Dupilumab for treating moderate to severe atopic dermatitis

3.1 Atopic dermatitis is a chronic, recurrently flaring, generalised skin condition that can be life-limiting, debilitating and isolating. It can affect all aspects of life (physical, psychological, social and financial). Severe disease is associated with intolerable itch that disrupts sleep, and there is a higher risk of depression and suicide. The committee noted that having treatments that improve the condition and which are associated with few or manageable adverse effects is important to people with atopic dermatitis.

3.2 The committee understood that there is variability in how clinicians assess severity in atopic dermatitis. They assess severity based on clinical signs and on patient-reported symptoms including effect on sleep and work, and how much patients need to use topical corticosteroids or systemic therapy. The consensus-based Harmonising Outcome Measures for Eczema (HOME) initiative recommends using the Eczema Area and Severity Index (EASI) to assess signs (for example, skin lesions) and the Patient Oriented Eczema Measure (POEM) to assess symptoms (for example, itch). The clinical experts explained that the POEM is easier to administer in practice than the EASI. The committee understood that NHS clinicians routinely use the Dermatology Life Quality Index (DLQI) to assess quality of life in other skin conditions. It concluded that the EASI, DLQI and POEM are appropriate for assessing the severity of atopic dermatitis in NHS practice.

3.3 Although clinicians individualise therapy for patients, a typical treatment pathway involves emollients and topical corticosteroids (first line), topical calcineurin inhibitors (second line), phototherapy (third line) and systemic immunosuppressant therapies (fourth line) including ciclosporin (the only licensed drug), methotrexate, azathioprine and mycophenolate mofetil. These systemic therapies can have serious adverse effects and, if a drug is no longer effective, it will be stopped and another drug will be offered. For people whose disease does not respond to multiple systemic therapies, the only remaining treatment option is best supportive care, which may include education, psychological support, emollients, topical corticosteroids, bandages and hospitalisation. Managing exacerbations (flares) in atopic dermatitis includes using short-term potent topical corticosteroids, oral corticosteroids and systemic therapy.

3.4 The marketing authorisation for dupilumab is for 'moderate to severe atopic dermatitis in adults who are candidates for systemic therapy'. The company only submitted evidence for dupilumab as a fifth-line treatment, after systemic immunosuppressant therapies, as an alternative to best supportive care. The clinical experts explained that people are likely to have had at least 1 systemic therapy before dupilumab in clinical practice. The committee concluded that it would appraise dupilumab for moderate to severe atopic dermatitis, compared with best supportive care.

3.5 The company defined best supportive care in its economic model as 'emollients, low-to-mid potency topical corticosteroids, and rescue therapy with higher potency topical or oral corticosteroids or topical calcineurin inhibitors'; it also included phototherapy and psychological support in its revised model, submitted in response to the appraisal consultation document. However, it excluded bandages because these were captured within 'day case' treatment and education because no reliable data were available. The ERG agreed with the company's revised approach in defining best supportive care. The committee concluded that the company's revised definition of best supportive care was adequate for decision-making.

3.6 The main evidence for dupilumab came from 4 trials: 2 on dupilumab monotherapy (SOLO‑1 and SOLO‑2) and 2 on dupilumab plus topical corticosteroids as needed (CAFÉ and CHRONOS). All patients had best supportive care. The clinical experts explained that dupilumab is likely to be offered alongside topical corticosteroids. The committee therefore agreed to focus on the evidence on dupilumab 'combination therapy' with topical corticosteroids. CAFÉ and CHRONOS were randomised double-blind trials that included a total of 1,065 patients who had had chronic moderate to severe atopic dermatitis for at least 3 years that had not been controlled with topical medications for at least 6 months. Patients may or may not have had immunosuppressant therapy. The trials compared 2 doses of dupilumab (300 mg every week [unlicensed] or 300 mg every other week [licensed]) with placebo. The committee agreed to focus only on the data for the licensed dose of dupilumab. The primary endpoints were assessed at the end of the 'induction period' (that is, 16 weeks after starting treatment):

3.7 In response to the appraisal consultation document, the company provided data for up to 100 weeks from the start of an ongoing, open-label extension study. It included patients from previous dupilumab trials who had not had any adverse effects that led them to stop the trial, or patients screened for the SOLO studies but unable to enter them because of closure of the trials. Patients had weekly dupilumab (unlicensed dose) and could also use topical medications as needed. The company provided data for 2 subgroups: patients who had not had dupilumab before the study ('dupilumab-naive') or patients who had previously had dupilumab but with treatment gaps ranging from less than 6 weeks to more than 13 weeks ('dupilumab-exposed'). The committee concluded that evidence from this extension study, particularly that from the 'dupilumab-exposed' subgroup, would help in the understanding of dupilumab's long-term clinical effectiveness and to inform the assumptions in the economic model (see section 3.15 and section 3.17).

3.8 Because the company considered that dupilumab would be used as a fifth-line treatment, after systemic therapies, it focused its base case on a subgroup of 299 patients from CAFÉ and CHRONOS who could not have ciclosporin, or whose condition had not responded to ciclosporin. The company used data from the placebo groups to represent best supportive care in its economic model. The committee concluded that the subgroup was sufficiently large to provide reliable estimates of clinical effectiveness.

3.9 The subgroup identified by the company included patients who were on average 38 years old; 60% were men and 91% were 'white'. Patients had atopic dermatitis for an average of 29 years, which covered an average of 58% of their body, and they had average scores of 34 on the EASI, 20 on the POEM and 15 on the DLQI. The clinical experts confirmed that the baseline characteristics of these patients were similar to those likely to be seen in the NHS. The committee concluded that the trial subgroup population generally reflected people who would be treated with dupilumab in NHS clinical practice.

