in the placebo group than the mepolizumab group had had more than 1 surgery (60% versus 48%). Approximately half the patients had received at least 1 course of OCS for nasal polyps in the 12 months before screening. At baseline, the overall mean total endoscopic score, nasal obstruction VAS score, overall symptom VAS scores, and SNOT-22 total scores were 5.5 (SD = 1.29), 8.97 (SD = 0.83), 9.07 (SD = 0.74), and 64.1 (SD = 18.32), respectively. All were similar between the treatment groups.

Seventy-one percent of patients had a diagnosis of asthma at screening. Of these, some patients had experienced an asthma exacerbation (20%) or required systemic corticosteroid for an asthma exacerbation that did not require hospitalization or an emergency room visit (16%) in the 12 months before screening.

Table 6: Summary of Baseline Demographic and Disease Characteristics — ITT Population

ITT = intention to treat; OCS = oral corticosteroids; SD = standard deviation; SNOT-22 = Sino-Nasal Outcome Test 22; VAS = visual analogue scale.

^aHigher score indicates greater disease severity.

^bHigher scores indicate worse quality of life.

^cDenominator of percentages is the number of patients with asthma.

Source: SYNAPSE Clinical Study Report.⁸

Interventions

Intervention

Patients were randomized to receive either mepolizumab 100 mg/mL or matching placebo during a 52-week treatment period. Both treatments were administered in combination with standard of care. Mepolizumab and placebo were identical in appearance and provided as solution for injection in a blinded prefilled syringe, assembled as a safety syringe device for subcutaneous administration in the thigh, abdomen, or upper arm every 4 weeks by a health care professional. The last dose of the investigational product was administered at week 48.

Standard of Care

Patients received standard of care treatments for CRSwNP throughout the study (run-in, treatment, and no-treatment follow-up periods). Standard of care medication for CRSwNP was provided by the study site. Standard of care treatment included daily MF and, if required, saline nasal douching and/or occasional short courses of high-dose OCS (prednisolone, prednisone, or methyl-prednisolone for Republic of Korea only) for CRSwNP and/or antibiotics for CRSwNP. Patients with a concurrent asthma diagnosis maintained their baseline standard of care asthma treatment. The use of rescue medications, such as OCS, was allowed at any time during the study.

At the start of the run-in period and throughout the study, patients were placed on MF at the maximum prescribed dose (if not already) according to the local label, if available, or in line with local standard of care. The maximum dose was 2 actuations (50 mcg per actuation) in each nostril twice daily, which equalled a total daily dose of 400 mcg. For patients who were intolerant to this dose, a lower dose of 200 mcg could be used (2 actuations [50 mcg per actuation] in each nostril once daily). Changes in dosing regimen between screening and end of the study were not allowed.

Concomitant Therapy

Concomitant use of LTRAs and allergen immunotherapies was permitted, but their use could not be initiated, nor the dosing regimen changed, between screening and end of the study. Change in the dosing regimens of inhaled corticosteroids from screening to end of the study was also not permitted.

The following medications were not permitted during the study period: investigational monoclonal antibodies, omalizumab, or other monoclonal antibodies; experimental anti-inflammatory drugs; and immunosuppressive medications, including regular systemic corticosteroids, methotrexate, troleandomycin, cyclosporin, azathioprine, oral gold, chemotherapy used for conditions other than asthma; insertion of any non-drug or drug eluting nasal stents (e.g., propel stents), and direct steroid injections into nasal polyps.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trial is provided in Table 7. These end points are further summarized below. Detailed discussion and critical appraisal of the outcome measures are provided in Appendix 4.

Table 7: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

AE = adverse event; HRQoL = health-related quality of life; MCS = mental component summary; PCS = physical component summary; PnIF = peak nasal inspiratory flow; SAE = serious adverse event; SF-36 = Short Form (36) Health Survey; SNOT-22 = Sino-Nasal Outcome Test 22; VAS = visual analogue scale; WPAI = Work Productivity and Activity Impairment.

Source: SYNAPSE Clinical Study Report.⁸

Severity of Nasal Polyps and Nasal Obstruction

Endoscopic nasal polyp score was a co-primary end point in the SYNAPSE trial. Endoscopic nasal polyp score was determined using predefined parameters, as summarized in Table 8 and Figure 3.

Endoscopic nasal polyp assessment was performed on site by a trained health care professional, usually an ear, nose, and throat surgeon. Endoscopies were performed at baseline and then within a 3-day window before dosing for each study visit. The image recordings of the nasal endoscopies were sent to a central lab for blinded assessment. Endoscopies conducted at screening, randomization (baseline), and week 52 were assessed by 2 independent members of the centralized team. For all other visits, the blinded central read was conducted by a single assessor, and whenever possible by the same individual.

The total endoscopic nasal polyp score was the sum of the right and left nostril score. Scores ranged from 0 to 8, with higher scores indicating worse status. Using an anchor-based method, a 1-point or greater improvement (decrease) in total endoscopic nasal polyp score is considered a clinically MID in adult patients with CRSwNP that is medically managed.³¹

Table 8: Description of Nasal Polyp Score

Source: SYNAPSE Clinical Study Report.⁸

Figure 3: Diagrammatic Representation of Nasal Polyp Score

IT = Inferior turbinate; MT = middle turbinate.

Source: SYNAPSE Clinical Study Report.⁸

Nasal Obstruction

Nasal obstruction was a co-primary end point in the SYNAPSE trial. Nasal obstruction was assessed using a VAS. The VAS was presented as an electronic diary (eDiary) and collected daily in the morning from screening to the end of the study period. Each day, patients were asked to indicate on the VAS the severity of their nasal obstruction, with the prompt, “Please rate your nasal obstruction at its worst over the previous 24 hours.” The VAS was presented as a measurement scale from 0 to 100, which was pixelated to allow patients to select all integers within the scales. The scale was anchored on the left-hand side with 0 representing “none” and on the right-hand side with 100 representing “as bad as you can imagine.” The method of data collection employed was demonstrated to be equivalent to the 10 cm VAS typically used for paper data collection.^32-35 Values for the VAS collected on the eDiary were divided by 10 and reported to 1 decimal place across the range 0 (none) to 10 (as bad as you can imagine). Currently, there is no established MID for nasal obstruction VAS score. According to the clinical expert consulted by CADTH, a change of score between 2 and 5 is considered clinically meaningful for VAS scores in the CRSwNP population.

Symptoms

The SYNAPSE trial assessed symptoms related to CRSwNP via VAS score, including the composite nasal symptom score (secondary end point) and the individual symptom of loss of smell.

Each day, patients were asked to indicate on a VAS the severity of their nasal obstruction, nasal discharge, mucus in the throat, loss of smell, and facial pain. Patients were presented with 1 VAS for each of the symptoms. VAS scores for each symptom were collected and scored as described above for nasal obstruction. The nasal symptom composite score combined the individual scores of nasal obstruction, nasal discharge, mucus in the throat, and loss of smell. The nasal symptom and facial pain composite score combined the individual scores of nasal obstructions, nasal discharge, mucus in the throat, loss of smell, and facial pain. Loss of smell alone was also recorded.

Nasal Congestion

Nasal congestion was assessed via PnIF, which was measured using an In-Check flow meter. Patients were instructed to blow their nose and then inspire forcefully from the residual volume to total lung capacity with their mouth closed. All measurements were made in the sitting position. The highest value of 3 consecutive (maximal) readings was recorded. The MID in PnIF is a change of more than 20 L/min.³⁶

Health-Related Quality of Life

HRQoL was assessed using SNOT-22³⁷ and the SF-36, version 2,³⁸ in the SYNAPSE trial.

SNOT-22 was designated as a secondary end point. SNOT-22 is a 22-item self-reported questionnaire used to assess symptoms and impacts related to CRS. The 22 items are categorized into the following 5 domains: nasal, non-nasal, ear and facial, sleep and fatigue, and emotional consequences. Questions are self-completed by patients based on their recall of their symptoms over the past 2 weeks. Patients are asked, “Considering how severe the problem is when you experience it and how often it happens, please rate each item below on how ‘bad’ it is.” The response to each question ranges from 0 (no problem) to 5 (the problem is as bad as it can be). The final score is the sum of the individual scores from each question and ranges from 0 to 110. Higher scores indicate a greater negative impact of CRS on HRQoL. The MID for SNOT-22 is an improvement (decrease) in score of at least 8.9.³⁷

The SF-36, version 2, is a generic self-reported health assessment questionnaire that has been used in clinical trials to study the impact of chronic disease on HRQoL. The SF-36 consists of 8 domains: physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional health problems, and mental health. The SF-36 also provides 2 component summaries: the PCS and the MCS, which are scores created by aggregating the 8 domains.³⁹ The PCS, MCS, and individual domains are each measured on a scale of 0 to 100, with an increasing score indicating improvement in health status.³⁹ Currently, there is no established MID for the CRSwNP population.

