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Inducing immunity

More targeted immunotherapies may provide future relief for allergic rhinitis sufferers

Allergic rhinitis is caused by inflammation of the mucous membranes of the nose, and results in symptoms such as sneezing, nasal congestion, itchy eyes and nose, rhinorrhea, and headaches.

Seasonal allergic rhinitis, more commonly known as hay fever, occurs in spring and summer and is caused by a reaction to allergens, such as grass, tree or plant pollen. While, perennial allergic rhinitis is present all year round and can be caused by exposure to dust mites, animals or mould.

Allergic rhinitis develops after a patient becomes sensitised to an allergen, which often occurs during childhood, even though allergy symptoms may often only manifest later in life. After exposure to an allergen, patients develop raised levels of IgE antibodies to the specific allergen, which bind to receptors on the surface of mast cells.

Upon re-exposure to the allergen, cross linking of adjacent IgE antibodies occurs and mast cells degranulate, releasing inflammatory mediators such as histamine, leukotrienes and prostaglandins.

Although allergic rhinitis is not usually life-threatening, it is a widespread disorder affecting approximately 14 per cent of the global population, and the prevalence appears to be rising.

Early phase relief
Antihistamines, or histamine H1 receptor antagonists, are the most widely used drugs for the treatment of allergic rhinitis. Currently available antihistamines include, Loratadine (Clarytin), cetirizine (Zyrtec), and fexofenadine (Telfast).

Although these are effective in relieving early-phase symptoms of allergic rhinitis, it is not effective in relieving late-phase symptoms, such as nasal congestion, therefore oral and nasal decongestants, such as pseudoephedrine (Sudafed) and xylometazoline (Otrivine) are commonly used in conjunction with traditional anti-histamine therapy.

Despite being effective at alleviating the symptoms of allergic rhinitis, most anti-allergic drugs only produce temporary relief and do not address the underlying cause of the disorder - hypersensitivity to a normally harmless substance. A more comprehensive treatment that is rapidly gaining in popularity worldwide is immunotherapy.

Immunotherapy (or desensitisation) involves down-regulating the patient's immune response by administering increasing concentrations of an allergen extract over a 3-5 year time period. This process shifts the immune response from a predominantly T-lymphocyte (Th2) response to a 'non-allergic' T-lymphocyte (Th1) response, and attenuates symptoms for several years after the therapy has been discontinued. Traditional subcutaneous immunotherapy has been used for the treatment of allergic disease since the 1900s and is still the only approved route of administration in the US.

Subcutaneous immunotherapy is effective, but it is time consuming and must be administered by a health professional. Increasingly, drug companies are looking to develop more convenient and `user-friendly' sublingual immunotherapies which can be self-administered.

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Seasonal allergic rhinitis
In November 2006, ALK-Abello's Grazax was launched in Germany for the treatment of seasonal allergic rhinitis resulting from grass pollen. Grazax is a dissolvable sublingual tablet that contains a grass pollen extract, and is designed to be taken once daily, beginning four months before the start of the grass pollen season, and throughout the pollen season.

The tablet formulation gives Grazax an advantage over existing sublingual immunotherapy products on the market which are administered as drops under the tongue. Grazax is now also available in the UK, Denmark and Norway.

Hot on the heels of Grazax is Stallergenes' Oralair Grasses, which is expected to be launched in Europe in 2007.

The Danish company, Curalogic, is also developing oral immunotherapeutics, and its microencapsulated grass pollen, ragweed, and cat hair extracts are currently undergoing phase II clinical trials.

A slightly different approach to immunotherapy is being used by Dynavax Technologies in the US. The firm is developing Tolamba, a subcutaneously administered ragweed allergen extract conjugated to a short immunostimulatory DNA sequence (ISS). The ISS DNA is capable of promoting Th1 immune responses and shutting off Th2 immune responses. Linking of ISS to the allergen extract ensures that both ISS and the ragweed allergen are presented simultaneously to the same immune cells, producing a highly specific and potent inhibitory effect and suppressing Th2 cells.

The treatment also reprogrammes the immune response away from the Th2 response and toward a Th1 memory response so that on subsequent exposure to the allergen, long-term immunity is achieved.

During the second quarter of 2006, Dynavax initiated the phase III placebo-controlled DARTT trial to compare high and low dosing regimens of Tolamba. An interim analysis of one-year data from the trial was presented in January 2007. However, results showed that because of a lack of measurable ragweed-specific allergy disease in the study population during the ragweed season, it was not possible to measure the therapeutic effect of Tolamba treatment. The company has yet to determine the future of the programme.

Similarly, Cytos Biotechnology is using its Immunodrug technology to develop therapies for allergic rhinitis. The company's two product candidates, CYT003-QbG10 and CYT005 AllQbG10, both consist of the Immunodrug carrier QbG10, combined with natural allergen extracts.

QbG10 comprises the virus-like particle Qbeta, loaded with a special DNA-based, immunostimulatory sequence termed G10. G10 serves as an adjuvant, enhancing the establishment of the Th1 type immune response to balance an existing Th2 type immune response. Phase II trials of these compounds are underway in Europe for both perennial and seasonal allergic rhinitis.

Understanding the causes
While the prevalence of allergic rhinitis continues to rise, the availability of more effective treatments is also set to increase as company's invest in the development of more effective treatments. A greater understanding of the underlying cause of allergic inflammation, combined with modern synthetic DNA technology is enabling scientists to develop more targeted immunotherapies which may one day abolish the need for reliever medication.

The author
Pipeline was written by Catherine Henson of Adis International, using data derived from Adis Clinical Trials Insight and R&D Insight.

13th March 2007

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