ID6221 nemolizumab atopic dermatitis DG to PM for consultation [NoCON] indev.docx

Atopic dermatitis (eczema) is a common, chronic and flaring inflammatory skin condition. The exact cause is unknown but involves genetic susceptibility and environmental triggers. Symptoms include dry, flaky and inflamed skin, which can be intensely itchy, and painful lesions typically affecting the hands, eyelids and flexures (skin folds). Patient experts explained that atopic dermatitis is often thought to be a minor condition, but for people with moderate to severe atopic dermatitis, the condition takes over all aspects of life. Symptoms such as the inability to regulate temperature, weeping sores, pain and constant itch substantially impact quality of life. As well as the physical symptoms, another patient expert highlighted the substantial impact on sleep, education and the ability to form relationships. These all substantially impact mental health, leading to anxiety, depression and suicidal thoughts. They added that the effects of the condition can be particularly hard for younger people because of a lack of acceptance among peers and the false expectation that they may grow out of the condition after childhood. There is also a huge sense of responsibility and burden for parents of younger people with the condition. Patient expert submissions described the frustrating, and often unsuccessful, process of 'trial and error' to find a treatment that works. They added that even if a treatment works initially, the effects often wear off over time, resulting in an unmet need for new and effective treatments. A patient expert noted that current treatments can have troubling side effects (such as eye problems) that could be avoided with nemolizumab. Patient experts added that the reduced injection frequency of nemolizumab is also a notable advantage compared with current treatments. The committee concluded that there is an unmet need for additional effective treatments for atopic dermatitis and that nemolizumab has a reduced administration frequency compared with current treatments.

Moderate to severe atopic dermatitis is initially treated with emollients, topical corticosteroids and topical calcineurin inhibitors. When the condition has not responded adequately to topical treatment, first-line systemic immunosuppressants may be offered. These include azathioprine, ciclosporin, methotrexate and mycophenolate mofetil. If the condition does not respond to first-line systemic immunosuppressants, or if these are not tolerated or not suitable, then a biological medicine (dupilumab, lebrikizumab or tralokinumab) or a Janus kinase (JAK) inhibitor (abrocitinib, baricitinib or upadacitinib) can be offered. The company positioned nemolizumab after first-line systemic treatments or if these treatments are not suitable. The clinical experts agreed with the company's positioning. The committee concluded that nemolizumab was appropriately positioned. The committee added that, in practice, adults would likely have biological medicines such as nemolizumab as a second-line systemic treatment after first-line systemic immunosuppressants, but young people would likely have these at first line. This is because typical first-line systemic options in adults are not suitable for young people.

Comparators to nemolizumab in the company's model included the JAK inhibitors abrocitinib, baricitinib or upadacitinib, and the biological medicines dupilumab, lebrikizumab or tralokinumab, but not first-line systemic treatments such as ciclosporin or methotrexate. In its submission, the company noted that the previous NICE technology appraisal recommendations for baricitinib, dupilumab and tralokinumab were for adults only, so the company did not initially include these treatments as comparators for young people. The EAG highlighted in its report that the marketing authorisations for dupilumab and tralokinumab have since been extended (to people 6 months and over for dupilumab and 12 years and over for tralokinumab). Clinical advice to the EAG was that both dupilumab and tralokinumab are used in young people so these should also be included as comparators. The company updated its model at clarification stage to include dupilumab and tralokinumab for young people. A clinical expert at the committee meeting explained that treatment choice is highly individual. Comorbidities, the safety profiles of treatments, individual preference for an injection or oral medicine, and how fast a response is needed all impact treatment choice. The clinical expert added that JAK inhibitors may be used by people who prefer an oral medicine. JAK inhibitors are also faster acting than biological medicines. But JAK inhibitors may not be suitable for everyone because they have a higher risk of venous thromboembolism and cardiovascular events. The committee concluded that both JAK inhibitors and biological medicines were relevant comparators and noted that this was in line with previous appraisals of biological medicines for moderate to severe atopic dermatitis.