3.10 In its revised base case, the company presented results from analyses that considered patients to be 'non-responders' if they had not provided data at week 16, or if they had rescue therapy or withdrew from the study. The committee concluded that these analyses were appropriate because the clinical experts stated that systemic treatments are usually stopped when they are no longer effective at controlling the condition and patients need rescue therapy.

3.11 To model the cost effectiveness of dupilumab, the company defined a clinical benefit in its base case of an EASI 50 (at least a 50% reduction in the EASI score from when treatment started) plus an improvement in the DLQI of at least 4. The clinical experts explained that EASI 50 and an improvement in the DLQI of at least 4 are sensitive to changes in treatment outcomes and more clinically relevant than an EASI 75 (at least a 75% reduction in the EASI score from when treatment started). The committee concluded that the composite endpoint of an EASI 50 plus an improvement in the DLQI of at least 4 was appropriate for decision-making.

3.12 The committee noted that patients having dupilumab plus topical corticosteroids as needed had a clinically and statistically significantly higher response rate in the EASI 50 plus an improvement in the DLQI of at least 4 at week 16 (73% of 130 patients) than patients having placebo plus topical corticosteroids as needed (28% of 169 patients). The committee noted that these results also included patients who had rescue therapy. It concluded that dupilumab was substantially more clinically effective than placebo, although it would have preferred to have seen the results of the analyses in which patients who had rescue therapy were considered to be 'non-responders' (see section 3.10).

3.13 The committee queried the high response rate seen in the placebo group (see section 3.12). One clinical expert explained that this was likely because nurses in the trials closely supervised topical therapy regimens, which can improve adherence and maximise effectiveness. While this level of supervision is feasible in a short-term trial, it is not sustainable for prolonged periods (after 6 months), so any 'placebo response' is likely to decline over time. The committee agreed that any benefit from supervision should have been applied equally to both the dupilumab and placebo groups, which should not have affected how the treatments performed relative to one another in the trial. The company noted that, in CAFÉ, there was a higher reduction in topical corticosteroid use in the dupilumab arm than the placebo arm. The committee concluded that the 'placebo response' in the trials was unlikely to have affected the treatment effect of dupilumab relative to placebo.

3.14 The company's model consisted of 2 components:

3.15 The company assumed that 3.7% of people having dupilumab plus topical corticosteroids as maintenance therapy stop treatment every year for any reason, and move onto best supportive care. This reflected the proportion of people in CHRONOS whose condition responded to treatment at 16 weeks who withdrew from the trial by 52 weeks. In response to the appraisal consultation document, the company provided sensitivity analyses on a range of stopping rates based on data from its open-label extension study, ranging from 2.1% in 'responders' at week 24 to 6.4% in the whole population at 52 weeks. The ERG agreed that the original stopping rate appear reasonable and consistent with the available data. The committee noted that the different stopping rates had minimal impact on the cost-effectiveness estimates, and agreed that the company's original stopping rate of 3.7% is plausible.

3.16 In its revised model, the company assumed that, if atopic dermatitis did not respond to dupilumab plus topical corticosteroids:

3.17 In its revised base case, the company assumed in both treatment states that part of the clinical benefit of treatment (as determined at week 52 of the trials), and the associated utility benefit, were lost from year 2 after starting treatment onwards:

3.18 In its revised model, the company included the costs of 4 adverse events: injection site reactions, allergic conjunctivitis, infectious conjunctivitis and oral herpes. It used annual rates for injection site reactions. The company also revised its accident and emergency visit costs from £137.82 to £159.78. The ERG agreed with the company's changes. The committee accepted these changes but noted that these changes had a minor effect on the cost-effectiveness estimates.

3.19 The incremental cost-effectiveness ratios for dupilumab plus topical corticosteroids as needed compared with best supportive care alone in the company's revised base case and plausible sensitivity analyses (see section 3.17) ranged from £27,410 to £28,495 per quality-adjusted life year (QALY) gained. The committee concluded that dupilumab plus topical corticosteroids is a cost-effective use of NHS resources for treating atopic dermatitis that has not responded to other systemic therapies, such as ciclosporin, methotrexate, azathioprine and mycophenolate mofetil, or when these options are contraindicated or not tolerated.

3.20 The committee understood from the summary of product characteristics that 'consideration should be given to discontinuing treatment in patients who have shown no response after 16 weeks of treatment'. The committee was aware that a similar 'induction' phase was implemented in the clinical trials (see section 3.6) and applied by the company in the economic model. An adequate response is defined as at least a 50% reduction in the EASI score and at least a 4‑point reduction in DLQI from when treatment started in the economic model. The committee agreed that it would be appropriate to stop treatment with dupilumab after 16 weeks if treatment response is inadequate.

3.21 The committee noted comments from stakeholders that the effect of moderate to severe atopic dermatitis on the quality of life of families and carers should be taken into account. Although the committee acknowledged that there could potentially be an effect on the quality of life of families and carers, it agreed that it had not seen any evidence to support this.

3.22 The committee noted potential equality issues, namely that:

3.23 Feedback from patient and professional organisations highlighted that there are specific cytokine pathways in atopic dermatitis in different ethnic groups. For example, interleukin‑4 and interleukin‑13 cytokines predominate in most populations whereas, in some Asian populations, interleukin‑17 cytokines predominate. The committee understood that there is insufficient evidence to determine the extent to which different cytokine pathways modify treatment effect. Therefore, it did not consider that it needed to account for the variation in cytokine expression in different ethnic groups.

3.24 Patient and professional feedback highlighted the significant and substantial health-related benefits associated with treatment with dupilumab. The committee agreed that dupilumab is innovative and a step change in managing atopic dermatitis. However, it did not hear that there were any additional gains in health-related quality of life over those already included in the QALY calculations.