Response to Treatment

Response to treatment was designated as an exploratory end point in the SYNAPSE trial and assessed using the endoscopic nasal polyp score and SNOT-22. Both outcome measures have been described above. Response to treatment as assessed by each of the instruments was matched to the appropriate MID.^31,37 A response to treatment as indicated by change in endoscopic nasal polyp score was defined as a 1-point or greater decrease in total baseline endoscopic nasal polyp score based on centrally read data at a given time point in the absence of surgery or sinuplasty.³¹ Response to treatment as indicated by SNOT-22 was defined as an 8.9-point or greater decrease from baseline at week 52.³⁷

Nasal Polyp Surgery

Time to nasal polyp surgery was a key secondary outcome in the SYNAPSE trial. Nasal polyp surgery was defined as any procedure involving instruments resulting in incision and removal of tissue (polypectomy) in the nasal cavity. Dilation of the air passage in the nasal cavity (e.g., balloon sinuplasty) was not considered a surgical event.

Work Productivity

Work productivity was designated as an exploratory end point in the SYNAPSE trial and measured using the WPAI-GH. The WPAI-GH is a self-administered 6-item questionnaire with a 7-day recall period that measures the impact of health problems on absenteeism (percentage of work time missed), presenteeism (percentage of impairment while working), percentage of overall work impairment due to health (combined absenteeism and presenteeism), and percentage of daily activity impairment. Patients completed the WPAI-GH using the eDiary at randomization and at each subsequent visit until study completion or early withdrawal. WPAI-GH outcomes are scored as impairment percentages (0% to 100%), with higher percentages indicating greater impairment of work productivity and daily activity.

Statistical Analysis

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

Sample Size Determination

Sample size calculations were based on the co-primary efficacy end points of total endoscopic nasal polyp score and nasal obstruction VAS score at week 52 and on the key secondary end point of time to actual surgery. A sample size of 200 patents per treatment arm was estimated to provide the study more than 90% power to observe statistical significance at a 2-sided 5% level for both the co-primary end points and for the key secondary end point of time to actual surgery. Calculations were based on the analysis of study MPP111782,⁴⁰ which demonstrated the following:

• 27% of patients in the placebo group experienced a 1-point improvement in nasal polyp score compared to 52% of patients in the mepolizumab group.

• For nasal blockage, 39% of patients in the placebo group experienced a 1-point improvement in nasal polyp score compared to 70% of patients in the mepolizumab group.

• For surgery, 20% of patients in the placebo group and 9% of patients in the mepolizumab group received surgery; a greater proportion of patients receiving surgery was expected in SYNAPSE.

Primary Efficacy Analysis

For each of the co-primary efficacy end points, the P value for comparing the treatment groups was based on the non-parametric Wilcoxon rank sum test. The difference in median change from baseline with a 95% CI was estimated by quantile regression using the bootstrap approach.^41,42 Covariates included in the statistical analysis models of the co-primary efficacy end points included randomized treatment group, region, baseline total nasal polyp score, and baseline log_e blood eosinophil count.

Key Secondary Efficacy Analysis

Time to first nasal surgery was analyzed by a Cox proportional hazard model. Hazard represented the probability of nasal surgery for a patient at a given point in time following the first dose of the investigational product, given the patient had not experienced the event before that time. Nasal surgery times were included in the analysis regardless of whether the surgery occurred before or after discontinuation of the investigational product. The nasal surgery time event was censored at the time of study withdrawal if a patient withdrew from the study before week 52 and before experiencing nasal surgery. Covariates included in the statistical analysis model of time to first nasal surgery were randomized treatment group, region, baseline total endoscopic nasal polyp score, baseline nasal obstruction VAS, baseline log_e blood eosinophil count, and number of previous surgeries (1, 2, > 2 as an ordinal variable).

Secondary Efficacy Analysis

Analysis for change from baseline VAS symptom scores, including overall VAS symptom score, mean composite VAS score, mean loss of smell, and SNOT-22 total score, was based on the non-parametric Wilcoxon rank sum test. The difference in median change from baseline with 95% CI was estimated by quantile regression using a bootstrap approach with adjusted covariates as detailed for the co-primary end point of change from baseline in mean nasal obstruction VAS score.

A logistic regression model was used to compare the proportion of patients requiring systemic steroids for nasal polyps. The odds ratio comparing treatment groups was estimated using the observed marginal distribution of the sample covariates. Covariates included randomized treatment group, region, baseline total nasal polyp score, baseline nasal obstruction VAS, baseline log_e blood eosinophil count, and number of OCS courses for nasal polyps in the previous 12 months (0, 1, > 1 as an ordinal variable).

Multiple Comparison and Multiplicity

Statistical significance for the first secondary end point in the hierarchy was dependent on statistical significance having been achieved for the 2 co-primary end points. Statistical significance for all other subsequent secondary end points was dependent on statistical significance having been achieved for the previous end point in the hierarchy. A closed testing procedure was used to control multiplicity according to the following predefined hierarchy:

1. Time to first nasal surgery

2. Change from baseline in overall VAS symptom score

3. Change from baseline SNOT-22 total score

4. Proportion of patients requiring systemic steroids for nasal polyps

5. Change from baseline in the mean composite VAS symptom score (nasal obstruction, nasal discharge, mucus in the throat, and loss of smell)

6. Change from baseline in mean individual VAS symptom score for loss of smell

Subgroup Analysis

For each co-primary end point, exploratory subgroup analyses were performed within the following subgroups: concurrent asthma and number of previous surgeries for nasal polyps. No formal hypothesis testing in the subgroups was performed.

Analysis Populations

Seven populations were defined for the purpose of data analysis. Definitions of the populations are summarized in Table 10.

Table 9: Statistical Analysis of Efficacy End Points

CI = confidence interval; MCS = mental component summary; MI = myocardial infarction; NP = nasal polyp; NR = not reported; PCS = physical component summary; PnIF = peak nasal inspiratory flow; SF-36 = Short Form (36) Health Survey; SNOT-22 = Sino-Nasal Outcome Test 22; VAS = visual analogue scale; WPAI = Work Productivity and Activity Impairment.

Table 10: Summary of Analysis Populations

ITT = intention to treat; PP = per protocol; SAP = statistical analysis plan.

Results

Patient Disposition

Patient disposition is summarized in Table 11.

Of the 854 patients who signed an informed consent form, 30 did not attend the screening visit (pre-screen failures) and 432 were withdrawn before randomization because they did not meet the entry criteria (27%) or did not meet the continuation criteria at the end of the run-in period (21%). Of the 414 patients randomized, 7 were randomized in error and did not receive any study treatment. Accordingly, 407 patients were included in the intention-to-treat (ITT) population, with 201 patients randomized to receive placebo and 206 randomized to receive mepolizumab. Patients were encouraged to remain in the study even if they discontinued the study treatment protocol; 92% completed the study to week 52 as scheduled. Withdrawal from the study treatment before week 52 was greater in the placebo group (16.9%) than in the mepolizumab group (11.2%). More patients in the mepolizumab group self-withdrew from the study treatment (52.2% versus 44.1%), and more patients in the placebo group discontinued treatment due to lack of efficacy (32.3% versus 21.7%).

Table 11: Patient Disposition

IP = investigational product; ITT = intention to treat; PP = per protocol.

^aProtocol-specific withdrawal included patient meeting GlaxoSmithKline-defined liver chemistry stopping criteria, pregnancy, and meeting QT corrected for heart rate withdrawal criteria.

^bWithdrawal by patient included the following reasons: relocation, frequency of visits, burden of procedures, and withdrawal due to serious adverse event (placebo).

^cExcludes randomized patients who did not receive any dose of the IP.

Source: SYNAPSE Clinical Study Report.⁸

Protocol Deviations

Protocol deviations are summarized in Table 12.

Major protocol deviations were documented for 65% and 55% of patients in the placebo and mepolizumab groups, respectively. The most frequently reported protocol deviations were related to assessment or time point completion and were mainly attributable to missing clinical chemistry, hematology, and/or urinalysis due to spoiled samples. Other frequently reported categories of protocol deviations were visit completion (17%); study procedures (14%); and wrong study, treatment, administration, or dose (9%).

After unblinding it was found that 4 patients (< 5%) had received a single dose of treatment that did not correspond to their randomization treatment: Two patients in the mepolizumab group received a single dose of placebo each; 2 patients in the placebo group received a single dose of mepolizumab each.

Table 12: Protocol Deviations

SAE = serious adverse event.

