Upadacitinib for previously treated moderately to severely active Crohn’s disease

3.1 Crohn's disease is a life-long inflammatory condition of the gastrointestinal tract. It is characterised by recurrent relapses with acute exacerbations and periods of remission. Symptoms include diarrhoea, abdominal pain, fatigue, weight loss and blood or mucus in stools. The patient experts explained that the disease is unpredictable and can have a profound and devastating impact on all aspects of life, including work, education and social life. Treatments for moderately to severely active Crohn's disease include conventional therapy such as glucocorticoids and immunomodulators. This is followed by biological treatments if there is inadequate response, intolerance or contraindication to conventional therapy. The clinical experts explained that there is an unmet need for new treatments for Crohn's disease, particularly for people whose disease is refractory or has lost response to treatment. They also explained that upadacitinib has a different mechanism of action to other treatments. Therefore, it may be effective for a proportion of people whose disease does not respond to these existing treatments. The patient experts explained that having more treatment options available is important, because not all available treatments work for everyone. They also highlighted that upadacitinib is an oral drug, which is a benefit over other treatment options. The committee concluded that more treatment options for severely to moderately active Crohn's disease would be welcomed.

3.2 The company proposed that upadacitinib should be considered for moderately to severely active Crohn's disease in adults who have had a biological therapy that was not tolerated or did not work well enough, or when a tumour necrosis factor (TNF)‑alpha inhibitor is unsuitable. It would be an alternative to the biological treatments ustekinumab and vedolizumab. This is a narrower population than the marketing authorisation for upadacitinib, which also allows use after conventional therapy only, or if conventional therapy is not tolerated or is contraindicated (see section 2.1). The clinical experts explained that the company's positioning of upadacitinib is appropriate and would reflect its use in clinical practice. The EAG highlighted that, in addition to ustekinumab and vedolizumab, the TNF-alpha inhibitors infliximab and adalimumab may also be relevant comparators, because they are recommended for severe Crohn's disease (NICE's technology appraisal guidance on infliximab and adalimumab for the treatment of Crohn's disease). The clinical experts explained that TNF-alpha inhibitors are usually used as first-line advanced therapy. They explained that if ustekinumab is used as first-line advanced therapy, in line with NICE's technology appraisal guidance on ustekinumab for moderately to severely active Crohn's disease after previous treatment, it is usually because TNF‑alpha inhibitors are unsuitable. In this case, it is inappropriate to use TNF‑alpha inhibitors and so vedolizumab is usually used as second-line biological treatment. The committee concluded that the company's positioning of upadacitinib as an alternative to vedolizumab and ustekinumab was appropriate.

3.3 The clinical expert submissions highlighted a safety review of Janus Kinase inhibitors, such as upadacitinib. The safety review led to an update of the special warnings and precautions for use in the summary of product characteristics for upadacitinib. It states that for some people, upadacitinib should only be used if there are no other suitable treatments. It applies to people aged 65 years and older, people with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, and people with malignancy risk factors. The clinical experts explained that clinical judgement is needed to determine the suitability of upadacitinib for each person based on the risks and benefits of treatment. They stated that ustekinumab and vedolizumab remain the relevant comparators for the subgroups highlighted in the special warning. This is because there are no treatment alternatives for these people and retreatment would be offered instead of best supportive care. The committee concluded that ustekinumab and vedolizumab were relevant comparators for the whole population proposed by the company.

