Allergen immunotherapy in the treatment of hayfever

Subcutaneous allergen immunotherapy is highly effective in hayfever sufferers who fail to respond to anti-allergic drugs, but carries the risk of severe allergic side-effects. Professor Durham‟s group at Imperial College have defined the mechanisms and shown that sublingual tablet immunotherapy is an effective, safer alternative that induces long-term disease remission. The tablet approach is now widespread in Europe and is being successfully extended to other allergies (housedust mite) and internationally (ragweed allergy in USA and Japanese Cedar pollen allergy). The work is quoted in guidelines internationally, and regulatory bodies now recognise the disease-modifying potential of immunotherapy and its ability to induce long-term remission.

Underpinning research

Allergen immunotherapy involves the repeated administration of allergen extracts to IgE-sensitised allergic subjects. Professor Durham‟s group at Imperial showed that allergen injection immunotherapy was highly effective in severe seasonal allergic rhinitis (hayfever), with or without seasonal asthma. In contrast to anti-allergic drugs immunotherapy was able to induce long-term clinical and immunological tolerance. The Imperial group defined the underlying mechanisms and showed that immunotherapy could also be administered effectively, safely and conveniently via the sublingual route (under the tongue) whilst retaining disease-modifying properties.

Prior to 1993, allergen immunotherapy was practiced rarely. In 1986, the Committee on Safety of Medicines (CSM) reported a series of fatalities in the UK, questioned the safety of the treatment particularly in asthmatics, and consequently mandated a 2 hour observation period following injections. In 1993, Imperials group initiated a series of prospective long-term, double-blind, placebo-controlled clinical trials of immunotherapy. A parallel initiative in 1996, also at Imperial, was the development of novel techniques of immuno-histochemistry and in situ hybridisation in the nasal mucosa, peripheral T cell assays and functional assays of serum "blocking" IgG antibodies. This enabled a detailed and unbiased evaluation of the underlying mechanisms of immunotherapy that could be related directly to the clinical response to treatment.

Imperial researchers showed that subcutaneous immunotherapy suppressed Th2-T cell-driven allergic inflammation in the skin and nasal mucosa, and that this was due to either immune deviation in favour of Th1 responses and/or the induction of a population of regulatory T cells. These immunological findings prompted the hypothesis that immunotherapy, unlike conventional anti-allergic drugs, was disease-modifying. In 1999, we showed subcutaneous grass pollen immunotherapy to be highly effective in severe hayfever and 3 years of treatment could induce at least 3-4 years disease remission accompanied by prolonged suppression of target organ sensitivity, a decrease in cutaneous Th2 responses and persistent IgG-blocking activity that correlated with the clinical response to treatment.

Despite high efficacy, the injection route was associated with 10-20% mild-moderate systemic allergic reactions and the risk of anaphylaxis. Consequently, Professor Durham and colleagues performed a double-blind trial of a sublingual (under the tongue) grass pollen allergen extract in liquid form from ALK Denmark that gave promising results. The same allergen extract was used by ALK to produce a fast-dissolving daily sublingual tablet (Grazax®). Professor Durham co-developed and was principal investigator on a Europe-wide study in 2006 that showed that sublingual tablet immunotherapy was similarly effective. We showed that the mechanism was shown to be very similar (suppression of Th2 responses, induction of IgG4 and IgA2 blocking antibodies). Additionally we demonstrated the induction by immunotherapy of phenotypic T regulatory cells at the site of vaccine delivery within the sublingual mucosa by use of triple immunofluorescence studies of sublingual mucosal biopsies. During a 5 year follow up, 3 years double-blind treatment with sublingual grass allergy tablets was shown to result in prolonged benefit that persisted for 2 years after discontinuation and associated with persistent blocking antibody responses.

Details of the impact

Allergic rhinitis (“hayfever”) affects 1 in 4 in the UK and has a major impact on work/school performance and quality of life. Community surveys in primary care show that at least 40% of sufferers remain uncontrolled despite use of antihistamines and intranasal steroids. Research from Imperial has had an impact on this unmet need as allergen immunotherapy is highly effective in patients who fail to respond to usual anti-allergic drugs. The sublingual tablet approach is novel, more convenient and safer than the subcutaneous route, and has disease modifying properties that result in long-term disease remission.

The UK and Europe-wide regulatory approval of Grazax® sublingual tablets represents the first registration of an allergy vaccine in Europe for 35 years. The EMA (2013) quotes Imperial‟s study as evidence of long-term efficacy of sublingual tablet immunotherapy and have stated that in future all paediatric investigational plans for immunotherapy products should include a study to demonstrate long-term efficacy in children. Imperial‟s long-term study of Grazax resulted in the German regulatory authorities accepting alteration of the Grazax® product label to include an indication for long-term efficacy and disease modifying effect.

Imperial's research is frequently quoted in international guidelines as primary evidence for efficacy and long-term benefits of allergen immunotherapy. The WHO position paper on sublingual immunotherapy (2009) quotes Professor Durham‟s work on the long-term benefits of immunotherapy and recommends the earlier introduction of immunotherapy in the treatment paradigm for allergic rhinitis. Similarly Professor Durham‟s work is quoted in the British Society (BSACI) position paper on allergen Immunotherapy (2011), the European Allergic Rhinitis and its Impact on Asthma (ARIA) revised guideline (2010) and in the British Thoracic Society and Scottish „Sign‟ Asthma Guideline (2012). Imperial‟s work has been showcased by the charity Asthma UK as a key impact of their research funding strategy over the past 15 years (2012).

An independent budget impact analysis (2013) showed that Grazax® was cost saving compared to subcutaneous immunotherapy, saving approximately €1291 per patient per treatment course. This also implies that an additional 40% of patients could be treated sublingually without influencing the current cost for the subcutaneous treatment.

On the basis of Imperial‟s research, ALK Denmark have changed their strategy in Europe to focus on sublingual rather than subcutaneous immunotherapy.

Immunotherapy is widely practiced in the USA where there is considerable interest in sublingual immunotherapy (Professor Durham’s work is quoted in the American Academy of Allergy, Asthma and Immunology Practice Parameters, JACI 2010). ALK have successfully partnered with Merck who have the franchise for sublingual tablet immunotherapy within the USA. Merck have completed a pivotal study in adults that has replicated the European data for Grazax® and extended fast-dissolving tablet technology to sublingual immunotherapy for autumnal ragweed pollen allergy.