12 SQ-HDM SLIT for treating allergic rhinitis and allergic asthma caused by house dust mites (review of TA834)

Allergic respiratory disease (ARD) is a group of respiratory conditions that are triggered by allergens, which can include house dust mites. An inflammatory response occurs when people who are sensitised to house dust mites are exposed to house dust mite-derived allergens. This can create an allergic reaction in the upper or lower respiratory tract that can lead to symptoms of rhinitis, such as nasal congestion, and asthma, such as wheezing, chest tightness and coughing. It may also cause red, itchy or watery eyes. The patient experts explained the challenges associated with the condition. Experiencing these symptoms can impact physical and mental health. Sleeping difficulties can cause significant fatigue. Allergic rhinitis and allergic asthma can impact all aspects of daily life. It can affect the ability to attend a workplace or school, and limit employment opportunities. Avoiding house dust mites is almost impossible, and there is a high burden of trying to eliminate house dust mites by cleaning. The patient experts explained that family members can have feelings of guilt when they cannot successfully remove house dust mites and their relative continues to have symptoms. One patient expert explained that while symptom-relieving medicine is available, for some people this does not fully control the symptoms and most people would prefer to avoid prolonged use of corticosteroids. The patient experts stated that people would welcome a treatment option such as 12 standard quality house dust mite sublingual lyophilisate (SQ‑HDM SLIT). This treatment aims to target the root cause of their condition by desensitising them to house dust mites, which may potentially reduce their corticosteroid burden. The committee concluded that allergic rhinitis and allergic asthma caused by house dust mites can impact people's quality of life and day-to-day activities. There is an unmet need for an additional treatment to symptom-relieving medicine, which does not adequately control rhinitis and asthma in everyone.

Allergic rhinitis is treated in line with the British Society for Allergy & Clinical Immunology (BSACI) rhinitis guideline and the Allergic Rhinitis and its Impact on Asthma (ARIA) guideline in secondary care. Oral or intranasal antihistamines are the first-line treatment for mild to moderate, intermittent, or mild persistent symptoms. Intranasal corticosteroids are recommended for moderate to severe persistent symptoms, or if initial treatment is not effective. Combinations of oral antihistamines and intranasal corticosteroids can be used if symptoms continue. Further add-on treatments can be considered. These can include intranasal anticholinergics, oral antihistamines, intranasal decongestants and leukotriene receptor antagonists (LTRAs), depending on symptoms. The company considered that 12 SQ‑HDM SLIT would be an additional treatment for allergic rhinitis to be taken alongside symptom-relieving medicine. The committee recognised that the BSACI guideline positioned allergy immunotherapy, if symptoms are mainly because of 1 allergen, after all other treatment options had been considered. The clinical experts stated that this would be the most appropriate positioning. The committee concluded that for people with house dust mite allergic rhinitis, 12 SQ-HDM SLIT would be used in addition to symptom-relieving medicine, after all appropriate symptom-relieving medicine had been tried and symptoms continued.

In clinical practice asthma treatment follows the NICE guideline on asthma: diagnosis, monitoring and chronic asthma management, the Global Initiative for Asthma (GINA) guidelines (Redell et al. 2021) and the British Thoracic Society (BTS) and Scottish Intercollegiate Guideline Network (SIGN) British guideline on the management of asthma. These guidelines involve a stepwise approach to assessing, treating and monitoring asthma control, in which additional treatments are added if symptoms are not controlled. If asthma becomes uncontrolled despite inhaled corticosteroids (usually offered with another treatment such as long-acting beta 2 agonists or LTRAs), then low-dose oral corticosteroids or biological treatments are added. Biological treatments may be offered if asthma is not controlled well enough by maintenance treatment with high-dose inhaled corticosteroids plus a long-acting beta 2 agonist or another treatment. The committee noted the current BTS and SIGN guideline does not define when to use allergy immunotherapy for treating allergic asthma. The company stated that 12 SQ‑HDM SLIT was expected to be an addition to the existing treatment options for asthma. The marketing authorisation for 12 SQ‑HDM SLIT states that people would be eligible for the treatment if their asthma is categorised as 'not well controlled by inhaled corticosteroids'. The company considered that the positioning of 12 SQ‑HDM SLIT would align with steps 2, 3 and 4 of the GINA guidance. The company considered that 12 SQ‑HDM SLIT was not an alternative option for severe asthma as an alternative to biological treatments, because this would be beyond the marketing authorisation. 12 SQ‑HDM SLIT would be expected to be used before biological treatments and was not expected to replace them. The clinical experts considered that 12 SQ‑HDM SLIT would be best positioned within steps 2 to 3 of the BTS and SIGN guideline. That is, it would be used at the same position as existing treatments for asthma control. The committee concluded that for people with allergic asthma not well controlled by inhaled corticosteroids and associated with allergic rhinitis, 12 SQ‑HDM SLIT would be used in addition to symptom-relieving medicine, but before biological treatments.

