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"Contrave contains a sustained release formulation of naltrexone which webelieve will improve tolerability, enhance patient compliance and improveweight loss outcomes in patients with obesity, a disorder which afflicts morethan 75 million Americans," said Gary Tollefson, M.D., Ph.D., OrexigenPresident and CEO. "The Phase 3 formulation of naltrexone in an oralsustained release form may be a key factor in allowing more patients toachieve the potential benefits associated with greater weight loss."
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About the Clinical Trials
The primary objective of the naltrexone sustained release (SR) developmentprogram was to improve tolerability by slowing the rate at which naltrexonedissolves, slowing its entry into the bloodstream (Tmax) and reducing the peakconcentration it achieves in the blood (Cmax). A series of studies wasconducted to validate this approach.
-- Relative bioavailability was assessed in 40 patients randomized tonaltrexone 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 acomparable exposure or area-under-the-curve (AUC) to the IR formulation. TheTmax or time to peak concentration was approximately 36 minutes slower fornaltrexone SR compared to naltrexone IR.
-- Preliminary evidence for improved tolerability with naltrexone SR camefrom a trial utilizing a multiple dose, parallel design in 60 healthyvolunteers randomized to either naltrexone SR 37.5mg / bupropion SR 270mg ornaltrexone IR 36mg / bupropion SR 270mg. Patients were treated for up to 14days. Naltrexone SR / bupropion SR patients spontaneously reported fewer GIadverse events (10.3% vs. 16.7%) or CNS adverse events (10.3% vs. 23.3%). GIevent severity was also subjectively lowered with the naltrexone SRformulation.
-- In a preliminary effort to evaluate apparent improvements intolerability associated with naltrexone SR, pooled 24 week data from the Phase2 NB-201 Contrave trial (N=212) with naltrexone IR was compared with the 24week blinded data from a series of four Phase 3 Contrave trials (N=3,943evaluable patients), all employing naltrexone SR. These Phase 3 trials allhave varying designs, doses and patient populations; the discontinuation dueto 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 wereevident across the four pooled Phase 3 trials. In study NB-301 (N=1,689evaluable patients), the trial with dosing most similar to the Phase 2 NB-201trial, nausea, headache, or dizziness were all less frequent than in the priorPhase 2 trial, as was the overall rate of early discontinuation due to anyadverse event (13.8% versus 16.0%).
-- Across the Contrave Phase 3 trial experience to date, only 7.6% of allreported adverse events led to an early discontinuation from the trials.
In summary, naltrexone SR met its primary objectives by providing a lowerpeak plasma concentration (Cmax) than the legacy IR formulation whileretaining a similar total plasma exposure (AUC). This held true both for theparent molecule (naltrexone) and its principal active metabolite(6-beta-naltrexol). In a Phase I pilot study, improved tolerability wassuggested amongst those who received naltrexone SR / bupropion SR than thosereceiving the prior Phase 2 formulation containing naltrexone IR. Finally, ina blinded, pooled analysis of preliminary Phase 3 data, results suggest thatnaltrexone SR / bupropion SR may be associated with decreased rates oftreatment-emergent nausea, headache, dizziness, or discontinuation due to anadverse event.
About Orexigen(R) Therapeutics
Orexigen Therapeutics, Inc. is a biopharmaceutical company focused on thetreatment of obesity and other central nervous system-related disorders. TheCompany's lead combination product candidates targeted for obesity areContrave(R), which is in Phase 3 clinical trials, and Empatic(TM), which is inthe later stages of Phase 2 clinical development. Each product candidate isdesigned to act on a specific group of neurons in the central nervous systemwith the goal of achieving appetite suppression and sustained weight loss.Beyond obesity, Orexigen is developing drug combinations for use inschizophrenia and obsessive-compulsive disorder. Further information aboutthe company can be found at http://www.Orexigen.com.
About Contrave(R)
Contrave is an investigational weight loss medication with a mechanism ofaction that works at two sites within the central nervous system. The firstis a hypothalamic site that controls the balance of food intake andmetabolism. We believe that Contrave is possibly the first treatment forobesity to address a second site, the reward system in the brain that controlsfood preference and food cravings. In clinical trials, Contrave has initiatedand sustained significant weight loss over one year of treatment(approximately 8.0% - 10.7% in patients completing 48 weeks of therapy) byreducing appetite, increasing metabolism [0]and allowing the body to continuelosing weight by offsetting its natural tendency to fight back and slow downthe weight loss process. We expect to receive data from the first of ourContrave Phase 3 trials in January of 2009 and the remaining three trials bymid next year.
About Empatic(TM)
Empatic is a fixed dose combination of bupropion SR with our proprietarysustained release formulation of zonisamide. Research indicates thatzonisamide inhibits AgRP, a system associated with increasing appetite whilebupropion increases metabolism. Based on the strength of these results andthe unique Empatic mechanism of action, the Company selected this productcombination to complement our Contrave clinical development program.
Forward-Looking Statements
Orexigen cautions you that statements included in this press release thatare 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 similarexpressions are intended to identify forward-looking statements. Thesestatements are based on the Company's current beliefs and expectations. Theseforward-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 obtainregulatory approval for, and effectively treat obesity with, Contrave andEmpatic, and the potential for naltrexone SR to improve tolerability. Theinclusion of forward-looking statements should not be regarded as arepresentation by Orexigen that any of its plans will be achieved. Actualresults may differ from those set forth in this release due to the risk anduncertainties inherent in the Orexigen business, including, withoutlimitation: the progress and timing of the Company's clinical trials; thepotential that earlier clinical trials may not be predictive of futureresults; the ability for Contrave or Empatic to receive regulatory approval ona timely basis or at all; the potential for adverse safety findings relatingto Empatic or Contrave to delay or prevent regulatory approval orcommercialization, or result in product liability claims; the ability ofOrexigen and its licensors to obtain, maintain and successfully enforceadequate patent and other intellectual property protection of its productcandidates; and other risks described in the Company's filings with theSecurities and Exchange Commission. You are cautioned not to place unduereliance on these forward-looking statements, which speak only as of the datehereof, and Orexigen undertakes no obligation to revise or update this newsrelease to reflect events or circumstances after the date hereof. Allforward-looking statements are qualified in their entirety by this cautionarystatement. This caution is made under the safe harbor provisions of Section21E of the Private Securities Litigation Reform Act of 1995.
SOURCE Orexigen Therapeutics, Inc.
