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OREXIGEN THERAPEUTICS, INC. filed this Form S-1/A on 04/09/2007
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clinical trial that zonisamide SR exhibits a considerably improved side effect profile compared to the IR product. Specifically, we have shown a reduction in frequency of adverse events from 44% to 8% in this trial. We are currently utilizing our proprietary zonisamide SR formulation in a large ongoing Phase IIb clinical trial of Empatic. Our initial Phase II clinical trial used an IR formulation of zonisamide. In commercial form, if approved, zonisamide SR and bupropion SR would be paired in a single tablet given orally twice a day.
Scientific Rationale
Like Contrave, Empatic employs bupropion to increase α-MSH secretion via POMC stimulation. The second component in Empatic, zonisamide, has been shown in our research to synergistically increase the firing rate of POMC neurons by up to eight-fold in the presence of bupropion. However, we also believe that zonisamide may have one or more additional effects. Within the hypothalamus, a set of neurons acts in a reciprocal way to POMC. These are referred to as the Neuropeptide Y/Agouti-related peptide, or NPY/AgRP, neurons. Stimulation of NPY/AgRP neurons results in the release of AgRP, which competes with α-MSH for access to the MC-4 receptor. Binding of AgRP at the MC-4 receptor results in an increase in appetite and energy conservation, which tends to counteract the weight loss promoting activity of α-MSH. The pharmacology of zonisamide has been hypothesized to also inhibit the firing of NPY/AgRP neurons. Strategies that minimize AgRP competition for the MC-4 receptor and maximize α-MSH activation of the MC-4 receptor thus may have the potential to lead to substantive weight loss. We plan to continue to explore the combination of increased POMC firing and reduced NPY/AgRP activity in our clinical development of Empatic.
Empatic Clinical Results
Phase II Clinical Trial.  We initiated clinical testing of Empatic with a Phase II proof-of-concept clinical trial in 2004. This trial enrolled 127 patients across five clinical sites in a similar protocol to our Phase II clinical trial of Contrave. Patients accepted for the Empatic Phase II clinical trial had a BMI between 30 to 40, were non-smokers and did not have diabetes or other significant medical complications. On average, patients enrolled in this trial weighed approximately 94 kilograms, or 207 pounds, at baseline. Patients were randomly placed into one of two treatment groups:
  •      combination therapy, which consisted of 300mg bupropion SR plus 400mg zonisamide IR; or
  •      zonisamide monotherapy, which consisted of 400mg zonisamide IR plus placebo.
Since the design was nearly identical to our Phase II clinical trial of Contrave, and because it was performed immediately following that trial and conducted at a subset of the same investigative sites, the analysis plan anticipated utilizing the placebo and bupropion monotherapy data from the Contrave Phase II clinical trial for comparative purposes. The primary endpoint for the Empatic Phase II clinical trial was percent change in body weight measured 16 weeks after the start of treatment, with secondary endpoints that included the percent change in body weight 24 weeks after the start of treatment and the percent of subjects who lost at least 5% and 10% of their baseline weight 16 and 24 weeks after the start of treatment. The trial design also included a re-randomization option at week 28 where Empatic subjects could continue either at their same dose or a reduced dose for up to an additional 20 weeks of open-label treatment.