Circassia Holdings Ltd

The global allergy market is currently underserved, despite the huge numbers of sufferers. Estimates suggest that allergies affect 25% of the population in the US and Europe, and this figure is growing at 2.5% per annum. Despite this, traditional allergy treatments have a number of drawbacks, either simply providing short-term relief from symptoms, or requiring extended periods of therapy under expert supervision due to potential serious and even life-threatening adverse reactions.

However, clinical experience with Circassia's lead ToleroMune T-cell vaccine shows that the company's unique technology has the potential to treat sufferers with a short and simple dosing regime. This compares favourably with current therapies, for which patients often endure several years of carefully supervised treatment.

Circassia’s ToleroMune T-cell technology identifies short peptide sequences, typically 10 to 20 amino acids long, from the allergen proteins that are responsible for causing allergic reactions in sufferers. These peptides are selected for their ability to bind promiscuously to multiple Major Histocompatibility Class II (MHC Class II) molecules on the surface of antigen presenting cells. Circassia's ToleroMune technology selects an optimal peptide mixture to ensure broad coverage across the multiple different MHC class II alleles in the population.

The peptides are short sequences of amino acids that can be chemically synthesised and readily standardised. Administration of these epitopes induces regulatory T-cells, which down regulate the T cell, B cell and mast cell components of the allergic response to the allergens from which the peptide was originally derived. This leads to the development of tolerance. As the peptides selected by Circassia’s ToleroMune technology are linear they do not contain B-cell epitopes, which are present in whole allergens and cause the cross-linking of IgE on the surface of mast cells that is associated with itchy eyes, runny nose and, in some cases, asthmatic responses that allergic individuals suffer on exposure to allergens. Cross-linking of IgE can also cause anaphylactic-type reactions. As a result Circassia’s approach offers the potential of effective allergy treatments without the need for dose escalation or the serious adverse reactions associated with traditional immunotherapies.

The patient benefits offered by Circassia's unique approach, combined with the technical and commercial advantages, provide the Company with a strong franchise in the allergy field.

• Potential for dramatically improved efficacy without the clinical complexity and significant safety issues of traditional treatments
• Phase II clinical validation achieved
• Optimal short dosing regimens identified for late-stage development
• Single standardised doses: no need for dose escalation
• Extensive experience in hundreds of subjects
• Low risk approach: next generation refinement of currently used approach proven over decades
• Strong intellectual property
• Broad application across range of allergies
• Established, proven and straightforward GMP manufacture
• Product well controlled and fully characterised using established analytical methods

Circassia's ToleroMune cat allergy T-cell vaccine utilises seven specific epitopes derived from cat dander. The vaccine has achieved phase II clinical validation, and clinical studies have identified the optimal dosing regimes for the final stages of clinical testing. The encouraging data from phase II clinical trials show that the ToleroMune T-cell vaccine can greatly reduce patients’ symptoms while proving extremely well tolerated. As a consequence Circassia is rapidly progressing its cat allergy programme into late-stage development. The vaccine is also undergoing phase II testing in patients with cat allergies and asthma as many sufferers have both conditions.

Ragweed is an important allergen, particularly in the USA. Consequently, Circassia has an active programme developing a ragweed T-cell vaccine. The company licensed a series of patents on the sequence of the major ragweed allergen and subsequently identified a number of T-cell epitopes to form the base of its treatment. Circassia began a phase II clinical trial with the vaccine in April 2009, and results are expected in the first half of 2010.

House dust mites are responsible for a significant proportion of allergies. As a consequence, Circassia has applied its ToleroMune technology to the field and identified the optimal mix of epitopes for its T-cell vaccine candidate. This vaccine entered phase II testing in November 2009.

While grass is potentially responsible for more allergies than any other source, it is a complicated area to address because of the many different species that can cause reactions in patients. Circassia’s T-cell vaccine includes epitopes from the key grasses responsible for allergies. The ToleroMune T-cell vaccine candidate has completed GMP manufacture, undergone pre-clinical testing and will move into clinical testing in the first half of 2010.

Circassia has acquired ground-breaking ToleroTrans anti-rejection technology, which has demonstrated the ability to selectively suppress immune responses to transplanted organs. Present approaches use non-selective immuno-suppressant drugs, such as cyclosporine, to prevent rejection. This approach has the significant disadvantage that it leaves patients significantly more vulnerable to opportunistic infections and cancers.

In contrast, Circassia's ToleroTrans T-cell technology suppresses the specific immune responses to the tissue of the transplanted organ while not affecting immune defences against infection and potential cancer-causing cell mutation.