COLAL-PRED^®

Currently around 2 million people in major territories suffer from UC, of which an estimated 700,000 are in the US. A ‘safe steroid’ for the treatment of ulcerative colitis would represent a significant improvement over existing treatments, with potential sales in excess of US$250 million per annum.

COLAL-PRED^® is a proprietary gastrointestinal product developed by Alizyme for the treatment of ulcerative colitis ("UC"). It has arisen from combining Alizyme’s proprietary colonic drug delivery system, COLAL^®, with an approved generic steroid (prednisolone sodium metasulfobenzoate). It has the potential to be an effective anti-inflammatory treatment for UC without the typical side effects of steroids.

UC - treatment of active disease and maintenance of remission.

UC is an inflammatory disease of the colon, which causes symptoms such as abdominal pain, bleeding, cramping, fatigue and diarrhoea. The condition is characterised by episodes of acute flare of the disease, followed by periods of remission. In severe cases, surgery may be required to remove the diseased tissue.

Mild cases are treated with non-steroidal anti-inflammatory drugs based on 5-amino-salicylic acid (“5-ASA”), which are also used in the maintenance of remission. In moderate cases, anti-inflammatory steroids, such as prednisolone, are used, but they are limited by their severe side effects to short-term use. Severe cases may be treated with expensive anti-TNF drugs such as Remicade^® (infliximab) and Humira^® (adalimumab).

Currently around 2 million people in major territories suffer from UC, of which an estimated 700,000 are in the US. This market is dominated by anti-inflammatory steroids and 5-ASA products, which have safety and/or efficacy issues.

COLAL-PRED^® is being developed to treat active UC and for the maintenance of remission of UC, providing potential sales of more than US$250 million per annum. There are currently no competitor products, either on the market or in development, with the same product profile, whilst biological products are likely to be restricted in their use by cost. A ‘safe steroid’ product with the profile of COLAL-PRED^® would represent a significant advance in the management of UC.

COLAL-PRED^® is the combination of Alizyme’s proprietary colonic drug delivery system, COLAL^®, and prednisolone sodium metasulfobenzoate (“PMSBS”), an approved steroid in Europe. Achieving colonic release with conventional oral dosage forms has proved difficult because of the variation between individuals in transit times and conditions within the gastrointestinal tract.

COLAL-PRED^® comprises small pellets containing PMSBS, with a coating of ethylcellulose and a specific form of amylose (derived from starch) that is broken down only in the colon by enzymes from locally occurring bacteria. This enables PMSBS to be taken orally and delivered topically to the colon, rather than systemic delivery, since release in the stomach and small intestine is prevented. This makes possible the effective treatment of ulcerative colitis without the usual debilitating side effects typically associated with such steroids. It has been shown in a Phase III clinical trial to provide a significantly improved risk-benefit profile to that of conventional oral prednisolone.

In a series of Phase I clinical trials on approximately 100 healthy volunteers, COLAL-PRED^® was shown to reliably and effectively deliver the steroid directly to the colon, with a consequently low level of drug absorbed into the blood, providing a mechanistic basis for the target product profile.

An EU Phase III clinical trial in approximately 800 patients with active moderate to severe UC was completed in July 2008. The study endpoints were comparisons of efficacy, safety and the combination of safety and efficacy, between COLAL-PRED^® and conventional prednisolone. COLAL-PRED^® demonstrated superior safety and superior combined safety and efficacy. A co-primary endpoint based on the Disease Activity Index of efficacy of COLAL-PRED^® to conventional prednisolone was not met. However, COLAL PRED^® did show equivalent efficacy compared to conventional prednisolone after 8 weeks’ dosing in the treatment of acute UC, based on patient reported symptoms. Thus COLAL-PRED^® was demonstrated to be a potentially safe and well tolerated treatment for acute UC with a superior risk benefit profile compared to conventional prednisolone in the treatment of UC. The results also suggest the potential for use in the maintenance of remission of UC.

Norgine, Alizyme’s partner for COLAL-PRED^® in Europe, South Africa, Australia and New Zealand, is primarily responsible for further development and submission of a Marketing Authorisation Application (“MAA”) for the EU.

Prometheus Laboratories Inc, Alizyme’s partner for COLAL-PRED^® in North America, commenced a Phase II study for UC in the US in 2008.

TSD Japan Inc, Alizyme’s partner for COLAL-PRED^® in Japan, commenced a Phase I study in Japan for UC in 2008.

The results of the Phase I study in Japan and the Phase II study in the US are awaited. The strategy for submission of the EU Marketing Authorisation Application (“MAA”) is being progressed with Norgine in conjunction with ongoing discussions with regulatory authorities.

Note: COLAL^® and COLAL-PRED^® are registered trademarks of Alizyme Therapeutics Limited.