Buprenorphine/samidorphan

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Buprenorphine/samidorphan
Buprenorphine and samidorphan.svg
Buprenorphine (top) + samidorphan (bottom)
Combination of
Buprenorphine Opioid modulator
Samidorphan Opioid antagonist
Clinical data
Other namesALKS-5461
Routes of
administration 		Sublingual [1]
Legal status
Legal status
Identifiers
CAS Number

Buprenorphine/samidorphan (developmental code name ALKS-5461) is a combination formulation of buprenorphine and samidorphan which is under development as an add on to antidepressants in treatment-resistant depression (TRD). [2]

Contents

ALKS-5461 failed to meet its primary efficacy endpoints in two trials from 2016. [3] On the basis of a third study that did meet its primary endpoints, Alkermes initiated a rolling New Drug Application with the FDA. [4]

In November 2018, an FDA panel voted against recommending approval, finding that evidence was insufficient. [5] As such, approval of the medication was rejected in 2019. [6] It is a κ-opioid receptor (KOR) antagonist and is being developed by Alkermes.

Pharmacology

Pharmacodynamics

ALKS-5461 is a (1:1 ratio) combination of: (1) buprenorphine, a weak partial agonist of the μ-opioid receptor (MOR), antagonist/very weak partial agonist of the κ-opioid receptor (KOR), and, to a lesser extent, antagonist of the δ-opioid receptor (DOR) and weak partial agonist of the nociceptin receptor (NOP); [7] [8] [9] [10] and (2) samidorphan, a preferential antagonist of the MOR (but also, to a slightly lesser extent, weak partial agonist of the KOR and DOR). [11] [12] [13] [14] The combination of these two drugs putatively results in what is functionally a blockade of KORs with negligible activation of MORs. [9] [12]

κ-Opioid receptor antagonism

It has been known since the 1980s that buprenorphine binds to at high affinity and antagonizes the KOR. [15] [16]

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, [17] induce dysphoria and stress-like responses in both animals and humans, [18] as well as psychotomimetic effects in humans, [19] [20] and are thought to be essential for the mediation of the dysphoric aspects of stress. [21] 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. [17] [21] [22] 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). [23] Accordingly, KOR antagonists show robust efficacy in animal models of depression, anxiety, anhedonia, drug addiction, and other stress-related behavioral and physiological abnormalities. [17] [18] [24] [25]

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). [26] However, a subsequent study found that the MOR may play an important role in the antidepressant-like effects of buprenorphine in animals. [27]

Buprenorphine is not a silent antagonist of the KOR but rather a weak partial agonist. [28] [29] 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. [29] 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%. [13] [14] As such, ALKS-5461 may possess both antagonistic and agonistic potential at the KOR. [28] 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. [26] [30]

History

ALKS-5461 was granted Fast Track Designation by the Food and Drug Administration (FDA) for treatment-resistant depression in October 2013. [31] During June and July 2014, three phase III clinical trials were initiated in the United States for treatment-resistant depression. [1] Alkermes reported that the first two trials failed in 2016. [1] [3] 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. [4] On 31 January 2018, Alkermes submitted a New Drug Application for ALKS-5461 to the FDA for the adjunctive treatment of major depressive disorder. [32] The submission was accepted by the FDA on 9 April 2018 after initially serving a refuse-to-file letter due to insufficient evidence of overall effectiveness. [33]

In November 2018, an FDA advisory committee voted 21–2 against recommending approval of ALKS-5461 for MDD, setting the medication up for likely rejection. [5] The main reason cited was insufficient evidence of effectiveness. [5] The panel voted in favor of adequate safety having been demonstrated. [5]

See also

Related Research Articles

Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neo-endorphin. Depolarization of a neuron containing prodynorphin stimulates PC2 processing, which occurs within synaptic vesicles in the presynaptic terminal. Occasionally, prodynorphin is not fully processed, leading to the release of “big dynorphin.” “Big Dynorphin” is a 32-amino acid molecule consisting of both dynorphin A and dynorphin B.

<span class="mw-page-title-main">Buprenorphine</span> Opioid used to treat pain & opioid use disorder.

Buprenorphine is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection, as a skin patch (transdermal), or as an implant. For opioid use disorder, it is typically started when withdrawal symptoms have begun and for the first two days of treatment under direct observation of a health-care provider. In the United States, the combination formulation of buprenorphine/naloxone (Suboxone) is usually prescribed to discourage misuse by injection. Maximum pain relief is generally within an hour with effects up to 24 hours. Buprenorphine affects different types of opioid receptors in different ways. Depending on the type of receptor, it may be an agonist, partial agonist, or antagonist. In the treatment of opioid use disorder buprenorphine is an agonist/antagonist, meaning that it relieves withdrawal symptoms from other opioids and induces some euphoria, but also blocks the ability for many other opioids, including heroin, to cause an effect. Unlike full agonists like heroin or methadone, buprenorphine has a ceiling effect, such that taking more medicine will not increase the effects of the drug.

