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, allergy treatments have a number of drawbacks, either simply addressing the symptoms, or requiring expert supervision due to potential serious, even life-threatening, adverse reactions.

However, clinical experience with Circassia's lead allergy treatment suggests that the company's unique technology has the potential to treat sufferers with just four administrations, and potentially an annual booster. This compares favourably with current therapies, for which patients need to endure several years of injections.

Circassias ToleroMune technology identifies short peptide sequences, typically 10 to 20 amino acids long, from the sequence of proteins. 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. Once the peptide is bound to the MHC class II molecule it activates the T cell receptor of T lymphocytes. Circassia's ToleroMune technology selects an optimal peptide mixture to ensure broad population coverage across the multiple different MHC class II alleles. The peptides are short sequences of amino acids that can be readily synthesised and standardised. Administration of these T cell epitopes induces regulatory T cells which down regulate the allergic response to the allergens from which the peptide was originally derived. This leads to the development of tolerance to the allergen. Because the peptides selected by Circassia’s ToleroMune technology are linear they do not contain the B cell epitopes which are present in whole allergen and which cause the cross-linking of IgE on the surface of mast cells. Cross-linking of IgE on the surface of mast cells is associated with itchy eyes, runny nose and, in some cases, asthmatic responses that allergic individuals suffer on exposure to allergen. Cross-linking of IgE can also cause anaphylactic type reactions.

The advantages to the patients offered by Circassia's unique approach provide the company with a strong franchise in the allergy field.

• Clinically validated in a phase II study; further phase II study underway
• Extensive experience with over 500 clinical administrations
• Relatively low risk technology: a next generation refinement of the currently used approach proven over decades
• Potential for improved efficacy without the clinical complexity and significant safety issues of current treatments
• Strong intellectual property
• Broad application across a range of allergies
• Established, proven and straightforward GMP manufacture
• Established analytical methods

Circassia's ToleroMune technology has been validated in the clinic in a phase II study utilising epitopes derived from cat dander. The encouraging data from the clinical trial showed that patients may develop tolerance to cat allergens after just 4 administrations. As a consequence Circassia is now rapidly progressing the development programme. The treatment, which is based on seven specific T-cell epitopes is currently undergoing further testing in a phase II trial.

House dust mites are responsible for a significant proportion of allergies. As a consequence, Circassia has applied its ToleroMune technology to the field, and has identified several epitopes that form the basis of a potential treatment. These epitopes are currently undergoing further preclinical testing and refinement, before moving to the clinic.

Ragweed is an important allergen, particularly in the USA. Circassia has licensed a series of patents which claim the sequence of the major ragweed allergen and also identify a number of T-cell epitopes on which to base its treatment. The company is currently testing these to determine the final product mix that will move into clinical testing.

While grass is potentially responsible for more allergies than any other source, it is more complicated because of the many different species that can cause reactions in patients. Circassia has identified several potential T-cell epitopes from relevant grasses, and is conducting a number of tests over the coming months to refine the final product that it will take into clinical trials.

Circassia acquired ground breaking technology which demonstrated that it is possible to selectively suppress immune responses to transplanted organs. Present approaches use non-selective immuno-suppresants such as cyclosporine to prevent rejection. This has the significant disadvantage that it renders the patient significantly more vulnerable to opportunistic infections and cancers.

Circassia's technology suppresses immune responses to the tissue of the organ being transplanted leaving untouched the bodies defences to infection and cell mutation.

In addition to general rejection, some patients make antibodies to the common tissue types. These people represent 30% of the current transplant waiting list so it is a large problem. People may make antibodies for several reasons; child birth, blood transfusions or previous organ transplants are common reasons. Current approaches mean that these patients will probably die before an organ is found which will not be immediately rejected or require too much immuno-suppressant.

Circassia's technology can suppress the production of antibodies in these patients and enable a satisfactory transplant without the need to use excessive immuno-suppressant.