BioWorld International Correspondent
Shares in NeuroSearch A/S gained almost 22 percent Monday on news that its candidate obesity drug tesofensine attained an average weight reduction of about 10 ten percent in a Phase IIb clinical trial.
The stock on the Copenhagen Exchange (NEUR) closed at DKK339 Monday, having ended the previous week at DKK278 (US$63.09).
The compound, a triple monoamine reuptake inhibitor formerly called NS2330, previously was the subject of a development agreement in Parkinson's disease and Alzheimer's disease between Ballerup, Denmark-based NeuroSearch and Boehringer Ingelheim GmbH, of Ingelheim, Germany. BI terminated its interest in the compound, however, when it failed to demonstrate efficacy in either indication.
NeuroSearch decided to move ahead in the obesity indication after seeing weight loss after 14 weeks among a subgroup of obese patients who participated in either the Alzheimer's or the Parkinson's study. (See BioWorld International, Feb. 1, 2006).
The Phase IIb trial, which was conducted at five centers in Denmark, extended the treatment period to 24 weeks. That was preceded by a two-week induction phase to introduce a diet and exercise program. A total of 203 subjects, with a body mass index of between 30 and 40, were recruited. They were randomized to a placebo arm (n=52) and three different dose groups: 0.25 mg daily (n=52), 0.5 mg daily (n=50), and 1 mg daily (n=49). A total of 156 participants completed the protocol. The dropout rate was lower than the company had anticipated, and randomization was maintained.
The placebo group attained an average weight loss vs. baseline of 2 percent, whereas those in the low-, medium- and high-dose groups attained average weight losses of 6.5 percent, 11.2 percent and 12.6 percent, respectively, with, in all cases, a high level of statistical significance (p<0.0001). The absolute weight reductions were numerically similar to the percentage reductions, as the average weight of the trial participants was close to 100 kg (220 pounds).
"There is a very clear - as clear as clear can be - indication of a dose response," NeuroSearch Chief Medical Officer Dieter Meier said on a conference call. Secondary endpoints, including reductions in BMI, reductions in waist circumference and patient-reported increased feelings of satiety, also were attained with a high level of statistical significance.
Adverse events were mostly of a mild to moderate character, NeuroSearch said, with the most prevalent being dry mouth, nausea, constipation, diarrhea and insomnia. Slight increases in pulse and blood pressure were seen in those receiving tesofensine, but they were not "clinically significant abnormal changes from baseline," as defined in FDA guidelines, the company said.
Meier said that, to his knowledge, there are no other therapies in development that have demonstrated comparable levels of efficacy. Moreover, those that have come closest are combination therapies. "It is notoriously difficult to register combination therapies. One has to prove the rationale for the combination, which is very tricky," he said.
San Diego based Orexigen Therapeutics Inc. has two late-stage combination therapies in development. Contrave, a proprietary fixed-dose combination of bupropion and naltrexone, is undergoing a Phase III clinical trial. Empatic, a combination of zonisamide and bupropion, recently completed a Phase IIb clinical trial. Arena Pharmaceuticals Inc., also of San Diego, also reported Phase IIb data on its obesity drug Lorcaserin hydrochloride, which selectively stimulates the 5-HT2C serotonin receptor.
NeuroSearch plans to seek a development partner before embarking on a Phase III trial. "We will need a big partner because it is a big indication," CEO Flemming Pedersen said on the conference call.
The compound already is causing excitement among the Danish investor community. "If you can confirm the data in a Phase III trial, it couldn't be anything other than a blockbuster," Peter Bertram Andersen, senior equity analyst at Silkeborg-based Jyske Markets, told BioWorld International. "The risk is obvious. This is only a Phase II trial. It has only been tested in a couple of hundred patients."
The recent withdrawal by Paris-based Sanofi Aventis Group of an NDA for rimonabant (Zimulti), following a negative FDA advisory panel vote on the cannabinoid receptor antagonist, has left the obesity market wide open, but also underlined the importance of a mild side-effect profile in that drug category. Rimonabant was rejected because it appeared to increase suicidal thoughts among some patients who took the drug. "I would be surprised if there were problems with depression with [tesofensine]. It should work the other way," Andersen said.
Andersen has maintained a buy recommendation on NeuroSearch, and has raised his 12-month target price from DKK350 to DKK430.