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Phase III clinical product development update

09 Oct 2007

Alizyme plc announces an update on its Phase III clinical product development

CAMBRIDGE, UK, USA | October 8, 2007 | We are pleased to announce the completion of patient recruitment into the first Phase III

pivotal efficacy study of renzapride in constipation-predominant irritable bowel syndrome (IBS-C).

The study (Study 038), a multi-centre, randomised, double-blind, placebo-controlled, parallel group, pivotal efficacy study, has recruited over 1,800 female patients with IBS-C. Patients are treated for a 12-week period. The primary endpoint is patients' self assessment of relief of their overall IBS symptoms. Secondary endpoints include adequate relief of abdominal pain/discomfort and of bowel problems. Headline trial results are expected to be reported in April 2008.

At the end of the 12-week treatment period in Study 038, patients can elect to continue into an open label extension study (Study 052) to evaluate the long-term safety and tolerability of renzapride taken for 12 months. Patients continue to be recruited into this study with results expected to be reported in Q2 2009.

We are also pleased to announce that agreement has been reached with FDA on the clinical protocol for the second Phase III pivotal efficacy study (Study 109) of renzapride in IBS-C under the Special Protocol Assessment ('SPA') procedure. Recruitment into Study 109 is expected to commence in 2008.

COLAL-PRED(R)

• Patient recruitment on track in EU Phase III clinical trial and due to complete by end of 2007

• Headline results expected in Q2 2008

Recruitment into our EU Phase III registration clinical trial in up to 750 patients with active moderate to severe ulcerative colitis remains on target for completion in 2007. Subject to the recruitment being completed this year, headline results are expected to be reported in Q2 2008.

Successful results from the EU Phase III trial would allow a Marketing Authorisation Application (MAA) to be submitted for the EU in H2 2008.

Commenting, Tim McCarthy, Chief Executive Officer said:

'We are delighted to have closed recruitment for this key pivotal study with renzapride. The headline results, expected in April 2008, will mark the completion of the first Phase III clinical trial of renzapride and are expected to confirm its product profile and competitive position. We anticipate commencement of a second Phase III study in 2008, which has now been agreed with FDA under the SPA procedure.

The first half of 2008 will see significant clinical news flow from the renzapride and COLAL-PRED(R) Phase III clinical trials and emphasises the late stage nature of our product portfolio.

In addition, I continue to be pleased with the ongoing discussions with potential partners for the further development and commercialisation of our products and remain confident of successfully concluding a number of deals across the portfolio this year.'

Alizyme plc
Alizyme is a speciality biopharmaceutical development company, focused on the therapeutic areas of metabolic disorders, gastrointestinal disorders and cancer supportive care. It is developing cetilistat for the treatment and management of obesity and related diseases, such as Type II diabetes, renzapride for the treatment of irritable bowel syndrome ('IBS'), COLAL-PRED(R) for ulcerative colitis, and ATL-104 for mucositis, a side effect of cancer therapy.

Special Protocol Assessment (SPA)
In conjunction with the reauthorisation of the Prescription Drug User Fee Act of 1992 (PDUFA) in November 1997, FDA agreed to specific performance goals for special protocol assessment and agreement. These goals provide that, upon request, FDA will evaluate certain protocols (i.e. carcinogenicity protocols, stability protocols, and Phase III protocols for clinical trials that will form the primary basis of an efficacy claim) to assess whether they are adequate to meet scientific and regulatory requirements.

Once FDA and the sponsor concur, under the Special Protocol Assessment, the Agency documents agreement that the design and planned analysis of a study adequately address objectives in support of a regulatory submission.

As stated in the PDUFA goals for Special Protocol Assessment and agreement, having agreed to the design, execution, and analyses proposed in protocols reviewed under this process, the Agency will not later alter its perspective on the issues of design, execution, or analyses unless public health concerns unrecognized at the time of protocol assessment under this process are evident.

Cetilistat
Alizyme's metabolic product, cetilistat, is being developed for the treatment of obesity and associated conditions. It is a gastrointestinal lipase inhibitor that blocks fat digestion and absorption, leading to reduced energy intake, and thus weight loss. It is distinct from most other anti-obesity agents as it does not act on the brain to reduce appetite, but acts peripherally. The compound remains in the gastrointestinal tract with no significant absorption into the body. It can, therefore, be expected to have a superior risk-benefit profile to centrally acting drugs. Accordingly, cetilistat is not subject to the safety concerns generally associated with centrally acting drugs.