The marketing authorisation for 12 SQ‑HDM SLIT states that house dust mite allergy must be confirmed. ARD is mostly diagnosed in primary care and some tests of sensitisation such as a radioallergosorbent test may be done by GPs. But further testing such as skin prick testing and taking a clinical history to determine house dust mites as the allergen would be done in secondary care. 12 SQ‑HDM SLIT is a sublingual immunotherapy (SLIT) that contains a standardised allergen extract from the house dust mites Dermatophagoides pteronyssinus and Dermatophagoides farina. The committee noted that the marketing authorisation states that 'treatment should be initiated by physicians with experience in treatment of allergic diseases'. The clinical experts explained that they expected 12 SQ‑HDM SLIT would be prescribed in secondary care. A patient expert who was also a GP agreed, but noted that some GPs would have enough experience to prescribe. The committee concluded that 12 SQ‑HDM SLIT would be prescribed in secondary care.

A clinical expert stated that they expected a minority of people with ARD caused by house dust mites would need 12 SQ‑HDM SLIT. The committee noted that the marketing authorisation indication is for 'house dust mite allergic asthma not well controlled by inhaled corticosteroids'. But, the clinical trial assessing 12 SQ‑HDM SLIT for asthma (see section 3.7) included people with asthma that could be considered controlled. It was unclear how 'asthma not well controlled by inhaled corticosteroids' would be defined in clinical practice. A clinical expert stated that they would expect to start 12 SQ‑HDM SLIT when a person with uncontrolled asthma was having fewer exacerbations. The committee concluded that it remained uncertain about the eligibility criteria for 12 SQ‑HDM SLIT for people with allergic asthma with allergic rhinitis in clinical practice. This uncertainty included whether people would start treatment when their asthma was not well controlled, or whether they would need to wait for a reduction in exacerbations before starting treatment.

The EAG identified many methodological limitations across the trials that it considered to have important implications on the applicability of the trial results to the NHS. These included specifically for MT‑04:

• People had to report that their asthma symptoms were partially controlled (ACQ score between 1.0 and 1.5) before randomisation. People with an ACQ score of more than 1.5 at randomisation (suggesting asthma was not well controlled) were not eligible to take part in MT‑04. The EAG considered that this meant that there was limited data for people whose asthma was not well controlled with inhaled corticosteroids.

• People in MT‑04 had a mandated reduction of inhaled corticosteroids by 50% over the first 3 months of the efficacy period and these were stopped completely for the second 3 months of the efficacy period. This would not reflect clinical practice if 12 SQ‑HDM SLIT was used.

• Part of the MT‑04 protocol required people who had more than 3 asthma exacerbations to withdraw from the trial in the assessment phase. The EAG considered this restricted outcome data for people who might have had multiple exacerbations.

The allergic rhinitis trials reported rhinitis symptoms using the total combined rhinitis score (TCRS):

• In MT-06 a statistically significant mean difference in TCRS was seen between the groups during period 2 (visit 5: -1.41, 95% confidence interval [CI] -2.14 to -0.68; visit 6: -1.22, 95% CI -1.99 to -0.46) and in period 3 (visit 7 to 8: -1.09, 95% CI -1.84 to -0.35). This suggested the placebo group reported worse symptoms and more medicine use compared with the 12 SQ‑HDM SLIT group. Since analysis of data in period 3 was adjusted to account for missing data, the EAG considered this data had better internal validity.

• In P001 the placebo group reported statistically significantly higher on the TCRS (5.49) compared with the 12 SQ‑HDM SLIT group (4.67), mean difference -0.82 (95% CI -1.24 to -0.40), which suggested worse symptoms. Because this analysis only included the full analysis set, in which many people had stopped having treatment, the EAG considered that the results were biased.

