A company-sponsored scientific symposium held last year during the 34th European Academy of Allergy and Clinical Immunology (EAACI) congress, in Barcelona, Spain, has signalled the need for a more integrated treatment approach of HDM respiratory allergic disease. HDM allergy is one of the most common causes of respiratory allergic disease in the world. It can have symptoms that manifest in both the upper (allergic rhinitis [AR]) and lower (allergic asthma [AA]) airways.1
AA and AR are frequently found to co-exist, with numerous studies demonstrating clinical and immunological inter-relationships between the two entities.1 Despite this, AA and AR are often treated separately in clinical practice.
Currently, inhaled corticosteroids (ICS) are the foundation of asthma management and are highly effective for controlling the condition.2 In AR, antihistamines and nasal corticosteroids are cornerstones in symptomatic treatment.3 However, a significant number of asthma and AR patients are poorly controlled and experience moderate-to-severe symptoms despite the use of pharmaco therapy.4,5 Allergy immunotherapy (AIT) addresses the underlying cause of allergy through immuno modulation, thus treating both manifestations of respiratory allergic disease.6 The HDM sublingual AIT (SLIT) tablet (SQ®HDM SLIT-tablet; ALK, Hørsholm, Denmark) is approved in 11 European countries and available in Denmark and Germany under the brand name ACARIZAX®. The SQ®HDM SLIT-tablet is also being developed for a number of other markets around the world in collaboration with ALK’s partners – by MSD (known as Merck in the USA and Canada) for North America, Abbott for Russia and South-East Asia, and Torii for Japan (launched under the brand name MITICURETM). Together, these development activities have involved more than 6000 patients worldwide. Positive results of phase 2 and 3 trials have demonstrated efficacy of the SQ®HDM SLIT-tablet in both HDM-induced AA and AR individually, and when the two are present simulta neously. These exciting new data suggest that the SQ®HDM SLIT-tablet is effective in treating the underlying cause of HDM respiratory allergic disease, providing clinical benefit in patients with HDM allergy regardless of the dominant manifestation in the airway.
Phase 3 results confirm efficacy of the SQ®HDM SLIT-tablet in treating AA and AR
Allergy and clinical immunology specialist Dr Jörg Kleine-Tebbe began the symposium by presenting an update on the SQ®HDM SLIT-tablet clinical development programme, with a focus on the MITRA (MT-04) and MERIT (MT-06) phase 3 trials in AA and AR patients, respectively.
The MITRA trial evaluated efficacy and safety of the SQ®HDM SLIT-tablet compared to placebo in 834 patients with HDM AA not fully controlled with medium- to high-dose ICS, but with a lung function >70% of predicted FEV1 and no recent exacerbations. Patients were randomised to two active doses, 6 SQ-HDM or 12 SQ-HDM, or placebo. MITRA met its primary clinical endpoint of a significant reduction in the risk of moderate-to-severe asthma exacerbations, as measured as hazard ratio during ICS reduction with both doses. Time-to-first exacerbation experienced by 25% of subjects was >180 days in the 12 SQ-HDM group, compared with 170 days for 6 SQ-HDM and 100 days for placebo.
Dr Kleine-Tebbe also presented the positive phase 3 results shown in AR patients. The MERIT trial evaluated efficacy and safety of the SQ®HDM SLIT-tablet compared to placebo in 992 patients who had moderate-to-severe HDM AR despite having received symptomatic treatment. Patients were randomised 1:1:1 to 6 SQ-HDM, 12 SQ-HDM or placebo. The MERIT trial also met its primary clinical endpoint of reduction in the Total Combined Rhinitis Score (TCRS). After one year of treatment, both SQ-HDM doses met the predefined criteria of an absolute reduction in TCRS of >1. A statistically significant effect was evident already after 14 weeks with the 12 SQ-HDM dose that was evident for the entire course of the trial, indicating a year-round treatment effect of the SQ®HDM SLIT-tablet.
Dr Kleine-Tebbe stressed that as well as demonstrating efficacy in both AR and AA patient groups, the SQ®HDM SLIT-tablet has shown promise in treating patients with concomitant AR and AA. He commented on results from the double-blind phase 2 environmental exposure chamber trial, which included adults with HDM AR of ≥1 year in duration who reported moderate-to-severe rhinitis symptoms during a screening HDM exposure challenge. Participants were randomised to 6 SQ-HDM, 12 SQ-HDM or placebo. At the end of the trial (week 24), the reduction in the primary endpoint, total nasal symptom score (TNSS), was 27% for 6 SQ-HDM and 49% for 12 SQ-HDM, supporting both efficacy and robustness of the dose response. Approximately 24% of patients also had AA, and a numerical dose-dependent reduction in asthma symptoms was found to accompany the reduction in AR symptoms.7
Dr Kleine-Tebbe also noted that in all three of the clinical trials the SQ®HDM SLIT-tablet was well tolerated in both the AR and AA populations.