Cetilistat has completed an extensive Phase II development programme achieving both statistically significant weight loss and statistically significant reduction in diabetes marker HbA1c. Following successful end of Phase II discussions with the US FDA in 2006, outline plans for the Phase III clinical development programme, comprising three studies involving obese patients and obese patients with Type II diabetes or other associated co-morbidities, were agreed. The protocol for the first pivotal Phase III clinical trial was approved by FDA in April 2007 under SPA.

Roche's Xenical(R) is an approved obesity product and is also a peripherally acting lipase inhibitor. However, in clinical trials, cetilistat has been demonstrated to be much better tolerated than Xenical(R) which has side effects that detrimentally affect patient compliance.

Renzapride
Alizyme's gastrointestinal product, renzapride, is being developed for the treatment of constipation-predominant IBS ('IBS-C') and for mixed-symptom IBS ('IBS-M'). It aims to be a more effective treatment for IBS-C than is currently available and also to become the first line treatment for IBS-M. IBS is a functional gastrointestinal disorder characterised by recurrent symptoms of abdominal pain and discomfort associated with disturbed bowel function, which may also be accompanied by a feeling of bloating. Patients may have IBS-C, IBS-M or diarrhoea-predominant IBS ('IBS-D').

There are currently few effective drug treatments available for IBS. IBS is one of the most frequent disorders seen by physicians with estimates of up to 22% of the general population experiencing symptoms of IBS at some time, of whom around 35% have IBS-C and around 40% have IBS-M, both of which renzapride aims to address. The remainder of around 25% have IBS-D.

Renzapride is both a 5-HT4 receptor full agonist (which acts as a pro-kinetic, enhancing motility) and a 5-HT3 receptor antagonist (which acts to reduce GI motility, thus helping to reduce diarrhoea, abdominal pain and discomfort). This dual mode of action is unique and gives renzapride the potential to normalise bowel function rather than move from one extreme of constipation or diarrhoea to the other. It may, therefore, provide benefit in both IBS-C and IBS-M, covering up to 75% of the IBS patient population.

Renzapride has the opportunity to be the market leader as it has been shown in Phase II studies to have the potential to be more effective than Novartis' Zelnorm(R), which is not approved for use in the EU and has currently been suspended from sale in the US and other countries. Prior to its suspension, Zelnorm(R) achieved annual sales of $561 million for 2006. This, therefore, represents a significant commercial opportunity for renzapride.

COLAL-PRED(R)
COLAL-PRED(R) is a proprietary gastrointestinal product developed by Alizyme for the treatment of ulcerative colitis ('UC'). UC is an inflammatory disease of the colon, which causes symptoms such as abdominal pain, bleeding, cramping, fatigue and diarrhoea. These conditions are characterised by episodes of acute flare of the inflammation, followed by periods of remission. In severe cases, surgery may be required to remove the diseased tissue. Currently around 1 million people in major territories suffer from UC. This market is dominated by anti-inflammatory steroids and 5-ASA products, which have safety and/or efficacy issues.

COLAL-PRED(R) is the combination of Alizyme's proprietary colonic drug delivery system, COLAL(R), and prednisolone sodium metasulphobenzoate, an approved steroid in Europe. COLAL-PRED(R) has a starch coating that is only broken down in the gut by bacteria occurring in the colon. This leads to topical delivery of prednisolone to the colon rather than systemic delivery. It has been shown in a Phase II clinical trial to provide levels of efficacy comparable to that reported for prednisolone, but without the side effects of steroids.

ATL-104
ATL-104 is being developed by Alizyme as an orally administered mouthwash for the treatment of mucositis of the mouth and gastrointestinal tract arising during cancer treatment. This provides ease and convenience of administration and enables local delivery of treatment for oral and gastrointestinal mucositis with no significant absorption into the body. ATL-104 has successfully completed a Phase IIa 'proof of concept' clinical trial in patients with lymphoma and myeloma. ATL-104 is currently being assessed for the optimum route for further development through discussion with FDA, EMEA and our advisors.

Globally there are over 4 million new cases of cancer each year. Oral mucositis occurs in 40% of all cancer patients. In bone marrow transplant patients, over 70% of patients suffer from mucositis, and in head and neck cancer treatments, mucositis occurs in up to 80% of patients. Mucositis is characterised by severe ulceration, bleeding and pain in the mouth and gastrointestinal tract, caused by damage to the cells that line these tissues by cancer chemotherapy and radiotherapy. These symptoms can be very painful, requiring the administration of opiates, can reduce the ability of the patient to receive nutrition orally, can be a source of infection and can be potentially life threatening.

The identification of compounds for successful research, their progress through development and the obtaining of regulatory approvals or authorisations before marketing, manufacture and/or distribution of products is not certain or a formality.

SOURCE: Alizyme plc

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