Note: Patients can have more than 1 important protocol deviation.

Source: SYNAPSE Clinical Study Report.⁸

Exposure to Study Treatments

Extent of Exposure

Mean exposure to study treatment was 11.2 months (SD = 2.33 months) and 11.3 months (SD = 2.21 months) in the placebo and mepolizumab treatment groups, respectively. A total of 134 patients continued in the follow-up after week 52;, the overall mean duration of time in the follow-up period was 5.40 months (SD = 0.55 months). The mean duration of time spent in the no-treatment follow-up period was similar between placebo and mepolizumab groups at 5.42 months (SD = 0.45 months) and 5.37 months (SD = 0.63 months), respectively.

Treatment Adherence

A total of 160 patients (80%) in the placebo group and 180 patients (87%) in the mepolizumab group received all 13 treatment administrations. The mean number of treatments administered between the groups was similar (placebo: 12.0 [SD = 2.53]; mepolizumab: 12.2 [SD = 2.4]). The median number of treatments administered was 13 in both groups.

Prior Medications

The medications used before beginning treatment with the investigational product are summarized in Table 13.

Overall, 98% of patients were receiving medications before the start of the study treatment. The most common medications were in the Anatomical Therapeutic Chemical classes of “respiratory system” (98%) and “dermatological” (88%). Across those classes, the proportion of patients receiving medications was similar between treatment groups.

Sixty-one patients (15%) and 6 patients (1%) were documented using LTRA or allergen immunotherapy, respectively. Leukotriene receptor antagonists were initiated before the first dose of the investigational product in 17% and 12% of patients in the placebo and mepolizumab groups, respectively. Allergen immunotherapy was initiated before the first dose of the investigational product in 2% and 0.97% of patients in the placebo and mepolizumab groups, respectively.

Table 13: Medications Started Prior to Treatment — ITT Population

ATC = Anatomical Therapeutic Chemical; ITT = intention to treat; LTRA = leukotriene receptor antagonist.

Note: Includes medications started before the first dose of investigational product. A medication may be included in more than 1 ATC category and appear more than once.

^aMedication is reported in individual ATC class if used by more than 10% in either the placebo or mepolizumab group.

Source: SYNAPSE Clinical Study Report.⁸

Concomitant Medications

Concomitant medications started during the treatment period are summarized in Table 14.

Overall, 87% of patients in the placebo group and 82% of patients in the mepolizumab group started medication during the treatment period. The 2 most common concomitant medications started during the treatment period related to the respiratory system (placebo: 66%; mepolizumab: 56%) and alimentary tract and metabolism (placebo: 56%; mepolizumab: 52%).

A greater proportion of patients in the placebo group than in the mepolizumab group started systemic corticosteroid for any reason during the treatment period (46% compared with 34%).

Six patients were on LTRA treatment during the study period. Leukotriene receptor antagonist was initiated in 4 patients (2%) in the placebo group and 2 patients (1%) in the mepolizumab group. While concomitant use of allergen immunotherapies was permitted in the SYNAPSE trial, their use could not be initiated, or their dosing regimen changed, between screening and the end of the study period. Thus, no patients were started on allergen immunotherapy during the study period.

Concomitant treatment with rescue or reliever inhaler with short-acting beta2-agonist during the study treatment period was documented in 20 patients, with a greater proportion of patients in the placebo group reporting its use (placebo: 9%; mepolizumab: 1%).

Table 14: Concomitant Medications Started During the Treatment Period — ITT Population

ATC = Anatomical Therapeutic Chemical; ITT = intention to treat; LTRA = leukotriene receptor antagonist.

Note: Includes medications started between first and last dose plus 28 days (inclusive) of investigational product. A medication may be included in more than 1 ATC category and appear more than once.

^aMedications are reported in individual ATC class if used by more than 10% in either the placebo or mepolizumab group.

Source: SYNAPSE Clinical Study Report.⁸

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported below. Refer to Appendix 3 for detailed data on exploratory symptom end points.

Severity of Nasal Polyps

The co-primary end point of total endoscopic nasal polyp score is summarized in Table 15.

At the end of the 52-week treatment period, the mean change in total endoscopic nasal polyp score from baseline was –0.1 (SD = 1.46) and –0.9 (SD = 1.90) in the placebo and mepolizumab groups, respectively. The median change from baseline in the placebo and mepolizumab groups was 0 (IQR, –1.0 to 1.0) and –1.0 (IQR, –2.0 to 0.0), respectively. The adjusted median difference in change from baseline to week 52 was statistically significant in favour of mepolizumab compared to placebo (–0.73; 95% CI, –1.11 to –0.34; P < 0.001).

Table 15: Total Endoscopic Nasal Polyp Score — ITT Population

CI = confidence interval; IQR = interquartile range; ITT = intention to treat; SD = standard deviation.

Note: Patients with nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before nasal surgery or sinuplasty. Patients with no nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before study withdrawal. Patients with missing visit data were assigned their worst observed score before the missing visit.

^aQuantile regression with covariates of treatment group, geographic region, baseline score, and log(e) baseline blood eosinophil count.

^bBased on Wilcoxon rank sum test.

Source: SYNAPSE Clinical Study Report.⁸

Responder Analysis

Response to treatment according to the total endoscopic nasal polyp score is summarized in Table 16. Response to treatment was defined as a patient who had an improvement (decrease) of 1.0 point or more from baseline in the absence of surgery or sinuplasty.

Twenty-eight percent and 50% of patients in the placebo and mepolizumab groups demonstrated a 1-point or greater improvement in their total endoscopic nasal polyp score at the end of the 52-week treatment period. The odds ratio of being a responder in the mepolizumab group compared to in the placebo group was 2.74 (95% CI, 1.80 to 4.18).

Subgroup Analysis

Results of the subgroup analyses in patients with or without concurrent asthma and in patients with or without prior surgery for nasal polyps in terms of change from baseline in total endoscopic nasal polyp score at week 52 are summarized in Table 17. No formal hypothesis testing was done; therefore, whether the effect of mepolizumab differs between these subgroups is unknown.

Table 16: Response to Treatment Based on Total Endoscopic Nasal Polyp Score at Week 52 — ITT Population

CI = confidence interval; ITT = intention to treat.

Note: Patients with nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before nasal surgery or sinuplasty. Patients with no nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before study withdrawal. Patients with missing visit data were assigned their worst observed score before the missing visit.

^aDefined as a patient with a 1-point or greater improvement from baseline in endoscopic nasal polyp score and the absence of surgery or sinuplasty before that visit.

^bAnalysis performed using a logistic regression model with covariates of treatment group, geographic region, baseline score, and log(e) baseline blood eosinophil count.

Source: SYNAPSE Clinical Study Report.⁸

Table 17: Subgroup Analysis of Change From Baseline in Total Endoscopic Nasal Polyp Score at Week 52 — ITT Population

CI = confidence interval; ITT = intention to treat.

Note: Patients with nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before nasal surgery or sinuplasty. Patients with no nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before study withdrawal. Patients with missing visit data were assigned their worst observed score before the missing visit.

^aDefined as a patient with a 1-point or greater improvement from baseline and the absence of surgery or sinuplasty before that visit.

^bQuantile regression with covariates of treatment group, region (except in the analysis by region), baseline score, and log(e) baseline blood eosinophil count (except in the analysis by baseline blood eosinophil count).

Source: SYNAPSE Clinical Study Report.⁸

No-Treatment Follow-Up Period

At the end of the no-treatment follow-up period at week 76, the median and mean change from baseline in the total endoscopic nasal polyp score for patients in the placebo group were 0.0 (IQR, –1.0 to 1.0) and –0.1 (SD = 1.59), respectively. For patients in the mepolizumab group, the median and mean change from baseline were –1.0 (IQR, –2.0 to 0.0) and –1.2 (SD = 1.80), respectively.

Nasal Obstruction

The co-primary end point of nasal obstruction VAS score is summarized in Table 18.

In the 4-week period from week 49 to week 52, the mean change in nasal obstruction VAS score from baseline was –2.45 (SD = 3.15) and –4.24 (SD = 3.42) in the placebo and mepolizumab groups, respectively. The median change from baseline in the placebo and mepolizumab groups was –0.82 (IQR, –4.84 to 0.0) and –4.41 (IQR, –7.27 to –0.36), respectively. The adjusted median difference in change from baseline to week 52 was statistically significant in favour of mepolizumab compared to placebo (–3.14; 95% CI, –4.09 to –2.18; P < 0.001).

Twenty-three percent and 44% of patients in the placebo and mepolizumab groups, respectively, demonstrated a greater than 5-point improvement in their nasal obstruction VAS score.

