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PRIORITY PRESS - European Academy of Allergy and Clinical Immunology Congress

Barcelona, Spain / June 6-10, 2015

Barcelona - Sublingual immunotherapy (SLIT) is working its way into allergy clinics with two oral tablets approved for use in patients with allergic rhinitis to grass pollen in Canada¹. This type of therapy has been available in Europe since 2005 and has recently gained FDA approval in the USA (in 2014²). SLIT involves giving patients small doses of an allergen, under the tongue, with the aim of increasing immunity over time. Pollen is one of the most common causes of allergic rhinitis globally³ and the World Health Organization has recommended SLIT as a therapeutic option for patients with allergic rhinitis since 1998⁴. Currently both grass pollen tablets are indicated for use in patients 5 years of age and older with signs and symptoms of grass allergic rhinitis. Further research, including safety studies that looked at oral tablets for grass allergy in patients with allergic rhinitis continues to be positive. Another common allergen, worldwide, is house dust mite (HDM) and studies are currently assessing SLIT tablets for this group of patients. In addition, recent phase 3 studies have been assessing the therapeutic option for allergic asthma, and as reported at the EAACI 2015, the outlook is promising with a good safety profile.

Over the past 50 years allergic disease has increased to epidemic proportions globally with a substantial increase in hospital admissions for severe disease⁵ with grass pollen and house dust mites (HDMs) being some of the most common allergens. Allergen immunotherapy is a disease-modifying treatment option that involves treating the cause of an allergy by giving patients small incrementing doses of a standardized quality (SQ) allergen with the aim of increasing immunity and reducing allergic symptoms over time.⁶ Allergen immunotherapy has traditionally been administered by subcutaneous injections (subcutaneous immunotherapy [SCIT]), and has been an effective treatment option for patients with allergic rhinitis and asthma but now sublingual options are becoming a more widely accepted and easier treatment in the clinic as regulatory agencies approve these medications for use in patients. The World Health Organization has endorsed SLIT as a viable alternative to SCIT.⁷ Particularly as this type of treatment option is the first to be able to stop progression of symptoms and there is a suggestion that early therapy may prevent wider pattern of sensitivities or stop the progression of asthma.⁸ Currently two tablet formulations have been approved for use by Health Canada which are indicated for the treatment of allergic rhinitis due to grass pollen. Other allergens are currently being tested in sublingual tablet formulation but the only ones approved for use in patients currently are grass pollen tablets, and there is also one tablet for ragweed pollen. Progress has been made with several phase 3 studies assessing sublingual HDM allergens.

Efficacy

Overall 77 randomized clinical trials investigating SLIT, 39 trials with grasses and five with HDM extracts⁹, have been conducted. Most trials consistently report clinic efficacy, as only five of the 77 were negative.⁹ New trials were reported on in Barcelona.

In a study, including 327 patients and looking at the safety of the 5-grass pollen SLIT tablet in patients with allergic rhinoconjunctivitis, a substantial number of patients reported stopping medication for their hayfever symptoms altogether (Hadler M et al. EAACI 2015: Abstract 116). “More than 40% of our patient population actually stopped taking symptomatic medication,” said Dr. Meike Hadler. None of the patients in the study required oral corticosteroids while on sublingual therapy and only five patients needed nasal corticosteroids, explained Dr. Hadler.

Another study assessed the Timothy grass SLIT tablet in 181 patients who were also receiving additional allergy immunotherapy for tree pollen or HDMs by SCIT or SLIT (Wolf H et al. EAACI2015: Abstract 1608). Dr. Hendrik Wolf and colleagues reported that, in that study, there was no increase in frequency of adverse events compared with previous studies and tolerability of the SQ grass SLIT-tablet was still good when given together with other allergen immunotherapies.

Safety Profile

In the 1980s there were concerns over safety of allergen therapy when some deaths were reported with SCIT.¹⁰ However large well-designed European and North American studies have since shown that sublingual tablets for grass pollen are safe and adverse events are rare.² In fact several clinical trials have demonstrated that SLIT tablets are safer than SCIT.² In more than 20 years of clinical trials and everyday use there were only six cases of anaphylaxis reported with SLIT, and these were with mixtures of allergens and the use of non-standardized extracts.¹⁰ Only two patients had a severe reaction after the first dose of a grass tablet.¹⁰

Further post-marketing studies assessing the safety of the already approved 5-grass pollen sublingual tablet showed favorable safety and tolerability in 170,000 patients (Didier A et al. EAACI 2015: Abstract 522). “If we look at the type of adverse reaction we can see that most were local reactions like mouth edema or throat irritation. Anaphylaxis was very rare,” said Dr. Alain Didier, Larrey Hospital, Toulouse, France.