3.4 Three clinical trials compared upadacitinib with placebo: U‑EXCEL, U‑EXCEED and U‑ENDURE. U‑EXCEL and U‑EXCEED were studies of upadacitinib induction treatment. They both included a randomised-controlled period for 12 weeks (part 1) and an extended treatment period. U‑EXCEL (n=526 for part 1) included people whose disease had had inadequate response or were intolerant to conventional therapy only (conventional care failure) or to biological treatment (biological failure). U‑EXCEED (n=495 for part 1) included only a biological failure population. The committee noted that it was appropriate to consider the biological failure subgroup because this was in line with where the company had positioned upadacitinib in the treatment pathway (see section 3.2). For the biological failure population, both trials showed a statistically significant improvement in the rate of clinical remission and endoscopic response with a 45‑mg induction dose of upadacitinib compared with placebo at 12 weeks. The third study, U‑ENDURE, was a study of upadacitinib maintenance treatment. It was a randomised controlled trial that also included people who had had conventional care failure or biological failure. Cohort 1 of U‑ENDURE (n=502) included people who had had clinical response after 12 weeks of upadacitinib in either U‑EXCEL or U‑EXCEED. For the biological failure population, cohort 1 of U‑ENDURE showed a statistically significant improvement in rates of clinical remission and endoscopic response with a 15‑mg and 30‑mg maintenance dose of upadacitinib compared with placebo at 52 weeks. The data is confidential and cannot be reported here. The committee concluded that upadacitinib was more clinically effective than placebo in the biological failure population for both induction and maintenance treatment.

3.5 There were no trials directly comparing upadacitinib with ustekinumab or vedolizumab. So, the company did network meta-analyses to indirectly compare the clinical effectiveness of these treatments. It presented separate network meta-analyses for induction and maintenance treatment for the biological failure and conventional care failure subgroups. The EAG explained that for induction treatment in the biological failure population, the network meta-analysis indicated that upadacitinib is more effective than ustekinumab and vedolizumab for the outcome of clinical remission. For clinical response it has similar efficacy. For maintenance treatment in the biological failure population, the network meta-analysis indicated that upadacitinib has similar efficacy to ustekinumab and vedolizumab for the outcome of clinical remission. The EAG highlighted that only people who had achieved clinical response during induction treatment were enrolled into the trials of maintenance treatment in the network meta-analysis. Therefore, the EAG considered that a limitation of the maintenance treatment network meta-analysis was that it could not provide evidence of effectiveness for people whose disease had not previously responded to upadacitinib. However, the clinical experts explained that only people whose disease has responded to induction treatment would be offered maintenance treatment in practice. The company also explained that all the trials in the maintenance network meta-analysis were designed so that only people whose disease had responded to induction treatment were included in the maintenance treatment trial. Therefore, it believed the studies included in the network meta-analysis were comparable. The EAG accepted that there was no better method that could have been used to demonstrate clinical effectiveness of maintenance treatment given the available evidence for upadacitinib and its comparators. The committee concluded that the network meta-analyses results supported the company's position that upadacitinib has similar clinical effectiveness to ustekinumab and vedolizumab.

3.6 The company presented network meta-analyses for induction and maintenance treatment to compare the adverse event outcomes of upadacitinib with ustekinumab and vedolizumab. The results showed that for both induction and maintenance treatment, serious adverse events were comparable between arms, with the credible intervals spanning the line of no effect for all comparisons. The EAG highlighted that discontinuation of treatment due to adverse events occurred more often with upadacitinib. However, the credible intervals crossed the line of no effect for all comparisons. The clinical expert explained that discontinuation rates are low for all the drugs and are therefore of limited relevance in clinical practice. The committee concluded that the network meta-analyses indicated that upadacitinib was likely to have a similar adverse event profile to ustekinumab and vedolizumab.

3.7 The company presented a base case cost-comparison analysis that modelled the total costs of upadacitinib, ustekinumab and vedolizumab over 1 year. This included the costs for induction and maintenance treatment. It also presented an analysis that showed the total costs of each treatment in the second and subsequent years of treatment. It considered that the clinical evidence available supported the assumption of clinical equivalence between upadacitinib, ustekinumab and vedolizumab. The company and the EAG also ran several scenario analyses that demonstrated the impact on the total costs of each treatment compared with the base case. This included changing the proportion of people having the different available doses of each drug and using different sources for intravenous drug administration costs. Taking into account the confidential prices for upadacitinib, ustekinumab and vedolizumab, the committee concluded that the total costs associated with upadacitinib were similar to or lower than the costs for ustekinumab and vedolizumab. The discounts for all treatments are confidential, so the incremental costs cannot be shared here.

3.8 The committee concluded that the criteria for a cost comparison recommendation were met because: