Omalizumab and recent NICE guidance

The monoclonal antibody to immunoglobulin E (IgE), omalizumab, an add-on therapy for atopic asthma, was first licensed for use in the UK in 2005. In 2007, the National Institute for Health and Care Excellence (NICE) recommended its use for patients aged ≥12 years with severe persistent allergic asthma (NICE technology appraisal (TA) guidance 133).(1) Since then, there have been two further reviews (NICE TA 201 and 278).(2,3) The draft guidance for TA 278 proposed that omalizumab would not be recommended for any patients with asthma. This caused a furore and following consultation resulted in a U-turn by NICE and the recommendation instead to extend the use of omalizumab. Omalizumab is currently recommended as an add-on therapy for patients with severe, atopic asthma aged ≥6 years.

Omalizumab (Xolair© Novartis Pharmaceuticals UK) is a recombinant humanised monoclonal antibody that binds to IgE. IgE plays an important role in the allergic cascade and high levels of IgE are associated with asthma severity and risk of exacerbations.(4) Omalizumab selectively binds to IgE forming an omalizumab–IgE complex. This prevents IgE binding to the FcεR1 receptor on mast cells and basophils. Removal of free IgE also results in downregulation of these receptors. These processes prevent degranulation and decrease the release of pro-inflammatory mediators such as histamine normally triggered by exposure to allergens, thus decreasing allergic inflammation.

Omalizumab first received approval by the US Food and Drug Administration in 2003 for treating patients aged 12 years and older with moderate-to-severe allergic asthma. In England and Wales, use of omalizumab has largely been determined by two key bodies: the European Medicines Agency (EMA) and NICE. The EMA operates a system of licensing for European-wide use based on safety, efficacy and quality data. In 2005, the EMA issued a marketing licence for the use of omalizumab as an add-on therapy for patients with allergic asthma aged 12 years and older. In 2009, the licence was extended to include children aged from six to 11 years.

NICE is an independent organisation responsible for providing national guidance and standards on the promotion of good health and the treatment of ill health. Technology appraisals are carried out to provide recommendations on the use of new and existing medicines and treatments within the NHS in England and Wales. NICE first issued guidance relating to omalizumab in 2007 (TA 133).(1) Omalizumab was recommended as an add-on treatment for severe persistent allergic asthma for patients aged 12 years or older, in keeping with the marketing licence. When the license was extended NICE undertook a further appraisal in 2010, focussing only on children aged from six to 11 years (TA 201).(2) Despite the extension of the licence, NICE did not recommend the use of omalizumab in this age group.

In contrast, in 2010, the Scottish Medicines Consortium approved the use of omalizumab in Scottish children aged 6–11 years prescribed systemic corticosteroids. In 2012, NICE undertook a review of the guidance for all age groups from six years upwards (TA 278).(3) The draft guidance concluded that omalizumab would not be recommended for any age groups, but that its use could continue in those already prescribed omalizumab. Following a period of consultation, the final guidance stated that omalizumab would be recommended for severe persistent asthma for all age groups from six years onwards.

The recommendations (Table 1) were in keeping with the licensed indications for omalizumab. The guidance also stated that standard therapy should first be optimised, including documented compliance with high-dose inhaled corticosteroid, long-acting β-2-agonist plus other add-on medications, including leukotriene receptor antagonists, theophyllines, oral corticosteroids and β-2-agonists.

The evidence supporting the use of omalizumab was largely provided by the INNOVATE study.(5) This was a randomised placebo-controlled trial that enrolled 482 patients aged 12–75 years with severe asthma (>1000mcg/day of beclomethasone or equivalent plus a long-acting b-2 agonist (LABA)). There was a 28-week active treatment phase. This study demonstrated a significantly lower rate of clinically significant exacerbations (following adjustment for between group differences in pre-treatment exacerbation rates) in the omalizumab arm compared with placebo (0.68 versus 0.91, rate ratio 0.738, 95% confidence interval (CI) 0.552–0.988; p=0.042).

The severe exacerbation rate (defined as peak flow or forced expiratory volume in one second (FEV1) <60% of personal best, requiring treatment with systemic corticosteroids) was halved in the omalizumab group compared to placebo (0.24 versus 0.48, p=0.002) with 49 severe exacerbations experienced by 16.8% (35 of 209) of patients. For the placebo group, there were 100 severe exacerbations among 26.2% (55 of 210) of patients.

The number needed to treat (NNT) in one year to prevent one clinically significant exacerbation was 2.2. In considering the cost analysis, NICE concluded that treatment with omalizumab would be long-term rather than having a defined endpoint.

In 2009 the EMA marketing authorisation for omalizumab was extended for children aged six to 11 years with ‘severe persistent allergic asthma, a positive skin test or in vitro reactivity to a perennial aeroallergen, frequent daytime symptoms or night-time awakenings, and multiple documented severe exacerbations of asthma despite daily high-dose inhaled corticosteroids plus a LABA’.(6)

In response to this, NICE undertook an appraisal focussing only on this age group (TA 201).2 Marketing approval was based largely on a double blind randomised controlled trial of omalizumab in 570 children conducted by Novartis.(7) The entry criteria for this study were children with moderate-to-severe asthma treated with fluticasone propionate (FP) ≥200mcg/day. There was a reduction in the rate of clinically significant exacerbations (defined as worsening of asthma symptoms requiring doubling of baseline inhaled corticosteroid dose and/or treatment with rescue systemic corticosteroids for three days) for the omalizumab-treated group compared with placebo (0.45 versus 0.64; p=0.007, rate ratio (RR), 95% CI 0.69 (0.53–0.90), at 24 weeks. This reduction in exacerbations remained significant over a period of 52 weeks (0.78 versus 1.36; p<0.001), (RR 95% CI 0.57 (0.45–0.73). A subgroup with more severe asthma (FP ≥500mcg/day plus a LABA) were defined a priori and analysed separately.(8) In this subgroup (n=235) there was also a reduction in the rate of clinically significant exacerbations in the omalizumab group compared with placebo at 24 weeks (RR 0.662, 95% CI 0.44–0.995) and at 52 weeks (RR 0.504, 95% CI 0.350–0.725).

There are a number of limitations of this study. First, the study population had much milder asthma than those children for whom omalizumab would be considered as an add-on therapy in clinical practice. Indeed, only six would be classified as step 5 of the British Thoracic Society/SIGN guidelines.(9) Second, the definition of an exacerbation is very broad. When severe exacerbations (requiring a course of oral corticosteroids) are considered in the severe group, there was no statistically significant difference between the omalizumab and placebo groups at 24 weeks (RR 0.665, 95% CI 0.302–1.421) or at 52-weeks treatment phase (RR 0.545, 95% CI 0.27–1.084) nor were there significant differences in hospitalisation rates, accident and emergency visits or unscheduled doctor visits. However, a significant reduction in exacerbations was seen in children who had had three or more admissions in the previous year.

Although NICE acknowledged that there was likely to be clinical benefit for some children, the cost per quality adjusted life year (QALY) gained (£65,900 upwards, depending on subgroup and duration of treatment) was far higher than the range of £20,000–30,000 per QALY per patient gained that NICE considers cost effective. Therefore, omalizumab was not approved for this age group (see Table 2).

The QALY calculated for children aged 6–11 years was far higher than that for adolescents and adults. The main reason for this is the low mortality in children with asthma compared to adults and QALYs are weighted towards this. The total cost for the population who may benefit from a treatment is not taken into account. The fact that only a small number of children within the younger age range would be suitable candidates for omalizumab and therefore the total costs would be far less that that for adolescents and adults was not considered. Shortly after publication of TA201, some of the UK’s leading paediatric respirologists published an editorial highlighting the unfairness of NICE’s methods and the way in which QALYs are calculated:(10)

“There was an apparent lack of appreciation of the importance of exacerbations, disrupted schooling and the effects on the wider family when measuring paediatric quality adjusted life years.”

In 2012, NICE undertook a review of TA 133 and TA 201 (TA 278).3 By the time this appraisal was undertaken, there were far more studies included in the assessment of the clinical effectiveness for omalizumab: nine conducted in adults and adolescents;(5,11–17) one in children (aged 6–11 years)(7) and one in children and adolescents.(18) The pooled findings were largely the same as those for the previous appraisals: omalizumab as an add-on to conventional therapy reduces the rate of clinically significant exacerbations and clinically significant severe exacerbations in adults, adolescents and children, although the reduction in clinically significant severe exacerbations in children did not reach statistical significance. The assessment panel also concluded that studies had demonstrated improvements in asthma related quality of life in adults and adolescents but felt that the single study in children only, had been underpowered to detect differences. Despite the clinical benefits, NICE did not recommend omalizumab for adults or children in the draft guidance.

This was mostly due to uncertainties about cost-effectiveness, partly because of changes to the dosing schedule, which led to the prescription of higher doses of omalizumab, and partly because of doubt about the mortality risk in those eligible for omalizumab. The ‘most optimistic’ cost per QALY gained in those with the most severe asthma was estimated to be between £31,000 and £42,000. During the consultation process, a storm of protest from the medical and lay communities ensued, with one memorable headline declaring “Omalizumab: NICE to USE you, to LOSE you NICE”.(19)

The final guidance issued by NICE some five months later completely overturned the draft recommendations (Table 3). The final guidance quotes similar costs as the draft guidance and the two previous TAs; £31,573–32,398 for adults and adolescents (lowest for those requiring frequent course of oral corticosteroids who have not necessarily been hospitalised in the preceding year) and £61,096–62,945 for children. It is not entirely clear, therefore, what led to this change: the most positive scenario is that NICE listened to those who participated in the consultation process.

In the final guidance, there is acknowledgement of evidence from a patient expert who reported a marked improvement in her child’s quality of life, including the ability to attend school, participate in sports and play in the park. The panel also supported the conclusion of clinical experts that those receiving omalizumab in clinical practice in the UK were more severe than those enrolled in studies, and thus trial evidence may under-estimate the benefit gained. Another plausible and more cynical explanation is that the change of heart was brought about by the deal struck with Novartis that omalizumab would be made available at an (undisclosed) discount.

Whatever the reasons, there are a number of important changes from the previous TAs, most strikingly, the reversal of the decision from TA 201, to approve omalizumab for children as well as adolescents and adults. The necessity for a hospital admission was also removed. In part, this is due to the lower QALY for those requiring frequent oral corticosteroids without necessarily being hospitalised and partly this was an acknowledgment of advice from clinical specialists and patients, that those with very severe asthma are less likely to be hospitalised as they are more used to managing their asthma at home, even during an exacerbation.

The cost of omalizumab is £256.15 for a 150mg vial and £128.07 for a 75mg vial.(20) It is administered by subcutaneous injection every 2 to 4 weeks up to a maximum dosage of 600mg every two weeks. The cost ranges from £1665 per patient per year (75mg every four weeks) to £26,640 per patient per year (600mg every two weeks). The discount that Novartis has agreed with the Department of Health is confidential.

The change in guidance should not be seen as carte blanche to give omalizumab to all those with poorly controlled asthma. In our practice we go beyond the NICE guidelines in selecting suitable patients. It is vital that omalizumab be targeted at the right patients. At least half of those referred to specialists with apparently severe asthma have potentially modifiable causes for their poor control, such as suboptimal adherence, allergen exposure and psychosocial factors.(21) Patients must undergo a thorough evaluation first to address all other potentially modifiable factors, which may be contributing to poor symptom control and ongoing exacerbations. There is a recommended 16-week trial period and only if there is objective evidence of benefit should treatment continue. We have a continuous process of re-evaluation to ensure that clinical benefit is maintained.

The evolution of NICE guidance from 2007–2013 is a reflection of the available evidence and change in the terms of the marketing licence for omalizumab. However, what is much less easily explained is the dramatic volte face between November 2012 (when the draft proposal for TA278 was released) and publication of the final guidance (in April 2013). Certainly,the strength of feeling among the medical community and patient groups was very clear. This change in position also likely highlights the gap between published data, which forms the bedrock on which the draft guidance is based, and real-life use, which may have become more apparent during the consultation period. Whatever the reasons, it is reassuring to know that the consultation period is not simply a paper exercise, but one that NICE takes seriously and the views of patients with severe asthma and those involved in their care are listened to.

This is not the final chapter in the NICE–omalizumab story. The guidance will be reviewed in March 2016. There are ongoing clinical studies and increasing published data on real-life use that will inform future guidance.(9,22–24) Currently, NICE have limited their appraisal to the use of omalizumab in allergic asthma. However there are other potential uses for omalizumab including seasonal rhinitis,(25) peanut allergy,(26) chronic urticarial,(27) and as an adjunct to immunotherapy,(28,29) which may in future warrant appraisal. This story is likely to be repeated as other expensive monoclonal antibodies such as mepolizumab (anti-IL5) and lebrikizumab (anti-IL13) become more widely available. For those involved in the care of patients with severe asthma, it is important that we take responsibility for the judicious use of omalizumab. Of paramount importance is patient selection. This is not a drug for those who are non-adherent to adequate standard treatments, such as inhaled corticosteroids, or for those with mild-to-moderate asthma. For those with true, severe asthma, omalizumab can offer benefit as an add-on treatment, particularly in the reduction of exacerbations, and has provided hope and improved quality of life to many, for whom treatment options are otherwise very limited.

Omalizumab is recommended as a possible treatment for adults and young people aged over 12 years with severe persistent allergic asthma when all of the following circumstances apply:

When the person has had at least two asthma attacks within the past year that have needed admission to hospital, or when the person has had three or more severe asthma attacks within the past year, one of which has needed admission to hospital and the other two have needed additional treatment in an accident and emergency department.

Omalizumab treatment should be given along with the person’s current asthma medicines. It should be prescribed by a doctor who is experienced in asthma and allergy medicine at a specialist centre.

If omalizumab does not control the asthma after 16 weeks, treatment should be stopped.

NICE does not recommend omalizumab for children aged 6–11 years with severe persistent allergic asthma.

Omalizumab does not provide enough benefit to children aged 6–11 years to justify its high cost.

Omalizumab is recommended as an option for treating severe persistent confirmed allergic IgE-mediated asthma as an add-on to optimised standard therapy in people aged six years or older:

Optimised standard therapy is defined as a full trial and, if tolerated, documented compliance with, inhaled high-dose corticosteroids, LABAs, leukotriene receptor antagonists, theophyllines, oral corticosteroids, and smoking cessation if clinically appropriate