Reimbursement Review

Nemolizumab (Nemluvio)

Sponsor: Galderma Canada Inc.

Therapeutic area: Prurigo nodularis

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

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

Table 1: Background Information on the Application Submitted for Review

NOC = Notice of Compliance; PN = prurigo nodularis; SC = subcutaneous.

Sources: Nemluvio Product Monograph;¹ sponsor’s Summary of Clinical Evidence.²

Introduction

Prurigo nodularis (РΝ) is a rare, neuroimmune, inflammatory skin disease characterized by the presence of chronic (≥ 6 weeks) itch; history and signs of repeated scratching, such as excoriation and scars; and multiple, localized or generalized, hyperkeratotic, symmetrically distributed pruritic nodules on the extensor surfaces of the extremities and trunk.^3-7 Exact incidence and prevalence estimates for Canada are unknown; however, based on the expected prevalence of PN published in a study by Bahloul et al. (2024),⁸ there are an estimated 6,000 patients with moderate to severe PN in Canada. ΡN can occur in all age groups, without sex preferences, but it primarily affects older adults,⁴ with approximately 69% of patients aged 51 years or older.^5,9-11 PN leads to significantly reduced quality of life (QoL) because symptoms like itch and skin lesions affect patients’ personal and social lives.^12,13 The negative impact on QoL from PN is primarily driven by the increased incidence and intensity of pruritus.¹⁴ Furthermore, patients with PN may be affected by insomnia and sleep disturbances, a higher level of absenteeism at work (full or partial days), decreased productivity or presenteeism, and lower work performance.¹⁵ PN symptoms also affect patients’ ability to get dressed, engage in self-care or personal hygiene, plan activities, and complete chores.¹³ PN is associated with the presence of chronic obstructive pulmonary disease (COPD), chronic hepatitis C, HIV, and atopic dermatitis (AD),¹⁴ resulting in an increased burden for these patients. It is estimated that approximately 43% of patients with PN are initially misdiagnosed.¹⁶ Therefore, additional bloodwork may be necessary to ascertain the underlying causes of symptoms (e.g., chronic kidney disease, liver disease, thyroid disease, HIV infection, parasitic infection, or malignancy).^4,17,18 However, clinical experts consulted by Canada’s Drug Agency (CDA-AMC) for this review noted that if PN is diagnosed by a dermatologist, a biopsy is not required to confirm the diagnosis. Given the burden of PN and its associated comorbidities, patients with PN have high rates of health care and specialty care utilization.¹⁹

According to clinical experts consulted by CDA-AMC, PN is often initially managed with high-potency topical corticosteroids (TCSs). Other initial treatment options include topical calcineurin inhibitors (TCIs) or anesthetics, oral antihistamines, intralesional corticosteroid injections, topical capsaicin, and UV light treatment (i.e., phototherapy). The clinical experts commented that systemic immunosuppressants, such as cyclosporine and methotrexate, may be prescribed for severe or treatment-resistant disease. Other medications that may be considered to treat PN include gabapentin, pregabalin, carbamazepine, doxepin, mirtazapine, mycophenolate mofetil, and low-dose naltrexone. Clinical experts highlighted that PN is difficult to treat and that the aforementioned treatment options may provide only partial or short-term symptomatic relief; in addition, the use of these treatments is often limited by side effects and feasibility issues.

International guidelines detail several medication options for the treatment of PN, most of which have limited evidence supporting efficacy and are used off-label.^20-22 In Canada, dupilumab is currently the only treatment indicated for PN.^2,23 Clinical experts agreed with patient and clinician groups that there is a need for highly effective, disease-modifying, systemic PN therapies that provide sustained relief, are safe for long-term use, and are convenient and accessible.

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of nemolizumab 30 mg per 0.49 mL for subcutaneous (SC) injection in the treatment of moderate to severe PN. The approved Health Canada indication is for nemolizumab to be used for the treatment of adults with moderate to severe PN whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. This review is based on the sponsor’s initial reimbursement request for nemolizumab to be used for the treatment of moderate to severe PN. The sponsor has revised the reimbursement request to align with the approved Health Canada indication; however, the revision did not warrant a substantial update to the report.

Perspectives of Patient, Clinicians, and Drug Programs

The information in this section is a summary of the input provided by the patient and clinician groups who responded to our call for input and from the clinical expert(s) consulted for the purpose of this review.

Patient Input

A single patient group, the Canadian Skin Patient Alliance (CSPA), provided input for this submission. CSPA is a national charity that supports the health and well-being of people across Canada affected by skin, hair, and nail conditions through collaboration, advocacy, and education. Information regarding the experiences of people living with PN was compiled from a patient and caregiver survey conducted from September 12, 2024, to November 29, 2024. A total of 9 survey responses were received from participants in Canada. None of the patients had experience with nemolizumab.

Five survey respondents indicated that they had had PN for less than 5 years; most reported severe (n = 3) or moderate (n = 1) PN. Respondents indicated that their PN diagnosis affected their family relationships, intimate relationships, work life, mental health, social life, daily activities, sleep, self-esteem, finance, and sex life. Respondents highlighted the following symptoms: itchy skin, itchy bumps (nodules), burning or stinging skin, scratching, pain, and hyperpigmentation (dark spots).

The caregiver respondent reported that the disease affected their loved one with regards to family balance and relationships, mental health, and intimacy. Additionally, they shared that it was difficult having to encourage their loved one to continue taking treatments for PN.

The respondents pointed to effectiveness, lack of side effects, and affordability as the top 3 unmet needs. They also said there is a need for treatments that are easy to take or apply and conducive to patients’ schedules. The caregiver respondent noted the cost of medication as an important unmet need.

Clinician Input

Input From Clinical Experts Consulted for This Review

Clinical experts consulted by CDA-AMC expressed an unmet need for disease-modifying, systemic therapies for PN that are highly effective in achieving treatment goals (e.g., itch relief, treatment of lesions), provide sustained disease control and symptom relief, are safe for short- and long-term use across diverse patient populations (e.g., all ages, those with comorbidities), and are convenient and accessible. Clinical experts commented that, along with dupilumab, nemolizumab is expected to cause a shift in the current treatment paradigm for PN in Canada. Clinical experts expected that traditional therapies (e.g., TCSs) would still be used for the initial management of PN; they stated that nemolizumab would be best suited for patients with moderate to severe or refractory PN, particularly those with persistent pruritus and many chronic lesions for whom conventional treatments have failed. According to clinical experts, the patients least suited for nemolizumab would be those with mild PN or mild symptoms that can be managed with conventional treatments. Clinical experts stated that nemolizumab or dupilumab would likely be the preferred systemic treatment options over systemic immunosuppressants. They also noted that nemolizumab would likely be combined with some existing PN treatments, such as topical or intralesional corticosteroids. According to clinical experts, treatment response in patients with PN is assessed in clinical practice based on improvement in the number of lesions, reduction in pruritus, and improvement in QoL; physicians may prioritize these outcomes differently. They noted that assessments of treatment response in clinical practice do not usually use the grading tools used in clinical trials as stringently. Clinical experts stated that response would typically be assessed 3 to 6 months after initiating PN treatment and at the same interval while the disease is active, with annual follow-up if the disease is controlled. When deciding to discontinue treatment with nemolizumab, the clinical experts would evaluate whether the patient had achieved the desired clinical outcomes within a 6-month time frame. Clinical experts identified that a clinically important response would be a decrease in lesion count from 20 or more at the start of therapy to 5 or fewer, or a decrease in peak itch severity of at least 4 points out of 10 on the numerical rating scale (NRS). Clinical experts also acknowledged that that the decision to stop treatment in a patient with a partial response would consider whether the patient wants to continue therapy and if any other effective treatment options are available. Additional factors for discontinuation may include serious adverse events (SAEs) or the emergence of comorbidities requiring other treatments. Clinical experts agreed that due to the complexity of diagnosing PN, it is essential that treatment of PN with nemolizumab is prescribed only by dermatologists.

Clinician Group Input

Two clinician groups, the Atlantic Dermatology Group and the Dermatology Association of Ontario (DAO), provided input for this submission. Input was provided by 5 clinicians, and information was gathered from sessions related to PN at the September 2024 European Academy of Dermatology and Venerology in Amsterdam as well as from the literature. Input from the DAO was provided by 7 clinicians, and information was gathered from clinical trial data, available literature retrieved through PubMed, and experience with the use of nemolizumab from clinical trialists in Canada.

Both clinician groups highlighted that currently, there are no specific clinical practice guidelines for PN in Canada. They indicated that current therapies include topical treatments, such as corticosteroids and emollients, dupilumab, and off-label regimens (i.e., systemic immunosuppressants, thalidomide, lenalidomide, tricyclic antidepressants, Janus kinase inhibitors, neurokinin-1 receptor antagonists, and monoclonal antibodies targeting interleukin [IL]-4 pathways). The DAO also highlighted that nondrug treatments, such as UVB phototherapy and psychosocial approaches, had been attempted with limited availability and success in addressing the psychological burden of PN and improving overall QoL. The Atlantic Dermatology Group further highlighted evidence from a systematic review, which concluded that while phototherapy, corticosteroids, cyclosporin, and methotrexate are viable options, the potential benefits are limited because of the risks of relapse and potential side effects.

The DAO highlighted the following unmet needs in PN treatment: therapies that provide rapid and sustained relief from severe itch; improve skin lesions; address the psychosocial impacts of the disease; improve tolerance and/or convenience compared with current treatments; and target the underlying neuroimmune mechanisms driving PN. Atlantic Dermatology Group clinicians noted the need for therapy that provides clinically significant reductions in itch, improved physician global assessment of skin lesions, and improved QoL.

The Atlantic Dermatology Group indicated that nemolizumab will cause a shift in the current treatment paradigm because it can be used as a first-line therapy in patients with PN, in patients who are intolerant to dupilumab, TCSs, or phototherapy, and in patients for whom these treatments have failed. They also noted that nemolizumab would be used as a stand-alone treatment. However, the DAO indicated that nemolizumab would also fit as a targeted second- or third-line option in patients for whom topical therapies and phototherapy produced an insufficient disease response or for whom these treatments have failed.

The DAO clinician group noted that the patients best suited for treatment with nemolizumab would be those with moderate to severe PN who did not achieve adequate relief with topical therapies or phototherapy or those unable to access or tolerate these treatments. This would include those who have persistent and intense pruritus, widespread nodular lesions, and/or significant impairment in QoL. The Atlantic Dermatology Group highlighted that patients with moderate to severe PN with an itch score of 7 or higher with at least 20 lesions would be in most need and be best suited for treatment. The DAO further noted that patients with contraindications (such as known hypersensitivity to nemolizumab), patients with milder disease that responds to topical steroids, and patients with conditions that significantly compromise immune function (unless the benefits outweigh the risks) would not be suitable for treatment with nemolizumab.

The DAO clinician group noted that to identify the patients most likely respond to nemolizumab, a clinician assessment of the intensity and persistence of itch, extent of nodular lesions, and impact on daily functioning and QoL was sufficient. However, the Atlantic Dermatology Group noted that no clinical, pathological, or chemical markers exist to identify the patients most likely to exhibit a response to treatment.

The Atlantic Dermatology Group noted that misdiagnoses are unlikely if patients are managed by dermatologists in clinical practice. The group emphasized the consideration of other diagnoses, including pemphigoid nodularis, mastocytosis, lichen planus, nodular scabies, arthropod bites, lymphocytoma cutis, lymphomatoid papulosis, amyloidosis, reticulohistiocytosis, and cutaneous T-cell lymphoma. However, the DAO indicated that PN may be underdiagnosed or misdiagnosed as other pruritic dermatoses, and that clinician education and awareness are key to improving diagnostic accuracy.

Both clinician groups noted that a 4-point improvement in a patient’s Peak Pruritus Numerical Rating Scale (PP-NRS) score should be used to determine if a patient is responding to treatment. The Atlantic Dermatology Group and the DAO noted that a physician global assessment or Investigator’s Global Assessment (IGA) of clear or almost clear and a reduction of at least 2 points from baseline, respectively, are the outcomes used to determine treatment response. In addition, the Atlantic Dermatology Group noted that the Dermatology Life Quality Index (DLQI) should be used, and the DAO noted that subjective feedback on daily comfort and sleep quality should be assessed.

Both clinician groups agreed that treatment discontinuation should be considered if there is a lack of meaningful reduction in PP-NRS or if there are persistent nodular lesions as assessed by the IGA. The Atlantic Dermatology Group noted that treatment should be discontinued after 6 months of therapy if there is a lack of response. Additional criteria for discontinuation were noted by the DAO, including significant adverse events (AEs) (i.e., hypersensitivity, injection-site reaction, or long-term safety issues, including recurrent infections). Disease progression (e.g., worsening lesions), complications such as skin infections, and patient-reported dissatisfaction were also noted as important factors requiring treatment reassessment. In cases where systemic immunosuppressants or other biologics are required to manage refractory disease, nemolizumab may no longer be an optimal choice.

The Atlantic Dermatology Group indicated that PN should be managed by dermatologists experienced in both the diagnosis and management of PN and the use of biologics. The group also noted that dermatologists should be experienced in measuring DLQI, IGA, and PP-NRS, as well as counting nodules. The DAO noted that, in addition to dermatologists, allergists or immunologists may also be involved in managing patients with PN where PN overlaps with other atopic or immune-mediated conditions. The group highlighted that while the diagnosis, treatment initiation, and monitoring of patients requires the expertise and oversight of specialists, nemolizumab may be prescribed in various clinical settings (such as community clinics, hospital outpatient departments, and specialty dermatology or allergist clinics) and administered by patients at home.

Drug Program Input

Input was obtained from the drug programs that participate in the reimbursement review process. The following items were identified as key factors that could affect the implementation of a recommendation for nemolizumab: relevant comparators; considerations for the prescription, initiation, continuation, renewal, and discontinuation of therapy; generalizability; care provision issues; and system and economic issues. The details of the drug program input along with advice from the clinical experts consulted for this review are available in Table 4.

Clinical Evidence

Systematic Review

Description of Studies

The OLYMPIA 1 (N = 286) and OLYMPIA 2 (N = 274) trials were both phase III, randomized, double-blind, placebo-controlled studies investigating the efficacy and safety of nemolizumab versus placebo for the treatment of adult patients with PN. The studies were conducted in a total of 16 countries (77 sites for the OLYMPIA 1 trial and 55 sites for the OLYMPIA 2 trial), including 8 sites in Canada that randomized a total of 44 patients. In both trials, patients were randomized 2 to 1 to receive nemolizumab or matched placebo by SC injection every 4 weeks. The treatment periods were 24 weeks and 16 weeks in the OLYMPIA 1 and OLYMPIA 2 trials, respectively; follow-up was 8 weeks in each study. The primary end points in the OLYMPIA 1 and OLYMPIA 2 trials were the proportion of patients with at least a 4-point improvement from baseline in PP-NRS at week 16 and the proportion of patients reporting IGA success, defined as an IGA response of 0 (clear) or 1 (almost clear) and at least a 2-point reduction from baseline, at week 16. Key secondary and other secondary end points included measures of improvement in Sleep Disturbance NRS (SD-NRS), itch reduction (as measured using the PP-NRS), lesion clearance (IGA success), health-related QoL (HRQoL) (as measured using the DLQI). Harms outcomes were also assessed.

Patients eligible for participation in both of the OLYMPIA pivotal trials were adults aged 18 years or older with a clinical diagnosis of PN for at least 6 months with pruriginous nodular lesions on the upper limbs, lower limbs, and/or trunk; at least 20 nodules on the entire body, with bilateral distribution; and an IGA score of at least 3 (indicating moderate or severe global severity). Eligible patients were also required to have severe pruritus, defined as a PP-NRS score of at least 7. In the OLYMPIA 1 and OLYMPIA 2 trials, most patients were female, white, and aged 18 to 65 years (details are provided in Table 13). Patients were not eligible for participation in the trials if they had uncontrolled or exacerbated asthma, COPD, chronic bronchitis, certain infections, or active AD within the previous 3 months.

Efficacy Results

Improvement of 4 or More Points From Baseline in PP-NRS Score at Weeks 16 and 24

In the OLYMPIA 1 trial, the proportions of patients with improvements of 4 or more points from baseline in weekly average PP-NRS score at week 16 were 58.4% in the nemolizumab group and 16.7% in the placebo group (strata-adjusted proportion difference = 40.1%; 95% confidence interval [CI], 29.4 to 50.8; P < 0.0001). For the same end point in the OLYMPIA 2 trial, the proportions of patients were 56.3% in the nemolizumab group and 20.9% in the placebo group (strata-adjusted proportion difference = 37.4%; 95% CI, 26.3 to 48.5; P < 0.0001). The proportion difference between the groups was statistically significant in favour of nemolizumab in both trials, and clinical experts consulted by CDA-AMC considered the differences to be clinically meaningful. The results at week 24 in the OLYMPIA 1 trial roughly maintained those reported at week 16.

IGA Success at Weeks 16 and 24

In the OLYMPIA 1 trial, the proportions of patients with IGA success at week 16 were 26.3% in the nemolizumab group and 7.3% in the placebo group (strata-adjusted proportion difference = 14.6%; 95% CI, 6.7 to 22.6; P = 0.0025). For the same end point in the OLYMPIA 2 trial, the proportions of patients with IGA success were 37.7% in the nemolizumab group and 11.0% in the placebo group (strata-adjusted proportion difference = 28.5%; 95% CI, 18.8 to 38.2; P < 0.0001). The proportion difference between groups was statistically significant in favour of nemolizumab in both trials, and clinical experts consulted by CDA-AMC considered the differences to be clinically meaningful. The week 24 results in the OLYMPIA 1 trial were consistent with those reported at week 16.

Improvement of 4 or More Points From Baseline in SD-NRS Score at Week 16

In the OLYMPIA 1 trial, the proportions of patients with improvement of 4 or more points from baseline in weekly average SD-NRS score at week 16 were 50.0% in the nemolizumab group and 11.5% in the placebo group (strata-adjusted proportion difference = 38.0%; 95% CI, 27.8 to 48.2; P < 0.0001). For the same end point in the OLYMPIA 2 trial, the proportions of patients with improvement of 4 or more points from baseline in weekly average SD-NRS score were 51.9% in the nemolizumab group and 20.9% in the placebo group (strata-adjusted proportion difference = 31.9%; 95% CI, 20.7 to 43.2; P < 0.0001). The proportion difference between groups was statistically significant in favour of nemolizumab in both trials. (Input regarding the clinical meaningfulness of these differences was not received from clinical experts consulted by CDA-AMC.)

Improvement of 4 or More Points From Baseline in DLQI Score

In the OLYMPIA 1 trial, at week 16, the proportions of patients with an improvement of 4 or more points from baseline in DLQI total score were 70.5% in the nemolizumab group and 42.7% in the placebo group (strata-adjusted proportion difference = 27.5%; 95% CI, 15.8 to 39.2); at week 24, the proportions were 71.1% and 35.4%, respectively (strata-adjusted proportion difference = 35.5%; 95% CI, 23.9 to 47.2). In the OLYMPIA 2 trial, at week 16, the proportions of patients with an improvement of 4 or more points from baseline in DLQI total score were 74.9% in the nemolizumab group and 39.6% in the placebo group (strata-adjusted proportion difference = 37.4%; 95% CI, 25.7 to 49.0). The clinical experts consulted by CDA-AMC considered these differences to be clinically meaningful.

There were no published between-group minimum important difference values provided by the sponsor for the PP-NRS, IGA success, and DLQI end points assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE); as such, the thresholds used to judge the target of certainty in the GRADE assessment (Table 2) are based on input from the clinical experts consulted by CDA-AMC.

Harms Results

In the OLYMPIA 1 trial, at least 1 AE was reported in 71.7% of patients in the nemolizumab group and 65.3% of patients in the placebo group. The most common AEs (nemolizumab versus placebo) were COVID-19 (8.0% versus 14.7%), nasopharyngitis (6.4% versus 8.4%), headache (7.0% versus 2.1%), cough (4.8% versus 5.3%), dyspnea (3.2% versus 5.3%), neurodermatitis (9.6% versus 20.0%), and eczema (5.3% versus 1.1%). At least 1 SAE was reported in 8.6% of patients in the nemolizumab group and 10.5% of patients in the placebo group; AEs leading to study drug withdrawal occurred in 4.8% and 3.2% of patients, respectively. One patient in the placebo group died during the OLYMPIA 1 trial. At least 1 adverse event of special interest (AESI) was reported in 17.1% of patients in the nemolizumab group and 18.9% of patients in the placebo group. The most commonly reported AESI in the nemolizumab and placebo groups was infection (10.7% versus 16.8%). The AESI of newly diagnosed asthma or worsening of asthma was reported in 3.7% of patients in the nemolizumab group and in 2.1% of patients in the placebo group.

In the OLYMPIA 2 trial, at least 1 AE was reported in 61.2% and 53.8% of patients in the nemolizumab and placebo groups, respectively. In the OLYMPIA 2 trial, the most common AEs were headache (6.6% versus 4.4%), neurodermatitis (3.8% versus 11.0%), and AD (5.5% versus 0%). At least 1 SAE was reported in 2.2% of patients in the nemolizumab group and 5.5% of patients in the placebo group; AEs leading to study drug withdrawal occurred in 2.7% and 2.2% of patients, respectively. No patient deaths occurred during the OLYMPIA 2 trial. At least 1 AESI was reported in 11.5% of patients in the nemolizumab group and in 9.9% of patients in the placebo group. The most commonly reported AESI in the nemolizumab and placebo groups was infection (5.5% versus 6.6%). The AESI of newly diagnosed asthma or worsening of asthma was reported in 2.7% of patients in the nemolizumab group and in 1.1% of patients in the placebo group.

Critical Appraisal

The OLYMPIA 1 and OLYMPIA 2 trials were both phase III, randomized, double-blind, placebo-controlled, multicentre studies. Methods of randomization and treatment allocation in the trials were adequate. Reported baseline characteristics were generally balanced across the nemolizumab and placebo groups in both trials. Some differences between arms were noted; however, clinical experts consulted for this review did not anticipate that these differences would affect the interpretation of the results. For both pivotal trials, the prespecified sample size was achieved, and the screening failure rates approached or slightly exceeded the expected rates. Both trials were powered for the primary end points of the proportion of patients with at least a 4-point improvement in PP-NRS and the proportion of patients with IGA success (both at week 16). The multiple testing procedure included all primary and key secondary end points. Analyses of other secondary end points were not adjusted for multiplicity; therefore, conclusions cannot be drawn regarding statistical significance for these end points. Loss to follow-up was low, and rates of discontinuation were similar between treatment arms in both studies. Due to differences in treatment response between arms (e.g., reduction in pruritus), patients and investigators could have become aware of treatment allocation, which may have introduced bias with respect to the subjective end points, such as PP-NRS and DLQI. In both trials, there was a disproportionate use of rescue treatment between study arms, with a higher percentage of patients in the placebo arms requiring rescue therapy than in the nemolizumab arms. This imbalance in rescue treatment could have exaggerated the itch reduction response with placebo, thereby minimizing the comparative benefit of nemolizumab. However, the clinical experts consulted by CDA-AMC did not expect the differences in rescue therapy use between groups to affect the interpretation of the efficacy results.

The clinical experts stated that the characteristics of the patients randomized in the OLYMPIA pivotal trials were a reasonable reflection of patients who would receive nemolizumab for moderate to severe PN in Canada. In both OLYMPIA trials, most patients were white, and patients with certain medical conditions (e.g., active AD, uncontrolled asthma, chronic infections) were not eligible. These factors present potential generalizability limitations. The trial populations do not adequately represent the racial diversity of patients with PN. In addition, the clinical experts noted that PN generally affects older people with comorbidities, such as eczema, severe asthma, or hepatitis, who may qualify for treatment with nemolizumab in clinical practice. Topical and systemic medications and procedures were prohibited during the trials, and nemolizumab was given as monotherapy (unless rescue therapy was used). Clinical experts expressed that, although nemolizumab may be used on its own in clinical practice, it is likely that concomitant treatments, such as topical or intralesional corticosteroids, would also be prescribed as needed. An important limitation of the OLYMPIA 1 and OLYMPIA 2 trials is that nemolizumab was compared to placebo, which does not represent the standard of care for treatment of PN. The clinical experts noted that dupilumab would be the most relevant comparator to nemolizumab for the indication under review. However, dupilumab was not indicated for treatment of PN at the time of the OLYMPIA 1 and OLYMPIA 2 trials. The main efficacy and harms outcomes assessed in the OLYMPIA 1 and OLYMPIA 2 trials align with the outcomes of importance identified by patients and clinicians.

GRADE Summary of Findings and Certainty of the Evidence

The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• pruritus response (i.e., the proportion of patients with an improvement of ≥ 4 from baseline in PP-NRS)

• global severity of PN (i.e., the proportion of patients with IGA success)

• HRQoL (i.e., the proportion of patients with an improvement of ≥ 4 in DLQI)

• harms (i.e., AESI of newly diagnosed asthma or worsening of asthma).

Table 2: Summary of Findings for Nemolizumab vs. Placebo for Patients With Moderate to Severe PN

CI = confidence interval; DLQI = Dermatology Life Quality Index; HRQoL = health-related quality of life; IGA = Investigator’s Global Assessment; PN = prurigo nodularis; PP-NRS = Peak Pruritus Numerical Rating Scale; RCT = randomized controlled trial; vs. = versus.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aThe PP-NRS is a patient-reported, daily scale that asks patients for a unit score on an 11-point scale (0 to 10) where 0 is “no itch” and 10 is “worst itch imaginable.” The PP-NRS was used to assess the maximum intensity of pruritus during the previous 24 hours. It asked patients to rate their itch at the worst moment during that time period. Based on clinical expert input, the threshold for a clinically important between-group difference was 200 per 1,000 for the proportion of patients with at least a 4-point reduction from baseline at 16 weeks.

^bThe thresholds used to judge the target of certainty in the GRADE assessments were based on input from clinical experts.

^cThe IGA is a 5-point scale used to evaluate the global severity of PN. Based on a review of the patient’s skin, the investigator assigned a score of 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), or 4 (severe). Treatment response (i.e., IGA success) was defined as 0 (clear) or 1 (almost clear) and at least a 2-point improvement from baseline. Based on clinical expert input, the threshold for a clinically important between-group difference was 150 per 1,000 for the proportion of patients with IGA success at 16 weeks.

^dThe DLQI is a patient-reported, 10-item questionnaire covering the domains of symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment to measure how much a patient’s skin problem has affected their life over the last week. Patients rate each question from 0 (not at all) to 3 (very much). The DLQI total score is calculated as the sum of the score of each question, resulting in a minimum score of 0 and a maximum score of 30; a higher total score indicates greater impairment in quality of life. Based on clinical expert input, the thresholds for a clinically important between-group difference for the proportion of patients with at least a 4-point reduction from baseline were 200 per 1,000 at 24 weeks and 150 to 200 per 1,000 at 16 weeks.

^eNo statistical tests were performed. Rated down 1 level due to serious study limitations (i.e., the potential for unblinding with a self-reported measure).

^fBetween-group difference and corresponding 95% CI results were not available.

^gNo statistical tests were performed. There was no known minimum important difference; therefore, the target of certainty appraisal was any effect. Rated down 2 levels due to very serious imprecision; between-group differences and CIs were not available. Therefore, it is unknown if the CIs include the possibility of no difference, fewer harms, or increased harms. Clinical experts consulted by Canada’s Drug Agency commented that a greater incidence of worsening of asthma may occur in clinical practice versus what was reported in the OLYMPIA pivotal trials.

Sources: Sponsor’s Summary of Clinical Evidence;² OLYMPIA 1 Clinical Study Report;²⁴ OLYMPIA 2 Clinical Study Report;²⁵ sponsor’s Response to Request for Additional Information.²⁶ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Long-Term Extension Studies

Description of Studies

The OLYMPIA long-term extension (LTE) study (NCT04204616) is an ongoing, phase III, prospective, single-arm, multicentre, open-label study to evaluate the long-term safety and efficacy of nemolizumab in adult patients with PN. The efficacy results summarized in this review are from Interim Analysis 2 (data available as of July 21, 2024) supplemented with data from Interim Analysis 1 (data cut-off date: March 10, 2023). Patients from a previous phase IIa study who had completed all screening assessments 28 days before the baseline visit or first dose of study drug were eligible to enrol. In addition, patients from the phase III trials (i.e., the OLYMPIA 1 and OLYMPIA 2 trials) were eligible to enrol within 56 days following their last visit.

Each patient’s participation in the study will be up to 196 weeks. The study consists of a screening period (up to 4 weeks), a treatment period (up to 184 weeks with final dose administered), and an 8-week follow-up period.

The dose received in the LTE study (1 or 2 injections) is based on the patient’s body weight and previous treatment assignment in the nemolizumab PN studies.

For patients enrolling from the phase IIa study:

• Patients who weighed less than 90 kg at baseline receive 30 mg nemolizumab (with a 60 mg loading dose at baseline) every 4 weeks.

• Patients who weighed 90 kg or more at baseline receive 60 mg nemolizumab (as 2 injections of 30 mg, with no loading dose) every 4 weeks.

For patients enrolling from the phase III studies:

• The day 1 or baseline dose in the LTE study was based on the blinded study treatment assigned during the pivotal trial to maintain the blinding of the study. Therefore, patients received either 2 blinded 30 mg injections of nemolizumab or 1 blinded 30 mg injection of nemolizumab and 1 blinded injection of placebo.

• After day 1, the same dosing regimen is used as in the phase III study (i.e., 1 or 2 SC injections of 30 mg nemolizumab, based on patient weight at baseline in the phase III study).

Key efficacy outcomes include IGA success (defined as an IGA score of 0 [clear] or 1 [almost clear]) and improvements in PP‑NRS, SD-NRS, and DLQI scores.

No sample size calculation was performed. However, the plan was to enrol approximately 450 patients in this study, depending on the rollover rate from the lead-in studies. The safety population consisted of all patients who received at least 1 dose of nemolizumab (blinded or open label). All efficacy analyses were performed on the safety population and were descriptive in nature. The efficacy analyses were carried out using observed cases without imputing missing data. For binary secondary end points, efficacy data collected on or after the use of rescue therapy were treated as failure of treatment, with the exception of observed cases analysis (in which observed data are used regardless of the use of rescue therapy).

All efficacy assessments were summarized by LTE study treatment and previous treatment at each analysis visit. Data were summarized under the following headings for efficacy:

• continuous nemolizumab (i.e., patients with a < 12-week interval between the last nemolizumab dose in the lead-in study and the first dose in the LTE study [N = 307]; used to evaluate the persistence of nemolizumab effect)

• placebo to nemolizumab (includes patients who had never received nemolizumab before the LTE study)

• re-treatment (i.e., patients with a ≥ 12-week interval between the last nemolizumab dose in the lead-in study and the first dose in the LTE study [N = 27]; used to assess any loss of response).

Overall, 508 patients were enrolled in the LTE study. The mean age was 55.40 years, and the mean body weight was 82.44 kg. Most of the patients were white (87.20%) and female (60.40%). Overall, 32.10% of patients had a moderate IGA score and 15.70% of patients had a severe IGA score. A higher proportion of patients were in the placebo-to-nemolizumab group (moderate: 43.10%; severe: 31.60%) than in the continuous nemolizumab group (moderate: 26.10%; severe: 6.20%). At the lead-in baseline, patients’ weekly average PP-NRS score was 8.25. Their weekly average SD-NRS score was 7.09, and the mean DLQI total score was 16.90. The majority of patients had no atopy background (continuous nemolizumab group: 64.20%; placebo-to-nemolizumab group: 64.90%). The average time since PN diagnosis was 101.63 months.

Efficacy Results

IGA Success From LTE Study Baseline

The proportions of patients with IGA success (defined as an IGA of 0 [clear] or 1 [almost clear]) at the LTE study baseline were 40.1% and 12.6% for patients who were continuing treatment with nemolizumab (i.e., the continuous nemolizumab group) and patients who transitioned from placebo to treatment with nemolizumab (i.e., the placebo-to-nemolizumab group), respectively. At week 28, the proportions of patients with IGA success were similar across the 2 groups (continuous nemolizumab group: 53.3%; placebo-to-nemolizumab group: 56.3%). Continuous improvements in skin clearance at week 100 were observed among the 2 groups (continuous nemolizumab group: 73.4%; placebo-to-nemolizumab group: 75.2%).

Improvement of 4 or More Points in PP-NRS Score From Baseline Lead-In

More than 80% of patients experienced an improvement of 4 or more points in PP-NRS score at week 28 in the continuous nemolizumab group (88.8%) and the placebo-to-nemolizumab group (82.4%). At week 100, results indicated consistent improvement in itch relief in the continuous nemolizumab group (92.1%) and the placebo-to-nemolizumab group (94.1%); however, the sample sizes steadily decreased over time.

Improvement of 4 or More Points in SD-NRS Score From Baseline Lead-In

Following nemolizumab treatment in the LTE study, the proportion of patients with an improvement of 4 or more points in SD-NRS score from the lead-in baseline generally increased over time in all patients and in each group. A consistent improvement of greater than or equal to 4 points from baseline lead-in was observed across the groups at week 100 (continuous nemolizumab group: 86.4%; placebo-to-nemolizumab group: 87.3%). However, the sample sizes steadily decreased over time.

Improvement of 4 or More Points in DLQI Score From Baseline Lead-In

At week 28, the proportions of patients achieving an improvement of 4 or more points from baseline lead-in were 87.8% versus 90.5% in the continuous nemolizumab group and the placebo-to-nemolizumab group, respectively. Continuous improvements were observed in patients in both groups at week 52 (continuous nemolizumab group: 90.1%; placebo-to-nemolizumab group: 91.0%) and week 100 (continuous nemolizumab group: 89.9%; placebo-to-nemolizumab group: 93.1%).

Harms Results

For Interim Analysis 1, a total of 407 patients (80.1%) experienced at least 1 AE during the overall study period. The most frequently reported AEs included infections and infestations (54.3%), skin and SC tissue disorders (36.8%), musculoskeletal and connective tissue disorders (26.0%), respiratory, thoracic, and mediastinal disorders (17.0%), and nervous system disorders (15.4%). SAEs were reported in 54 patients (10.6%). SAEs experienced by more than 1 patient were neurodermatitis (4 patients [0.8%]), myocardial infarction (3 patients [0.6%]), and angina pectoris, cardiac failure congestive, cholelithiasis, pneumonia, osteoarthritis, and carotid artery stenosis (2 patients [0.4%] each). A total of 35 patients (6.9%) had an AE leading to withdrawal from the study. AESIs occurred among 319 patients (62.8%). The most commonly reported AESIs were infections (54.5%) and injection-related reactions (31.7%). Newly diagnosed asthma or worsening of asthma was reported in 5.7% of patients. Two patients (0.4%) experienced AEs leading to death. The causes of death were myocardial infarction and end-stage renal disease; however, both patients had medical histories of comorbidities, and neither death was considered related to the study drug.

Critical Appraisal

The OLYMPIA LTE study is a phase III, prospective, single-arm, multicentre, open-label study. The single-arm design of the study limits the ability to draw conclusions about the long-term efficacy of nemolizumab. The open-label nature of the study may increase the risk of bias in the evaluation of subjective outcomes. The cumulative exposure to study treatment and treatment adherence were not summarized by group (i.e., continuous nemolizumab, re-treatment, or placebo to nemolizumab); this further compromised our ability to judge the potential patterns of correlation between treatment exposure and outcome over the long term. Patients receive treatment in the LTE study based on their previous enrolment in nemolizumab studies. The impact of these differing dosing regimens on efficacy results is unknown.

Data from patients contributing to the analyses steadily decreased over time as patients discontinued treatment (around 30% at Interim Analysis 2). Those patients who discontinued the LTE study (17.9% versus 14.9% in the continuous nemolizumab and placebo-to-nemolizumab groups, respectively) could be systematically different from those who remained in the study. Therefore, the trend of relative stable treatment effect over time could be biased as a result of survival or attrition bias. The sample size in the re-treatment group was small, limiting the ability to draw conclusions regarding efficacy results. Most patients received at least 1 concomitant therapy during the treatment period; the effect of these on efficacy outcomes cannot be determined. The harms data aligned with the evidence from the pivotal studies.

Indirect Comparisons

Description of Studies

Due to the lack of direct evidence comparing nemolizumab with other existing, relevant therapies for the treatment of patients with PN, the sponsor submitted 1 indirect treatment comparison (ITC), a network meta-analysis (NMA) comparing nemolizumab with dupilumab, vixarelimab, nalbuphine, and placebo. The outcomes assessed in the NMA included PP-NRS change from baseline, PP‑NRS response, IGA success, composite PP-NRS and IGA response, DLQI, and AEs at time points ranging from week 4 to week 24. This ITC summary focuses on the comparison of nemolizumab with dupilumab because vixarelimab and nalbuphine are not relevant in clinical practice settings in Canada.

Efficacy Results

The NMA demonstrated a favourable benefit of nemolizumab when compared with dupilumab. However, the favourable effect was not consistent. It was influenced by the outcomes measured (such as PP-NRS change from baseline, PP-NRS response, IGA success, composite PP-NRS and IGA response, and DLQI change from baseline), the time points assessed, and the choice of the model fit (i.e., fixed-effects model versus random-effects model). Overall, although the findings of the NMA are subject to considerable limitations due to the significant heterogeneity between the trials included in the analyses, the clinical experts consulted for this review indicated that the results overall aligned with their expectations that the effects of nemolizumab would be comparable to those of dupilumab in clinical practice.

Sensitivity analyses were conducted based on the non-TCS and/or non-TCI populations. Based on the fixed-effects model, for PP‑NRS response at week 12, a favourable effect of nemolizumab was reported. No favourable effect of nemolizumab was reported for other outcomes. Based on the random-effects model, a favourable effect for nemolizumab was observed for PP-NRS response at week 12, while no favourable effect for nemolizumab was observed for other outcomes (e.g., composite PP-NRS and IGA response at week 24).

Harms Result

Based on both the fixed- and random-effects models, the NMA did not show a favourable safety profile for nemolizumab compared with dupilumab.

Critical Appraisal

Overall, the NMA was conducted according to accepted methodological guidance. The potential key limitations of the NMA were the considerable heterogeneity across the included studies in terms of study and patient characteristics (e.g., eligibility criteria, population, and trial duration). For example, the dupilumab trials required patients to have a history of a 2-week course of a medium-potent to superpotent TCS having failed, or for it to be medically inadvisable for them to use a TCS; however, this was not required in the nemolizumab trials. Therefore, the NMA results may be biased in favour of nemolizumab because patients with a history of treatment refractoriness (in the dupilumab trial) may have a relatively poorer response during the trial than patients without such a history. The significant differences in patient and trial characteristics across the included studies may threaten the transitivity assumption for the NMA analysis.

Studies Addressing Gaps in the Evidence From the Systematic Review

No studies addressing gaps in the systematic review evidence were submitted by the sponsor.

Conclusions

Evidence from the OLYMPIA 1 and OLYMPIA 2 trials demonstrated that, compared to placebo, treatment with nemolizumab resulted in greater improvements in itch response, lesion clearance, and HRQoL in adult patients with moderate to severe PN. The GRADE assessment suggested that, at 16 weeks, compared to placebo, nemolizumab results in a clinically meaningful increase in the proportion of patients with at least a 4-point improvement in PP-NRS score and in the proportion of patients with IGA success. The GRADE assessment also suggested that nemolizumab likely results in a clinically meaningful increase in the proportion of patients with at least a 4-point improvement in DLQI score compared to placebo at 16 weeks (evidence from the OLYMPIA 2 trial) and 24 weeks (evidence from the OLYMPIA 1 trial).

In the OLYMPIA 1 and OLYMPIA 2 trials, most patients in the nemolizumab and placebo groups experienced at least 1 AE. In both trials, the proportions of patients who experienced the AESI of newly diagnosed asthma or worsening of asthma were low, and the GRADE assessment suggested low certainty regarding the effect of nemolizumab on this AESI compared to placebo.

The ability to draw conclusions regarding the long-term efficacy of nemolizumab is limited by the single-arm, open-label design of the OLYMPIA LTE study and by the patient attrition that occurred throughout the study. The harms results in the LTE study aligned with those of the pivotal trials, with no new AEs identified.

The NMA demonstrated a favourable benefit of nemolizumab compared with dupilumab. However, the favourable effect was not consistent, and it was influenced by the outcomes measured and time points assessed. The NMA may suggest a comparable clinical efficacy and overall safety profile between nemolizumab and dupilumab in the treatment of patients with PN; however, the findings of the NMA are subject to considerable limitations.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of nemolizumab 30 mg per 0.49 mL for SC injection in the treatment of moderate to severe PN. The approved Health Canada indication is for nemolizumab to be used for the treatment of adults with moderate to severe PN whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. This review is based on the sponsor’s initial reimbursement request for nemolizumab to be used for the treatment of moderate to severe PN. The sponsor has revised the reimbursement request to align with the approved Health Canada indication; however, the revision did not warrant a significant update to the report.

Disease Background

The contents of this section have been informed by materials submitted by the sponsor and by clinical expert input. The following information has been summarized and validated by the review team.

PN is a rare, neuroimmune, inflammatory skin disease characterized by the presence of chronic (≥ 6 weeks) itch; history and signs of repeated scratching, such as excoriation and scars; and multiple, localized or generalized, hyperkeratotic, and symmetrically distributed pruritic nodules on the extensor surfaces of the extremities and trunk.^3-7 РΝ is frequently associated with a history of AD.⁴ The etiology and pathophysiology of PN are still unclear; however, it is thought to be associated with IL-31–driven neuroimmune dysfunction, immune and neuronal dysregulation, and skin tissue remodelling.²⁷ Itch is the most burdensome symptom for patients with PN.²⁸ Itching and scratching cause severe skin barrier damage, thickening and crusting of nodules, and scarring once the nodules heal.²⁹ Nodules resulting from PN are disfiguring and affect large body surface areas.³⁰ Different etiologies may trigger pruritus (induction phase), which leads to the scratching that leads to neuronal sensitization (chronicity phase) and the development of the pruriginous lesions (disease stage).^20,31

The exact incidence and prevalence of PN in Canada are unknown. In an epidemiological study of adults in the US aged 18 to 64 years, the estimated prevalence was 72 per 100,000 persons.⁴ ΡN can occur in all age groups and without sex preferences. However, it primarily affects older adults,⁴ with approximately 69% of patients aged 51 years or older.^5,9-11 In addition, in the US, PN seems to be more common among African Americans than among people from other ethnic origins.⁴

PN is associated with an increased prevalence of comorbidities of dermatologic, systemic, neurologic, and/or psychiatric origin.^14,32,33 PN leads to significantly reduced QoL because the symptoms, such as itch and skin lesions, affect patients’ personal and social lives.^12,13 PN interrupts sleep quality due to the nocturnal itch-scratch cycle; it is strongly associated with fatigue.¹⁵ It also disrupts day-to-day activities, such as getting dressed, self-care or personal hygiene, planning activities, and performing chores.¹³

Diagnosis of PN requires a physical examination and assessment of clinical symptoms; the symptoms may be similar to those associated with other chronic itch or excoriating disorders. It is estimated that 43% of patients with PN are initially misdiagnosed;¹⁶ additional bloodwork may be required to differentiate patients with an unknown underlying cause (e.g., chronic kidney disease, liver disease, thyroid disease, HIV infection, parasitic infection, or malignancy). ^4,17,18 However, the clinical experts consulted by CDA‑AMC noted that if PN is diagnosed by a dermatologist, a biopsy is not required to confirm the diagnosis. Given the burden of PN and its associated comorbidities, patients with PN have high rates of health care and specialty care utilization.¹⁹

Standards of Therapy

The contents of this section have been informed by materials submitted by the sponsor and by clinical expert input. The following information has been summarized and validated by the review team.

According to clinical experts consulted by CDA-AMC, the primary goals of therapy for patients with PN are to reduce the severity of pruritus, treat existing lesions (i.e., reduce both the number and size of nodules), prevent the formation of new lesions, and improve HRQoL while minimizing any adverse effects of treatment. In Canada, no formal practice guidelines for the management of PN exist. International guidelines and published literature describe the use of various medications and procedures for the treatment of PN using a stepwise and multimodal approach, considering factors such as the patient’s age, comorbidities, the severity of PN, QoL, concomitant medications, and the treatment side effect profile.^10,20-22 The guideline recommendations include emollients for PN of any severity and topical medications (e.g., corticosteroids, calcineurin inhibitors, capsaicin), intralesional corticosteroids, and H₁ antihistamines as initial-tier treatment options. Guidelines state that various systemic medications (e.g., methotrexate, cyclosporine, gabapentinoids, thalidomide, dupilumab) and UV phototherapy are used as later-tier options, but note that that patients may be considered for treatment at any tier, based on clinical presentation. Most medications for PN are used off-label and have limitations with respect to evidence of efficacy; certain treatment options (e.g., methotrexate and cyclosporine) are also associated with safety concerns.^20-22 In Canada, dupilumab is currently the only treatment with an approved indication for the treatment of PN.^2,23

Clinical experts consulted by CDA-AMC stated that PN is often managed initially with high-potency TCSs to reduce inflammation and alleviate itching. Other initial treatment options include TCIs, topical anesthetics, and oral antihistamines. Clinical experts noted that intralesional corticosteroid injections are often effective for flattening nodules and reducing itch, but that these treatments may not be suitable for multiple lesions. Other therapies that may be considered for PN include topical capsaicin, gabapentin, pregabalin, carbamazepine, doxepin, mirtazapine, mycophenolate mofetil, low-dose naltrexone, and UV light treatment (i.e., phototherapy). Clinical experts commented that systemic immunosuppressants (i.e., methotrexate or cyclosporine) may be considered for severe or treatment-resistant disease, but noted that these may cause significant side effects and may not be appropriate for long-term use, older patients, or those with polypharmacy. Clinical experts highlighted that PN is difficult to treat; in addition, the currently available treatment options may provide only partial and/or short-term symptomatic relief, and the use of these treatments is often limited by side effects, safety risks, and access and feasibility issues. Clinical experts expressed the need for highly effective, disease-modifying, systemic PN therapies that provide sustained relief, are safe for long-term use, and are convenient and accessible.

Drug Under Review

The key characteristics of nemolizumab are summarized in Table 3 along with other treatments available for PN.

According to the product monograph,¹ nemolizumab is available as an SC injection, and the dosing is weight-based. For patients who weigh less than 90 kg, nemolizumab is recommended to be administered at an initial dose of 60 mg through 2 injections of 30 mg each, followed by 30 mg administered every 4 weeks. For patients who weigh 90 kg or more, nemolizumab is recommended to be administered at an initial dose of 60 mg through 2 injections of 30 mg, followed by 60 mg every 4 weeks. The patient may self-inject or the caregiver may administer nemolizumab. Before the first injection, patients and/or caregivers should be given proper instructions for preparing and administering nemolizumab.

Nemolizumab is a humanized immunoglobulin G2 monoclonal antibody that inhibits IL-31 signalling by binding selectively to the IL‑31 receptor alpha. IL-31 is a cytokine that is involved in pruritus, inflammation, epidermal dysregulation, and fibrosis. Although the mechanism of action of nemolizumab has not been fully established, the drug inhibits IL-31–induced responses, including the release of proinflammatory cytokines, such as IL-6.¹

Nemolizumab has not been previously reviewed by CDA-AMC.

Nemolizumab has been approved for the treatment of adults with PN by the FDA in the US.³⁴ It has also been approved by the European Medicines Agency (in the European Union) for the treatment of adults with moderate to severe PN who are candidates for systemic therapy.³⁵ Nemolizumab is currently under review for the treatment of PN in adults by the National Institute for Health and Care Excellence in England.³⁶

At the time of this CDA-AMC review, nemolizumab was also under review by Health Canada and CDA-AMC for AD, with the following requested reimbursement criteria submitted to CDA-AMC: treatment of moderate to severe AD in patients aged 12 years and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable, and/or who are refractory to or ineligible for systemic immunosuppressant therapies.³⁷

Table 3: Key Characteristics of Nemolizumab and Dupilumab

SC = subcutaneous.

^aHealth Canada–approved indication.

Sources: Product monographs for nemolizumab¹ and dupilumab.²³

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

A single patient group, the CSPA, provided input for this submission. The CSPA is a national charity that supports the health and well-being of people across Canada affected by skin, hair, and nail conditions through collaboration, advocacy, and education. The CSPA gathered information regarding the experience of people living with PN through a patient and caregiver survey conducted from September 12, 2024, to November 29, 2024. Nine survey responses (from 8 patients and 1 caregiver) were received from people in Canada (New Brunswick [n = 1], Quebec [n = 1], Ontario [n = 5], Alberta [n = 1], and Northwest Territories [n = 1]). None of the survey respondents had experience with nemolizumab.