The primary outcome in MT-04 was time to first moderate or severe asthma exacerbation during the efficacy assessment phase. MT-04 reported a statistically significant (31%) risk reduction of a moderate or severe asthma exacerbation compared with placebo (hazard ratio [HR] 0.69, 95% CI 0.50 to 0.96, p=0.027), in the full analysis set with multiple imputation (to adjust for missing data). Asthma symptoms were also reported using ACQ scores. At visit 13, which happened during the mandated withdrawal phase of the trial, there was no statistically significant difference in ACQ score between the 12 SQ‑HDM SLIT arm and the placebo arm (mean difference -0.12, 95% CI -0.25 to 0.01). One clinical expert explained that if there was no difference seen in clinical practice for an asthma treatment, then the asthma treatment would be stopped.

The company provided 2 Markov models to calculate lifetime costs and quality-adjusted life years (QALYs) for treatment with 12 SQ‑HDM SLIT compared with established clinical management. One model was for the allergic rhinitis only population and 1 for the allergic asthma with allergic rhinitis population. Each model was comprised of 3 mutually exclusive health states to describe what could happen to the population of interest over time. The health states for the allergic rhinitis population were defined based on a modified version of the ARIA severity classification (Valero et al. 2007). The health states were mild, moderate and severe and populated using data from MT-06. The 3 health states for the allergic asthma with allergic rhinitis population were defined to reflect asthma control according to the GINA guidelines (Reddel et al. 2021). The states were uncontrolled asthma, partly controlled asthma and well controlled asthma. The company used ACQ data from MT‑04 and mapped this to the GINA classification health states. Both models compared 12 SQ‑HDM SLIT taken alongside established clinical management with established clinical management alone. The established clinical management people had in each health state was a blend of the treatments people with each allergic rhinitis severity, or asthma level of control, would have in clinical practice. The EAG had the following concerns with the company's modelling approach:

• Each model had a 1‑year cycle length. So the company assumed an average level of disease control or severity throughout the year rather than potential fluctuations throughout the year.

• The models were informed by the MT-04 and MT-06 trials, which the EAG had noted had methodological limitations. Also, to estimate the proportion of people in each health state in the models the company had used a post-hoc analysis from the MT-04 and MT-06 trials, which added to the uncertainty.

• The allergic asthma with allergic rhinitis model did not explicitly model rhinitis outcomes and asthma exacerbations were assumed to be the same across asthma control health states, which was implausible.

• The allergic rhinitis model did not include data from young people aged 12 to 17 years. The company's approach for both models did not reflect a stepping up of treatment when symptoms persist and stepping down of treatment when symptoms are well controlled.

• The allergic asthma with allergic rhinitis model did not include people with an ACQ score reflecting uncontrolled asthma, that is, 1.5 or more.

The company used data from the adult population in MT-06 and generalised this to people aged 12 to 17 years to model the clinical effectiveness for people 12 and over with house dust mite allergic rhinitis. This implicitly assumed that there was no difference in effectiveness between the 2 subgroups. The EAG noted that subgroup evidence from P001 suggested there was a larger difference in the TCRS scores in people aged 12 to 17 compared with the adult subgroups (see section 3.8). But the EAG was unable to explore the impact of the difference in its critique. The committee considered this remained an area of uncertainty that would need to be resolved by additional evidence on health-related quality of life for this subpopulation.

There was no clinical trial data beyond 2 years. In both models the company assumed that having 12 SQ‑HDM SLIT would improve health from 2 to 10 years, whereas on established clinical management people would remain stable (stay in the same health states over the whole of the modelled period). Treatment waning was modelled in the 12 SQ‑HDM SLIT arm from 15 years onwards. By year 20, 80% of people having 12 SQ‑HDM SLIT would match the distribution of people having standard care. The company assumptions were informed by clinical opinion collected in a Delphi panel. The company had supplemented its long-term effectiveness assumptions with evidence from the REACT study (Fritzsching et al. 2021). This was a German retrospective cohort study of people with allergic rhinitis and asthma who had, and had not, had allergic immunotherapy (subcutaneous or sublingual against various antigens). This assessed group differences across 9 years of follow up and found that over this period people who had allergen immunotherapy had fewer rhinitis and asthma prescriptions than people who had not. The EAG considered that there was no evidence beyond 10 years and preferred to assume that from 2 to 10 years people stayed in the same health states in the 12 SQ‑HDM SLIT arm and then after 10 years matched the distribution across health states of standard care. A clinical expert specialising in treating allergic rhinitis gave anecdotal evidence that for sublingual immunotherapy for pollen allergy, results were variable but they would expect 10 years of benefits. The effects of immunotherapies were likely transferable for different allergens. A patient expert reported that a person who had 3 courses of 12 SQ‑HDM SLIT would have a treatment effect lasting 20 years. The committee concluded that it was plausible that an allergen immunotherapy could have a persistent effect, but further evidence was needed for assuming a class effect across immunotherapies for different allergens and routes of administration. The committee also noted that the current models assumed 1 course of treatment and if retreatment is expected in clinical practice the updated models should reflect that.