Table 18: Nasal Obstruction VAS Score — ITT Population

CI = confidence interval; IQR = interquartile range; ITT = intention to treat; SD = standard deviation; VAS = visual analogue scale.

Note: Patients with nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before nasal surgery or sinuplasty. Patients with no nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before study withdrawal. Patients with missing visit data were assigned their worst observed score before the missing visit.

^aQuantile regression with covariates of treatment group, geographic region, baseline score, and log(e) baseline blood eosinophil count.

^bBased on Wilcoxon rank sum test.

Source: SYNAPSE Clinical Study Report.⁸

Subgroup Analysis

Subgroup analyses in patients with or without asthma and with or without previous surgery were carried out on the median difference in change from baseline in nasal obstruction VAS score at week 49 to week 52; this is summarized in Table 19. No formal hypothesis testing was conducted; therefore, whether the effect of mepolizumab differs between these subgroups is unknown.

Table 19: Subgroup Analysis of Change From Baseline Nasal Obstruction VAS Score at Weeks 49 to 52 — ITT Population

CI = confidence interval; ITT = intention to treat; VAS = visual analogue scale.

^aQuantile regression with covariates of treatment group, region (except in the analysis by region), baseline score, and log(e) baseline blood eosinophil count (except in the analysis by baseline blood eosinophil count).

Source: SYNAPSE Clinical Study Report.⁸

No-Treatment Follow-Up Period

At the end of the no-treatment follow-up period, at weeks 73 to 76, the median change from baseline in the nasal obstruction VAS score for patients in the mepolizumab group was –3.89 (IQR, –6.76 to –0.72). For patients in the placebo group, the median change from baseline was –0.80 (IQR, –5.25 to 0.00).

Symptoms

Nasal Symptom Composite VAS Score

The secondary end point of nasal symptom composite VAS score is summarized in Table 20.

In the 4-week period from week 49 to week 52, the mean change in nasal symptom composite VAS score from baseline was –2.19 (SD = 2.82) and –3.81 (SD = 3.19) in the placebo and mepolizumab groups, respectively. The median change from baseline in the placebo and mepolizumab groups was –0.89 (IQR, –4.06 to 0.0) and –3.96 (IQR, –6.68 to –0.32), respectively. The adjusted median difference in change from baseline to week 52 was statistically significant in favour of mepolizumab compared to placebo (–2.68; 95% CI, –3.44 to –1.91; P = 0.020).

Twenty percent and 37% of patients in the placebo and mepolizumab groups, respectively, demonstrated a greater than 5-point improvement in their nasal symptom composite VAS score.

Table 20: Nasal Symptoms Composite VAS Score, Weeks 49 to 52 — ITT Population

CI = confidence interval; IQR = interquartile range; ITT = intention to treat; SD = standard deviation; VAS = visual analogue scale.

Note: Patients with nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before nasal surgery or sinuplasty. Patients with no nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before study withdrawal. Patients with missing visit data were assigned their worst observed score before the missing visit.

^aNasal symptom composite VAS score is composed of the individual VAS scores of nasal obstruction, nasal discharge, mucus in the throat, and loss of smell.

^bQuantile regression with covariates of treatment group, geographic region, baseline score, and log(e) baseline blood eosinophil count.

^cBased on Wilcoxon rank sum test.

^dMultiplicity controlled through testing end points following a predefined hierarchy.

Source: SYNAPSE Clinical Study Report.⁸

Nasal Symptom and Facial Pain Composite VAS Score

The other end point of nasal symptom and facial pain composite VAS score is summarized in Table 21.

In the 4-week period from week 49 to week 52, the mean change in nasal symptom and facial pain composite VAS score from baseline was –2.24 (SD = 2.88) and –3.80 (SD = 3.18) in the placebo and mepolizumab groups, respectively. The median change from baseline in the placebo and mepolizumab groups was –0.99 (IQR, –4.29 to 0.0) and –3.88 (IQR, –6.45 to –0.25), respectively. The adjusted median difference in change from baseline to week 52 favoured the mepolizumab group compared to the placebo group (–2.50; 95% CI, –3.33 to –1.67).

Twenty-one percent and 38% of patients in the placebo and mepolizumab groups, respectively, demonstrated a greater than 5-point improvement in their nasal symptom and facial pain composite VAS score.

Table 21: Nasal Symptom and Facial Pain Composite VAS Score, Weeks 49 to 52 — ITT Population

CI = confidence interval; IQR = interquartile range; ITT = intention to treat; SD = standard deviation; VAS = visual analogue scale.

Note: Patients with nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before nasal surgery or sinuplasty. Patients with no nasal surgery/sinuplasty who withdrew from study before visit were assigned their worst observed score before study withdrawal. Patients with missing visit data were assigned their worst observed score before the missing visit.

^aNasal symptom and facial pain composite VAS score is composed of the individual VAS scores of nasal obstruction, nasal discharge, mucus in the throat, loss of smell, and facial pain.

^bQuantile regression with covariates of treatment group, geographic region, baseline score, and log(e) baseline blood eosinophil count.

^cBased on Wilcoxon rank sum test.

Source: SYNAPSE Clinical Study Report.⁸

Loss of Smell

The secondary end point of loss of smell VAS score is summarized in Table 22.

In the 4-week period from week 49 to week 52, the mean change in loss of smell VAS score from baseline was –1.38 (SD = 2.65) and –2.83 (SD = 3.61) in the placebo and mepolizumab groups, respectively. The median change from baseline in the placebo and mepolizumab groups was 0 (IQR, –1.28 to 0.0) and –0.53 (IQR, –5.60 to 0.0), respectively. The adjusted median difference in change from baseline to week 52 was statistically significant in favour of mepolizumab compared to placebo (–0.37; 95% CI, –0.65 to –0.08; P = 0.020).

Thirteen percent and 30% of patients in the placebo and mepolizumab groups, respectively, demonstrated a 5-point or greater improvement in their loss of smell VAS score.

No-Treatment Follow-Up Period

At the end of the no-treatment follow-up period, at week 76, the median change from baseline in the loss of smell VAS score was 0.0 (IQR, –3.56 to 0.0) for patients in the placebo group and –1.22 (IQR, –5.89 to 0.0) for patients in the mepolizumab group.

Table 22: Loss of Smell VAS Score, Weeks 49 to 52 — ITT Population

CI = confidence interval; IQR = interquartile range; ITT = intention to treat; SD = standard deviation; VAS = visual analogue scale.

Note: Patients with nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before nasal surgery or sinuplasty. Patients with no nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before study withdrawal. Patients with missing visit data were assigned their worst observed score before the missing visit.

^aQuantile regression with covariates of treatment group, geographic region, baseline score, and log(e) baseline blood eosinophil count.

^bBased on Wilcoxon rank sum test.

^cMultiplicity controlled through testing end points following a predefined hierarchy.

Source: SYNAPSE Clinical Study Report.⁸

Nasal Congestion

The exploratory outcome of nasal congestion as assessed by PnIF is presented in Table 23.

At week 52, the mean change from baseline in PnIF was greater in the mepolizumab group than in the placebo group (32.5 [SD = 57.98] and 11.2 [SD = 65.78], respectively). Similarly, the median change from baseline to week 52 in PnIF was greater in the mepolizumab group than in the placebo group (30.0 [IQR, 0.0 to 60.0] and 0.0 [IQR, –20.0 to 50.0], respectively).

Table 23: Peak Nasal Inspiratory Flow at Week 52 — ITT Population

IQR = interquartile range; ITT = intention to treat; SD = standard deviation.

Note: Patients with nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before nasal surgery or sinuplasty. Patients with no nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before study withdrawal. Patients with missing visit data were assigned their worst observed score before the missing visit.

^aMethod used to calculate the mean and median change from baseline to week 52 as well as the difference in change from baseline between placebo and mepolizumab groups was not available in the Clinical Study Report of SYNAPSE.

Source: SYNAPSE Clinical Study Report.⁸

Health-Related Quality of Life

Sino-Nasal Outcome Test 22The secondary end point of SNOT-22 is summarized in Table 24 and Figure 4.

At the end of the 52-week treatment period, the mean change in total SNOT-22 score from baseline was –15.7 (SD = 23.93) and –29.4 (SD = 24.67) in the placebo and mepolizumab groups, respectively. The median change from baseline in the placebo and mepolizumab groups was –14.0 (IQR, –31.0 to 0.0) and –30.0 (IQR, –46.0 to –4.0), respectively. The adjusted median difference in change from baseline to week 52 was statistically significant in favour of mepolizumab compared to placebo (–16.49; 95% CI, –23.57 to –9.42; P = 0.003).

Table 24: SNOT-22 Total Score at Week 52 — ITT Population

CI = confidence interval; IQR = interquartile range; ITT = intention to treat; SD = standard deviation; SNOT-22 = Sino-Nasal Outcome Test 22.

