Avacopan for treating severe active granulomatosis with polyangiitis or microscopic polyangiitis

3.1 Antineutrophil cytoplasmic antibody (ANCA)‑associated vasculitis is a group of rare autoimmune conditions characterised by blood vessel inflammation. The 2 most common types are GPA and MPA. Eosinophilic GPA is the rarest type of ANCA‑associated vasculitis and was not a proposed indication for this appraisal. The patient experts explained that people with GPA or MPA can have severe symptoms and the conditions can be life threatening. They explained that symptoms can include extreme pain, fatigue, night sweats and rashes. They added that ANCA‑associated vasculitis can affect the sinuses, kidneys, lungs, abdomen, skin and joints. They also explained that the condition can have a detrimental effect on everyday life, including people's ability to work and participate in family life. The clinical experts commented that, when the kidneys are involved, people can develop end-stage renal disease (ESRD), which can be life threatening. The committee recognised that people with severe active GPA or MPA can have severe symptoms.

3.2 The clinical experts explained that GPA and MPA are usually treated in 2 phases. The first phase aims to control inflammation and reduce damage associated with the conditions by inducing disease remission (see section 3.4). The second phase of treatment (maintenance treatment) aims to prevent the conditions from relapsing and causing further damage (see section 3.5). Patient and professional organisations commented that quickly inducing and sustaining disease remission are important to reduce the risk of organ damage. The clinical experts agreed that the treatment pathway for people with severe active GPA or MPA is generally well defined. They explained that induction treatment usually includes cyclophosphamide or rituximab with high-dose corticosteroids (usually prednisolone, which is an active metabolite of prednisone). They added that maintenance treatment is usually azathioprine with a tapered dose of corticosteroids. The clinical experts also explained that disease relapses are treated by re-inducing remission in a similar way to initial inductions. Both patient and clinical experts commented on the side effects and toxicity of corticosteroids. The company also noted that relapses are associated with an increased risk of corticosteroid-mediated morbidity. The patient experts commented that mood swings, weight gain, diabetes, osteoporosis and cataracts are all potential side effects of corticosteroid treatment. They explained that weight gain can affect self-confidence and means that some people feel like they no longer recognise themselves. One patient organisation commented that regular monitoring for the side effects by several types of clinicians can be needed. For example, people having corticosteroids for a prolonged time may regularly visit a pain clinic, an ophthalmologist and a rheumatology and orthopaedic combined clinic to manage corticosteroid side effects. One clinical expert commented that infection and cardiovascular disease, which are the most common causes of death in this population, are both associated with corticosteroid use. The clinical experts also commented that the side effects of corticosteroids are generally dose related. So, they explained that a treatment which could sustain disease remission and reduce corticosteroid use would be beneficial. The committee concluded that people with GPA or MPA, and clinicians, would welcome such a new treatment option.

3.3 The NICE scope did not specify which types of ANCA‑associated vasculitis would be considered in the appraisal. The company explained that only people with GPA or MPA were included in the clinical trial (see section 3.6). It also noted that the marketing authorisation only covered people with severe active GPA or MPA, and specified that avacopan would be used with a cyclophosphamide or rituximab regimen. The committee recognised that NICE's remit is to appraise a technology within its marketing authorisation, so agreed that the company's positioning was appropriate.

3.4 The clinical experts explained that people with severe disease are usually offered cyclophosphamide or rituximab with high-dose corticosteroids for induction treatment. They added that the decision to use rituximab instead of cyclophosphamide depends on many factors. They commented that people with more severe GPA or MPA may be offered cyclophosphamide because there is less evidence for rituximab for severe disease. The clinical experts also commented that anti‑CD20 antibody treatments (such as rituximab) can reduce response to vaccinations by depleting B‑cells. So, there is a general desire to avoid using these treatments in the context of the COVID‑19 pandemic. The committee concluded that the relevant induction treatment comparators were cyclophosphamide or rituximab with high-dose corticosteroids.

3.5 The committee recalled that, after the initial induction treatment, people will usually have maintenance treatment. The clinical experts explained that, after induction of remission with cyclophosphamide, most people would switch to azathioprine. The clinical experts also noted that, during the maintenance phase of treatment, corticosteroid dose is usually tapered. They explained that people who initially have rituximab induction would only have rituximab maintenance in specific circumstances, in accordance with the NHS Clinical Commissioning Policy on rituximab for treating ANCA-associated vasculitis in adults. This states that rituximab maintenance is only commissioned if the disease has relapsed and re-induction treatment is needed after rituximab-induced remission or if rituximab is needed to induce remission for cyclophosphamide-refractory disease. The clinical experts commented that, in clinical practice, around 30% to 40% of people who have had rituximab as induction treatment have rituximab maintenance treatment. People who are not eligible for rituximab maintenance treatment would have azathioprine instead. The committee concluded that the relevant maintenance comparators were azathioprine with tapered corticosteroids and rituximab with tapered corticosteroids.

3.6 The company provided clinical evidence for avacopan from several clinical trials including ADVOCATE, a phase 3 trial. ADVOCATE was a randomised, active-controlled trial comparing oral avacopan 30 mg twice daily with oral prednisone on a tapering schedule. Everyone also had either cyclophosphamide followed by azathioprine, or rituximab followed by nothing. The trial included people with a clinical diagnosis of GPA or MPA who had at least 1 major item, 3 minor items or 2 renal items of proteinuria and haematuria on the Birmingham Vasculitis Activity Score (BVAS). The primary endpoint was the proportion of people with disease remission at weeks 26 and 52. At week 26, disease remission was defined as a BVAS of 0, and no corticosteroids in the previous 4 weeks. Sustained remission was defined as disease remission at week 26, and a BVAS of 0 at week 52, no corticosteroids in the 4 weeks before week 52 and no disease relapse between weeks 26 and 52. In the intention-to-treat population, at week 26, 72% of people in the avacopan group compared with 70% in the prednisone group had disease remission (estimated common difference 3.4%, 95% confidence interval [CI] -6.0 to 12.8; p<0.001 for non-inferiority and p=0.240 for superiority). At week 52, 66% of people in the avacopan group compared with 55% in the prednisone group had sustained disease remission (estimated common difference 12.5%, 95% CI 2.6 to 22.3; p<0.001 for inferiority and p=0.007 for superiority). The trial also evaluated corticosteroid toxicity. At week 26, the mean Corticosteroid Toxicity Index Cumulative Worsening Score was 39.7 in the avacopan group compared with 56.6 in the prednisone group (a larger score represents worsening toxicity; p=0.0002). The committee concluded that avacopan with a cyclophosphamide or rituximab regimen was effective at sustaining disease remission and reducing corticosteroid-induced toxicity compared with a prednisone-based regimen in the intention-to-treat population of ADVOCATE.

3.7 In ADVOCATE, people in both the avacopan and prednisone groups could have non-study supplied corticosteroids as needed. This was, for example, to treat disease relapse or hypoadrenalism from previous use of high-dose corticosteroids. The company explained that this as-needed use of corticosteroids was in line with how they would be used in clinical practice if avacopan was available. The clinical experts agreed. The mean cumulative corticosteroid dose during the treatment period was 1,349 mg in the avacopan group compared with 3,655 mg in the prednisone group. The ERG noted that although total corticosteroid use was lower in the avacopan group, non-study supplied corticosteroid use was higher in the avacopan group. The mean non-study supplied corticosteroid use during the treatment period was 1,349 mg in the avacopan group compared with 1,265 mg in the prednisone group. The ERG also noted that a large proportion of people (87.3%) in the avacopan group had non-study supplied corticosteroids during the treatment period. It was concerned that the use of non-study supplied corticosteroids in the avacopan group could have biased the effect estimates from the trial. It was also concerned about the meaningfulness of the apparent comparison of avacopan with lower-dose corticosteroids compared with higher-dose corticosteroids. The company explained that non-study supplied corticosteroid use was reasonably well balanced between the avacopan and prednisone groups, so the benefits seen in ADVOCATE could be attributed to avacopan. The committee understood the ERG's concerns, and queried whether there were differences in the proportions of people who had pulsed high-dose corticosteroids. One clinical expert explained that most non-study supplied intravenous corticosteroids at 4 weeks were for prophylaxis for rituximab treatment rather than for treating relapse. The committee commented that, overall, people in the avacopan group had about one-third less corticosteroids than those in the prednisone group. The committee recalled that a reduction in corticosteroid use would be beneficial for people with GPA or MPA (see section 3.2). It concluded that the non-study supplied corticosteroids in the intervention group reflected expected use in clinical practice.

3.8 The company provided a Markov model that was similar to the one used in NICE's technology appraisal guidance on rituximab in combination with glucocorticoids for treating anti-neutrophil cytoplasmic antibody-associated vasculitis. The model included 9 health states: active disease, 3 disease-remission states, 3 disease-relapse states, ESRD and death. The cohort's mean starting age (60 years), proportion of people having rituximab induction treatment (65%) and adherence to avacopan (86%) were from ADVOCATE. The clinical efficacy for avacopan was based on the results of ADVOCATE, and included disease remission at 26, 52 and 60 weeks, change in estimated glomerular filtration rate (eGFR) and health-related quality of life. In the company's base case, people were modelled to have standard care or standard care with avacopan. Standard care was defined as high-dose corticosteroids and either cyclophosphamide or rituximab followed by lower-dose corticosteroids with azathioprine. The company explained that modelling azathioprine maintenance treatment after rituximab induction was a deviation from ADVOCATE, but was based on an assumption explored in NICE's technology appraisal guidance on rituximab. At the first meeting, the committee was concerned about how maintenance treatment was modelled (see section 3.9). But it concluded that the company's overall model structure was appropriate for decision making.

3.9 The committee recalled that some people are eligible to have rituximab in the maintenance phase if it was used in the induction phase and other criteria are met (see section 3.5). The company noted that there were no randomised controlled trials assessing maintenance treatment with avacopan plus rituximab. At clarification, the company provided a rituximab maintenance treatment option in the model. It explained that it had adjusted the baseline hazard ratio for relapse to reflect treatment with rituximab instead of azathioprine. It cautioned that the non-adjusted naive comparison should be treated as exploratory. The ERG commented that the rituximab maintenance scenario was uncertain. At the first meeting, the committee agreed that it would have preferred analyses in which 30% to 40% of people who had rituximab as induction treatment continued rituximab as maintenance treatment, with the remaining proportion having azathioprine. This was based on the clinical experts' comments (see section 3.5). In response to consultation, the company updated its base case to include rituximab maintenance treatment for 35% of people who had it as induction treatment. It also provided scenarios that assumed 30% and 40% of this population would continue to have rituximab. The company noted that there was no additional real-world evidence to inform the modelling. The ERG commented that, in the absence of real-world observational data, the company's naive approach was pragmatic. The committee concluded that the company's modelling of rituximab maintenance treatment was appropriate and considered all scenarios during decision making.

3.10 In the company's model, people could transition to an ESRD state. The company considered it relevant to include a separate health state because ESRD is a significant complication of ANCA‑associated vasculitis. Disease progression to ESRD was modelled by a change in eGFR. The probability of ESRD in the active and remission health states was adjusted based on the improvement in eGFR in ADVOCATE. In the company's base case, the hazard rate, and probability of ESRD was adjusted based on the hazard ratio for ESRD per ml/min change in eGFR from Gercik et al. (2020; hazard ratio [HR] 0.90, 95% CI 0.86 to 0.95). However, the ERG noted that the company had provided several other options for the hazard ratio in the model. The ERG originally explored a pooled hazard ratio by combining estimates from Gercik et al., Ford et al. (2014) and Brix et al. (2018). The company disagreed with the ERG's pooled approach, explaining that estimates from Cox proportional hazards models were dependent on other covariates in the model. It explained that it would be inconsistent to pool coefficients from models that adjust for different covariates. During technical engagement, the ERG noted the company's concerns about pooling estimates. It re-evaluated the pooled studies and noted that the estimate from Ford et al. was for ESRD or death. The ERG did not consider it appropriate to include the Ford et al. hazard ratio in the pooled estimate. But the ERG reiterated that both the Gercik et al. and Brix et al. studies were relevant and preferred to pool them using an inverse variance approach (pooled HR 0.95, 95% CI 0.90 to 1.00). The committee understood the company's statistical concerns about pooling estimates. However, it agreed with the ERG that both the Gercik et al. and Brix et al. studies were relevant for consideration. The committee noted that the Gercik et al. study did not provide much detail and was published as a letter. It further noted comments from a clinical expert that the risk of ESRD is dependent on the population being studied. This meant that it may have been appropriate to pool estimates from studies that limited the inclusion criteria. The committee was concerned that the company's approach might have applied a hazard ratio from a single study with a narrower population to the broader, modelled population. The committee would have liked to see additional information from the company about why Brix et al. was not relevant. At the first meeting, the committee concluded that it was relevant to consider scenarios using the Gercik et al. and Brix et al. hazard ratios, both individually and pooled. In response to consultation, the company updated its base case to use the pooled hazard ratio estimated by the ERG (HR 0.95). The company commented that the pooled approach was conservative because evidence from the Gopaluni et al. (2019) paper suggested that the true hazard ratio could be less than 0.95 but was likely greater than 0.90. Consistent with the committee's preference from the first meeting, the company also provided results using the Gercik et al. and Brix et al. estimates individually. The committee noted that the incremental cost-effectiveness ratio (ICER) was sensitive to the individual and pooled hazard ratios. No evidence had been presented to suggest either Gercik et al. or Brix et al. estimates were not relevant. So, the committee concluded that the company's analyses using the individual and pooled estimates were relevant for decision making.

3.11 The company noted that the average length of hospital stay in ADVOCATE (13.8 days in the avacopan group and 19.6 days in the prednisone group) was longer than the mean length of stay reported in the 2019/20 NHS reference costs. The company explained that it adjusted hospital costs to account for the longer stays in ADVOCATE using excess bed day costs from 2017/18. It did this because the 2019/20 NHS reference costs no longer separately report excess bed day costs (as previous versions did). At technical engagement, the company updated its base case to use unit and excess bed day costs from 2017/18 inflated to 2020 prices. The ERG explained that it was uncertain whether the difference between mean length of stay in ADVOCATE compared with NHS reference costs implied excess bed days. Additionally, the ERG noted that NHS reference costs appeared to be calculated differently between 2017/18 and 2019/20 because the more recent version does not separately report excess bed day costs. NHS England confirmed that the 2019/20 reference costs included all hospitalisation costs, but no longer disaggregated costs into unit and excess bed days. At the first meeting, the committee noted a preference for hospitalisation costs using 2019/20 unit costs with no adjustment for excess bed days. This was because it was more reflective of costs in the NHS in England. In response to consultation, the company updated its base case to use 2019/20 unit costs with no adjustment for excess bed days. The company noted this approach was conservative because:

3.12 The ERG noted the crude modelled annual healthcare costs for the standard care group were substantially lower than the costs in the Clinical Practice Research Datalink (CPRD) study. The CPRD study was a retrospective observational study using real-world evidence to evaluate resource use and adverse event rates for people with GPA or MPA in England. The company explained that the CPRD study costs were not appropriate for modelling because there is no information about change in resource use with avacopan. The company also noted that the CPRD included aggregate costs of all hospital episodes, including treatment of unrelated comorbidities, and the model did not account for these costs. The company added that costs for specific episodes were similar between the model and CPRD. It also explained that larger costs from worsening ANCA‑associated vasculitis would favour avacopan so the model was likely conservative. The ERG noted it was uncertain why the ICER increased when adverse event costs from CPRD were used. It explained that it was not possible to explore the CPRD data further because the database included limited detail on exact resource use and did not include people who had avacopan treatment. At the second committee meeting, the committee noted that the CPRD study may have underrepresented people with MPA. People with MPA are more likely to have renal involvement so there may be higher costs associated with their care because they have high-cost treatments such as dialysis. The committee recalled that higher costs for the standard care group would favour avacopan because it is effective at sustaining disease remission, reducing ESRD and reducing corticosteroid use and so toxicity. The committee concluded that although there was some uncertainty in the modelled healthcare costs, the company's base case was appropriate and likely conservative.

3.13 The committee recalled that its preferred assumptions were:

3.14 The committee understood a potential equality issue about the use of cyclophosphamide had been raised in NICE's related technology appraisal guidance on rituximab. In that appraisal, the committee considered that cyclophosphamide reduces fertility in everyone. But it was aware that the peak age of onset for ANCA‑associated vasculitis in England is between 60 and 70 years. The committee agreed that the number of people with ANCA‑associated vasculitis who have not completed their family is likely to be very small. The committee recalled that avacopan is proposed as an add-on to standard care. It considered that its recommendation for avacopan would not affect prescription rates for cyclophosphamide. So, it concluded that its recommendation for avacopan would not have a different effect on people protected by the equality legislation than on the wider population.

3.15 The committee recalled that, during the COVID‑19 pandemic, clinicians are being careful about using anti‑CD20 antibody treatments (like rituximab, see section 3.4). It also recalled that avacopan was proposed as an add-on to standard care so would not directly replace rituximab. But it also considered that a larger proportion in the avacopan group had sustained remission at week 52 than in the prednisone group. The clinical experts explained that a drug that could maintain disease remission may reduce future need for re-induction treatment with rituximab. The committee also recognised that the model mainly captured benefits of disease remission rather than the potential health benefits from a long-term reduction in corticosteroids. The committee concluded that there may be some benefits of avacopan not captured in the cost-effectiveness analysis. These included reducing the future need for rituximab and a long-term reduction in corticosteroid use. It took these factors into consideration when making its recommendation.

3.16 The committee recalled that GPA and MPA are rare, severe and potentially life-limiting conditions. It recognised that current treatment usually includes corticosteroids, which are associated with significant side effects. The committee understood that people with severe active GPA or MPA would welcome a treatment option that could reduce corticosteroid use and its associated toxicity. It recognised that avacopan with a cyclophosphamide or rituximab regimen compared with standard care sustained disease remission for a larger proportion of people, and reduced corticosteroid-induced toxicity. The committee noted that, after consultation, the company and ERG agreed on all assumptions. It also noted that these assumptions were consistent with the committee's preferences. These included: