Orexigen Therapeutics Presents Data on Its Proprietary Formulation of Naltrexone Sustained Release (SR) Used in Contrave

- Improved Pharmacokinetic Characteristics of Naltrexone SR Associated with Better Tolerability in Clinical Trials -

PHOENIX, Oct. 6 /PRNewswire-FirstCall/ -- Orexigen Therapeutics, Inc. (NASDAQ:OREX) , a biopharmaceutical company focused on the treatment of obesity and other central nervous system-related disorders, today presented data showing the investigational drug, Contrave(R) (naltrexone SR / bupropion SR), successfully achieved key objectives (lowered naltrexone Cmax, increased Tmax, comparable AUC) in two Phase 1 clinical trials. In addition, preliminary analysis of blinded data from nearly 4,000 patients participating in a series of four ongoing Phase 3 trials supports that the naltrexone SR formulation improvements are associated with tolerability advantages. Results from this series of investigations have been selected for presentation at The Obesity Society Annual Scientific Meeting.
 

"Contrave contains a sustained release formulation of naltrexone which we believe will improve tolerability, enhance patient compliance and improve weight loss outcomes in patients with obesity, a disorder which afflicts more than 75 million Americans," said Gary Tollefson, M.D., Ph.D., Orexigen President and CEO. "The Phase 3 formulation of naltrexone in an oral sustained release form may be a key factor in allowing more patients to achieve the potential benefits associated with greater weight loss."
 

About the Clinical Trials
 

The primary objective of the naltrexone sustained release (SR) development program was to improve tolerability by slowing the rate at which naltrexone dissolves, slowing its entry into the bloodstream (Tmax) and reducing the peak concentration it achieves in the blood (Cmax). A series of studies was conducted to validate this approach.
 

-- Relative bioavailability was assessed in 40 patients randomized to naltrexone SR 40mg or naltrexone immediate release (IR) 36mg in a single dose, crossover PK assessment. Analyses revealed that, on a dose-normalized basis, naltrexone SR was associated with a 43.3% lower peak concentration but a comparable exposure or area-under-the-curve (AUC) to the IR formulation. The Tmax or time to peak concentration was approximately 36 minutes slower for naltrexone SR compared to naltrexone IR.
 

-- Preliminary evidence for improved tolerability with naltrexone SR came from a trial utilizing a multiple dose, parallel design in 60 healthy volunteers randomized to either naltrexone SR 37.5mg / bupropion SR 270mg or naltrexone IR 36mg / bupropion SR 270mg. Patients were treated for up to 14 days. Naltrexone SR / bupropion SR patients spontaneously reported fewer GI adverse events (10.3% vs. 16.7%) or CNS adverse events (10.3% vs. 23.3%). GI event severity was also subjectively lowered with the naltrexone SR formulation.
 

-- In a preliminary effort to evaluate apparent improvements in tolerability associated with naltrexone SR, pooled 24 week data from the Phase 2 NB-201 Contrave trial (N=212) with naltrexone IR was compared with the 24 week blinded data from a series of four Phase 3 Contrave trials (N=3,943 evaluable patients), all employing naltrexone SR. These Phase 3 trials all have varying designs, doses and patient populations; the discontinuation due to adverse event rates associated with them ranged from 13.8% to 22.8%. However, compared to the Phase 2 trial experience, lower rates of nausea were evident across the four pooled Phase 3 trials. In study NB-301 (N=1,689 evaluable patients), the trial with dosing most similar to the Phase 2 NB-201 trial, nausea, headache, or dizziness were all less frequent than in the prior Phase 2 trial, as was the overall rate of early discontinuation due to any adverse event (13.8% versus 16.0%).
 

-- Across the Contrave Phase 3 trial experience to date, only 7.6% of all reported adverse events led to an early discontinuation from the trials.
 