The clinical evidence for nemolizumab came from the ARCADIA 1 (n=941), ARCADIA 2 (n=787) and ARCADIA-CYCLO (n=276) trials. ARCADIA 1 and ARCADIA 2 were phase 3, double-blind, randomised controlled trials comparing nemolizumab with placebo in adults and young people over 12 years with moderate to severe atopic dermatitis. ARCADIA-CYCLO was a phase 3b, double-blind, randomised controlled trial comparing nemolizumab with placebo in adults whose condition was not adequately controlled with ciclosporin or for whom ciclosporin was unsuitable. In all trials, best supportive care with treatments such as emollients, topical corticosteroids and topical calcineurin inhibitors was used alongside nemolizumab or placebo. The primary outcomes in ARCADIA 1 and ARCADIA 2 were assessed at week 16. These included EASI 75 response (a reduction of at least 75% from baseline Eczema Area and Severity Index [EASI] score) and Investigator's Global Assessment (IGA) success (defined as an IGA of 0 [clear] or 1 [almost clear], and at least a 2-point reduction from baseline). The primary outcomes in ARCADIA-CYCLO were EASI 75 and Peak Pruritus Numerical Rating Scale (PP-NRS), a measure of itch intensity. In ARCADIA 1 and ARCADIA 2 there was a statistically significantly greater proportion of people with EASI 75 response for nemolizumab compared with placebo at week 16 (ARCADIA 1, 43.5% versus 29.0%; ARCADIA 2, 42.1% versus 30.2%). This response was continued in the pooled maintenance period up to week 48. Similarly, there was a statistically significantly greater proportion of people with IGA success for nemolizumab compared with placebo at week 16 (ARCADIA 1, 35.6% versus 24.6%; ARCADIA 2, 37.7% versus 26.0%). This was continued in the pooled maintenance period up to week 48. Results of ARCADIA-CYCLO are considered confidential by the company so cannot be reported here. The committee concluded that nemolizumab was more effective than placebo.

There were no clinical trials directly comparing nemolizumab with the relevant comparators (see section 3.3). So, the company did a network meta-analysis (NMA) for a range of efficacy, quality of life and adverse event outcomes. EASI 75 response at week 16 was the efficacy outcome used in the economic model (see section 3.7). Separate NMAs were done for:

• adults (18 years or over), second-line treatment (ciclosporin-experienced)

• young people (12 to 17 years), first-line treatment (ciclosporin-naive).

Where results of the company's NMA did not show a statistically significant difference between nemolizumab and each of the comparators (see section 3.5), the company assumed clinical equivalence. That is, the company assumed that each of the comparators had the same efficacy as nemolizumab, by applying an odds ratio of 1 in its economic model. The EAG did not agree with the company's approach. It preferred to use point estimates for the odds ratios based on the EAG's own NMA in its cost-utility base case (EAG base case 2). The EAG also presented a cost-comparison base case (EAG base case 1) assuming the efficacy of all the biological medicines was identical. The EAG noted that if nemolizumab could be assumed to have the same efficacy as biological medicines, then it could potentially be recommended based on a comparison of costs alone. Clinical experts considered whether all the biological medicines could be assumed to have the same efficacy. One clinical expert explained that they each have different mechanisms of action, which is likely to result in them having different efficacy and tolerability profiles. But, the expert explained that the current biological medicines target the same immune pathway. They also noted that nemolizumab may improve symptoms of itching more than other biologics because of its unique mechanism of action. The committee noted that point estimates from the NMA showed quite substantial differences between treatments (odds ratios not close to 1). It added that the wide credible intervals suggested high uncertainty around the relative benefits. The committee noted that not finding a statistically significant difference in efficacy between treatments is not the same as the treatments being clinically equivalent. The committee concluded that it could not assume equal efficacy across all the biological medicines in either adults or young people. The committee concluded that it preferred a cost-utility analysis, using the EAG's approach (in base case 2) with point estimates of odds ratios from the EAG's NMA, rather than assuming clinical equivalence.

The company's economic model was a hybrid model that consisted of a short-term (1-year) decision tree followed by a long-term Markov model (year 2 onwards). At baseline, people in the model had nemolizumab or comparators for a 16-week induction period. People whose condition had responded to treatment at week 16 were described as 'responders', and were able to continue having maintenance treatment with nemolizumab or a comparator up to week 52. 'Non-responders' were people who initially had a treatment response at week 16 that was then lost, or people who stopped treatment for any reason including side effects by week 52. After week 52, responders and non-responders entered different phases of the long-term Markov model. The long-term Markov model included 3 mutually exclusive health states: maintained response, no response, and dead. Transitions between health states were informed by probabilities of losing response, discontinuation and death. For the long-term Markov model, an annual cycle length with a half-cycle correction was applied. The model assumed a time horizon of 60 years and applied an annual discount rate of 3.5% for costs and quality-adjusted life years (QALYs). The company's model base case assumed clinical equivalence between treatments where NMA results were not statistically significantly different (see section 3.5). This meant that the QALY gain for nemolizumab in the company's model was small and resulted from nemolizumab having a better side effect profile and lower probability of flare-ups. The EAG corrected several model programming errors and other minor issues with the company's model, including increasing the time horizon to cover an entire life time. The committee concluded that the corrected model was suitable for decision making.

