Cetilistat – Investigational Drug for Obesity, Japan

Developed by Alizyme, a specialist biopharmaceutical company in collaboration with Takeda Pharmaceutical, cetilistat (ATL-962) is an experimental treatment for obesity. Cetilistat restricts pancreatic lipases and acts as an agent to treat obesity and related diabetes or dyslipidemia.

It results in weight loss and absorbs fat from diet. The drug acts peripherally to reduce the appetite, without affecting the brain.

In December 2008, Takeda started a Phase III clinical study of cetilistat in Japan. Progress to pivotal Phase III trials followed encouraging Phase II clinical trial data that showed cetilistat promoted significant weight loss and was generally well tolerated in clinically obese patients.

Takeda evaluated European Phase II data of cetilistat in August 2003 and in January 2004 made an agreement with Alizyme to exclusively develop, manufacture and market cetilistat in Japan.

In October 2012, Takeda submitted a New Drug Application (NDA) for Cetilistat to Japan’s Ministry of Health, Labour and Welfare for the treatment of obesity.

Alizyme’s current research and development is focused on treatments for gastrointestinal disorders, obesity, cancer and diabetes.

Obesity predisposes to serious illness

Obesity is now the most common nutritional disorder in western industrialised countries. Defined as a body mass index of greater than 30, it arises from the accumulation of excess fat in the body from over consumption of fatty foods.

Prevalence of obesity in the US and Europe has reached epidemic levels. Data from the WHO’s MONICA (Multinational MONItoring of trends and determinants in CArdiovascular disease) project show that in some parts of Europe over 70% of men aged 55 to 64 are clinically obese or overweight (BMI >25) as well as almost 70% of women in this age group. One in five of all Americans is obese and one in three overweight. Furthermore, increasing rates of childhood obesity are likely to exacerbate the trend towards increasing obesity in adulthood.

There is a strong association between obesity and increased risk of cardiovascular disease and diabetes and possibly certain cancers, such as breast and colorectal cancer. The dramatic rise in the incidence of type 2 diabetes is largely due to the increased prevalence of obesity. Increases in body weight lead to changes in blood lipid and cholesterol levels, predisposing to increased risk of atherosclerosis.

Therapeutic approaches to treatment of obesity

The growing prevalence of obesity has stimulated the search for drugs to treat this condition. Various therapeutic strategies have been explored, including:

 

• Serotonin and noradrenaline reuptake inhibitors (anorectic agents)
• Lipase inhibitors
• b 3-adrenoreceptor agonists
• Leptin agonists
• Melanocortin-3 agonists
• Endocannabinoid receptor antagonists

 

Cetilistat is a lipase inhibitor, with a similar mode of action to Roche’s anti-obesity medication orlistat (Xenical®) which received regulatory approval in 1997. These drugs act in the gastrointestinal tract to inhibit lipases, enzymes involved in the breakdown of dietary fats. By inhibiting the breakdown and subsequent absorption of fats from the gut, lipase inhibitors reduce fat intake and calories, thus aiding weight loss.

Evidence of efficacy and tolerability in obese adults

The clinical efficacy and safety of cetilistat has been demonstrated in a series of Phase II trials. A Phase IIb clinical trial in 612 clinically obese diabetic patients showed that over a 12-week treatment period, cetilistat 80mg and 120mg promoted significant weight loss compared with placebo (3.85kg and 4.32kg versus 2.86kg respectively), thus meeting the trial’s primary endpoint.

Cetilistat-induced weight loss was similar to that achieved with Xenical® (3.78kg). Both active treatments also produced statistically significant reductions in HbA1c, a marker of diabetic control. In this trial, patients had a BMI of between 28 and 45 at study entry and received metformin for control of diabetes.

While cetilistat achieved similar degrees of weight loss to Xenical® in this patient population, it was better tolerated. Rates of premature discontinuation for adverse events were 2.5%, 5.0% and 2.5% for cetilistat 40mg, 80mg and 120mg respectively.

This compared with 6.4% for placebo and 11.6% for Xenical®. Troublesome gastrointestinal side effects are known to reduce the long-term clinical utility of Xenical®.

Safety and tolerability results of cetilistat in this trial were consistent with those seen in earlier trials.

Takeda submitted the NDA for Cetilistat based on data obtained from three Phase III clinical trials. The three studies included a 52-week placebo-controlled study that evaluated the efficacy and safety of Cetilistat, and 24-week and 52-week open-label safety studies that were conducted on obese patients with type 2 diabetes and dyslipidemia.

The results of these studies demonstrated that patients administered with 120mg of Cetilistat three times a day showed 2.776% reduction in average body weight when compared to 1.103% in placebo-administered patients. Cetilistat reduced HbA1c and LDL cholesterol and was also well tolerated in clinical studies.

Marketing commentary

The market for weight-reducing drugs has had a somewhat chequered history, characterised by major product withdrawals. Although the statistics suggest a market with enormous opportunity, pharmaceutical companies have so far been unable to capitalise on the need for anti-obesity agents.

According to the WHO, there are about 400 million clinically obese people while there are 1.6 billion overweight adults globally. However, only 6% are treated pharmacologically since there is a dearth of productive medications. Only two drugs are approved for long-treatment of obesity: orlistat (Xenical®) and sibutramine (Meridia®). Troublesome side effects have, however, reduced their overall clinical effectiveness.

Since successful management of obesity is likely to require long-term compliance with prescribed medication, cetilistat may have benefits over currently marketed anti-obesity drugs with respect to better toleration. Encouragingly, the FDA has allowed Alizyme the opportunity to consider a separate IND for the use of cetilistat for diabetic patients, potentially extending its use in the huge market for diabetes treatments.