Five respondents provided their ages. All were older than 35 years, with more than half older than 55 years. Of those who answered the question, 5 respondents had had PN for fewer than 5 years; most respondents reported having severe (n = 3) or moderate (n = 1) PN, and none reported mild PN. All survey respondents reported their arms and backs being affected by the condition, while 75% reported impacts on their legs and 50% reported impacts on their buttocks. All the patients reported itchy skin, itchy bumps (nodules), burning or stinging skin, scratching, pain, and hyperpigmentation (dark spots). Three patients reported skin scarring because of PN. One patient reported experiencing side effects of flares and hypopigmentation (light spots).

The survey respondents mentioned that PN affects the following aspects of their lives: family relationships, intimate relationships, work life, mental health, social life, daily activities, sleep, self-esteem, finance, and sex. Twenty-five percent of respondents shared that they miss work 5 to 10 times monthly. The CSPA highlighted that caregivers were also affected, given that witnessing their loved ones endure emotional pain, insecurity, and social withdrawal caused a psychological burden and left them feeling helpless. Additionally, the caregiver in the survey shared that it can be difficult to encourage their loved one to continue with treatments for PN.

All respondents had used TCSs in the past and rated their experience as either “did not work very well” (60%) or “no change” (40%). In addition, 80% of respondents indicated that they had used topical capsaicin, oral antihistamines, and methotrexate, and 60% had tried TCIs, narrow-band UVB phototherapy, and medical cannabis. However, they noted that these did not work very well or that there was no change. Two respondents reported the use of dupilumab in the past, but they had “no change” in their condition.

Patients reported experiencing side effects with currently available treatments, including a racing heart, skin irritation, nausea, vomiting, hypopigmentation, and hyperpigmentation. One respondent stopped treatment for PN because of side effects, and 3 respondents stopped their treatments because of a lack of efficacy. The CSPA highlighted that 4 of 5 respondents strongly agreed that they would be interested in a new treatment for PN and that they wished there was a better PN treatment option for them. Of the 5 respondents, 3 respondents disagreed — and 2 respondents strongly disagreed — with the statement that they were satisfied with their current treatment for PN. Respondents also shared that financial challenges affected their access to PN treatments.

The respondents identified effectiveness, affordability, and lack of side effects as the top priority characteristics of a new PN treatment. Others included the treatment being easy to take or apply and conducive to the patient’s schedule. According to the patient group input, in addition to managing itch, psychological and social relief are the motivations underlying these desired outcomes. The caregiver respondent disclosed that the cost of medication is the most important aspect of a new treatment for them.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC 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 drug’s potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of PN.

Unmet Needs

Clinical experts consulted by CDA-AMC expressed that there is an unmet need for disease-modifying, systemic therapies that address the underlying pathophysiological mechanisms of PN; are highly effective in achieving treatment goals (e.g., itch relief, treatment of lesions); provide sustained disease control and symptom relief; are safe for short- and long-term use; and are convenient and accessible. Clinical experts noted a need for treatments that are safe across diverse patient populations (e.g., all ages, particularly older patients; those with comorbidities, such as chronic kidney disease, chronic liver disease, HIV, and hepatitis; and patients who are pregnant). Clinical experts highlighted the limitations of traditional treatment options. For example, topical therapies (e.g., high-potency topical steroids) may provide limited benefit, may be impractical or unsafe for extensive disease, and may be inconvenient. Intralesional corticosteroid injections may be painful and cannot address multiple lesions simultaneously. Systemic immunosuppressants (e.g., methotrexate and cyclosporine) lack disease specificity, have limited efficacy, require regular monitoring, and are associated with significant adverse effects and contraindications that preclude their use in the population of patients typically affected by PN. Phototherapy has significant limitations in terms of access and patients’ ability to adhere to treatment. Clinical experts highlighted that resistance to treatments can occur, with patients experiencing recurrent symptoms or worsening of disease.

Place in Therapy

Clinical experts commented that, along with dupilumab, nemolizumab is expected to cause a shift in the current treatment paradigm for PN in Canada. Clinical experts expect that, as novel drugs targeting pathways that play a major role in PN pathogenesis, biologic therapies will redefine the treatment approach, providing benefit beyond the symptomatic management offered by conventional treatments. Clinical experts expected that traditional, less expensive therapies (e.g., TCSs) would still be used for the initial management of PN because these are generally well-tolerated and can effectively manage mild to moderate cases; nemolizumab would be an appropriate choice for patients with moderate to severe PN who do not respond to these treatments. According to clinical experts, nemolizumab would also be expected to be used in patients with more severe, chronic, or refractory disease when standard therapies have failed to provide adequate relief. Clinical experts noted that it would be reasonable for patients to try TCSs or other first-line therapies initially, but that for patients with moderate to severe PN who do not respond, initiating nemolizumab earlier would be appropriate to avoid unnecessary delays in relief. Clinical experts stated that nemolizumab or dupilumab would likely be the preferred systemic treatment options over systemic immunosuppressants because biologic therapies offer safer, more targeted options. Clinical experts stated that, based on their experience with previously approved biologic medications across different indications, there are instances where the biologic on its own is sufficient, and this may be the case with nemolizumab. However, they noted that nemolizumab would likely be combined with TCSs (especially when starting nemolizumab) and/or intralesional corticosteroids (as needed). Clinical experts also noted that, although less likely, nemolizumab could be combined with phototherapy if patients are not experiencing an adequate response and that nemolizumab may be combined with methotrexate in very severe cases. (However, combining nemolizumab and cyclosporine therapy would be very unlikely.)

Patient Population

Clinical experts stated that nemolizumab would best suit patients with moderate to severe or refractory PN, particularly those with persistent pruritus and large numbers of chronic lesions for whom conventional treatments have failed. Clinical experts also commented that the patients most in need of treatment are those who have chronic disease that significantly affects their QoL (e.g., severe itch, sleep disruption, social isolation) as well as those who have contraindications to conventional systemic therapies. According to clinical experts, the patients who are least suited for nemolizumab would be those with mild PN or mild symptoms that can be managed with conventional treatments; nemolizumab may not be recommended for individuals with compromised immune function or those with active infections, although clinical experts noted that this can be debated. In clinical practice, suitable patients would be identified using clinical judgment, based on an assessment of the number of lesions, symptom severity, and QoL. Clinical experts expressed that PN is a clinical diagnosis; they noted that skin biopsy may be performed, but PN on biopsy can be similar to other chronic itch or excoriating disorders, and biopsy results are not entirely specific to PN. Clinical experts also commented that underdiagnosis of PN is possible due to its similarities with other pruritic skin conditions (e.g., eczema, psoriasis).

Assessing the Response to Treatment

According to clinical experts, treatment response in patients with PN is assessed in clinical practice based on improvement in the number of lesions, reduction in pruritus, and improvement in QoL; physicians may prioritize these outcomes differently. The clinical experts noted that assessment of treatment response in clinical practice does not usually rely on the grading tools used in clinical trials as stringently. Disease severity may be assessed using lesion count (including subjective improvement) or scoring systems like physician global assessment, with a clinically meaningful response being a score of 0 or 1 (i.e., 5 or fewer nodules). Clinical experts noted that itch intensity may be measured using an NRS, with a reduction of 4 or more points considered clinically meaningful; however, it may also be measured subjectively, with patient-reported “good to excellent” improvement being considered clinically meaningful. QoL may be assessed using the DLQI or other indicators, such as improvement in daily life, sleep, and social well-being. Clinical experts indicated that response would typically be assessed 3 to 6 months after the initiation of PN treatment and at the same interval while the disease is active, with annual follow-up if the disease is controlled (with or without therapy). The experts indicated that the initial treatment response for a biologic would usually be assessed after 6 months.

Discontinuing Treatment

When deciding to discontinue treatment with nemolizumab, the clinical experts would evaluate whether the patient had achieved the desired clinical outcomes within a 6-month time frame. Specifically, a clinically important response would be a decrease in the lesion count from 20 or more at the start of therapy to 5 or fewer, or a decrease in peak itch severity by at least 4 points out of 10 on the NRS. The clinical experts emphasized that some patients may not meet these specific parameters, but for patients experiencing some improvement who wish to continue, therapy would not be stopped. In patients with a partial response to therapy, the decision to stop treatment would consider whether any other effective treatment options were available. Moreover, clinical experts expressed that they take a patient-centred approach and consider patient-reported happiness when deciding whether to continue therapy. The experts also noted that pruritus may improve before lesions or vice versa, and that both may not always show simultaneous improvement. If neither outcome is achieved, discontinuation due to lack of improvement would be considered. Additional factors supporting discontinuation may include SAEs or the emergence of comorbidities requiring other treatments; however, the primary focus is on achieving clinical milestones related to disease severity and symptom control.

Regarding the possibility of withdrawing nemolizumab in patients who achieve treatment goals, clinical experts noted that PN is a chronic, immune-mediated condition; as such, there may be risk of relapse if nemolizumab treatment is stopped. This has been observed in patients with PN who have stopped other therapies. As such, clinical experts expected that, based on current clinical knowledge, patients would continue to take nemolizumab over the long term to treat PN. No dose adjustment (i.e., lowering of the dose) would be expected to occur in patients who respond well to maintenance therapy with nemolizumab.

Prescribing Considerations

Both clinical experts agreed that, due to the complexity of diagnosing PN, nemolizumab treatment for PN should be prescribed only by dermatologists. PN can be underdiagnosed, overdiagnosed, or misdiagnosed by other providers. PN has a broad differential that requires the clinician to rule out other potential causes. Patients with PN can also have other underlying diagnoses. Clinical experts noted that dermatologists are best equipped to maximize nemolizumab treatment outcomes by optimizing the use of concurrent conventional therapies and that academic (hospital) and community dermatologists are well-equipped to diagnose PN and prescribe nemolizumab.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

Two clinician groups, the Atlantic Dermatology Group and the DAO, provided their input for this submission. The Atlantic Dermatology Group is a group of dermatologists practising in the Atlantic provinces (in hospitals, in academic positions in medical schools, and as investigators with extensive experience in clinical trials and research). Input was provided by 5 clinicians, and information was gathered from sessions related to PN at the September 2024 European Academy of Dermatology and Venerology in Amsterdam and from the literature. The DAO consists of community dermatologists as well as nationally and internally recognized experts in the treatment of acne. It provides a unified voice for Ontario dermatologists in promoting better patient care, promoting dermatology in Ontario, and supporting research and education within the community. Input was provided by 7 clinicians, and information was gathered from clinical trial data, available literature retrieved through PubMed, and experience with the use of nemolizumab from clinical trialists in Canada.

Both clinician groups highlighted that, currently, there are no specific clinical practice guidelines for PN in Canada. They indicated that current therapies include topical treatments, such as corticosteroids and emollients, dupilumab (approved by Health Canada for PN, but not publicly reimbursed), and off-label regimens (i.e., systemic immunosuppressants, such as methotrexate, cyclosporine, thalidomide, lenalidomide, tricyclic antidepressants, Janus kinase inhibitors, neurokinin-1 receptor antagonists, and monoclonal antibodies targeting IL-4 pathways). The DAO also highlighted that nondrug treatments, such as UVB phototherapy and psychosocial approaches, have been attempted, but that these have been associated with limited availability and success in addressing the psychological burden of PN and improving overall QoL. The Atlantic Dermatology Group further highlighted evidence from a systematic review that concluded that while phototherapy, corticosteroids, cyclosporin, and methotrexate represent viable options, the potential benefits are limited because of the risk of relapse and potential side effects.

The DAO clinician group highlighted the following unmet needs in PN treatment: therapies that provide rapid and sustained relief from severe itch, improve skin lesions, and address the psychosocial impacts of the disease (e.g., sleep disturbances and mental health issues). The group highlighted the poor tolerance and/or inconvenience associated with other current treatments and the need to target the underlying neuroimmune mechanisms that drive PN. The Atlantic Dermatology Group clinicians noted the need for a therapy that provides clinically significant reductions in itch and improves physician global assessment of skin lesions along with QoL.

The Atlantic Dermatology Group indicated that nemolizumab will shift the current treatment paradigm because it can be used as first-line therapy in patients with PN, including those who are intolerant to dupilumab, TCSs, or phototherapy, or for whom these treatments have failed. The group also noted that nemolizumab would be used as a stand-alone treatment. However, the DAO clinician group indicated that nemolizumab would fit as a targeted, second-or third-line option in patients for whom topical therapies and phototherapy produced an insufficient disease response or for whom these treatments have failed.

The DAO clinician group noted that the patients best suited for treatment with nemolizumab would be those with moderate to severe PN who did not achieve adequate relief from topical therapies or phototherapy, or those unable to access or tolerate these treatments. This would include those who have persistent and intense pruritus, widespread nodular lesions, or significant impairment in QoL. The Atlantic Dermatology Group highlighted that those patients with moderate to severe PN and an itch score of 7 or higher with at least 20 lesions would be in most need and best suited for treatment. The DAO clinician group further noted that patients with contraindications (such as a known hypersensitivity to nemolizumab), those with milder disease that responds to topical steroids, and those with conditions that significantly compromise their immune function (unless the benefits outweigh the risks) would not be suitable for treatment with nemolizumab.

The DAO clinician group noted that to identify the patients who would most likely respond to nemolizumab, a clinician assessment of the intensity and persistence of itch, the extent of nodular lesions, and the impact on daily functioning and QoL was sufficient. The Atlantic Dermatology Group noted that no clinical, pathological, or chemical markers exist to help clinicians identify the patients most likely to exhibit a response to treatment.

The Atlantic Dermatology Group noted that misdiagnoses were unlikely for patients managed by dermatologists in clinical practice. It emphasized the consideration of other diagnoses (i.e., pemphigoid nodularis, mastocytosis, lichen planus, nodular scabies, arthropod bites, lymphocytoma cutis, lymphomatoid papulosis, amyloidosis, reticulohistiocytosis, and cutaneous T-cell lymphoma). However, the DAO clinician group indicated that PN may be underdiagnosed or misdiagnosed as other pruritic dermatoses and that clinician education and awareness are key to improving diagnostic accuracy.

Both clinician groups noted that a 4-point improvement in PP-NRS score should be used to determine if a patient is responding to treatment. The Atlantic Dermatology Group and the DAO noted that a physician’s IGA finding of clear or almost clear and a reduction of at least 2 points from baseline are the outcomes used to determine treatment response. In addition, the Atlantic Dermatology Group highlighted that DLQI should be measured, while the DAO highlighted the importance of assessing subjective feedback on daily comfort and sleep quality.

Both clinician groups agreed that treatment discontinuation should be considered if there is a lack of meaningful reduction in PP-NRS or persistent nodular lesions as assessed by IGA. The Atlantic Dermatology Group noted that treatment should be discontinued after 6 months of therapy if there is a lack of response. Additional criteria for discontinuation were noted by the DAO, including significant AEs (i.e., hypersensitivity, injection-site reaction, and long-term safety issues, including recurrent infections). Disease progression (such as worsening lesions), complications such as skin infections, and patient-reported dissatisfaction were also noted as important factors requiring treatment reassessment. In cases in which systemic immunosuppressants or other biologics are required to manage refractory disease, nemolizumab may no longer be an optimal choice.

The Atlantic Dermatology Group indicated that PN should be managed by dermatologists experienced in both the diagnosis and management of PN and the use of biologics. The group also noted that dermatologists should be experienced in counting nodules and assessing patients through the DLQI, IGA, and PP-NRS. The DAO clinician group noted that, in addition to dermatologists, allergists or immunologists may be involved in managing patients with PN where PN overlaps with other atopic or immune-mediated conditions. The group highlighted that while the diagnosis, treatment initiation, and monitoring of patients requires the expertise and oversight of specialists, nemolizumab may be prescribed in various clinical settings (such as community clinics, hospital outpatient departments, and specialty dermatology or allergist clinics) and administered by patients at home.

Drug Program Input

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

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

AD = atopic dermatitis; AE = adverse event; CDA-AMC = Canada’s Drug Agency; CDEC = Canadian Drug Expert Committee; IGA = Investigator’s Global Assessment; NOC = Notice of Compliance; PN = prurigo nodularis; PP-NRS = Peak Pruritus Numerical Rating Scale.