In summary, naltrexone SR met its primary objectives by providing a lower peak plasma concentration (Cmax) than the legacy IR formulation while retaining a similar total plasma exposure (AUC). This held true both for the parent molecule (naltrexone) and its principal active metabolite (6-beta-naltrexol). In a Phase I pilot study, improved tolerability was suggested amongst those who received naltrexone SR / bupropion SR than those receiving the prior Phase 2 formulation containing naltrexone IR. Finally, in a blinded, pooled analysis of preliminary Phase 3 data, results suggest that naltrexone SR / bupropion SR may be associated with decreased rates of treatment-emergent nausea, headache, dizziness, or discontinuation due to an adverse event.
 

About Orexigen(R) Therapeutics
 

Orexigen Therapeutics, Inc. is a biopharmaceutical company focused on the treatment of obesity and other central nervous system-related disorders. The Company's lead combination product candidates targeted for obesity are Contrave(R), which is in Phase 3 clinical trials, and Empatic(TM), which is in the later stages of Phase 2 clinical development. Each product candidate is designed to act on a specific group of neurons in the central nervous system with the goal of achieving appetite suppression and sustained weight loss. Beyond obesity, Orexigen is developing drug combinations for use in schizophrenia and obsessive-compulsive disorder. Further information about the company can be found at http://www.orexigen.com/.
 

About Contrave(R)
 

Contrave is an investigational weight loss medication with a mechanism of action that works at two sites within the central nervous system. The first is a hypothalamic site that controls the balance of food intake and metabolism. We believe that Contrave is possibly the first treatment for obesity to address a second site, the reward system in the brain that controls food preference and food cravings. In clinical trials, Contrave has initiated and sustained significant weight loss over one year of treatment (approximately 8.0% - 10.7% in patients completing 48 weeks of therapy) by reducing appetite, increasing metabolism [0]and allowing the body to continue losing weight by offsetting its natural tendency to fight back and slow down the weight loss process. We expect to receive data from the first of our Contrave Phase 3 trials in January of 2009 and the remaining three trials by mid next year.
 

About Empatic(TM)
 

Empatic is a fixed dose combination of bupropion SR with our proprietary sustained release formulation of zonisamide. Research indicates that zonisamide inhibits AgRP, a system associated with increasing appetite while bupropion increases metabolism. Based on the strength of these results and the unique Empatic mechanism of action, the Company selected this product combination to complement our Contrave clinical development program.
 

Forward-Looking Statements
 

Orexigen cautions you that statements included in this press release that are not a description of historical facts are forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "indicates," "will," "intends," "potential," "suggests," "assuming," "designed" and similar expressions are intended to identify forward-looking statements. These statements are based on the Company's current beliefs and expectations. These forward-looking statements include statements regarding the enrollment, timing, execution and completion of clinical trials of its product candidates, the timing of an NDA submission for Contrave, the potential to obtain regulatory approval for, and effectively treat obesity with, Contrave and Empatic, and the potential for naltrexone SR to improve tolerability. The inclusion of forward-looking statements should not be regarded as a representation by Orexigen that any of its plans will be achieved. Actual results may differ from those set forth in this release due to the risk and uncertainties inherent in the Orexigen business, including, without limitation: the progress and timing of the Company's clinical trials; the potential that earlier clinical trials may not be predictive of future results; the ability for Contrave or Empatic to receive regulatory approval on a timely basis or at all; the potential for adverse safety findings relating to Empatic or Contrave to delay or prevent regulatory approval or commercialization, or result in product liability claims; the ability of Orexigen and its licensors to obtain, maintain and successfully enforce adequate patent and other intellectual property protection of its product candidates; and other risks described in the Company's filings with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Orexigen undertakes no obligation to revise or update this news release to reflect events or circumstances after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995.
 

Source: Orexigen Therapeutics, Inc.

CONTACT: Graham Cooper of Orexigen, +1-858-875-8600; or Liz Frank,
+1-212-301-7216, for Orexigen
 

Web site: http://www.orexigen.com/
 

 

 
 

Posted: October 2008

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