Note: Patients with nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before nasal surgery or sinuplasty. Patients with no nasal surgery or sinuplasty who withdrew from study before visit were assigned their worst observed score before study withdrawal. Patients with missing visit data were assigned their worst observed score before the missing visit.

^aQuantile regression with covariates of treatment group, geographic region, baseline score, and log(e) baseline blood eosinophil count.

^bBased on Wilcoxon rank sum test.

^cMultiplicity controlled through testing end points following a predefined hierarchy.

Source: SYNAPSE Clinical Study Report.⁸

Figure 4: Median Change From SNOT-22 Total Score by Visit — ITT Population

CI = confidence interval; ITT = intention to treat; SC = subcutaneous; SNOT-22 = Sino-Nasal Outcome Test 22.

Source: SYNAPSE Clinical Study Report.⁸

Responder Analysis

Response to treatment as measured by the SNOT-22 total score was defined as improvement (decrease) of 8.9 points or more from baseline at a given point of time, and is summarized in Table 25.

Fifty-four percent and 73% of patients in the placebo and mepolizumab groups, respectively, demonstrated an 8.9-point or greater improvement in their total SNOT-22 score at the end of the 52-week treatment period. The odds ratio of being a responder in the mepolizumab group compared to in the placebo group was 2.44 (95% CI, 1.60 to 3.73).

Table 25: Response to Treatment Based on SNOT-22 at Week 52 — ITT Population

CI = confidence interval; ITT = intention to treat; SNOT-22 = Sino-Nasal Outcome Test 22.

^aDefined as a patient with an 8.9-point or greater improvement (decrease) from baseline at a given time point and the absence of surgery or sinuplasty before that visit.

^bAnalysis performed using a logistic regression model with covariates of treatment group, geographic region, baseline score, and log(e) baseline blood eosinophil count.

Source: SYNAPSE Clinical Study Report.⁸

No-Treatment Follow-Up Period

At the end of the no-treatment follow-up period at week 76, the median and mean change from baseline in the SNOT-22 total score for patients in the placebo group were –10.0 (IQR, –32.0 to 0.0) and –16.7 (SD = 25.80), respectively. For patients in the mepolizumab group, the median and mean change from baseline were –26.5 (IQR, –46.0 to 11.5) and –28.5 (SD = 26.76), respectively.

Short Form (36) Health Survey

The exploratory end point of SF-36 is summarized in Table 26.

At the end of the 52-week treatment period, the median change from baseline for the PCS and MCS was 0.0 (IQR, –1.75 to 4.61) and 0.0 (IQR, –3.75 to 5.76), respectively, for the placebo group. For the mepolizumab group, the median change from baseline for the PCS and MCS was 6.75 (IQR, 0.0 to 12.59) and 1.20 (IQR, –2.60 to 10.08), respectively.

Table 26: Short Form (36) Health Survey at Week 52 — ITT Population

IQR = interquartile range; ITT = intention to treat; SD = standard deviation.

Note: Lower scores indicate worse quality of life.

^aDifferences in change from baseline to week 52 in the Short Form (36) Health Survey between placebo and mepolizumab groups were not available in the Clinical Study Report of SYNAPSE.

Source: SYNAPSE Clinical Study Report.⁸

Systemic Steroid Use for Nasal Polyps

The secondary end point of systemic steroid use for nasal polyps is presented in Table 27.

Over the 52-week treatment period, 37% and 25% of patients in the placebo and mepolizumab groups, respectively, required at least 1 course of systemic steroid treatment for nasal polyps.

The probability of systemic steroid use for nasal polyps was lower in the mepolizumab group than in the placebo group throughout the 52-week treatment period (Figure 5). By week 52, the probability of requiring an initial course of systemic steroids for nasal polyps was 37.5% (95% CI, 31.1% to 44.6%) in the placebo group and 25.4% (95% CI, 20.0% to 32.1%) in the mepolizumab group.

Table 27: Systemic Steroid Use for Nasal Polyps up to Week 52 — ITT Population

CI = confidence interval; ITT = intention to treat.

Note: Difference in the number of patients requiring systemic steroids for nasal polyps up to week 52 between placebo and mepolizumab groups was not available in the Clinical Study Report of SYNAPSE.

^aAnalysis using logistic regression model with covariates of treatment group, geographic region, number of oral corticosteroid courses for nasal polyps in last 12 months (0, 1, > 1 as ordinal), baseline total endoscopic score (centrally read), baseline nasal obstruction visual analogue scale score, and log(e) baseline blood eosinophil count.

^bMultiplicity controlled through testing end points following a predefined hierarchy.

Source: SYNAPSE Clinical Study Report.⁸

Figure 5: Kaplan-Meier Time to First Course of Systemic Steroids for Nasal Polyps — ITT Population

ITT = intention to treat; SC = subcutaneous.

Source: SYNAPSE Clinical Study Report.⁸

No-Treatment Follow-Up Period

At the end of the no-treatment follow-up period, at week 76, at least 1 course of systemic steroids for nasal polyps was required by 51% and 32% of patients in the placebo and mepolizumab groups, respectively.

Nasal Inflammation

Nasal inflammation was not assessed in the SYNAPSE trial.

Nasal Polyp Surgery

The key secondary end point of time to first nasal polyp surgery is summarized in Table 28.

By week 52, 23% and 9% of patients in the placebo and mepolizumab groups, respectively, had overgone nasal surgery.

The estimated risk of having surgery before week 52 was 23.6% (95% CI, 18.3% to 30.0%) in the placebo group and 9.2% (95% CI, 5.9% to 14.2%) in the mepolizumab group.

The probability of undergoing nasal surgery at any time before week 52 was statistically significantly lower in the mepolizumab group than in the placebo group (hazard ratio = 0.43; 95% CI, 0.25 to 0.76; P = 0.003).

No-Treatment Follow-Up Period

Sixty-five patients in the placebo group and 69 patients in the mepolizumab group entered the no-treatment follow-up period. By week 76, 31% and 9% of patients in the placebo and mepolizumab groups, respectively, had undergone nasal polyp surgery. The probability of nasal surgery was 30.8% (95% CI, 21.1% to 43.6%) in the placebo group and 8.7% (95% CI, 4.0% to 18.4%) in the mepolizumab group.

The probably of having nasal surgery before week 24 was 9.1% (95% CI, 5.8% to 14.0%) in the placebo group and 4.0% (95 CI, 2.0% to 7.8%) in the mepolizumab group.

Table 28: Time to First Nasal Polyp Surgery up to Week 52 — ITT Population

CI = confidence interval; ITT = intention to treat.

^aKaplan-Meier estimate.

^bEstimated from a Cox proportional hazard model with covariates of treatment group, geographic region, baseline total endoscopic score (centrally read), baseline nasal obstruction VAS score, log(e) baseline blood eosinophil count, and number of previous surgeries (1, 2, > 2 as ordinal).

^cMultiplicity controlled through testing end points following a predefined hierarchy.

Source: SYNAPSE Clinical Study Report.⁸

Figure 6: Kaplan-Meier Time to First Nasal Surgery up to Week 52 — ITT Population

ITT = intention to treat; SC = subcutaneous.

Source: SYNAPSE Clinical Study Report.⁸

Work Productivity

At week 52, improvements were observed across all WPAI-GH domains, except work time missed due to health (Table 29). At week 52, impairment while working due to health was reported by 22.9% and 18.5% of patients in the placebo group and mepolizumab group, respectively. Overall work impairment due to health was reported by 27.0% and 20.6% of patients in the placebo and mepolizumab groups, respectively. Activity impairment due to health was reported by 27.1% and 19.2% of patients in the placebo and mepolizumab groups, respectively. Finally, 6.4% and 4.3% of patients reported work time missed due to health in the placebo and mepolizumab groups, respectively.

Harms

Only those harms identified in the review protocol are reported below. Refer to Table 30 for detailed harms data.

Adverse Events

At least 1 AE was reported by 84% and 82% of patients in the placebo and mepolizumab groups, respectively. The 3 most common AEs reported were nasopharyngitis (placebo: 23%; mepolizumab: 25%), headache (placebo: 22%; mepolizumab: 18%), and sinusitis (placebo: 11%; mepolizumab: 5%). The following AEs were reported in less than 10% but greater than 5% of patients in either treatment group: epistaxis, asthma, nasal polyps, back pain, upper respiratory tract infection, acute sinusitis, cough, bronchitis, oropharyngeal pain, otitis media, and arthralgia.

Serious AEs

Serious AEs were reported in 7% and 6% of patients in the placebo and mepolizumab groups, respectively. No single serious AE was reported in more than 1% of patients in either treatment group.

