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S-1/A
OREXIGEN THERAPEUTICS, INC. filed this Form S-1/A on 02/16/2007
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There were two serious adverse events reported in this trial, both of which were designated by the investigators as unrelated to the study drugs. In addition, two patients (one patient in the combination group and one patient in the zonisamide plus placebo group) experienced suicidal ideation, which is a labeled adverse event for both bupropion and zonisamide. The symptoms resolved after discontinuation of study drugs. Among patients receiving Excalia, the rate of discontinuation of the trial at 24 weeks due to an adverse event was 37%, compared to 20% for the zonisamide IR monotherapy group. Adverse events were typically reported shortly after initiation of therapy and tended to resolve over time.
 
For those study participants who continued treatment on Excalia for an additional 20-week extension and remained on the 400mg zonisamide plus 300mg bupropion SR dose, mean weight loss at 36 weeks and 48 weeks was approximately 12% of baseline body weight.
 
We will need to conduct additional clinical trials, the results of which may not corroborate our earlier results, in order to provide enough evidence regarding efficacy and safety to submit an NDA to the FDA for potential regulatory approval. In addition, undesirable side effects of Excalia may delay or prevent regulatory approval. The most common side effects observed in our clinical trials of Excalia to date include gastrointestinal upset, insomnia and mild rash.
 
Future Excalia Clinical Development Plans
 
We recently initiated a Phase IIb clinical trial of Excalia. This Phase IIb clinical trial is a matrix design intended to determine the optimal dose ratio(s) of our proprietary zonisamide SR formulation and bupropion SR to evaluate in further clinical development. We have enrolled over 600 patients across 14 sites in seven groups, including six groups of varying active drug dosages as well as a seventh placebo group. The active groups utilize dosages ranging from 180mg to 360mg of zonisamide SR combined with dosages ranging from 280mg to 360mg of bupropion SR. The enrollment criteria for this trial are consistent with previous trials, although we are allowing patients with a BMI of up to 42 in accordance with FDA suggestion. The primary outcome measure for this trial will be percent change in body weight 24 weeks after the start of treatment. There will be an extension period providing an additional 24 weeks of exposure.
 
Based on the results of the ongoing Phase IIb clinical trial, we expect to take the optimal one or two Excalia dose ratios into pivotal Phase III clinical trials. Based on our April 2006 meeting with the FDA, our Phase III clinical development program for Excalia will be designed to provide exposure for approximately 1,500 patients for one year under double-blind, placebo-controlled conditions. Given the clinically significant magnitude of weight loss experienced in our first Excalia Phase II clinical trial among patients receiving the zonisamide/bupropion combination, we anticipate including patients in future pivotal trials with higher BMI levels, including for example patients who might be candidates for surgical intervention. We may also conduct studies that include patients with dyslipidemia, hypertension and/or diabetes. Zonisamide carries a Category C pregnancy rating, which means that women of childbearing age will be excluded from trial participation unless meeting pre-stated pregnancy prevention criteria. Assuming favorable results from the ongoing Phase IIb trial, we plan to initiate a clinical trial evaluating the optimal dose(s) of Excalia against individual monotherapies and placebo in late 2007. We would expect that subsequent pivotal studies would compare Excalia to placebo and that the results of all these trials will begin to become available in 2010 and provide the basis of an NDA submission for Excalia in 2011.
 
Sales and Marketing
 
We maintain worldwide commercial rights to our product candidates, and have the opportunity to build a specialty sales force to market and sell these products independently. However, we expect that Contrave and Excalia, if approved, will be prescribed predominantly by primary care physicians, including general practitioners, family practitioners and internists. In order to target this large group of potential prescribers, we may consider entering into a collaboration, either in the United States, outside the United States or both, with a pharmaceutical company that has the sales force and marketing resources to adequately address this physician audience. However, for the foreseeable future, we expect to maintain commercial rights to our product candidates and to continue to develop them independently.


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