Clinical Evidence

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of nemolizumab 30 mg per 0.49 mL powder and solvent solution for SC injection in the treatment of moderate to severe PN. The focus will be on comparing nemolizumab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of nemolizumab is presented in 4 sections, with our critical appraisal of the evidence included at the end of each. The first section, the Systematic Review, includes pivotal studies and randomized controlled trials (RCTs) that were selected according to the sponsor’s systematic review protocol. Our assessment of the certainty of the evidence in this first section, using the GRADE approach, follows the critical appraisal of the evidence. The second section includes sponsor-submitted LTE studies. The third section includes indirect evidence from the sponsor. The sponsor did not include additional studies addressing important gaps in the systematic review evidence (fourth section).

Included Studies

Clinical evidence from the following studies is included in the review and appraised in this document:

• 2 pivotal RCTs identified in the systematic review

• 1 LTE study

• 1 ITC.

Systematic Review

The contents of this section have been informed by materials submitted by the sponsor. The following information has been summarized and validated by the review team.

Description of Studies

Characteristics of the included studies are summarized in Table 5.

Table 5: Details of Studies Included in the Systematic Review

ACT = asthma control test; AD = atopic dermatitis; AP-NRS = Average Pruritus Numerical Rating Scale; DLQI = Dermatology Life Quality Index; HADS = Hospital Anxiety and Depression Scale; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HRQoL = health-related quality of life; IGA = Investigator’s Global Assessment; PAS = Prurigo Activity Score; PCR = polymerase chain reaction; PEF = peak expiratory flow; PGAD = Patient Global Assessment of Disease; PGAT = Patient Global Assessment of Treatment; PN = prurigo nodularis; PP-NRS = Peak Pruritus Numerical Rating Scale; PRO = patient-reported outcome; SD-NRS = Sleep Disturbance Numerical Rating Scale; TB = tuberculosis; ULN = upper limit of normal; WASO = wakefulness after sleep onset.

^aIGA success was defined as an IGA of 0 (clear) or 1 (almost clear) and an improvement of 2 or more points from baseline.

^bSecondary end points were assessed up to 24 weeks for the OLYMPIA 1 trial and up to 16 weeks for the OLYMPIA 2 trial.

Sources: Sponsor’s Summary of Clinical Evidence;² OLYMPIA 1 Clinical Study Report;²⁴ OLYMPIA 1 Clinical Study Protocol;⁴⁰ OLYMPIA 2 Clinical Study Report;²⁵ OLYMPIA 2 Clinical Study Protocol.⁴¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The OLYMPIA 1 and OLYMPIA 2 trials were both phase III, randomized, double-blind, placebo-controlled, parallel-group, multicentre studies investigating the efficacy and safety of nemolizumab versus placebo for the treatment of adult patients with PN. In the OLYMPIA 1 trial (N = 286) and OLYMPIA 2 trial (N = 274), patients were randomized 2 to 1 to receive nemolizumab or placebo across 77 sites (10 countries) and 55 sites (9 countries), respectively, including a total of 8 sites in Canada that randomized a total of 44 patients.^2,24,25 Randomization was done by interactive response technology and stratified by study site and baseline body weight (< 90 kg and ≥ 90 kg) using an interactive response technology system. Each study comprised 3 phases: screening for enrolment (4 weeks in each study), treatment (24 weeks in the OLYMPIA 1 trial and 16 weeks in the OLYMPIA 2 trial), and follow-up (8 weeks in each study).^2,40,41 The trial designs for the OLYMPIA 1 and OLYMPIA 2 studies are presented in Figure 1 and Figure 2, respectively. At the end of the 24-week OLYMPIA 1 or 16-week OLYMPIA 2 treatment periods, patients were eligible to enter an active treatment LTE study; participants in the LTE study were not required to complete the follow-up visit.^42,43

The primary end points in the OLYMPIA 1 and OLYMPIA 2 trials were the proportions of patients with improvements of at least 4 points from baseline in PP-NRS score at week 16 and the proportions of patients reporting IGA success (defined as an IGA response of 0 [clear] or 1 [almost clear] and at least a 2-point reduction from baseline) at week 16. The key secondary end points were the proportions of patients with an improvement of at least 4 points from baseline in PP-NRS score at week 4; a PP-NRS score of less than 2 at week 16; an improvement of at least 4 points from baseline in SD-NRS score at week 16; an improvement of at least 4 points from baseline in SD-NRS score at week 4; and a PP-NRS score of less than 2 at week 4.^2,40,41 Efficacy and safety assessments were performed at visits throughout the screening and treatment periods.^42,43

Throughout both studies, patient safety was reviewed and monitored by an independent data monitoring committee. In addition, an independent adjudication committee (IAC) reviewed all asthma-related events and assessed whether these represented new diagnoses or worsening of asthma; it also assessed severity as mild, moderate, or severe. The IAC did not assess relationship to study drug. For the OLYMPIA 1 trial, the results presented in this review are based on a database lock of April 11, 2023; for the OLYMPIA 2 trial, the final database lock was on June 16, 2022.^2,24,25

Protocol Amendments

Original protocols for both the OLYMPIA 1 and OLYMPIA 2 studies were finalized on February 21, 2020. Both trial protocols were amended a total of 4 times, and amendments occurred at the same time for both. The first 2 amendments (May 4, 2020, and June 25, 2020) were conducted before patient enrolment. The second 2 amendments (December 22, 2022, and November 19, 2021) occurred following the start of the studies and included updates to the eligibility criteria, clarifications of the protocol and statistical analysis plan, and the addition of the proportion of patients with PP-NRS score improvement of at least 4 points from baseline and IGA success at week 16, week 20, and week 24 as a secondary efficacy end point (week 20 and week 24 time points for the OLYMPIA 1 trial only). Amendments occurred before study unblinding and were not considered by the sponsor to affect the interpretation of the study results.^2,24,25

Figure 1: OLYMPIA 1 Trial Design

BL = baseline; Q4W = every 4 weeks; R = randomized; SC = subcutaneous; W = week.

Note: This schematic representation of the OLYMPIA 1 study reports the initial screening phase followed by the treatment period and follow-up period. The schematic was organized into 2 treatments groups of patients, those who weighed less than 90 kg and those who weighed 90 kg or more. The loading dose was 60 mg for patients who weighed less than 90 kg, while no loading dose was administered to patients who weighed 90 kg or more.⁴⁴

Sources: Sponsor’s Summary of Clinical Evidence;² sponsor’s data on file.⁴⁵

Populations

Inclusion and Exclusion Criteria

The inclusion and exclusion criteria were the same for the OLYMPIA 1 and OLYMPIA 2 trials; the key eligibility criteria are provided in Table 5. For both studies, those eligible for participation were female or male patients aged 18 years or older with a clinical diagnosis of PN for at least 6 months with pruriginous nodular lesions on the upper limbs, trunk, and/or lower limbs, at least 20 nodules on the entire body (with bilateral distribution), and an IGA score of at least 3. Eligible patients were also required to have had severe pruritus, defined as a PP-NRS score of at least 7 at the screening and baseline visits. Exclusion criteria included body weight less than 30 kg, chronic pruritus from an active condition other than PN, unilateral lesions of prurigo, presence or history of certain infections or comorbidities, and the use of restricted therapies. The exclusion criteria also included the presence of uncontrolled or exacerbated asthma, the presence of COPD and/or chronic bronchitis, and active AD within the previous 3 months.^2,40,41

Figure 2: OLYMPIA 2 Trial Design

BL = baseline; Q4W = every 4 weeks; R = randomized; SC = subcutaneous; W = week.

Note: This schematic representation of the OLYMPIA 2 study reports the initial screening phase followed by the treatment period and follow-up period. The schematic was organized into 2 treatments groups, 1 with patients who weighed less than 90 kg and 1 with those who weighed 90 kg or more. The loading dose was 60 mg for patients who weighed less than 90 kg, while no loading dose was administered to patients who weighed 90 kg or more.⁴⁴

Sources: Sponsor’s Summary of Clinical Evidence;² sponsor’s data on file.⁴⁵

Interventions

In both the OLYMPIA 1 and OLYMPIA 2 trials, the investigational treatment was nemolizumab. Patients in this treatment group were administered nemolizumab as an SC injection, with an initial dose of 60 mg, followed by either 30 mg every 4 weeks (for patients who weighed less than 90 kg at baseline) or 60 mg every 4 weeks (for patients who weighed 90 kg or more at baseline). Two 30 mg injections were used to administer a 60 mg dose.^2,40,41 Dose modifications were not permitted.^40,41 Nemolizumab was provided as a lyophilized powder in a dual-chamber syringe (DCS) for solution for injection. Patients randomized to the placebo arm of the OLYMPIA 1 and OLYMPIA 2 trials received matched SC placebo injections (also as lyophilized powder in a DCS for solution for injection) every 4 weeks, with the number of injections determined according to patient body weight at baseline, as done in the nemolizumab arm.^2,40,41 The treatment duration in the OLYMPIA 1 trial was 24 weeks (with the last injection at week 20); in the OLYMPIA 2 trial, the duration was 16 weeks (with the last injection at week 12).^40,41 Patients were trained on self-injection of the study drug and were permitted to do so at all subsequent visits while at the study centre and under staff supervision; for patients who did not wish to self-inject, study staff could administer the injection at each visit.^2,40,41 The pharmacist or other qualified personnel performed the DCS preparation, including reconstitution. All study drug injections occurred at the study centre.^40,41

Prohibited therapies for both the OLYMPIA 1 and OLYMPIA 2 trials are listed in Table 6. Except for these prohibited therapies, all therapies were authorized, including basic skin care (cleansing and bathing), moisturizers, bleach baths, and topical anesthetics. Patients could use daily moisturizers (if these did not contain any ingredients with anti-itch effect) starting from the screening visit; however, they should not have changed their moisturizers or emollients, nor should they have applied products for itch relief during the course of the trial. Antidepressants and sedatives (Table 6) were permitted, provided that these had been administered at a stable dose for at least 3 months before screening baseline and that dose changes were not planned during the trial.^2,40,41

Rescue therapies were permitted to be prescribed to patients during the studies if the investigator deemed that these were medically necessary (e.g., to control intolerable PN signs or symptoms). Per the protocol general guideline and per the judgment of the individual investigator, rescue therapy should not have been prescribed within the first 4 weeks of the study to allow a minimum time for study drug exposure. Rescue therapies included TCSs, TCIs, oral antihistamines, systemic or intralesional corticosteroids, biologics (including their biosimilars), systemic nonsteroidal immunosuppressants and/or immunomodulators, phototherapy, and gabapentinoids.^2,40,41 Investigators should first have prescribed topical medications or oral antihistamines before escalating to other systemic therapies, whenever possible. Unless the investigator judged there to be a concern, patients who received topical treatments, oral antihistamines, or UVB phototherapy as rescue therapy could continue to receive the study drug. Permanent discontinuation of study drug administration was required for patients who received systemic rescue therapy (other than oral antihistamines), intralesional corticosteroids, or oral psoralen plus UVA treatment; these patients were encouraged to complete the remaining scheduled study visits.^24,25,40,41 In the efficacy analysis, treatment was deemed a failure for patients who received any rescue therapy. Investigator efficacy assessments (including as unscheduled visits for patients needing therapy between scheduled visits) should have been performed before initiating rescue treatment.^2,40,41

Table 6: Prohibited Therapies in the OLYMPIA 1 and OLYMPIA 2 Trials

JAK = Janus kinase; NK1 = neurokinin-1; PDE-4 = phosphodiesterase type 4; PN = prurigo nodularis; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor.

^aUnless used as rescue therapy during the study.

Sources: OLYMPIA 1 Clinical Study Protocol;⁴⁰ OLYMPIA 2 Clinical Study Protocol.⁴¹

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 7, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as on any outcomes identified as important to this review, according to the clinical expert(s) consulted for this review and input from patient and clinician groups and public drug plans. Using the same considerations, we selected the end points that were considered most relevant to inform expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. Select efficacy end points and notable harms outcomes considered important for informing expert committee deliberations were assessed using GRADE.

Clinical experts consulted by CDA-AMC identified intensity of pruritus as the symptom of PN that has the greatest impact on patients. The proportion of patients with at least a 4-point improvement in PP-NRS at 16 weeks was considered a clinically relevant end point by the clinical experts and was a primary end point in both OLYMPIA pivotal trials. Disease severity, focusing on the clearance of lesions (i.e., IGA success), was also identified by clinical experts as an outcome of importance; the proportion of patients with IGA success at 16 weeks was a primary end point in both OLYMPIA trials. Similarly, clinician and patient groups identified reduction in itch and clearance of lesions as important outcomes for patients with PN. Clinical experts, clinician groups, and patient groups highlighted that PN may have a substantial impact on patients’ HRQoL; as such, the proportion of patients with at least a 4-point improvement from baseline in DLQI at 16 weeks (in the OLYMPIA 2 trial) or 24 weeks (in the OLYMPIA 1 trial) was selected as a key end point. Clinical experts consulted by CDA-AMC identified newly diagnosed asthma or worsening of asthma as the AESI of greatest clinical relevance. The aforementioned end points were assessed using GRADE.

Table 7: Outcomes Summarized From the Studies Included in the Systematic Review

DLQI = Dermatology Life Quality Index; IGA = Investigator’s Global Assessment; PP-NRS = Peak Pruritus Numerical Rating Scale; SD-NRS = Sleep Disturbance Numerical Rating Scale.

^aSecondary end points were assessed at up to 24 weeks in the OLYMPIA 1 trial. Given that the OLYMPIA 2 trial was 16 weeks in length, end points were assessed up to 16 weeks only.

^bStatistical testing for these end points was adjusted for multiple comparisons (e.g., hierarchal testing).

Sources: Sponsor’s Summary of Clinical Evidence;² OLYMPIA 1 Clinical Study Report;²⁴ OLYMPIA 1 Clinical Study Protocol;⁴⁰ OLYMPIA 2 Clinical Study Report;²⁵ OLYMPIA 2 Clinical Study Protocol.⁴¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The composite end point of the proportion of patients with at least a 4-point improvement in PP-NRS score and IGA success has been included in this review report because it informs the economic model. The results for the proportion of patients with at least a 4-point improvement in SD-NRS are also presented in this review report because improvement in sleep was identified as an important outcome by clinician and patient groups.

Peak Pruritus Numerical Rating Scale

The PP-NRS was completed by patients once daily in the evenings. The scale asked patients for a unit score on an 11-point scale (0 to 10) where 0 was no itch and 10 was the worst itch imaginable. The PP-NRS was used as an assessment of the maximum intensity of pruritus during the previous 24 hours, asking patients to rate their itch at the worst moment during that time period. Patients who did not complete the scale in the evening before a scheduled visit were permitted to complete the assessment at the clinic visit the following day.^2,40,41 The PP-NRS baseline score was determined based on the average of daily PP-NRS scores during the 7 days immediately preceding baseline; a minimum of 4 daily scores out of the 7 days immediately preceding baseline were required for this calculation. If there were fewer than 4 nonmissing assessments in the baseline diary window, the interval lower bound could be extended up to 7 additional days, 1 day at a time, to obtain the most recent 4 nonmissing values. The PP-NRS score was determined by an average at every week from baseline to week 24 (OLYMPIA 1 trial) or week 16 (OLYMPIA 2 trial).^42,43

Investigator’s Global Assessment

The IGA is a 5-point scale used by an investigator to evaluate the global severity of PN, as shown in Table 8. Based on review of the patient’s skin, the investigator assigned a score of 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), or 4 (severe). Treatment response (IGA success) was defined as 0 (clear) or 1 (almost clear) and at least a 2-point improvement from baseline.^{2,24,25,40,41}

Table 8: Investigator’s Global Assessment

Sources: Sponsor’s Summary of Clinical Evidence;² OLYMPIA 1 Clinical Study Protocol;⁴⁰ OLYMPIA 2 Clinical Study Protocol.⁴⁰

Sleep Disturbance Numerical Rating Scale

The SD-NRS was completed by patients once daily in the morning (within 1 hour of getting out of bed, if possible) to report the degree of PN-related sleep loss. The scale asked patients for a unit score on an 11-point scale (0 to 10) in answer to the following question: “On a scale of 0 to 10, with 0 being ‘no sleep loss related to the symptoms of my skin disease (PN)’ and 10 being ‘I did not sleep at all due to the symptoms of my skin disease (PN),’ how would you rate your sleep last night?” Patients who did not complete the scale in the morning before a scheduled visit were permitted to complete the assessment at the clinic visit.^2,40,41 The baseline SD-NRS score was determined based on the average of the daily SD-NRS score during the 7 days up to the treatment start; a minimum of 4 daily scores out of the 7 days up to baseline study day were required for this calculation. If there were fewer than 4 nonmissing assessments in the baseline diary window, the interval lower bound could be extended up to 7 additional days, 1 day at a time, to obtain the most recent 4 nonmissing values.^42,43

QoL Questionnaire

DLQI: The DLQI is a 10-item questionnaire covering domains including symptoms and/or feelings, daily activities, leisure, work and/or school, personal relationships, and treatment. The aim is to measure how much a patient’s skin problem has affected their life over the preceding week.^2,40,41,46 Patients rated each question from 0 (not at all) to 3 (very much). The DLQI total score was calculated as the sum of the score of each question, resulting in a minimum score of 0 and a maximum score of 30; a higher total score indicated greater impairment in QoL.^2,40,41

Table 9: Summary of Outcome Measures and Their Measurement Properties

AP-NRS = Average Pruritus Numerical Rating Scale; AP-VRS = Average Pruritus Verbal Rating Scale; DLQI = Dermatology Life Quality Index; HADS-A = Hospital Anxiety and Depression Scale – Anxiety; HADS-D = Hospital Anxiety and Depression Scale – Depression; ICC = intraclass correlation coefficient; IGA = Investigator’s Global Assessment; IGA-CNPG = Investigator’s Global Assessment of Chronic Nodular Prurigo; IGA-CPG = Investigator’s Global Assessment of Chronic Prurigo; ITT = intention to treat; MID = minimal important difference; NRS = numerical rating scale; PAS = Prurigo Activity Score; PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; PNS = Prurigo Nodularis Stage; PP-NRS = Peak Pruritus Numerical Rating Scale; PP-VRS = Peak Pruritus Verbal Rating Scale; QoL = quality of life; SD-NRS = Sleep Disturbance Numerical Rating Scale; t = Kendall’s correlation coefficient; WI-NRS = Worst Itch Numerical Rating Scale.

Adverse Events

AE assessments were performed beginning at the screening visit and throughout the treatment and follow-up periods at protocol-specified visits.^2,40,41 Treatment-emergent adverse events (TEAEs) were defined as AEs occurring after the first administration of study drug until the last study visit.^2,42,43 AEs were coded using the Medical Dictionary for Regulatory Activities Version 25.0.^42,43 Patient safety was reviewed and monitored by an independent data monitoring committee. In addition, the IAC reviewed all asthma-related events and assessed whether these represented new diagnoses or worsening of asthma; it also assessed severity (mild, moderate, or severe). However, the IAC did not assess relationship to study drug. For the purpose of the adjudication, asthma-related AEs were retrieved using the standardized Medical Dictionary for Regulatory Activities query, “asthma/bronchospasm.”^2,24,25 AESIs were considered noteworthy TEAEs for the study drug that should be monitored closely and reported promptly. These could be considered serious or nonserious; the following were considered AESIs in both the OLYMPIA 1 and OLYMPIA 2 trials:^24,25,42,43

• injection-related reactions

• newly diagnosed asthma or worsening of asthma

• infections

• peripheral edema (limbs, bilateral)

• facial edema

• elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (i.e., > 3 × upper limit of normal in combination with elevated bilirubin [> 2 × upper limit of normal]).

An SAE was defined as any untoward medical occurrence that was life-threatening; resulted in death, inpatient hospitalization, prolongation of existing hospitalization, or persistent or significant disability or incapacity; or was a congenital anomaly or birth defect.^24,25

Statistical Analysis

Statistical analyses for the OLYMPIA 1 and OLYMPIA 2 trial end points presented in this review report are summarized in Table 10.

Sample Size and Power Calculation

To achieve at least 90% power for both primary end points at a 5% significance level, 270 patients (180 in the nemolizumab group and 90 in the placebo group) were to be randomized to detect the following differences between treatment groups in the primary end points with a 2:1 randomization ratio, assuming a 15% dropout rate during the treatment period:

• NRS responders (≥ 4-point reduction from baseline): Based on phase IIa data, it was expected that the NRS response at week 16 would be 50% in the nemolizumab group and 20% in the placebo group.

• IGA response (0 or 1): It was expected that the IGA response at week 16 would be 30% in the nemolizumab group and 10% in the placebo group.^2,42,43

No power analyses were planned for the key secondary end points. No interim analyses were planned or performed for the OLYMPIA 1 and OLYMPIA 2 trials.^2,24,25

Multiple Testing Procedure

A fixed sequential testing approach was used to control the type I error at 5%. The primary end points were first tested in order (the PP-NRS end point followed by the IGA success end point) at a 5% significance level; testing of the key secondary end points would start only if both primary end points were successful at a 5% level of significance. Key secondary end points were tested in the following order, and testing was planned to be stopped when an end point did not test statistically significant (P > 0.05):

• proportion of patients with an improvement of 4 or more points from baseline in PP-NRS at week 4

• proportion of patients with a PP-NRS score of less than 2 at week 16

• proportion of patients with an improvement of 4 or more points from baseline in SD-NRS at week 16

• proportion of patients with an improvement of 4 or more points from baseline in SD-NRS at week 4

• proportion of patients with a PP-NRS score of less than 2 at week 4.^2,42,43

Other secondary end points were not adjusted for multiplicity.²

Subgroup Analyses

Subgroup analyses were prespecified and conducted for the following groups for the primary and key secondary end points:

• region (Europe and North America in the OLYMPIA 1 trial; Asia Pacific, Europe, and North America in the OLYMPIA 2 trial)

• age group (18 to 65 years and > 65 years)

• sex (female, male)

• race (African American or Black, Alaska Native or American Indian, Asian, Native Hawaiian or Pacific Islander, white, or other [including multiple]—wording of original sources)^42,43

• weight at randomization (< 90 kg, ≥ 90 kg)

• baseline IGA score (moderate [3], severe [4]).^2,42,43

The subgroup analyses were performed for the intention-to-treat (ITT) population and conducted in the same manner as for the primary end points. A forest plot was presented along with the subgroup analysis results.^2,42,43 Subgroup analyses were not adjusted for multiplicity.²

Table 10: Statistical Analysis of Efficacy End Points in the OLYMPIA 1 and OLYMPIA 2 Trials

ANCOVA = analysis of covariance; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; DLQI = Dermatology Life Quality Index; IGA = Investigator’s Global Assessment; ITT = intention to treat; LOCF = last observation carried forward; MAR = missing at random; MI = multiple imputation; MMRM = mixed-effect models for repeated measures; OC = observed case; PP-NRS = Peak Pruritus Numerical Rating Scale; SD-NRS = Sleep Disturbance Numerical Rating Scale.

^aWording of the original source.

^bIGA success was defined as an IGA of 0 (clear) or 1 (almost clear) and an improvement of 2 or more grades from baseline.

Sources: Sponsor’s Summary of Clinical Evidence;² OLYMPIA 1 Statistical Analysis Plan;⁴² OLYMPIA 2 Statistical Analysis Plan.⁴³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Analysis Populations

A summary of the analysis populations in the OLYMPIA 1 and OLYMPIA 2 trials is presented in Table 11.

Table 11: Analysis Populations in the OLYMPIA 1 and OLYMPIA 2 Trials

ITT = intention to treat.

Sources: Sponsor’s Summary of Clinical Evidence;² OLYMPIA 1 Clinical Study Protocol;⁴⁰ OLYMPIA 2 Clinical Study Protocol.⁴¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

Patient disposition in the OLYMPIA 1 and OLYMPIA 2 trials is presented in Table 12.

In the OLYMPIA 1 trial, a total of 482 patients were screened, of whom 286 were randomized to nemolizumab (N = 190) and placebo (N = 96) arms. Three patients (1.6%) in the nemolizumab arm and 1 patient (1.0%) in the placebo arm were randomized, but did not receive treatment.^2,24 In the OLYMPIA 2 trial, a total of 424 patients were screened, of whom 274 were randomized and received treatment with nemolizumab (N = 183) or placebo (N = 91).^2,25 In both the OLYMPIA 1 and OLYMPIA 2 trials, most patients who were screened out did not meet the eligibility criteria (94.4% and 92.7%, respectively). A similar percentage of patients completed treatment in the nemolizumab and placebo arms in the OLYMPIA 1 trial (88.4% and 88.5%, respectively); this was also seen in the OLYMPIA 2 trial (i.e., 95.6% in both arms). The most common reasons for discontinuation of treatment in the OLYMPIA 1 trial were AEs (nemolizumab: 5.8%; placebo: 4.2%) and patient request (4.2% in each arm). In the OLYMPIA 2 trial, the most common reasons for discontinuation of treatment were AEs (2.2% in each arm). The most common reasons for discontinuation from the study in the OLYMPIA 1 trial were AEs (nemolizumab: 6.3%; placebo: 4.2%) and patient request (nemolizumab: 5.3%; placebo: 6.3%); in the OLYMPIA 2 trial, the most common reasons for discontinuation from the trial were AEs (2.2% in each arm). In the OLYMPIA 1 trial, 81.6% of patients in the nemolizumab arm and 81.3% of patients in the placebo arm rolled over to the LTE study. In the OLYMPIA 2 trial, 93.4% and 94.5% of patients, respectively, rolled over to the LTE study.²

Table 12: Patient Disposition in the OLYMPIA 1 and OLYMPIA 2 Trials (ITT Population)

DHL = Dalsey, Hillblom, and Lynn; GI = gastrointestinal; ITT = intention to treat.

^aPatient 5489-001 was terminated from the study drug and the study at the investigator’s discretion.

Sources: Sponsor’s Summary of Clinical Evidence;² OLYMPIA 1 Clinical Study Report;²⁴ OLYMPIA 2 Clinical Study Report;²⁵ sponsor’s Response to Request for Additional Information.⁵¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Baseline Characteristics

A summary of baseline characteristics for the OLYMPIA 1 and OLYMPIA 2 trials is presented in Table 13.

In the OLYMPIA 1 trial, baseline characteristics were generally balanced across the nemolizumab and placebo groups, with exceptions subsequently described. There was a lower proportion of patients who were of Hispanic or Latino ethnicity in the nemolizumab arm than in the placebo arm (2.1% versus 5.2%), and the mean weight and proportion of patients who weighed 90 kg or more at baseline were higher in the nemolizumab group (87.07 kg and 38.4%, respectively) compared to the placebo group (80.81 kg and 30.2%, respectively). Imbalances between the nemolizumab and placebo groups existed for smoking status for people who had never smoked (57.4% versus 45.8%) and people who currently smoked (16.8% versus 25.0%). In addition, the proportion of patients with an IGA category of severe (i.e., 4) was higher in the nemolizumab arm (43.7%) than in the placebo arm (35.4%), and the mean time since PN diagnosis was shorter in the nemolizumab arm compared to the placebo arm (86.92 months versus 100.61 months).²

In the OLYMPIA 1 trial, most patients were female (58.0%), white (84.3%), not Hispanic or Latino (95.1%), and aged 18 to 65 years (71.3%), with a mean age of 57.5 years (details are provided in Table 13). Most participants were in Europe (74.1%) while the rest were in North America (25.9%). Most patients (64.13%) weighed less than 90 kg at baseline and had either never smoked (53.5%) or had previously smoked (26.9%). Overall, 59.1% of patients had moderate disease (i.e., IGA category 3), and 40.9% of patients had severe disease (i.e., IGA category 4). The mean DLQI score at baseline was 17.0. Most patients did not have a background of atopy (67.5%). The mean time since PN diagnosis was 91.51 months.^24,25

In the OLYMPIA 2 trial, baseline characteristics were generally balanced across the nemolizumab and placebo groups (exceptions are subsequently described). The proportion of patients older than 65 years was higher in the nemolizumab arm (25.1%) than in the placebo arm (15.4%). There was a lower proportion of patients of Hispanic or Latino ethnicity in the nemolizumab arm than in the placebo arm (2.7% versus 7.7%) and a lower proportion of Black of African American patients in the nemolizumab arm than in the placebo arm (2.7% versus 7.7%). Imbalances between the nemolizumab and placebo groups existed for smoking status for participants who had never smoked (59.6% versus 67.0%) and those who currently smoked (15.8% versus 11.0%). The proportion of patients with an IGA category of severe (i.e., 4) was lower in the nemolizumab arm (41.0%) than in the placebo arm (47.3%). In addition, the mean time since PN diagnosis was shorter in the nemolizumab arm compared to the placebo arm (104.16 months versus 108.60 months).²

In the OLYMPIA 2 trial, most patients were female (61.3%), white (78.5%), not Hispanic or Latino (92.0%), and aged 18 to 65 years (78.1%), with a mean age of 52.7 years (details are provided in Table 13). There were higher proportions of participants in Europe (66.8%) and North America (25.2%) than in the Asia Pacific region (8.0%). Most patients (72.6%) weighed less than 90 kg at baseline and had either never smoked (62.0%) or had previously smoked (23.7%). Overall, 56.9% and 43.1% of patients had moderate and severe disease, respectively. The mean DLQI score at baseline was 16.7. Most patients did not have a background of atopy (67.9%). The mean time since PN diagnosis was 105.64 months.^24,25

In both trials, all patients (100%) were reported to have at least 1 previous and ongoing medical condition, most commonly neurodermatitis and hypertension.^24,25

Table 13: Summary of Baseline Characteristics From the OLYMPIA 1 and OLYMPIA 2 Trials (ITT Population)

AP-NRS = Average Pruritus Numerical Rating Scale; DLQI = Dermatology Life Quality Index; IGA = Investigator’s Global Assessment; ITT = intention to treat; PAS = Prurigo Activity Score; PN = prurigo nodularis; PP-NRS = Peak Pruritus Numerical Rating Scale; SD = standard deviation; SD-NRS = Sleep Disturbance Numerical Rating Scale.

Notes: Percentages were based on the number of patients in each treatment group.

Weekly average PP-NRS scores and weekly average AP-NRS scores were calculated as the average of 7 consecutive days of data up to the target study day (excluding) and set to missing, if fewer than 4 days of data were available.

Weekly average SD-NRS scores were calculated as the average of 7 consecutive days of data up to the target study day (inclusive) and set to missing, if fewer than 4 days of data were available.

Baseline was defined as the last nonmissing value or weekly value before the first dose of study drug.

Racial categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Sources: Sponsor’s Summary of Clinical Evidence;² OLYMPIA 1 Clinical Study Report;²⁴ OLYMPIA 2 Clinical Study Report.²⁵ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Prior PN Therapies

Selected commonly used prior PN medications and procedures are presented in Table 14. Treatment with at least 1 medication for PN before study entry had been received by 63.7% of patients in the nemolizumab arm and 62.5% of patients in the placebo arm in the OLYMPIA 1 trial and by 83.6% and 86.8% of patients, respectively, in the OLYMPIA 2 trial. In both trials, the most commonly used prior PN therapies included TCSs (51.6% in the nemolizumab arm and 55.2% in the placebo arm of the OLYMPIA 1 trial; 78.1% and 79.1%, respectively, in the OLYMPIA 2 trial); systemic oral antihistamines (24.2% and 13.5% in the OLYMPIA 1 trial; 38.8% and 36.3% in the OLYMPIA 2 trial); systemic corticosteroids (14.7% and 11.5% in the OLYMPIA 1 trial; 19.7% and 23.1% in the OLYMPIA 2 trial); systemic nonsteroidal immunosuppressants (12.1% and 12.5% in the OLYMPIA 1 trial; 19.1% and 18.7% in the OLYMPIA 2 trial); and TCIs (10.0% and 8.3% in the OLYMPIA 1 trial; 15.3% and 12.1% in the OLYMPIA 2 trial). At least 1 prior PN procedure had been received by 22.6% of patients in the nemolizumab arm and 16.7% of patients in the placebo arm of the OLYMPIA 1 trial and by 28.4% and 33.0% of patients, respectively, in the OLYMPIA 2 trial. The most commonly received prior PN procedures were phototherapy (22.6% and 15.6% in the OLYMPIA 1 trial; 27.3% and 28.6% in the OLYMPIA 2 trial) and UV light therapy (20.0% and 13.5% in the OLYMPIA 1 trial; 21.3% and 20.9% in the OLYMPIA 2 trial).²

Table 14: Selected Commonly Used Prior PN Medications and Procedures (ITT Population)

ITT = intention to treat; PN = prurigo nodularis; PUVA = psoralen plus UVA.

