In the past couple of weeks, two companies have announced the results of pivotal Phase III trials of potential anti-obesity products. On September 9th, Vivus announced that obese patients treated with its experimental product Qnexa (phentermine and topiramate) experienced significant weight loss compared with patients on placebo (scripnews.com, September 11th), while just last week Arena Pharmaceuticals announced that patients receiving the selective 5HT2C receptor agonist lorcaserin had also achieved significant weight loss. Both companies are expected to submit NDAs for their respective products by the end of the year.

The Qnexa results involved two separate one-year studies, the EQUIP trial and the CONQUER trial. The average weight loss achieved by patients treated with Qnexa in the EQUIP trial was 17 kg, or 14.7% of their starting weight, while in the CONQUER trial the average was just under 14 kg. FDA efficacy benchmarks for weight loss agents were exceeded at all doses of Qnexa tested in the clinical programme.

Significantly, patients treated with Qnexa had reductions in blood pressure and triglyceride and cholesterol levels. The CONQUER patients, some of whom had type 2 diabetes, also experienced a highly significant fall in haemoglobin A1c levels, despite undergoing a significant reduction in the use of antidiabetic medications. Qnexa is being developed as a treatment for type 2 diabetes as well as for weight loss.

Arena’s results for lorcaserin were also based on two separate trials, and once again the results from each were broadly similar. Patients who took lorcaserin for a year achieved an average weight loss of 5.9% of their body weight, compared with 2.8% for patients on placebo.

Both companies were at pains to point out that the incidence of side-effects with their products was extremely low. Vivus said the most commonly reported side-effects with Qnexa were dry mouth, tingling, constipation, altered taste and insomnia. Arena said that lorcaserin was well tolerated, with no adverse event rate in the active treatment group exceeding the placebo group by more than 4%, and serious adverse events such as depression, anxiety and suicidal ideation equally infrequent in each treatment group

Over the years, clinical trials of potential appetite suppressants have been bedevilled by safety issues. The most recent example was Acomplia (rimonabant), a selective CB1 antagonist developed by Sanofi-Aventis. The product was introduced in a number of European countries beginning in 2006, although approval in the US proved more elusive. However, clinical use of the product was sometimes associated with psychiatric side-effects, such as depression, sleeping disorders, anxiety and aggression, and by 2008 the EMEA decided that its benefits no longer outweighed its risks. This led to Acomplia being withdrawn across the EU, which effectively killed its chances of ever receiving US approval.

Another casualty was Servier’s fenfluramine. Originally launched in the 1970s, it proved to be a moderately effective anti-obesity agent. Later, fenfluramine came to be used in combination with phentermine, as “fen-phen”, for the management of obesity, which was more effective than fenfluramine alone. However, by the mid-1990s the FDA had received a number of reports of serious side-effects, such as pulmonary hypertension and heart valve problems, which led to its use being discontinued and to a slew of litigation.

Significantly, in view of the latest data on Qnexa, the phentermine component was exonerated from having any role in the toxic effects of fen-phen. In fact, phentermine is generally well tolerated, although it occasionally causes side-effects consistent with its pharmacological action as a stimulant of catecholamine release (eg tachycardia, increased blood pressure). Such sympathetic effects did not feature among the side-effects reported for Qnexa.

The second component of Qnexa, topiramate, is marketed by J&J as an anticonvulsant under the brand name, Topamax. The prescribing information for Topamax refers to possible serious side-effects such as metabolic acidosis, hyperammonaemia, kidney stones and effects on thinking and alertness such as confusion, attention deficits and depression. There were two cases of kidney stones among patients taking part in the Qnexa trials, as well as occasional depression or depressed mood, but no evidence of suicidal ideation.

Similarly, the side-effects reported for lorcaserin do not give rise to immediate concern about the product’s safety. There were some reports of depression, anxiety and suicidal ideation, but these occurred equally frequently in each treatment group.

Unfortunately, there is to date relatively little clinical experience with 5HT2C agonists, so there must remain some element of uncertainty about the safety of this class in general. One 5HT2C agonist that has recently been launched on the market is Servier’s antidepressant Valdoxan (agomelatine), which does appear to have a favourable side-effect profile.

On the other hand, a number of other 5HT2C agonists previously in development for obesity have been discontinued, for various reasons. They include Biovitrum’s BVT-933, which had been licensed to GlaxoSmithKline before Biovitrum discontinued development; Athersys’s ATHX-105, whose development was suspended after the FDA requested further safety and tolerability details; and Organon’s Org-12962. All three were being evaluated as potential anti-obesity agents.

Globally, there are more than 1 billion overweight adults, at least 300 million of whom are obese, according to the WHO. The rewards for a company that can successfully develop and commercialise an effective and safe anti-obesity product are therefore potentially huge. The road to success contains many pitfalls, but as the recently reported results show, the race is very much still on.