The company initially used data from ARCADIA 1 and ARCADIA 2 to calculate the discontinuation probability for nemolizumab between week 16 and week 52. This probability was also used to determine the annual long-term discontinuation probability in the model. The EAG noted an error in the company's calculation, which the company corrected at clarification stage. This resulted in a different discontinuation probability for nemolizumab. The exact probability is confidential so cannot be reported here. The company stated that the recalculated probability was different to the discontinuation probability assumed for other biological medicines in previous NICE technology appraisals and so it preferred to use the probability from TA986. In TA986, discontinuation probabilities were applied according to treatment class (3.9% for biological medicines and 10.0% for JAK inhibitors). One clinical expert at the committee meeting could not think of a reason why discontinuation for nemolizumab should be different to that of other biological medicines, particularly because nemolizumab appeared to be better tolerated. Another clinical expert explained that the different probability may be because of the increased number of alternative treatment options currently available for this condition compared with when biological medicines were first recommended. The company added the discontinuation rate in ARCADIA 1 and ARCADIA 2 may have been impacted because the trials were done during the COVID-19 pandemic. The EAG used the discontinuation probability from TA986 in its base case and explored a scenario analysis using the discontinuation probability from ARCADIA 1 and ARCADIA 2. The EAG's scenario analysis had a large impact on the cost-effectiveness results. When assuming the TA986 probability, nemolizumab was cost effective compared with the other biological medicines. But when assuming the trial probability, nemolizumab was not cost effective compared with the other biological medicines. The committee noted that the different mechanism of action of nemolizumab compared with other biological medicines could result in differences in discontinuation. It further noted that, given nemolizumab was generally better tolerated with lower rates of adverse events, it was unclear why discontinuation should be different for nemolizumab compared with other biological medicines. In the absence of further information on why discontinuation probabilities in ARCADIA 1 and 2 were different to those assumed for other biological medicines, the committee opted to use the value from the trials. But the committee noted that more information from the company would be helpful, including but not limited to:

• discontinuation probabilities for the ARCADIA 1, ARCADIA 2 and ARCADIA-CYCLO trials separately with any differences explained

• corresponding discontinuation probabilities for the placebo arm

• the reasons for discontinuation of treatment in all trials across both treatment arms

• examples of other trials or treatments that have shown a trend for increased discontinuation because of the COVID-19 pandemic, for example, trials for nemolizumab in other indications

• if feasible, discontinuation rates from trials of other biological medicines

• if feasible, an NMA for discontinuation of nemolizumab compared with other biological medicines for the initial 16-week treatment period.

Health state utility values in the company's and EAG's models for responders (in years 1 and 2) and non-responders were based on the EQ-5D-3L data from ARCADIA 1 and ARCADIA 2 (for both adults and young people) and ARCADIA-CYCLO (for adults only). The health state utility value for responders (in year 3 and beyond) was based on a long-term extension study. The committee noted that some of the utility values seemed implausibly high when compared with general population utility values, and also higher than those used in TA986. The committee preferred to cap health state utility values in the model at general population levels.

NICE's manual on health technology evaluations notes that, above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. But it will also take into account other aspects including uncaptured health benefits. The committee noted the high level of uncertainty resulting from the company's NMA (see section 3.5). But it also recalled the potential benefit of nemolizumab's novel mechanism of action in reducing itch (see section 3.6) as well as the psychological impact of the condition, particularly on young people (see section 3.1). But it noted that, on balance, elements of these were already factored into the QALY calculation. It also noted nemolizumab's reduced administration frequency compared with other biological medicines (see section 3.1). So, the committee concluded that an acceptable ICER would be around the middle of the range NICE considers a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained), for both adults and young people.

Because of confidential discounts for nemolizumab and the comparators, the company's and EAG's cost-effectiveness results are confidential and cannot be reported here. The EAG presented results using a fully incremental analysis for all comparators (JAK inhibitors and biological medicines) and also calculated pairwise net monetary benefit for each comparator individually. Net monetary benefit was presented because the cost-effectiveness results spanned all quadrants of the cost-effectiveness plane. The EAG corrected minor errors and issues in the company's base case and also used point estimates for odds ratios (see section 3.6). The committee preferred the EAG's base case. In addition to this, the committee preferred using the discontinuation probability from ARCADIA 1 and ARCADIA 2 as in the EAG's scenario analysis (see section 3.8) and capping utility values at general population values (see section 3.9). The committee understood that nemolizumab would not be cost effective against any of the comparators in either adults or young people using its preferred assumptions.