Buprenorphine/samidorphan (developmental code name ALKS-5461) is a combination drug formulation of buprenorphine and samidorphan acting as a ?-opioid receptor (KOR) antagonist which is under development by Alkermes as an adjunct to antidepressant therapy in treatment-resistant depression (TRD).
Tope level data from two Phase III trials was released in 2016; ALKS-5461 failed to meet its primary efficacy endpoints. On the basis of a third phase III study, Alkermes initiated a rolling New Drug Application with the FDA.
Maps, Directions, and Place Reviews
Pharmacology
Activity profile
ALKS-5461 is a (1:1 ratio) combination of: (1) buprenorphine, a weak partial agonist of the ?-opioid receptor (MOR), antagonist/very weak partial agonist of the ?-opioid receptor (KOR), and, to a lesser extent, antagonist of the ?-opioid receptor (DOR) and weak partial agonist of the nociceptin receptor (NOP); and (2) samidorphan, a preferential antagonist of the MOR (but also, to a slightly lesser extent, weak partial agonist of the KOR and DOR). The combination of these two drugs putatively results in what is functionally a blockade of KORs with negligible activation of MORs.
?-Opioid receptor antagonist
Through activation of the KOR, dynorphins, opioid peptides that are the endogenous ligands of the KOR and that can, in many regards, be figuratively thought of as functional inverses of the morphine-like, euphoric and stress-inhibiting endorphins, induce dysphoria and stress-like responses in both animals and humans, as well as psychotomimetic effects in humans, and are thought to be essential for the mediation of the dysphoric aspects of stress. In addition, dynorphins are believed to be critically involved in producing the changes in neuroplasticity evoked by chronic stress that lead to the development of depressive and anxiety disorders, increased drug-seeking behavior, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. In support of this, in knockout mice lacking the genes encoding the KOR and/or prodynorphin (the endogenous precursor of the dynorphins), many of the usual effects of exposure to chronic stress are completely absent, such as increased immobility in the forced swimming test (a widely employed assay of depressive-like behavior) and increased conditioned place preference for cocaine (a measure of the rewarding properties and addictive susceptibility to cocaine). Accordingly, KOR antagonists show robust efficacy in animal models of depression, anxiety, anhedonia, drug addiction, and other stress-related behavioral and physiological abnormalities.
It has been known since the 1980s that buprenorphine binds to at high affinity and antagonizes the KOR.
A mouse study found that knockout of the MOR or DOR or selective pharmacological ablation of the NOP did not affect the antidepressant-like effects of buprenorphine, whereas knockout of the KOR abolished the antidepressant-like effects of the drug, supporting the notion that the antidepressant-like effects of buprenorphine are indeed mediated by modulation of the KOR by the drug (and not of the MOR, DOR, or NOP). However, a subsequent study found that the MOR may play an important role in the antidepressant-like effects of buprenorphine in animals.
Partial agonist activity
Buprenorphine is not a silent antagonist of the KOR but rather a weak partial agonist. In vitro, it has shown some activation of the KOR at concentrations of >= 100 nM, with an Emax of 22% at 30 µM; no plateau in maximal response (EC50) was observed at concentrations up to 30 µM. Samidorphan similarly shows activation of the KOR in vitro, but to an even greater extent, with an EC50 of 3.3 nM and an Emax of 36%.
As such, ALKS-5461 may possess both antagonistic and agonistic potential at the KOR. Because antagonism of the KOR seems to be responsible for the antidepressant effects of ALKS-5461, this property could in theory limit the effectiveness of ALKS-5461 in the treatment of depression.
Depression Drug Trials Video
History
ALKS-5461 was granted Fast Track Designation by the Food and Drug Administration (FDA) for treatment-resistant depression in October 2013. During June and July 2014, three phase III clinical trials were initiated in the United States for treatment-resistant depression. Alkermes reported that the first two trials failed in 2016. In August 2017, based on the third trial, Alkermes announced the initiation of a rolling submission of a New Drug Application for ALKS-5461 to the FDA.
Source of the article : Wikipedia
EmoticonEmoticon