Management costs in the company's base case included the costs for primary care and secondary care. In both models, 12 SQ‑HDM SLIT reduced primary and secondary care costs compared with standard care. In the allergic asthma with allergic rhinitis model, the company's base case assumed a 54.58% relative reduction of secondary care resource use with 12 SQ‑HDM SLIT compared with standard care, based on the number of emergency visits in MT-04. The EAG noted that the number of emergency visits in MT-04 was generally low across treatment arms. So there was high uncertainty in the company's assumption. In the allergic rhinitis only model the company assumed a relative reduction of 73.53%, based on El Qutob et al. (2016). This was a before-and-after study of subcutaneous immunotherapy for house dust mite allergic rhinitis and allergic asthma. So it was unclear whether the treatment effects would be generalisable to sublingually administered 12 SQ‑HDM SLIT. The EAG had noted that the before-and-after design of this study may have produced biased estimates. Assuming a smaller reduction in secondary care costs in the 12 SQ‑HDM SLIT arm had a large effect on the cost-effectiveness results. The EAG had noted that the company's approach to modelling the reduction in primary care visits in the allergic asthma with allergic rhinitis model was complicated. And was poorly aligned with the economic model. The estimates relied on strong assumptions to translate data from MT-04 on primary care visits to the modelled health states, which had not been justified. The committee was concerned that the modelling assumptions might overestimate savings in primary and secondary care costs of 12 SQ‑HDM SLIT. It recognised that it would need additional evidence to support the company's modelling assumptions for the extent of any reduction in primary or secondary care visits associated with 12 SQ‑HDM SLIT. The committee also concluded that if data was used from people having subcutaneous house dust mite immunotherapy to estimate the relative reduction in secondary care for 12 SQ‑HDM SLIT, it would need justification that reduced secondary care visits for subcutaneous immunotherapy could be generalised to sublingual immunotherapy.

In its base case for both models, the company applied a treatment-specific approach to model health-state specific utilities. This assigned a specific utility value to treatments. For the allergic asthma and allergic rhinitis population it used post-hoc data from MT-04 to transform SF-36 scores into preference-based utilities. For the allergic rhinitis only population, the company used a post-hoc analysis of EQ-5D data collected in MT-06. The EAG was concerned that a treatment-specific approach did not align with both model structures. It preferred to use health-state specific utilities that provide quantitative measures of how strongly a person values a certain health state. The EAG also noted that the EQ-5D measure the company used in the allergic rhinitis only model has only been validated for adults. So, results from this measure may not be applicable to people aged 12 to 17 years with allergic rhinitis. The company stated that it had used treatment-specific utilities because these could apply to people who were on or off treatment. It considered this was more appropriate than using health-state utility values, because it would capture other factors beyond allergic control. The company also noted that in the model for allergic asthma with allergic rhinitis, using treatment-specific utility values would allow 12 SQ‑HDM SLIT's effect on quality of life associated with allergic rhinitis to be captured in the utility values, because the health states modelled asthma only. The committee recognised that allergic rhinitis in addition to asthma can affect health-related quality of life. So it accepted this was a valid approach to modelling health-related quality of life. The committee concluded that in the updated models the utility values should be representative of the whole population within the marketing authorisation.

The committee considered that some people with allergic rhinitis and allergic asthma may have a disability, are an older age, or are pregnant. These are protected characteristics under the Equality Act 2010. But because its recommendation does not restrict access to treatment for some people over others, the committee agreed these were not potential equalities issues.

The committee's concerns about the clinical evidence and cost-effectiveness modelling meant that it was not confident that the results presented reflected the clinical and cost effectiveness of 12 SQ‑HDM SLIT as it would be used in the NHS. It could not recommend 12 SQ‑HDM SLIT. The committee suggested further data, analyses and necessary model revisions which may allow it to better understand the clinical and cost effectiveness of 12 SQ‑HDM SLIT in NHS clinical practice. It welcomes the company to provide these in response to consultation on its draft recommendations.