Cetilistat

According to the World Health Organisation there are up to 1.6 billion overweight adults worldwide, with at least 400 million of them clinically obese. An effective drug with no safety or patient compliance issues could have potential sales in excess of US$1 billion per annum.

Alizyme’s metabolic product, cetilistat, is being developed for the treatment of obesity and associated co-morbidities, including type 2 diabetes. Cetilistat was identified during Alizyme’s discovery programme into inhibitors of gastrointestinal lipases.

Clinically obese patients and obese patients with associated co-morbidities e.g. type 2 diabetes.

Clinical obesity is closely linked to increased incidence of several other serious medical conditions, including type 2 diabetes. Drug treatment is recommended for weight loss and weight loss maintenance in both clinically obese patients and in overweight patients with associated medical conditions.

Obesity has reached global epidemic proportions. According to the World Health Organisation there are up to 1.6 billion overweight adults worldwide, with at least 400 million of them clinically obese. However, it is estimated that only 6% of patients are treated pharmacologically, there being few effective treatments available.

The main prescription products currently approved for obesity are Roche’s Xenical^® (orlistat), Abbott’s Meridia^® (sibutramine) and sanofi-aventis’ Acomplia^® (rimonabant). These all have safety and/or patient compliance issues. However, Xenical^® and Meridia^® still achieve annual sales in excess of US$500 million and US$300 million respectively. In 2007, orlistat was approved for over-the-counter (“OTC”) use in the US, marketed by GlaxoSmithKline under the brand name of alli™. Acomplia^® was approved for marketing in the EU in 2006, although it is not approved by FDA for marketing in the US.

Patient compliance in taking medication is critical to a successful product in this patient population. An effective drug with no safety or patient compliance issues could have potential sales in excess of US$1 billion per annum.

Cetilistat 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, as a peripherally acting drug with a good safety profile demonstrated over a wide range of doses, cetilistat is not subject to the safety concerns relating to the consequences of deliberate or accidental overdose. As well as the inherent safer nature of peripherally acting drugs, there is less chance of interaction with concomitant medications being used to treat associated co-morbidities.

Xenical^® is an approved obesity product and, as such, has been shown to be suitable for long-term use. Both cetilistat and Xenical^® are peripherally acting lipase inhibitors. However, in clinical trials, although both have been demonstrated to be safe and exhibit similar efficacy, cetilistat has been demonstrated to be significantly better tolerated than Xenical^®, which has tolerability side effects that include anal leakage and oily spotting, and which detrimentally affect patient compliance. This superior tolerability side effect profile exhibited by cetilistat is attributable to the differences between the molecular structures of orlistat (Xenical^®) and cetilistat.

Other main competitors on the market and in development are centrally acting drugs that have a range of potential side effects such as depression, cardiovascular disorders, nausea and dizziness, as well as other compound specific side effects.

Evidence of the safety and efficacy of cetilistat has been established through extensive Phase I and Phase II studies involving approximately 1,400 subjects.

In a 12 week Phase IIb study involving clinically obese patients, cetilistat showed efficacy and a competitive side effect profile. It showed statistically significant weight loss compared to placebo, consistent with those of other approved obesity drugs. The level of side effects that affect patient compliance was similar to that seen with placebo.

In a second 12 week Phase IIb study involving clinically obese diabetics, cetilistat was compared with placebo and also with Xenical®. Cetilistat was shown to cause statistically significant weight loss, compared to placebo, and was also shown to cause statistically significant reductions in HbA_1c, acknowledged by FDA as a marker of diabetic control. Furthermore, the proportion of subjects discontinuing treatment for adverse events was lower with cetilistat than with placebo. Xenical^® showed weight loss and HbA_1c results similar to those for cetilistat, however, the proportion of subjects discontinuing for reasons of adverse events and the total number of gastrointestinal adverse events were substantially higher with Xenical^® than with cetilistat.

Cetilistat has successfully completed an extensive Phase I and Phase II clinical development programme and has been prepared for the commencement of Phase III development.

Takeda, Alizyme’s partner in Japan, is progressing clinical development of cetilistat in Japan. Takeda is commencing a Phase III clinical trial in clinically obese patients.

Following successful end of Phase II discussions, FDA approved Alizyme’s outline plan for the Phase III clinical development programme of cetilistat. This comprises three 12 month studies involving:

(i) obese patients without co-morbidities and obese patients with treated or untreated co-morbidities (other than type 2 diabetes);

(ii)obese patients without co-morbidities and obese patients with untreated co-morbidities (other than type 2 diabetes); and

(iii) obese patients with treated type 2 diabetes and who may have treated or untreated other co-morbidities.

In April 2007, Alizyme announced that the protocol for the first study was agreed with FDA under the SPA procedure. The protocols for the second and third studies have now also been agreed with FDA under the SPA procedure. The second study will involve a direct comparison with Xenical^®, as well as placebo.

FDA has corresponded directly with Alizyme in relation to its planned Phase III programme and recommended that Alizyme open a separate diabetes IND for cetilistat, since it is no longer requiring that a drug’s effect on glycemic control be independent of its effect on body weight in order for the drug to be considered for a stand alone diabetes indication. FDA has also indicated that a 12 month study would be sufficient as a pivotal study with cetilistat for obese diabetics.

The regulatory pathway for cetilistat as an obesity product is firmly established with FDA, giving clarity to potential partners with respect to the route to market for cetilistat. Further discussions with FDA with respect to opening an IND for diabetes are ongoing.