HDM AA and AR have a common pathophysiology
The SQ®HDM SLIT-tablet clinical trial data provide a new evidence base for the use of AIT in both HDM AR and AA, and support an integrated management approach to the treatment of HDM respiratory allergic disease. These new data have important implications for clinical practice, where upper and lower airways are often treated separately, and usually by different specialists.1
Clinical immunology and allergy expert Dr Santiago Quirce stressed the need for a management paradigm shift by explaining that AA and AR have a shared common pathophysiology that makes them inseparably linked.1 Indeed, figures show that approximately 50% of patients with HDM AR are reported to have concomitant AA, and up to 90% of AA patients experience symptoms of AR.8,9 Studies have demonstrated that local allergen exposure in the nose of patients with AR can quickly lead to significant allergic inflammation in the lungs, even without a previous history of asthma and bronchial hyper-responsiveness (BHR).1 Furthermore, upper airway symptoms such as AR have been confirmed to exacerbate AA.10 Additionally, Dr Quirce commented that AR has been identified as a strong risk factor for AA development.11 These findings have led to the conclusion that upper and lower airway disease are both manifestations of a single inflammatory process within the respiratory tract, referred to in the literature as united airway disease (UAD).1 Under this model, three stages of the disease, which increase in severity, are identified: (1) AR without BHR or AA; (2) AR with BHR; and (3) AR with AA.
Dr Quirce highlighted the importance of understanding the role of HDM allergy in the prevalence, sensitisation and symptom control of UAD. His presentation highlighted that various components of HDM and their associated faecal pellets have been shown to be important sources of indoor allergens. These activate both the adaptive and innate immune systems, resulting in immune-mediated pathology and airway hyper-responsiveness.12 To this effect, Dr Quirce advised that an integrated management approach that consists of pharmacotherapy and AIT should be utilised in patients with UAD to control symptoms and inflammation of the airways.
Recognising allergic rhinitis and allergic asthma as different manifestations of one disease with shared pathophysiology will improve the diagnosis and management of these common disorders.
A rhinologist’s perspective: HDM AR management should incorporate asthma treatment or prevention strategies
Consultant allergist and rhinologist Dr Glenis Scadding continued the symposium by providing an overview of the clinical management of the upper airway of UAD. AR, which primarily affects the nasal passages, is caused by sensitivity to allergens that exist in both indoor and outdoor environments. Of these allergens, sensitisations to HDM have been most strongly associated with AR, and it is well established that atopic patients exposed to HDM allergens are at an increased risk of developing AA.12,13 As such, Dr Scadding stressed the importance of investigating the presence of co-existing asthma in all AR patients during diagnosis.
Dr Scadding asserted that making a positive AR diagnosis can sometimes be challenging. An accurate AR diagnosis requires a detailed patient history, examination of potential triggers and exacerbation of symptoms, visual examination of the face, nose, chest and skin, and skin prick tests.14 Following a diagnosis, patients are treated according to Allergic Rhinitis and its Impact in Asthma (ARIA)3 and in the UK also the British Society for Allergy and Clinical Immunology (BSACI)14 guidelines. In patients with perennial exposure, intranasal steroids are the treatment of choice, with oral antihistamines if uncontrolled. Dr Scadding noted that HDM avoidance measures for AR are generally not recommended due to lack of documented efficacy.15
While pharmacotherapy may control AR symptoms in some patients, Dr Scadding observed that there is no evidence to suggest that it is able to prevent progression to AA. To date, AIT is the only treatment strategy demonstrated to address the underlying cause of the allergic disorder, and not only the symptoms that manifest.16,17 AIT has been shown to produce long-term remission of AR symptoms, reduce severity of associated asthma and reduce the risk of new sensitisations to allergens developing.5,17,18 Therefore, AIT therapy should be considered early in the UAD process.
Recapping on results of the phase 3 MERIT trial, Dr Scadding also drew attention to the clinical relevance of the SQ®HDM SLIT-tablet efficacy from a patient’s perspective; this demonstrated a year-round reduction in symptoms and medication.
Post-hoc analysis from MERIT showed that AR patients administered with the 12 SQ®HDM SLIT-tablet had a probability reduced to half of having an AR exacerbation day, defined as burdensome disease with moderate-to-severe symptoms. This, Dr Scadding commented, really makes a difference to the patient’s life.
With SQ®HDM SLIT, the probability of having burdensome symptoms can be halved. That really matters to your patients for their quality of life, their ability to go to work and school, and their ability to do well when they are there.
A pneumologist’s perspective: HDM AA management should incorporate AR treatment strategies
While asthma patients also manifest symptoms with non-allergic triggers, a significant number of people with asthma have allergen-induced symptoms, which can also present in the upper airways as AR.2 Global asthma specialist Professor J Mark FitzGerald highlighted that sensitisation and exposure to HDM allergens are a major risk factor for the development of AA,12 which is often associated with the co-existence of AR, and can promote the persistence of airway inflammation and likelihood of an asthma exacerbation.12,19 Testing for sensitivity to allergens is therefore an important part of asthma diagnosis.
Current Global Initiative for Asthma (GINA) guidelines recommend that all patients should undergo assessment regarding exacerbation of asthma symptoms, including examination of the upper airways.2 Once a diagnosis has been made, GINA guidelines recommend ICS as first-line therapy, which has been demonstrated to prevent asthma exacerbations and improve long-term lung function.17 Both GINA and ARIA guidelines recommend administering intranasal corticosteroids in patients with co-existing AR.2,3
Despite the availability of asthma therapies, results from a Canadian survey discussed by Professor FitzGerald revealed that only 47% of asthma patients had controlled disease.20 He commented that this is likely due to the fact that therapies are often not prescribed appropriately, or when prescribed, are not adhered to. He also expanded further on the phase 3 MITRA trial results, which demonstrated a reduced risk for moderate or severe asthma exacerbations with the SQ®HDM SLIT-tablet after ICS reduction.
Professor FitzGerald highlighted the fact that much of the previous literature related to immunotherapy had poor study design with flawed analyses. In particular, he highlighted a much quoted JAMA systematic review, which, in its conclusions, outlined many of these methodological issues.21 He commented that new emerging data, including that presented at the symposium, showed that the role of immunotherapy in asthma needed to be revisited.
In addition to its efficacy in AA, the SQ®HDM SLIT-tablet has also demonstrated efficacy in AR. Since a significant proportion of AA patients have co-existing AR that requires intranasal corticosteroids, AIT has the potential to minimise the number of drugs prescribed. Although this could potentially improve patient outcomes and reduce direct medical costs, appropriately designed studies need to show this. In addition, he highlighted the importance of patient education and the challenge of achieving adherence with all treatments.
Professor FitzGerald concluded by commenting on the MITRA trial in which an evaluation of patients’ ‘GINA asthma control level’ according to an algorithm previously described showed that 28% of subjects had GINA-defined uncontrolled asthma at randomisation (but fulfilling the exclusion criteria of having a lung function >70% predicted FEV1 and no recent exacerbations at initiation) and that no increase in treatment-related adverse events was seen in these patients. He commented that since AIT is somewhat controversial in this group of patients, this finding is particularly relevant.
In the MITRA trial, in patients with uncontrolled asthma, you don’t see any additional adverse event signals [versus the full trial population]. This is a very important factor in terms of prescribing immunotherapy.
J MARK FITZGERALD
Do current clinical practice guidelines support an integrated management approach?
Global allergy and clinical immunology specialist Professor Moisés A Calderón concluded the symposium by presenting a review of international guidelines on the management of HDM respiratory allergic disease.
Professor Calderón explained that since AA and AR are often seen as comorbid diseases, there is a need for an integrated approach to treating the conditions. However, he said that current evidence-based guidelines are largely imbalanced. While AIT is presented as an option for selected patients with HDM AR, the use of AIT to treat HDM AA is not widely recommended. Professor Calderón commented that this is largely due to the fact that evidence from high-quality studies and randomised controlled clinical trials is lacking.21 He said that existing studies vary substantially in their risk of bias and employ inconsistent diagnostic and severity criteria, clinical outcome measures, and dosing and treatment schedules. As such, evidence-based clinical guidelines are unable to provide widely supportive recommendations.
Professor Calderón emphasised that the SQ®HDM SLIT-tablet clinical development programme provides evidence from high-quality randomised trials that support its use in the HDM respiratory allergic patient population. The SQ®HDM SLIT-tablet has demonstrated efficacy in patients with AR and AA, and also when both manifestations are present simultaneously. This new evidence supports a ‘united respiratory’ approach to the treatment of allergic disease.
Professor Calderón concluded that there is now an urgent need for the level and quality of the available evidence on the treatment of AR and/or AA caused by HDM allergy to be presented in a form that the clinician can use to guide their practice. This can be achieved through consensus in international guidelines to take a more integrated approach to AIT in respiratory allergic disease caused by HDM.
ALK has shown the way forward to developing a more co-ordinated clinical approach to treating HDM-induced allergic asthma and rhinitis. Now we need a strong push and commitment from the medical community to translate these new data into clinical practice so that patients will directly benefit. Establishing solid, integrated, evidence-based guidelines is a crucial prerequisite to achieving this goal.
MOISÉS A CALDERÓN
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- Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA). Updated 2015 (www.ginasthma.org/local/uploads/files/GINA_Report_2015_Aug11.pdf; accessed 2 September 2015).
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- Sheikh A, et al. Cochrane Database Syst Rev 2010 Jul 7;(7):CD001563.
- World Allergy Organization. Disease summaries: in-depth review of allergic rhinitis. June 2005; updated June 2015 (www.worldallergy.org/professional/allergic_diseases_center/rhinitis/rhinitis_indepth.php; accessed 2 September 2015).
- Radulovic S, et al. Cochrane Database Syst Rev 2010 Dec 8;(12):CD002893.
- Zolkipli Z, et al. J Allergy Clin Immunol 2015 (Epub ahead of print, 13 June 2015. doi: 10.1016/j.jaci.2015.04.045).
- ten Brinke A, et al. Eur Respir J 2005;26:812–8.
- FitzGerald JM, et al. Can Respir J 2006;13:253–9.
- Lin SY, et al. JAMA 2013;309:1278–88.