^aMost commonly reported medications were reported based on an incidence of 4% or higher in either treatment group.

^bRefers to the group term that covers all types of phototherapies (i.e., group of procedures).

^cRefers to the preferred term that was used for coding when further information on the specific type of phototherapy was not available.

Sources: Sponsor’s Summary of Clinical Evidence;² OLYMPIA 1 Clinical Study Report;²⁴ OLYMPIA 2 Clinical Study Report;²⁵ sponsor’s Response to Request for Additional Information.⁵¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Exposure to Study Treatments

Treatment exposure during the OLYMPIA 1 and OLYMPIA 2 trials is summarized in Table 15.

In the OLYMPIA 1 trial, the treatment period was 24 weeks. The mean treatment durations were 131.1 days in the nemolizumab arm and 134.2 days in the placebo arm. The mean total nemolizumab dose administered was 248.5 mg. The proportions of patients who missed at least 1 dose were 9.1% in the nemolizumab arm and 8.4% in the placebo arm. There were more missed doses of the assigned study drug in the nemolizumab arm than in the placebo arm (29 doses and 19 doses, respectively).

In the OLYMPIA 2 trial, the treatment period was 16 weeks. The mean treatment durations were 82.4 days in the nemolizumab arm and 81.0 days in the placebo arm. The mean total nemolizumab dose administered was 170.5 mg. The proportions of patients who missed at least 1 dose were 2.2% in the nemolizumab arm and 8.8% in the placebo arm. There were fewer missed doses in the nemolizumab arm than in the placebo arm (5 doses and 12 doses, respectively).

Table 15: Summary of Patient Exposure in the OLYMPIA 1 and OLYMPIA 2 Trials (Safety Population)

SD = standard deviation.

Note: Treatment duration was calculated as: (date of last treatment minus date of first treatment) + 1.

^aThe total dose administered was calculated as the sum of all doses of study drug administered.

^bThe total dose planned was calculated as the sum of all doses of study drug planned (dispensed) according to the treatment schedule of the treatment group.

Sources: Sponsor’s Summary of Clinical Evidence;² OLYMPIA 1 Clinical Study Report;²⁴ OLYMPIA 2 Clinical Study Report;²⁵ sponsor’s Response to Request for Additional Information.⁵¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Concomitant Medications and Cointerventions

In the OLYMPIA 1 trial, at least 1 concomitant medication was received by 88.9% of patients in the nemolizumab group and 94.8% of patients in the placebo group, with the most commonly received medications being tozinameran (14.7% and 11.5%, respectively), atorvastatin (9.5% and 15.6%, respectively), and ibuprofen (11.6% and 9.4%, respectively). In the OLYMPIA 2 trial, at least 1 concomitant medication was received by 89.6% of patients in the nemolizumab group and 87.9% of patients in the placebo group, with the most commonly received medications being tozinameran (23.0% and 23.1%, respectively), paracetamol (13.7% and 8.8%, respectively), and acetylsalicylic acid (7.7% and 8.8%, respectively).^24,25

Rescue Treatment

Rescue medications and procedures received by patients in the OLYMPIA 1 and OLYMPIA 2 trials are summarized in Table 16. In both trials, the incidence of rescue therapy consisting of any topical or systemic medication was higher in the placebo group than in the nemolizumab group (OLYMPIA 1 trial: nemolizumab 6.3%, placebo 19.8%; OLYMPIA 2 trial: 4.9% and 15.4%, respectively), with the most commonly received rescue medications being TCSs.^24,25 In the OLYMPIA 1 trial, the incidence of any procedure as rescue therapy was 2.1% in the placebo group; no patients in the nemolizumab group received this rescue therapy.²⁴ No patients met the criteria for concomitant procedures as rescue therapy in the OLYMPIA 2 trial.²⁵

Table 16: Incidence of Rescue Therapy in the OLYMPIA 1 and OLYMPIA 2 Trials (ITT Population)

ITT = intention to treat.

Note: Patients are counted once where more than 1 rescue therapy was reported.

Sources: OLYMPIA 1 Clinical Study Report;²⁴ OLYMPIA 2 Clinical Study Report.²⁵

Treatment Adherence

In the OLYMPIA 1 and OLYMPIA 2 trials, mean treatment adherence was greater than 97% in both treatment arms, as presented in Table 17.

Table 17: Treatment Adherence in the OLYMPIA 1 and OLYMPIA 2 Trials (Safety Population)

Q1 = first quartile; Q3 = third quartile; SD = standard deviation.

Notes: Treatment adherence was calculated as the ratio (percentage) between the total number of actual injections and the total number of expected injections multiplied by 100.

The total number of actual injections was counted based on collected study drug administration data.

The total number of expected injections was counted based on the dosage schedule and dispensed as per protocol.

Sources: Sponsor’s Summary of Clinical Evidence;² OLYMPIA 1 Clinical Study Report;²⁴ OLYMPIA 2 Clinical Study Report.²⁵ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Efficacy

Results for the primary, key secondary, and secondary end points of interest for this review are summarized in Table 18.

Table 18: Summary of Primary, Key Secondary, and Secondary Efficacy End Points in the OLYMPIA 1 and OLYMPIA 2 Trials (ITT Population)

CI = confidence interval; DLQI = Dermatology Life Quality Index; IGA = Investigator’s Global Assessment; ITT = intention to treat; LS = least square; MI = multiple imputation; PP-NRS = Peak Pruritus Numerical Rating Scale; SD = standard deviation; SD-NRS = Sleep Disturbance Numerical Rating Scale; SE = standard error.

^aThe P value has been adjusted for multiple testing.

^bIGA success was defined as an IGA of 0 (clear) or 1 (almost clear) and an improvement of 2 or more points from baseline.

^cThe P values for secondary end points are nominal because the analyses have not been controlled for multiplicity.

Sources: OLYMPIA 1 Clinical Study Report;²⁴ OLYMPIA 2 Clinical Study Report.²⁵ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Primary End Points

Improvement of 4 or More Points From Baseline in PP-NRS Score at Week 16

OLYMPIA 1 trial: At week 16, the proportions of patients with improvements of 4 or more points from baseline in weekly average PP-NRS scores were 58.4% in the nemolizumab group and 16.7% in the placebo group (strata-adjusted proportion difference = 40.1%; 95% CI, 29.4 to 50.8; P < 0.0001).² The results of the sensitivity analyses were consistent with those of the primary analysis.²⁴

OLYMPIA 2 trial: At week 16, the proportions of patients with improvements of 4 or more points from baseline in weekly average PP-NRS scores were 56.3% in the nemolizumab group and 20.9% in the placebo group (strata-adjusted proportion difference = 37.4%; 95% CI, 26.3 to 48.5; P < 0.0001). The results of the sensitivity analyses were consistent with those of the primary analysis.²⁵

IGA Success at Week 16

OLYMPIA 1 trial: At week 16, the proportions of patients with IGA success were 26.3% in the nemolizumab group and 7.3% in the placebo group (strata-adjusted proportion difference = 14.6%; 95% CI, 6.7 to 22.6; P = 0.0025). The results of the sensitivity analyses were consistent with those of the primary analysis.²⁴

OLYMPIA 2 trial: At week 16, the proportions of patients with IGA success were 37.7% in the nemolizumab group and 11.0% in the placebo group (strata-adjusted proportion difference = 28.5%; 95% CI, 18.8 to 38.2; P < 0.0001). The results of the sensitivity analyses were consistent with those of the primary analysis.²⁵

Key Secondary End Points

Improvement of 4 or More Points From Baseline in SD-NRS Score at Week 16

OLYMPIA 1 trial: At week 16, the proportions of patients with improvements of 4 or more points from baseline in weekly average SD-NRS scores were 50.0% in the nemolizumab group and 11.5% in the placebo group (strata-adjusted proportion difference = 38.0%; 95% CI, 27.8 to 48.2; P < 0.0001). The results of the sensitivity analyses were consistent with those of the primary analysis.²⁴

OLYMPIA 2 trial: At week 16, the proportions of patients with improvements of 4 or more points from baseline in weekly average SD-NRS scores were 51.9% in the nemolizumab group and 20.9% in the placebo group (strata-adjusted proportion difference = 31.9%; 95% CI, 20.7 to 43.2; P < 0.0001). The results of the sensitivity analyses were consistent with those of the primary analysis.²⁵

Other Secondary End Points

Improvement of 4 or More Points From Baseline in PP-NRS Score at Week 24

OLYMPIA 1 trial: At week 24, the proportions of patients with improvements of 4 or more points from baseline in weekly average PP-NRS scores were 47.4% in the nemolizumab group and 14.6% in the placebo group (strata-adjusted proportion difference = 30.7%; 95% CI, 20.4 to 41.1).²⁴

IGA Success at Week 24

OLYMPIA 1 trial: At week 24, the proportions of patients with IGA success were 30.5% in the nemolizumab group and 9.4% in the placebo group (strata-adjusted proportion difference = 19.2%; 95% CI, 10.3 to 28.1).²⁴

Improvement of 4 or More Points From Baseline in PP-NRS Score and IGA Success

OLYMPIA 1 trial: At week 16, the proportions of patients with both improvements of 4 or more points from baseline in weekly average PP-NRS scores and IGA success were 22.6% in the nemolizumab group and 2.1% in the placebo group (strata-adjusted proportion difference = 16.0%; 95% CI, 9.5 to 22.5). At week 24, the proportions were 22.6% and 4.2%, respectively (strata-adjusted proportion difference = 16.6%; 95% CI, 9.1 to 24.1).²⁴

OLYMPIA 2 trial: At week 16, the proportions of patients with both improvements of 4 or more points from baseline in weekly average PP-NRS scores and IGA success were 29.5% in the nemolizumab group and 5.5% in the placebo group (strata-adjusted proportion difference = 26.1%; 95% CI, 17.4 to 34.8).²⁵

Dermatology Life Quality Index

OLYMPIA 1 trial: At week 16, the proportions of patients with improvements of 4 or more points from baseline in DLQI total score were 70.5% in the nemolizumab group and 42.7% in the placebo group (strata-adjusted proportion difference = 27.5%; 95% CI, 15.8 to 39.2). At week 24, the proportions were 71.1% and 35.4%, respectively (strata-adjusted proportion difference = 35.5%; 95% CI, 23.9 to 47.2).^2,24

At baseline, the least squares (LS) mean DLQI total scores were 17.1 (standard deviation [SD] = 6.97) in the nemolizumab group and 16.9 (SD = 6.74) in the placebo group. At week 16, the LS mean changes from baseline were −8.57 (standard error [SE] = 0.62) in the nemolizumab group and −2.18 (SE = 0.87) in the placebo group (LS mean difference = −6.39; 95% CI, −8.43 to −4.35). At week 24, the LS mean changes from baseline were −8.99 (SE = 0.64) in the nemolizumab group and −0.56 (SE = 0.91) in the placebo group (LS mean difference = −8.43; 95% CI, −10.54 to −6.31).^2,24

OLYMPIA 2 trial: At week 16, the proportions of patients with improvements of 4 or more points from baseline in DLQI total score were 74.9% in the nemolizumab group and 39.6% in the placebo group (strata-adjusted proportion difference = 37.4%; 95% CI, 25.7 to 49.0).^2,25

At baseline, the LS mean DLQI total scores were 16.5 (SD = 6.79) in the nemolizumab group and 17.1 (SD = 6.60) in the placebo group. At week 16, the LS mean changes from baseline were −8.91 (SE = 0.69) in the nemolizumab group and −0.75 (SE = 0.91) in the placebo group (LS mean difference = −8.15; 95% CI, −10.16 to −6.14).^2,25

Harms

A summary of key harms data from the OLYMPIA 1 and OLYMPIA 2 trials is presented in Table 19.

Adverse Events

In the OLYMPIA 1 trial, at least 1 AE was reported in 71.7% of patients in the nemolizumab group and 65.3% of patients in the placebo group; in the OLYMPIA 2 trial, at least 1 AE was reported in 61.2% and 53.8% of patients, respectively. In both trials, for the nemolizumab arm compared to the placebo arm, the most commonly reported AEs by system organ class were skin and SC tissue disorders (OLYMPIA 1 trial: 31.6% versus 29.5%; OLYMPIA 2 trial: 24.0% versus 23.1%) and infections and infestations (OLYMPIA 1 trial: 31.0% versus 29.5%; OLYMPIA 2 trial: 21.9% versus 20.9%). In the OLYMPIA 1 trial, the most common AEs (nemolizumab versus placebo) were COVID-19 (8.0% versus 14.7%), nasopharyngitis (6.4% versus 8.4%), headache (7.0% versus 2.1%), cough (4.8% versus 5.3%), dyspnea (3.2% versus 5.3%), neurodermatitis (9.6% versus 20.0%), and eczema (5.3% versus 1.1%). In the OLYMPIA 2 trial, the most common AEs were headache (6.6% versus 4.4%), neurodermatitis (3.8% versus 11.0%), and AD (5.5% versus 0%).²

Serious AEs

In the OLYMPIA 1 trial, at least 1 SAE was reported in 8.6% of patients in the nemolizumab group and 10.5% of patients in the placebo group; in the OLYMPIA 2 trial, at least 1 SAE was reported in 2.2% and 5.5% of patients in these groups, respectively. In the OLYMPIA 1 trial, the most common SAE was neurodermatitis (nemolizumab group: 1.6%; placebo group: 2.1%).² In the OLYMPIA 2 trial, none of the SAEs reported occurred in more than 1 patient in either treatment group.^2,25

Withdrawals Due to AEs

In the OLYMPIA 1 trial, AEs leading to study drug withdrawal occurred in 4.8% of patients in the nemolizumab group and in 3.2% of patients in the placebo group; in the OLYMPIA 2 trial, AEs leading to study drug withdrawal occurred in 2.7% and 2.2% of patients, respectively.²

In the OLYMPIA 1 trial, AEs leading to study discontinuation occurred in 4.8% of patients in the nemolizumab group and 4.2% of patients in the placebo group; in the OLYMPIA 2 trial, AEs leading to study discontinuation occurred in 2.2% of patients in each arm.^2,51

Mortality

In the OLYMPIA 1 trial, 1 patient in the placebo group died during the study. No patient deaths occurred during the OLYMPIA 2 trial.^2,24,25

Notable Harms

In the OLYMPIA 1 trial, at least 1 AESI was reported in 17.1% of patients in the nemolizumab group and 18.9% of patients in the placebo group; in the OLYMPIA 2 trial, at least 1 AESI was reported in 11.5% and 9.9% of patients, respectively. In both trials, the most commonly reported AESI in the nemolizumab and placebo groups was infections (OLYMPIA 1 trial: 10.7% versus 16.8%; OLYMPIA 2 trial: 5.5% versus 6.6%). In the OLYMPIA 1 trial, the AESI of newly diagnosed asthma or worsening of asthma was reported in 3.7% of patients in the nemolizumab group and in 2.1% of patients in the placebo group; in the OLYMPIA 2 trial, this AESI was reported in 2.7% and 1.1% of patients, respectively.²

Table 19: Summary of Harms Results in the OLYMPIA 1 and OLYMPIA 2 Trials (Treatment Period; Safety Population)

AE = adverse event; AESI = adverse event of special interest; SAE = serious adverse event.

Sources: Sponsor’s Summary of Clinical Evidence;² OLYMPIA 1 Clinical Study Report;²⁴ OLYMPIA 2 Clinical Study Report;²⁵ sponsor’s Response to Request for Additional Information.⁵¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Critical Appraisal

Internal Validity

The OLYMPIA 1 and OLYMPIA 2 trials were both phase III, randomized, double-blind, placebo-controlled, multicentre studies. The trials’ methods of randomization and treatment allocation (by interactive response technology) were adequate. Reported baseline characteristics were generally balanced across the groups in both trials; however, differences were noted (e.g., age group, IGA category, and time since PN diagnosis). Nevertheless, clinical experts consulted on this review did not anticipate that those differences would affect the interpretation of the efficacy or safety results. Because the incidence of AEs was similar between groups in both studies, it was unlikely that unblinding would have occurred due to AEs. However, due to differences in treatment response between arms (e.g., reduction in pruritus), patients and investigators could have become aware of treatment allocation, which may have introduced bias for subjective end points, such as PP-NRS and DLQI.