Withdrawals due to AEs

Two percent of patients in each group discontinued treatment due to any AE. The AEs contributing to withdrawal from treatment were not specified.

Mortality

Death occurred in 1 patient in the placebo group. The 1 death was related to a fatal myocardial infarction during the follow-up period after week 52.

Notable Harms

Potential opportunistic infections were reported by 3.48% and 1.46% of patients in the placebo and mepolizumab groups, respectively. Opportunistic infections reported by patients in the placebo group included herpes zoster, oral herpes, candida infection, and oropharyngeal candidiasis. In the mepolizumab group, herpes zoster, oral herpes, and candida infections were reported. Serious infections were reported by 2% and 0.49% of patients in the placebo and mepolizumab groups, respectively. Serious infections reported included acute sinusitis, cellulitis, and influenza in the placebo group and pneumonia in the mepolizumab group.

Local injection site reactions were reported by 1.0% patients in the placebo group and 2.43% of patients in the mepolizumab group. Systemic site reactions were reported in 0.50% and 0.97% of patients in the placebo and mepolizumab groups, respectively. There were no events meeting the criteria for an anaphylaxis event.

In the placebo group 0%, 1.0%, and 0.50% of patients reported, respectively, serious cardiac disorders; serious cardiac, vascular, and thromboembolic events; and serious ischemic events. In the mepolizumab group, serious cardiac disorders; serious cardiac, vascular, and thromboembolic events; and serious ischemic events were reported by 1 patient each.

Critical Appraisal

Internal Validity

The SYNAPSE trial employed appropriate methods for blinding, treatment allocation, and randomization. Baseline demographic and disease characteristics were generally balanced between the treatment groups, except that a greater proportion of patients in the placebo group than in the mepolizumab group had had 2 or more previous surgeries (60% versus 48%). Even though all the study patients had undergone at least 1 surgery, a higher proportion of patients with repeated surgery would have indicated that patients in the placebo group had more likely had recurrent disease than patients in the mepolizumab group in the past 10 years. While it is unclear whether the need for more surgery was a function of disease severity or disease duration, it is a potential marker of treatment resistance. Further, more patients had asthma at baseline in the placebo group than in the mepolizumab group (74% versus 68%). Also, a greater proportion of patients in the placebo group than in the mepolizumab group initiated therapy with LTRA before treatment with the study drug (17% versus 12%); a potential confounding effect of LTRA therefore cannot be ruled out. However, more patients in the mepolizumab group than in the placebo group experienced at least 1 asthma exacerbation in the 12 months before screening (26% versus 15%) and at least 1 asthma exacerbation requiring systemic corticosteroids but not requiring hospitalization or emergency room visit in the 12 months before screening (20% versus 12%). Overall, these baseline imbalances may have had an impact on the assessment of differences in treatment effects between groups, yet the magnitude and direction of the bias remain uncertain.

Other between-group imbalances — namely, greater use of concomitant medications and greater protocol deviations in the placebo group, as well as inclusion of patients who demonstrated improvement in nasal polyp scores between screening and randomization — may have influenced the treatment effect. During the treatment period, a greater proportion of patients in the placebo group than in the mepolizumab group initiated concomitant treatment with any systemic corticosteroid (46% versus 34%). Likewise, a greater proportion of patients in the placebo group than in the mepolizumab group, albeit a low percentage overall, made use of a rescue short-acting beta2-agonist inhaler (9% versus 1%). According to the clinical expert consulted by CADTH for this review, the use of systemic corticosteroids for any reason or the use of rescue corticosteroid (but not short-acting beta2-agonist) medication for asthma may improve nasal polyp symptoms, thereby potentially introducing bias against mepolizumab into the results. While the impact of these additional interventions could not be assessed due to the small percentage of patients requiring their use during the study period, it is possible that the placebo group benefited from the additional therapies. A greater proportion of patients in the placebo group than in the mepolizumab group discontinued treatment I (17% versus 11%), and a substantial proportion of patients were documented with an incomplete (42% versus 31%) or missing (6% versus 4%) end point assessment. I majority of missed or incomplete assessments were due to missing clinical chemistry, hematology, and/or urinalysis due to spoiled samples; however, missed visits or phone calls related to patient diary, HRQoL, and work productivity occurred in 10% and 5% of patients in the placebo and mepolizumab groups, respectively. To mitigate discontinuation and missed assessments, patients were assigned their worst observed score before withdrawal or missed assessment. However, the high percentage of major protocol violations (65% in the placebo group versus 55% in the mepolizumab group) may have compromised the quality of the data from this trial, thereby having an impact on the assessment of efficacy outcomes.

The primary efficacy outcomes were obtained with instruments that have been similarly used in other CRSwNP trials, and the process used to carry out the outcome measures was well described and assessed in a blinded fashion. The selected outcomes conformed with the FDA’s industry guidance for CRSwNP trials.⁴³ There appears to be low risk of bias due to the selection of the reported results, and the results presented followed a prespecified analysis plan.

SNOT-22, SF-36, and WPAI-GH were used to assess HRQoL, and symptom VAS scores were used to assess efficacy. The reliability and validity of these outcome measures, with the exception of SNOT-22, in the setting of CRSwNP were seldom studied or not studied. Recall bias would be highly likely across clinical or non-clinical settings, especially for self-administrated tools; the recall period of SNOT-22 was up to 2 weeks. The quality of the trial data on subjective efficacy outcomes is a significant concern, particularly in the large amount of missing or incomplete assessments (48% versus 35% for the placebo and mepolizumab groups, respectively). Overall, these limitations cast uncertainty on the true effect of mepolizumab as an add-on maintenance therapy in patients with CRSwNP on symptoms, quality of life, and work productivity.

While the SYNAPSE trial included a 6-month no-treatment follow-up period, only the first 200 patients were eligible to be included in that trial period. As the follow-up period was not designed for hypothesis testing, the follow-up period was not taken into consideration in the sample size determination. As a result, the long-term durability of the treatment effect associated with mepolizumab could not be adequately assessed. This raises the question of how much of the maintained treatment effect observed during the follow-up period in the mepolizumab group was due to mepolizumab versus standard of care with INCS, given that full onset of action of intranasal steroids may be delayed for some patients.⁹ Indeed, during the no-treatment follow-up period, the placebo group maintained some of the treatment effect experienced in the trial. However, the treatment effect observed for the mepolizumab group at the end of the treatment period (weeks 49 to 52) slowly declined to the end of the no-treatment follow-up period (weeks 73 to 76). As noted by the clinical expert consulted by CADTH for this review, adherence to persistent daily INCS may have led to the placebo group maintaining the modest improvement experienced during the treatment period. Consequently, uncertainty exists in how much of the treatment effect observed in the mepolizumab group was due to the efficacy of mepolizumab versus the effectiveness of MF therapy, although both groups were on INCS therapy.

Regarding the statistical analysis, the study was powered to assess the co-primary outcomes (i.e., change from baseline in total endoscopic nasal polyp score and change from baseline in mean nasal obstruction VAS score) and the key secondary outcome (i.e., time to first nasal surgery). All analyses were performed using the ITT method, ensuring that the prognostic balance created from randomization was maintained. Patients who stopped or deviated from the interventions were properly accounted for in the ITT approach. Secondary efficacy end points were addressed using the multiplicity hierarchical testing procedure, which controlled for type I error. Missing data or symptom assessments that occurred after surgery were addressed using nonresponder imputation. While the nonresponder imputation approach may be considered appropriate as patients are assigned the worst-case scenario, it may cause biased estimation in some cases. Sensitivity analyses were conducted using tipping point analysis and were per-protocol treated to confirm study results. The results were found to be consistent with the ITT results.

The study had prespecified the analysis of all continuous outcomes with the median instead of the mean. When the distribution of the data is extremely skewed, the median is the preferred alternative. Otherwise, the mean is the most appropriate option in estimating the central tendency of measures when the normal distribution is approximate, especially when all potential outliers are identified and excluded. When the normality assumption is nearly satisfied, a calculation of the mean and an estimation of the difference in the mean change from baseline to the end of the study would ideally represent the average treatment effect of the study drug, which would render the study results more interpretable than if the median were used; this would also be applicable to the difference in treatment effect between treatment arms.

Several subgroup analyses were performed to examine the consistency of the treatment effect observed for the co-primary and key secondary efficacy end points. However, the interpretation of the effect of mepolizumab between the subgroups is unknown because no formal hypothesis testing was conducted.

External Validity

Table 31 summarizes the generalizability of the evidence.

The demographic characteristics of the study population were considered by the clinical expert consulted by CADTH to be generally reflective of the relevant population with CRSwNP in Canada. There are a few notable details of the SYNAPSE trial that may, however, impact generalizability to the Canadian setting.

