In addition, preliminary analysis of blinded data from nearly 4,000 patients participating in a series of four ongoing Phase III trials supports that the naltrexone sustained release (SR) formulation improvements are associated with tolerability advantages.
The primary objective of the naltrexone 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 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 gastrointestinal (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 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 II formulation containing naltrexone IR. Finally, in a blinded, pooled analysis of preliminary Phase III 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.
Gary Tollefson, Orexigen’s president and CEO, said: “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. The Phase III 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.”