For both OLYMPIA pivotal trials, the prespecified sample size was achieved, and the screening failure rates approached or slightly exceeded the expected rates. The OLYMPIA 1 and OLYMPIA 2 trials were powered for the primary end points of the proportion of patients with at least a 4-point improvement in PP-NRS score and the proportion of patients with IGA success (both at week 16). The multiple testing procedure included all primary and key secondary end points and used a fixed sequential testing approach with a plan to stop testing if an end point did not test statistically significant. Analyses of other secondary end points were not adjusted for multiplicity; therefore, conclusions cannot be drawn regarding statistical significance for these end points.

In both trials, loss to follow-up was low and did not occur in most treatment arms; the exception was the nemolizumab arm of the OLYMPIA 2 trial, in which 1.1% of patients were lost to follow-up in the discontinuation from study disposition data. In both trials, the percentages of patients who discontinued treatment (including the percentage discontinuing due to AEs) were similar between the nemolizumab and placebo arms. However, a higher proportion of patients discontinued treatment in the OLYMPIA 1 trial (nemolizumab: 10.0%; placebo: 10.4%) than in the OLYMPIA 2 trial (4.4% in each arm). Clinical experts consulted by CDA-AMC noted that the rates of discontinuation were generally aligned with what would be anticipated for treatment with nemolizumab, but that the rates in the OLYMPIA 1 trial may be slightly higher than expected.

In both OLYMPIA pivotal trials, the mean treatment durations were similar for the nemolizumab and placebo arms. The overall treatment exposure was higher in the OLYMPIA 1 trial than in the OLYMPIA 2 trial due to the trials’ different treatment period lengths (24 weeks and 16 weeks, respectively). In both trials, the mean total dose administered closely approached the mean total dose planned. Mean treatment adherence was similar between treatment arms for OLYMPIA 1 and OLYMPIA 2 and was greater than 97% across all arms in both trials.

During the OLYMPIA pivotal trials, a range of topical and systemic medications and procedures were prohibited (some were allowed as rescue therapy), with washout periods required before study baseline. Basic skin care products (for cleansing and bathing), moisturizers, bleach baths, and topical anesthetics were permitted. In both trials, the proportions of patients requiring the use of concomitant rescue therapy (particularly TCSs and oral antihistamines) were higher in the placebo arms than in the nemolizumab arms. This imbalance in rescue treatment could have exaggerated the itch reduction response with placebo, thereby minimizing the comparative benefit of nemolizumab. In contrast, clinical experts consulted by CDA-AMC did not expect the differences between rescue therapy use between groups to affect the interpretation of the efficacy results.

For the OLYMPIA 1 and OLYMPIA 2 trials’ primary and key secondary end points reported in this review, several sensitivity analyses were performed, and the results were consistent with those of the primary analysis. In both trials, tipping point and multiple imputation analyses for these end points revealed that the primary results were robust to missing data. Sensitivity analyses were not performed for other secondary end points. The approach to handling missing data for other secondary end points was conservative. The results of subgroup analyses were not presented by the sponsor, and clinical experts consulted by CDA-AMC did not identify any subgroups of patients with moderate to severe PN that would be more or less likely to respond to treatment with nemolizumab.

Overall, the outcome measures in the OLYMPIA pivotal trials reported in this review have been validated in patients with PN or chronic prurigo, and the thresholds used to indicate clinically meaningful change in these measures are supported by the literature and/or by the clinical experts consulted by CDA-AMC.

External Validity

Clinical experts consulted by CDA-AMC commented that the inclusion criteria used in the OLYMPIA 1 and OLYMPIA 2 trials appropriately captured patients who would be considered candidates for nemolizumab in practice and reflected patients with a diagnosis of moderate to severe PN. Patients with certain medical conditions, such as uncontrolled asthma, active AD, and certain chronic infections, were not eligible for the OLYMPIA pivotal trials. Clinical experts noted that PN generally affects older people with comorbidities and expected that such patients may require treatment with nemolizumab in clinical practice. For instance, clinical experts stated that it would not be reasonable to exclude all patients with eczema from receiving treatment with nemolizumab. They also noted that it may be difficult to screen patients for severe asthma and exclude these patients in clinical practice. Clinical experts also expressed that the exclusion of patients with chronic infections, such as hepatitis or HIV, is standard in a clinical trial setting, but expected that patients with these conditions may require the use of nemolizumab in future practice, given that these patients may be more prone to having PN. Regarding the characteristics of the patients randomized in the OLYMPIA pivotal trials, clinical experts stated that these were a reasonable reflection of patients who would receive nemolizumab for moderate to severe PN in Canada and patients with PN whom clinical experts treat in practice. Clinical experts noted that the time since PN diagnosis was quite long and reflected the current lack of effective treatments for PN; this duration would be expected to decrease over time with the availability of medications such as dupilumab and nemolizumab. In both trials, most patients were white, and patients with certain comorbidities were excluded; these factors present potential generalizability limitations because the trial populations did not adequately represent the racial diversity or concomitant conditions of patients with PN. Of note, clinical experts identified that approximately one-third of patients with PN also have atopic diatheses (e.g., AD, asthma, allergic rhinitis). Both the OLYMPIA 1 and OLYMPIA 2 trials included study sites in Canada; clinical experts expressed that they did not have concerns regarding the generalizability of the trial findings based on study locations.

Most patients in both OLYMPIA pivotal trials had received prior medications and procedures for PN treatment, with washout required before study baseline. Clinical experts commented that these prior PN therapies were generally a reasonable reflection of what patients with moderate to severe PN would receive in practice, noting that a higher percentage of patients (80% to almost 100%) would be expected to have received a TCS. As previously mentioned, topical and systemic medications and procedures were prohibited during the trials, and nemolizumab was given as monotherapy (unless rescue therapy was used). Clinical experts stated that, based on experience with previously approved biologic medications across different indications, there are instances where a biologic medication on its own is sufficient to treat the condition, and that this may be true with nemolizumab. However, they noted that it is likely that patients prescribed nemolizumab would also require TCSs, especially when initiating nemolizumab; use of TCSs would be expected to decrease over time, but these drugs could still be used to spot-treat new lesions. Clinical experts also commented that intralesional corticosteroids may also be used in combination with nemolizumab as necessary, and that while it is less likely, concomitant phototherapy or methotrexate (only for very severe cases) may be used. Regarding the prohibition of concomitant therapies, clinical experts did not have concerns about this having an impact on the generalizability of the trial evidence. Regarding concomitant rescue therapies used in the OLYMPIA 1 and OLYMPIA 2 trials, clinical experts acknowledged that these would be used in patients who experience flares in PN or inadequate treatment response while receiving nemolizumab. An important limitation of the OLYMPIA 1 and OLYMPIA 2 trials is that nemolizumab was compared to placebo, which does not represent the standard of care for treatment of PN. Currently, dupilumab is approved by Health Canada for the treatment of patients with moderate to severe PN.²³ Clinical experts stated that dupilumab would be the most relevant comparator to nemolizumab for the indication under review. However, dupilumab was not indicated for treatment of PN at the time of the OLYMPIA 1 and OLYMPIA 2 trials.

According to clinical experts consulted by CDA-AMC, the primary goals of therapy for patients with PN are to reduce the severity of pruritus, treat existing lesions, prevent the formation of new lesions, and improve HRQoL while minimizing adverse effects of treatment. Similarly, outcomes of importance identified by clinician and patient groups included reduction in itch, clearance of lesions, improvement in sleep and HRQoL, and minimization of adverse effects. As such, the main efficacy and harms outcomes assessed in the OLYMPIA pivotal trials align with the key outcomes of importance to patients and clinicians.

According to clinical experts, outcomes used in clinical practice to assess response to treatment in patients with PN are improvement in the number of lesions, reduction in pruritus, and improvement in QoL; physicians may prioritize these outcomes differently. Clinical experts stated that assessments of treatment response in clinical practice do not usually rely on the grading tools used in clinical trials as stringently. They noted that disease severity may be assessed using lesion count (including subjective improvement) or scoring systems and that itch intensity may be measured subjectively or using an NRS. Clinical experts stated that QoL may be assessed using the DLQI or other indicators, such as improvement in daily life, sleep, and social well-being. According to clinical experts, 16 to 24 weeks is an appropriate amount of time to assess the trials’ primary end point outcomes (i.e., itch reduction and clearing of lesions); they noted that while 24 weeks may be ideal, 16 weeks is sufficient.

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for the outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^52,53

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Following the GRADE approach, evidence from the RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and its location relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The thresholds used for the presence or absence of an important effect were based on thresholds informed by the clinical experts consulted for this review for the PP-NRS, IGA success, and DLQI end points. For newly diagnosed asthma or worsening of asthma, the presence or absence of any non-null effect was used.

For the GRADE assessments, findings from the OLYMPIA 1 and OLYMPIA 2 trials were considered together and summarized narratively per outcome because these studies were similar in population, interventions, design, and outcome measures.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for nemolizumab versus placebo.

LTE Studies

The contents of this section have been informed by materials submitted by the sponsor. The following information has been summarized and validated by the review team.

Description of Studies

The OLYMPIA LTE study (NCT04204616) is an ongoing, phase III, prospective, single-arm, multicentre, open-label study to evaluate the long-term safety and efficacy of nemolizumab in adult patients with PN. The efficacy results summarized in this review are from Interim Analysis 2 (data available as of July 21, 2024) supplemented with data from Interim Analysis 1 (data cut-off date of March 10, 2023). Patients were eligible to enrol in the LTE study from the following previous studies of nemolizumab for PN:

• Phase IIa study (NCT03181503): Patients previously randomized to this study were considered for eligibility in the LTE study. Patients who enrolled into the open-label extension study from this phase IIa study must have completed all screening assessments within 28 days before the baseline visit or first dose of study drug.

• Phase III OLYMPIA 1 (NCT04501666) and OLYMPIA 2 (NCT04501679) trials: Patients completing the treatment periods of these studies may have been eligible to enrol in the open-label extension study immediately. Patients were not eligible to enrol in the LTE study more than 56 days following their last visit in the lead-in OLYMPIA studies.

At week 52, clinical responders, defined as patients with an IGA score of 0 or 1 and an improvement in PP-NRS score of 4 or more points from baseline of the lead-in study, may have been eligible to exit the LTE study and enter a 24-week durability study (NCT05052983). Patients who completed week 24 of the durability study or met the criteria for disease relapse at any point during the treatment period of the durability study were eligible to re-enter the LTE study. For re-entered patients, data were summarized by nemolizumab every 4 weeks overall (N = 17) from the durability study as well as by patients who experienced disease relapse (N = 9) and those who did not experience relapse (N = 8).

Each patient’s participation in the LTE study will be up to 196 weeks. The study consists of a screening period (up to 4 weeks), a treatment period (up to 184 weeks, with the final dose administered at week 180), and an 8-week follow-up period (12 weeks after the last injection of study drug). The primary end point is long-term safety (i.e., incidence and severity of AEs, including AESIs, TEAEs, and SAEs).

Populations

In addition to the inclusion criteria outlined in Table 5 of this report, to be enrolled in the LTE, patients must have been those who may benefit from study participation, in the opinion of the investigator, and participated in a prior nemolizumab study for PN by doing any of the following:

• completing the treatment period of a phase III pivotal study (i.e., the OLYMPIA 1 trial or OLYMPIA 2 trial) and enrolled within 56 days

• undergoing randomization in the phase IIa study of nemolizumab for PN (i.e., NCT03181503)

• completing week 24 of the phase IIIb durability study (NCT05052983) or exited the study due to relapse (these patients may have been eligible to re-enter the LTE study within 28 days at select countries and sites).

Patients were excluded from the LTE study if they experienced any AEs during any of the lead-in nemolizumab studies that may have resulted in unreasonable risk for patients, if they had a body weight of less than 30 kg, or if they received any restricted treatments within the prespecified time frame before baseline.

Interventions

The dose received in the LTE study (i.e., 1 or 2 injections) was based on the body weight and the previous treatment assignment in the nemolizumab PN studies (refer to Appendix 1, Table 36 and Table 37).

For patients who enrolled from the phase IIa study:

• Patients who weighed less than 90 kg at baseline received open-label 30 mg nemolizumab (with a 60 mg loading dose at baseline) every 4 weeks.

• Patients who weighed 90 kg or more at baseline received 60 mg nemolizumab (2 injections of 30 mg, with no loading dose) every 4 weeks.

For patients who enrolled from the phase III studies:

• The day 1 or baseline dose in the LTE study was based on the blinded study treatment assigned during the pivotal trial; this was done to maintain the blinding of the study. Therefore, patients received either 2 blinded 30 mg injections of nemolizumab or 1 blinded 30 mg injection of nemolizumab and 1 blinded injection of placebo.

• After day 1, the same dosing regimen was used as in the pivotal study (i.e., 1 or 2 SC injections of 30 mg nemolizumab, based on patient weight at baseline of the lead-in study).

For patients re-entering from the durability study:

• Patients received the same dose of nemolizumab that was assigned to them in the durability study

Outcomes

The efficacy end points assessed included IGA success (defined as an IGA of 0 [clear] or 1 [almost clear]) and improvements in PP‑NRS, SD-NRS, and DLQI scores. A detailed description of these end points is provided in the Systematic Review section.

Statistical Analysis

No formal sample size calculations were performed for this LTE study. The study planned to enrol approximately 450 patients, depending on the rollover rate from the lead-in studies, from approximately 160 study sites in Asia Pacific, Europe, and North America.

The safety population consisted of all patients who received at least 1 dose of nemolizumab (blinded or open label). All efficacy analyses were performed on the safety population and were descriptive in nature. The efficacy analyses were carried out using observed cases without imputing missing data. All efficacy assessments were summarized by LTE treatment and previous treatment at each analysis visit. Scheduled, unscheduled, and early termination visits were windowed based on the analysis visit window. No hypothesis testing was performed.

Data are summarized for all patients in the safety population (N = 508) under the following headings:

• Continuous nemolizumab: includes patients with an interval of less than 12 weeks between the last nemolizumab dose in the lead-in study and the first dose in the LTE study (N = 307); continuous nemolizumab was used to evaluate the persistence of the nemolizumab effect.

• Re-treatment: includes patients with an interval of 12 or more weeks between the last nemolizumab dose in the lead-in study and the first dose in the LTE study (N = 27); re-treatment was used to assess any loss of response. This group included patients from the phase III studies (i.e., the OLYMPIA 1 or OLYMPIA 2 studies) or phase IIa studies with an interval of 12 weeks or more after the last nemolizumab dose.

• Placebo to nemolizumab: includes patients who had never received nemolizumab before the LTE (e.g., patients who were on placebo during the lead-in or who enrolled directly in the LTE study [N = 174]).

Sensitivity Analyses

For binary secondary end points, efficacy data collected on or after the use of rescue therapy were classified as indicative of treatment failure, except in the observed cases analysis, in which observed data were used regardless of rescue therapy use. Continuous variables were set to the worst-case value, and the patient’s binary response was based on the underlying continuous value before the imputation of missing data. Continuous secondary end points were analyzed using multiple imputation, assuming that missing data were missing at random.

Results

Patient Disposition

Patients were enrolled from January 11, 2021, to March 10, 2023. A total of 510 patients were screened at 120 study sites, and 508 of those patients were enrolled and received the study drug. Of patients enrolled in the LTE, the majority were from the OLYMPIA 1 trial (N = 232) and the OLYMPIA 2 trial (N = 255). Given that this assessment is from an interim analysis, no patients had completed the LTE study; however, less than 20% had discontinued primarily due to AEs, patient request, or lack of efficacy (Table 20). Further, the proportion of patients who had discontinued treatment was similar among patients in the continuous nemolizumab and placebo-to-nemolizumab groups (18.9% and 17.2%, respectively), and slightly lower in the re-treated group (14.8%; Table 20). At Interim Analysis 2, ███% and ███% of patients in the continuous nemolizumab and placebo-to-nemolizumab groups, respectively, discontinued from treatment (Appendix 1, Table 38).

Table 20: Patient Disposition by Previous Treatment (Safety Population)