Enriched Patient Population

Overall, the study population represented patients who were more likely to adhere to the long-term use of the study drug. The 4-week run-in period further excluded patients who met the study eligibility criteria (severe CRSwNP with at least 1 surgery for recurrent nasal polyps and refractory to standard of care) but who were intolerant or poorly adherent to the study drug or procedures (21% did not meet the continuation criteria). An enrichment design tends to overestimate the treatment effectiveness in the clinical practice setting.

Prior Treatment With INCS

The SYNAPSE trial required patients to have had treatment with INCS for at least 8 weeks in the period before screening. Treatment with INCS is first-line treatment for CRSwNP in the Canadian setting. According to the clinical expert, the 8-week treatment period with INCS pre-screening employed in the SYNAPSE trial was an ideal choice since full relief from intranasal steroids may not be seen for at least 6 weeks with daily use. However, the clinical expert added that ideally patients should be on daily INCS for at least 3 months to determine their full effect.

Concurrent Asthma

Seventy-one percent of the study population were documented as having concurrent asthma. According to the clinical expert, a high proportion of patients with CRSwNP in clinical practice have concurrent asthma.

Standard of Care (Co-Interventions)

Mepolizumab was employed as an add-on therapy to standard of care in the SYNAPSE trial. Standard of care in the SYNAPSE trial was MF nasal spray. As noted by the clinical expert, use of MF nasal spray is reflective of standard of care in the Canadian practice setting. The clinical expert added that ideally patients should be on daily intranasal steroids for at least 3 months to determine their full effect. Additional interventions allowed in the SYNAPSE trial included saline nasal douching and/or an occasional short course of high-dose OCS and/or antibiotics when required. As with MF nasal spray, these additional interventions are consistent with standard of care in the Canadian practice setting.

Assessing Treatment Response

Endoscopic nasal polyp score and nasal obstruction VAS score were the defined co-primary end points in the SYNAPSE trial. In the clinical practice setting, the applicability of the nasal obstruction VAS symptom score and the endoscopic nasal polyp score to determine the course of treatment is limited. The clinical expert noted that SNOT-22 and change in polyp size are usually used to determine response to treatment. In practice, SNOT-22 is used by ear, nose, and throat specialists as 1 means of deciding whether to proceed with surgery. The European Position Paper on Rhinosinusitis and Nasal Polyps has identified a cut-off SNOT-22 score of greater than 40 as being indicative of severe CRSwNP.¹⁰ A score of greater than 30 was identified by Gallo et al. (2020) as predictive of the greatest likelihood of improvement from surgery, although the likelihood of meeting the MID was less likely in patients with a lower score.⁴⁴ The clinical expert added that if reduction in nasal polyp size or obstruction is not accompanied by improved symptoms, patients are unlikely to continue with treatment. As noted by the Canadian Rhinology Working Group, response to biologics in the treatment of CRSwNP should be based on both subjective and objective improvement.⁴⁵ Improvement should be noted in some or all of a patient’s major symptoms and in their endoscopy or CT scan.

Likewise, the PnIF was used in the SYNAPSE trial to objectively assess nasal congestion, yet it is not routinely used in clinical practice. The clinical expert noted that PnIF is an ideal outcome measure to objectively assess improvement since it is affected by both polyp size and nasal mucosa inflammation. However, the cost associated with its use has precluded it from routine use.

Setting

The SYNAPSE trial included 8 Canadian sites consisting of 34 patients; patients living in Canada accounted for 8.2% of the study population. The randomization schedule employed in the trial was stratified by country regions, taking into account standard of care and regulatory considerations. However, Canada was included in the Rest of World region, along with Argentina, Australia, Russia, and the Republic of Korea. It was unclear why Canada was not grouped with the US as part of North America, given the protocol’s stated intent of allocating countries into regions in part based on medical standard of care. This point was also recognized by Health Canada.²⁷ In follow-up, Health Canada requested additional analysis grouping Canada with North America, which the sponsor provided. The additional analysis demonstrated that the results were consistent with the primary analyses.²⁷ Overall, the clinical expert consulted by CADTH felt that the trial results were generalizable to the Canadian practice setting.

Table 31: Assessment of Generalizability of Evidence for Mepolizumab

CRSwNP = chronic rhinosinusitis with nasal polyps; INCS = intranasal corticosteroids; MF = mometasone furoate; PnIF = peak nasal inspiratory flow; SNOT-22 = Sino-Nasal Outcome Test 22; VAS = visual analogue scale.

Indirect Evidence

A focused literature search for indirect treatment comparisons dealing with CRSwNP was run in MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid on June 6, 2022. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. No indirect treatment comparisons were included in the sponsor’s submission to CADTH or identified in the literature search.

Other Relevant Evidence

No long-term extension studies or other relevant studies were included in the sponsor’s submission to CADTH or identified in the literature search.

Discussion

Summary of Available Evidence

The current CADTH systemic review included 1 phase III, multicentre, randomized, double-blind, placebo-controlled, parallel group trial: the SYNAPSE trial (N = 414). The SYNAPSE trial evaluated the clinical efficacy and safety of 100 mg/mL mepolizumab as an add-on maintenance treatment in adults with recurrent CRSwNP not adequately controlled on optimized medical treatment and who had had at least 1 prior nasal polyp surgery in the past 10 years. The SYNAPSE study comprised a 4-week run-in period followed by a 52-week treatment period in which patients were randomized to receive either mepolizumab 100 mg/mL or matching placebo delivered by subcutaneous injection using a prefilled safety syringe. I first 200 patients randomized into the study entered a 6-month no-treatment follow-up period following their week 52 visit to assess maintenance of response. All patients remained on standard of care treatment with daily MF nasal spray throughout the study. If required, saline nasal douching and/or an occasional short course of high-dose OCS and/or antibiotics were permitted. The co-primary efficacy end points were change from baseline in endoscopic nasal polyp score at week 52 and change from baseline in nasal obstruction VAS score during the 4 weeks before week 52. The key secondary end point was time to first actual surgery for nasal polyps by week 52. Other secondary end points of interest to this review included change from baseline in overall VAS symptom score, change from baseline in SNOT-22 score, the proportion of participants requiring systemic steroids for nasal polyps, change from baseline in composite VAS symptom score (combining VAS scores for nasal obstruction, nasal discharge, mucus in the throat, and loss of smell), and change from baseline in loss of smell VAS score.

The 414 patients were randomized to receive either mepolizumab or matching placebo, 207 in each group. The study population aligned with the Health Canada indication and with the sponsor’s reimbursement request and proposed reimbursement criteria. .

The SYNAPSE trial was limited by between-group imbalances at baseline: more patients in the placebo group were on LTRA at baseline and more patients in the placebo group had had more than 1 prior nasal polyp surgery. Furthermore, more patients in the placebo group made use of concomitant medications, and the group experienced greater protocol deviations. Finally, questions remain about how much of the treatment effect observed during the study period in the mepolizumab group was due to mepolizumab versus standard of care with MF nasal spray. Despite these limitations, the study results were found to be generalizable to the clinical setting. A small percentage of patients who experienced improvement in nasal polyp score between screening and baseline were included in the study despite having a nasal polyp score of less than 5 at baseline. The inclusion of patients with a nasal polyp score of less than 5 was also noted by Health Canada, and clarification was requested.²⁷ In clarification, the sponsor noted that the small number of patients who demonstrated an improvement between screening and baseline were still included in the study because all patients met all the randomization criteria, so despite improvement in nasal polyp score, the patients still presented with severe disease, and because the inclusion of these patents did not change the median score for either treatment group, which was the basis of the analysis plan to use medians with a non-parametric Wilcoxon rank test.

No indirect treatment comparisons or other evidence were included in the sponsor’s submission to CADTH or identified in the literature search.

Interpretation of Results

Efficacy

In the SYNAPSE trial, treatment with mepolizumab resulted in a statistically significant improvement compared to placebo in nasal obstruction as measured by the VAS and in endoscopic nasal polyp score. Treatment with mepolizumab also resulted in a statistically significant improvement compared to placebo in time to first nasal polyp surgery, change from baseline in SNOT-22 total score, composite VAS symptom score, individual VAS symptom score for loss of smell, and difference in the proportion of patients requiring systemic steroids for nasal polyps. Patients treated with mepolizumab reported less health-related impairment in work and activity.

