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 type 2 diabetes. Cetilistat was identified during Alizyme’s discovery programme into inhibitors of gastrointestinal lipases.

Clinically obese patients and obese patients with type 2 diabetes.

Clinical obesity is closely linked to increased incidence of type 2 diabetes as well as several other serious medical conditions. Type 2 diabetes is a progressive disease that may result in blindness, nerve or kidney damage, and in some cases limb amputations. Drug treatment is recommended for weight loss and weight loss maintenance in both clinically obese patients and in overweight patients with type 2 diabetes as well as other 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 rise in global obesity has been closely correlated with a similar rise in the rates of type 2 diabetes. The global incidence of diabetes is 246 million and is projected to rise to 380 million by 2026.

The main prescription products currently approved for obesity are Roche’s Xenical^® (orlistat) and Abbott’s Meridia^® (sibutramine). Both have safety and/or patient compliance issues. However, Xenical^® and Meridia^® still achieve annual sales in excess of US$400 million and US$300 million respectively. Orlistat is also approved for over-the-counter (“OTC”) use in the US and the EU, marketed by GlaxoSmithKline under the brand name of alli™, with annual sales in excess of US$100 million.

During the year, the CB1 antagonist class of drugs were either withdrawn from the market or abandoned in development due to the unacceptable side effect profile of this class of molecules.

Patient safety and 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 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 for obesity 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.

While there are a number of oral anti-diabetic medications on the market, many of them can result in body weight gain. A reduction in body weight is an important factor in the treatment of type 2 diabetes and is where a safe weight loss drug such as cetilistat could provide real patient benefit.

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 reduction in HbA1c 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 significantly higher with Xenical^® than with cetilistat.

Takeda have successfully completed a Phase IIb clinical study in obese patients with type 2 diabetes.

Takeda, Alizyme’s partner in Japan, has commenced a Phase III clinical trial in clinically obese patients in Japan.

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 in the West.

FDA have approved the protocols for Alizyme’s Phase III clinical development programme of cetilistat under the SPA procedure. The programme 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), including a direct comparison with Xenical^®; and

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

FDA has recommended that Alizyme open a separate IND for the investigation of cetilistat in the treatment of diabetes. 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 discussion is required with FDA to facilitate opening an IND for diabetes.