Other Allergens

There have been less randomized controlled trials (RCTs) assessing HDM allergens but positive results were recently reported on in Barcelona.

Data showed that a SQ of the HDM SLIT tablet was well tolerated in adults for both allergic rhinitis and allergic asthma (Emminger W et al. EAACI 2015; Abstract 1558). In 2500 patients from four randomized double-blind phase 2 and 3 trials, the most common adverse events were mild local allergic reactions, and these were dose dependent. There were no reports of anaphylaxis and there was one single case of adrenaline use for a mild local reaction on day one of 12 SQ-HDM therapy, and the patient continued treatment and completed the trial with only mild oral pruritus subsequently.“The majority of adverse events started on the first or second day of tablet intake and only lasted a few minutes, and started within 5 minutes of intake of the tablet. Over time the number of adverse events decreased. For instance only 10% of subjects had ongoing adverse events after three months,” investigators reported. The researchers also found that there was no indication of the risk of adverse events being greater for the 232 patients in the trials with uncontrolled asthma. Investigators were optimistic about the data and stated that they “hope [SLIT tablets for HDM] will be available soon.”

Other Indications and Patient Selection

Dr. Glenis Scadding, Royal National Throat, Nose and Ear Hospital, London, UK, reported on the efficacy of SLIT-tablets
for HDM in patients with both allergic rhinitis and allergic asthma (Scadding G et al. EAACI 2015: Abstract 977). Pointing to three efficacy trials assessing 6 or 12 SQ-HDM tablets against placebo she reported that patients with both allergic rhinitis and asthma benefited, even when patients had both manifestations. “The combined evidence shows the highest benefit in patients who are not well controlled on pharmacotherapy,” said Dr. Scadding.

There was a general theme among experts in Barcelona about the concept of allergic rhinitis and allergic asthma going hand in hand and a suggestion that an integrated clinical approach to treatment was needed. “Allergic rhinitis and allergic asthma have long been viewed as separate diseases,” said Dr. Santiago Quirce, Department of Allergy, Institute for Health Carlos III, Madrid. But these are often comorbid diseases, explained Dr. Quirce, and current treatment approaches are separated but perhaps an integrated management approach is needed.

Dr. Scadding also agreed, “To this audience I don’t need to stress the importance of looking at the airway as united. I think you are all well aware that patients with HDM sensitivity may present with allergic rhinitis, roughly 50%, the others will have allergic rhinitis plus asthma.”

In the past, there has been a question over how effective immunotherapy can be in asthma.^4,8 New evidence was presented in Barcelona showing that SLIT tablets for HDMs are highly effective in allergic asthma (Cardona V et al. EAACI 2015: Abstract 980). Reporting on a large randomized double-blind controlled trial including 834 patients with allergic asthma to HDM SLIT-tablets were well tolerated in patients with uncontrolled asthma and there were no safety findings of clinical concern. “This was the first trial demonstrating a clinically relevant reduced risk of asthma exacerbation with the SQ HDM SLIT-tablet,” said Dr. Frank Smeenk, Department of Pulmonology, Catharina, Hospital Eindhoven, The Netherlands.

Dr. Scadding was careful to mention that patients do need to be carefully selected for this type of treatment. “One must not do HDM immunotherapy simply because your patients has rhinitis and a positive skin test. You have got to know that the HDM is causing those symptoms and I think if you are not sure about that what you must do is a HDM allergen nasal challenge [test],” she reported. 

References:

1.http://www.newswire.ca/en/story/1298937/grastektm-an-allergy-immunotherapy-tablet-for-the-treatment-of-signs-and-symptoms-of-grass-allergy-is-now-available-in-canada
2. http://www.uptodate.com/contents/sublingual-immunotherapy-for-allergic-rhinoconjunctivitis-and-asthma
3.http://www.niaid.nih.gov/topics/allergicdiseases/documents/pollenallergyfactsheet.pdf
4. http://www.ncbi.nlm.nih.gov/pubmed?term=9802362
5. http://www.waojournal.org/content/7/1/6#B143
6. http://www.ctajournal.com/content/5/1/18
7.http://www.hopkinsmedicine.org/otolaryngology/specialty_areas/sinus_center/sublingual_immunotherapy.html
8.http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)78425-7/fulltext?version=printerFriendly
9. http://www.annallergy.org/article/S1081-1206(11)00506-0/abstract?cc=y=
10. http://www.waojournal.org/content/pdf/1939-4551-2-11-233.pdf