Detail

XVIII Congress of the European Academy of Allergy and Clinical Immunology (EAACI)

 

Specific sublingual immunotherapy


Response adapted to patient needs.

Respiratory allergic pathologies affect 20 to 25%¹ of the European population. They notably manifest themselves as allergic rhinitis, which, if left untreated, can cause asthma and further allergies.  In order to treat this pathology, a therapeutic alternative that is adapted to patient needs is being proposed: specific sublingual immunotherapy (or desensitization).

These treatments have been the subject of numerous clinical trials over the past few years.  Taken as a whole, these trials have generated reliable data, featuring significant panel sizes, sound efficacy criteria and rational procedures, identical from one study to the other.

Assessment of the therapeutic effect of specific sublingual immunotherapy

Until now, the trials that assessed specific sublingual immunotherapy treatments were very different in terms of follow-up time, inclusion criteria, statistical analysis of data and control over environmental variables.  However, the meta-analyses of these trials did support the advantages of these treatments, which are recognized as part of the ARIA consensus, but whose level of proof is insufficient with respect to current regulatory requirements.

A new EMEA Directive, dated November 2008, is aimed at putting rules into place to conduct clinical trials that assess specific immunotherapy products.  This Directive highlights the difficulties of the clinical development of these treatments, specifies the stages and criteria to assess clinical development with a view to registration (marketing authorization), points out the limitations of current criteria and suggests potential areas of improvement.

Issues surrounding the clinical development of specific immunotherapy are particularly complex, for the following 5 reasons:

1. The variability of pollen exposure according to the lifestyle and pollination.
2. Rather insensitive efficacy criteria, sometimes invalidated, whereas the thresholds of clinical relevance of the variances are seldom proven: assessment criteria of specific immunotherapy trials comprise 6 symptom scores, compared with only 4 or 5 for symptomatic treatments.
3. The impossibility to recruit patients at the time of the pollen season: in specific immunotherapy trials, patients are included before the pollen season and are based on the intensity of symptoms of the previous year, drawing on patients’ memories.  As for symptomatic treatments, patient inclusion is carried out based on symptom intensity at a consultation during the pollen season.  The average score at inclusion and during follow-up is thus much higher in trials on symptomatic treatment efficacy. 
4. The protective efficacy of specific immunotherapy is all the greater if the response to the pollen exposure is intense.
5. The impact of backup treatments on efficacy assessment.  Due to the duration of specific immunotherapy treatments, the use of backup treatments is recurring and leads to a reduction in the variance of symptomatic vs. placebo scores.

To conclude, the assessment of the clinical efficiency of specific immunotherapy faces methodological difficulties that have been highlighted by health authorities.  The impossibility to select patients during the season, pollen variations during the season and the impact of backup treatments all lead to average scores under placebo that are much lower than those traditionally noted in clinical trials on symptomatic treatments.  As a result, the efficacy of specific immunotherapy may be all the greater.   

     
Pharmacodynamics of a sublingual desensitization tablet: action time and clinical efficacy

For the first time, a pharmacodynamic study has been conducted in an allergen exposure chamber.  This randomized, double-blind, placebo-controlled, single centre (Austria), phase II study was conducted between the 2007 and 2008 pollen seasons on 40 randomized adults in each group.  The treatment phase lasted 4 months, completed by a 3-week follow up phase.  The effect and action time of the sublingual desensitization tablet were assessed after one week, 1 month, 2 months and 4 months following administration of the treatment.

The objectives of this study were to assess the effect and action time of the grass pollen sublingual desensitization tablet on rhino-conjunctivitis symptoms. Its primary criterion was the ARTSS (total rhinoconjunctivitis score, as a sum of the 6 individual scores) during the provocative test after 4 months of treatment.

Such a study in an allergen exposure chamber:

• Avoids pollen variability;
• Avoids patient exposure variability;
• enables to select patients who react positively to the pollen provocative test;
• provides an optimum patient follow up.

To conclude, it has been demonstrated that:

• Sublingual desensitization tablets are significantly (p=0.0003) effective after 4 months of treatment;
• The action time is rapid: the effect of the treatment is noted after 1 week and becomes significant after 1 month.  The effect of the treatment stabilizes between 2 and 4 months;
• All individual symptoms are clearly improved in the active vs. placebo group after 4 months;
• Treatment was well tolerated, as in clinical trials (adult and children, even without any initiation phase).

 

What specific immunotherapy treatment for allergic patients?

To be useful, a treatment must be safe (with little or no side effects), effective (data on clinical efficacy research) and used by patients (in line with their expectations and improving their quality of life).

- Tolerance: Satisfactory tolerance to specific sublingual immunotherapy treatments has been demonstrated on many patients, in particular in adult and children tablet trials.  Only light local effects of the oral pruritus and oral oedema type were reported with no real clinical consequences.

- Efficacy: Specific sublingual immunotherapy treatments now have significant clinical proofs, with a similar study procedure and protocols, from major panels and with understandable assessment criteria (response dosage, clinical score, quality of life).

These criteria are in agreement with EMEA guidelines:

• Efficacy on the symptomatic score from the first year, both in adults and children;
• Long-term efficacy: after 3 years of treatment
• Efficacy maintained after end of the treatment

- Compliance: Compliance depends on many factors relating to efficacy and treatment safety, patient preferences, benefits expected in terms of quality of life and adaptation to the constraints of the treatment. The treatment must also be in line with the rhythm of allergic rhinitis symptoms when they are intermittent: therapeutic compliance is inversely proportional to the duration of the treatment, which highly deteriorates after 6 months.  Thus, for pollen allergic rhinitis, a pre-co-seasonal treatment (before and during the pollen season) appears to be necessary.

To conclude, the registration of specific immunotherapy treatment and the granting of marketing authorizations confirm the demonstration of the efficacy and tolerance of these treatments according to the standards of evidence-based medicine.  Patients also have expectations regarding their treatment that the clinical development of treatments must respond to.

 
Contacts

BV CONSEiL Santé – 7, rue Greffulhe – 75008 Paris
Alexandra Dufrien – Laurent Mignon - Tel: +33 (0)1 42 68 83 40 - E-mail: bvconseil@bvconseil.com 

¹ References:
Burney P. Rev Epidemiol Santé Publique 1998; 46:491-6.
Asher et al. Lancet 368: 733-743.
Bauchau and Durham. Allergy 2005: 60: 350–353