Phase I clinical trials completed

Obesity represents a significant health problem in most developed countries. In 2004, the United States Health and Human Services agency declared obesity to be a disease, creating important changes to Medicare and health care reimbursement policy for obesity-related therapies. Industry studies indicate that obesity increases the risk of co-morbidities such as diabetes, cardiovascular diseases, and arthritis.

Neurogen’s obesity program has focused on blocking the melanin concentrating hormone receptor-1 (MCH1). Reported studies in rodents support MCH being an important mediator of caloric intake. Deletion of MCH or the MCH1 receptor gene resulted in lean animals, while over-production of MCH caused increased weight gain. Neurogen scientists presented data at the North American Association for the Study of Obesity (NAASO) in November 2004, which we believe was the first reported finding of the effectiveness of an MCH1 antagonist in a non-rodent species. Neurogen’s studies indicated that selectively blocking MCH1 was sufficient to achieve a significant reduction in food intake in a higher animal species.

Development Status

In early January 2008, we announced that we had completed the follow-up component of a Phase 1 multiple ascending dose (MAD) study with NGD-4715, Neurogen’s lead MCH-1 receptor antagonist for the treatment of obesity.

The initial phase of the MAD study was a randomized, placebo-controlled, double-blind evaluation of NGD-4715 utilizing three times per day dosing (tid) for 14 days in 45 healthy obese subjects exposed to a high caloric diet. As previously reported, during this phase, moderate induction of the liver enzyme CYP 3A4 occurred, increasing the probability of accelerating metabolism of other drugs administered concomitantly. In addition, during the initial phase of the MAD study, lipid lowering effects were observed.

The follow-up study reported in early January was designed to test the effect of twice per day dosing (bid) in 12 healthy obese subjects on a restricted caloric diet for 14 days. Using bid dosing, CYP3A4 induction was substantially reduced as measured by treatment with midazolam, a drug sensitive to changes in CYP 3A4 levels. With less frequent dosing and caloric restriction in the current trial, no effect on lipids was observed. As in the initial Phase 1 studies, no serious adverse events were observed. However, vivid dreams and awakenings were reported by half the drug treated subjects during the first week of dosing. These results suggest that the effect of MCH-1 receptor antagonism on caloric regulation and sleep architecture requires further study in humans.

Based on the results of the MAD studies, Neurogen has determined that we will not advance the compound into Phase 2 testing at this time, but will consider out-licensing the MCH program for potential development with a partner.

In November 2006, we had announced the start of Phase 1 clinical testing of NGD-4715. This Phase 1 clinical trial was a randomized, double-blind, placebo-controlled evaluation in healthy overweight and obese subjects of the safety and pharmacokinetics of single rising oral doses of NGD-4715. The study enrolled 71 male and female subjects. We announced results from the study in May 2007; NGD-4715 was studied across a broad range of doses in this trial and was safe and well tolerated at all doses. During the trial, blood levels of the compound exhibited a consistent dose dependent increase.

NGD-4715 and related compounds are a part of Neurogen’s wholly-owned obesity program.