The magnitude of change from baseline between groups in total endoscopic nasal polyp score was relatively modest. According to the clinical expert consulted by CADTH, patients with CRSwNP are treatment resistant. The implication of type 2 inflammation, presence of comorbid asthma and/or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease, high corticosteroid use, and/or sino-nasal surgical history that often accompany CRSwNP represent a difficult-to-treat population under existing treatment regimens.¹⁴ For these reasons, the clinical expert stated that even small improvements to total endoscopic nasal polyp scores are considered clinically relevant. Indeed, the MID associated with a clinically meaningful change is an improvement of at least 1 point.³¹ In the SYNAPSE trial, half of all patients in the mepolizumab group met the criteria for a clinically meaningful improvement in their total endoscopic nasal polyp score at the end of the treatment period. According to the clinical expert, the response to treatment as defined by the total endoscopic nasal polyp score would be considered acceptable in the clinical setting.

However, the clinical expert consulted by CADTH added that uptake of treatment should not be based on reduction in nasal polyp size alone. Endoscopic improvement must be also accompanied by improvement in CRSwNP symptoms. This sentiment was also expressed by the Canadian Rhinology Working Group.⁴⁵ In the SYNAPSE trial, significant improvement was observed in the co-primary end point of nasal obstruction VAS score and the secondary end points of overall VAS symptom score, composite VAS symptom score, and individual VAS symptom score for loss of smell. The magnitude of the treatment effect for nasal obstruction VAS score and composite VAS symptom score was modest yet acceptable according to the clinical expert. For loss of smell, however, the magnitude of the treatment effect was considered small. According to the clinical expert, it is difficult to regain smell once lost. While the VAS for total sino-nasal symptom severity is used to assess disease severity and monitor the course of the disease, and can be used for treatment decisions and to determine disease burden in the clinical setting,⁴⁶ there is no established MID on which to base response to treatment. According to the clinical expert, a change in the score between 20% and 50% of the baseline VAS score is considered acceptable in clinical practice. In the SYNAPSE trial, the change in mean score from baseline across the VAS end points fell within this range.

In the SYNAPSE trial, time to first nasal surgery was designated as the key secondary end point. The clinical expert consulted by CADTH gave surgery for nasal polyps a lower ranking of importance among CRSwNP outcomes since it is difficult to standardize across patients and surgeons. However, in the SYNAPSE trial, where all patients had had previous surgery and a quarter were felt to require surgery by the end of the treatment period, one could make the argument that it could have been ranked higher. Despite the clinical expert ranking of the end point, a reduced need for surgery was deemed to be important from the input received from the patient groups. In the SYNAPSE trial, the probability of undergoing nasal surgery at any time before the end of the study period was significantly lower in the mepolizumab group than in the placebo group. Moreover, the longer the duration of treatment, the greater the treatment effect on the probability of requiring surgery for nasal polyps. However, the durability of the treatment effect could not be assessed due to the short duration of, and the low number of patients entering, the follow-up period.

As noted by the clinical expert, SNOT-22 is used in clinical practice to determine response to treatment. In the SYNAPSE trial, the magnitude of change from baseline was both significant and clinically meaningful. In fact, almost three-quarters of the patients in the mepolizumab group were considered responders, exceeding the MID established for SNOT-22. Just over half the patients in the placebo group were also considered responders. Moreover, change from baseline in the placebo group exceeded the established MID for SNOT-22.³⁷ In fact, the treatment response in the placebo group was observed across multiple end points. In seeking clarification from the clinical expert about why the placebo group would exhibit such an improvement in SNOT-22 score, the expert noted that standard of care treatment with MF nasal spray is an effective treatment. Indeed, a 2016 systematic review demonstrated MF nasal spray to be an effective treatment of inflammatory diseases of the nose and paranasal sinuses while improving quality of life and other symptoms.⁴⁷ Due to the effectiveness of MF nasal spray, the clinical expert would have preferred the study protocol to require patients to be on daily MF treatment for 3 months before starting the trial. The clinical expert noted that the improvement observed in both the mepolizumab and placebo groups may not have been driven by improvement in nasal polyps alone. According to the clinical expert, the benefits derived from daily MF treatment may be reflecting improvement in sinusitis, nasal turbinate edema, and secretion, leading to symptomatic and objective improvement despite polyps being resistant to steroids. Consequently, this observation introduces uncertainty about how much of the treatment effect observed in the mepolizumab group was due to the efficacy of mepolizumab versus the effectiveness of MF therapy, although both groups were taking INCS. Further, recall bias could occur depending on the setting in which surveys were administered (i.e., clinical versus non-clinical), especially for self-administrated tools; the recall period for SNOT-22 was up to 2 weeks. Finally, the quality of the trial data on subjective efficacy outcomes is a concern due to missing or incomplete assessments related to patient diary, HRQoL, and work productivity (10% versus 5% for placebo versus mepolizumab).

The clinical expert explained that in clinical practice, response to treatment is primarily based on the severity of nasal congestion. The clinical expert noted that PnIF, a measure of nasal congestion, is an ideal outcome measure to assess objective improvement since it is affected by both polyp size and nasal mucosa inflammation. In the SYNAPSE trial, the mepolizumab group demonstrated an improvement in nasal congestion in excess of the MID for the PnIF. However, no analysis of treatment difference was conducted between the groups. Moreover, PnIF was absent from the statistical testing hierarchy. As a result, conclusions cannot be made about the efficacy of mepolizumab to improve nasal congestion. This represents a missed opportunity to demonstrate an objective treatment effect on an outcome that is considered important in the clinical setting.

Patient group input indicated a desire for decreased reliance on OCS and other steroids. Although a significantly lower proportion of patients in the mepolizumab group required at least 1 course of systemic steroids for nasal polyps than in the placebo group during the SYNAPSE trial, the overall proportion of patients requiring systemic steroids was low. According to the clinical expert, the low proportion of patients in the placebo group requiring systemic steroids may be a function of persistent use of the MF nasal steroids (standard of care). As discussed above, it is uncertain how much of the treatment effect observed in the mepolizumab group was due to the efficacy of mepolizumab versus the effectiveness of MF therapy.

The absence of any long-term extension studies hinders any conclusions about the durability of treatment with mepolizumab on CRSwNP efficacy end points.

Harms

Mepolizumab appeared to be well tolerated, with no concerning safety signals identified. The overall safety profile of mepolizumab in SYNAPSE appeared consistent with its established safety profile as add-on maintenance therapy across other indications.⁴⁵

The product monograph for mepolizumab documents the following common side effects of mepolizumab: headache, injection site reactions (pain, redness, swelling, itching, or a burning feeling at the injection site), back pain, and tiredness (fatigue). Mouth or throat pain and joint pain have also been reported with CRSwNP. The product monograph also contains warmings for serious side effects, including allergic (hypersensitivity) reactions such as anaphylaxis and herpes zoster infections that can cause shingles.

Other Considerations

The sponsor included in its submission application suggested reimbursement criteria related to the initiation, administration, and renewal of mepolizumab. The suggested reimbursement criteria and evidence of support for those criteria are detailed in Table 32.

The SYNAPSE trial and input from the clinical expert supports the use of mepolizumab in adult patients with a documented diagnosis of severe and recurrent CRSwNP inadequately controlled by INCS. However, how severity of nasal polyps and response to treatment were defined in the SYNAPSE trial differed from the definition used in clinical practice as noted by the clinical expert. In addition, the clinical expert suggested that the duration of time patients are on INCS before initiating treatment with mepolizumab should be longer than what was required by the SYNAPSE trial.

Table 32: Sponsor-Suggested Reimbursement Criteria and Evidence of Support

CRS = chronic rhinosinusitis; CRSwNP = chronic rhinosinusitis with nasal polyps; ENT = ear, nose, and throat specialist; INCS = intranasal corticosteroids; MF = mometasone furoate; SNOT-22 = Sino-Nasal Outcome Test 22; VAS = visual analogue scale.

Conclusions

Based on the SYNAPSE trial, mepolizumab as an add-on maintenance therapy in combination with standard of care was efficacious in achieving endoscopic improvement and relief of nasal obstruction as measured by the VAS in patients with severe recurrent CRSwNP inadequately controlled by inhaled nasal corticosteroids alone. Moreover, mepolizumab was found to be efficacious in prolonging time to nasal surgery, reducing the need for systemic corticosteroids for nasal polyps, and improving CRSwNP symptoms. However, the magnitude of the treatment effect was modest. Based on the response observed in the placebo group and on input from the clinical expert consulted by CADTH, the extent to which these improvements were due to treatment with mepolizumab remains uncertain. Mepolizumab appeared to be well tolerated. However, due to lack of head-to-head trials or availability of indirect treatment comparisons, it remains unknown how mepolizumab compares to other similar maintenance therapy for severe recurrent CRSwNP in efficacy and safety. Despite these limitations, mepolizumab fills an unmet need for more treatment options for patients with severe CRSwNP inadequately controlled with standard of care.

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