<span class="mw-page-title-main">Naltrexone</span> Medication

Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been found to be effective in the treatment of other addictions and may be used for them off-label. An opioid-dependent person should not receive naltrexone before detoxification. It is taken by mouth or by injection into a muscle. Effects begin within 30 minutes. A decreased desire for opioids may take a few weeks to occur.

<span class="mw-page-title-main">Tianeptine</span> Antidepressant

Tianeptine, sold under the brand names Stablon and Coaxil among others, is an atypical tricyclic antidepressant which is used mainly in the treatment of major depressive disorder, although it may also be used to treat anxiety, asthma, and irritable bowel syndrome.

Alkermes plc is a pharmaceutical company that focuses on central nervous system (CNS) diseases like schizophrenia, bipolar disorder, depression, addiction and multiple sclerosis. The company was founded in 1987 by Michael Wall. In September 2011 Alkermes, Inc. merged with Elan Drug Technologies (EDT), the former drug formulation and manufacturing division of Élan Corporation, plc. The company is headquartered in Dublin, and has an R&D center in Waltham, Massachusetts, and manufacturing facilities in Athlone, Ireland, and Wilmington, Ohio.

An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors.

κ-opioid receptor Protein-coding gene in the species Homo sapiens, named for ketazocine

The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the OPRK1 gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering nociception, consciousness, motor control, and mood. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.

<span class="mw-page-title-main">Nalmefene</span> Opioid antagonist

Nalmefene is an opioid antagonist medication used in the management of opioid overdose and alcohol dependence. It is taken by mouth.

δ-opioid receptor Opioid receptor named for the mouse vas deferens, where it was first characterized

The ∆-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous ligands. The regions of the brain where the ∆-opioid receptor is largely expressed vary from species model to species model. In humans, the ∆-opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain.

<span class="mw-page-title-main">Diprenorphine</span> Chemical compound

Diprenorphine, also known as diprenorfin, is a non-selective, high-affinity, weak partial agonist of the μ- (MOR), κ- (KOR), and δ-opioid receptor (DOR) which is used in veterinary medicine as an opioid antagonist. It is used to reverse the effects of super-potent opioid analgesics such as etorphine and carfentanil that are used for tranquilizing large animals. The drug is not approved for use in humans.

An atypical antidepressant is any antidepressant medication that acts in a manner that is different from that of most other antidepressants. Atypical antidepressants include agomelatine, bupropion, iprindole, mianserin, mirtazapine, nefazodone, opipramol, tianeptine, and trazodone. The agents vilazodone and vortioxetine are partly atypical. Typical antidepressants include the SSRIs, SNRIs, TCAs, and MAOIs, which act mainly by increasing the levels of the monoamine neurotransmitters serotonin and/or norepinephrine. Among TCAs, trimipramine is an atypical agent in that it appears not to do this. In August 2020, Esketamine (JNJ-54135419) was approved by the U.S. Food and Drug Administration (FDA) for the treatment for treatment-resistant depression with the added indication for the short-term treatment of suicidal thoughts.

<span class="mw-page-title-main">JDTic</span> Chemical compound

JDTic is a selective, long-acting ("inactivating") antagonist of the κ-opioid receptor (KOR). JDTic is a 4-phenylpiperidine derivative, distantly related structurally to analgesics such as pethidine and ketobemidone, and more closely to the MOR antagonist alvimopan. In addition, it is structurally distinct from other KOR antagonists such as norbinaltorphimine. JDTic has been used to create crystal structures of KOR [ PDB: 4DJH, 6VI4​].

<span class="mw-page-title-main">Samidorphan</span> Opioid antagonist

Samidorphan, is an opioid antagonist which in the form of olanzapine/samidorphan is used in the treatment of schizophrenia and bipolar disorder. Samidorphan reduces the weight gain associated with olanzapine. Samidorphan is taken by mouth.

<span class="mw-page-title-main">Aticaprant</span> Chemical compound

Aticaprant, also known by its developmental codes JNJ-67953964, CERC-501, and LY-2456302, is a κ-opioid receptor (KOR) antagonist which is under development for the treatment of major depressive disorder. A regulatory application for approval of the medication is expected to be submitted by 2025. Aticaprant is taken by mouth.

<span class="mw-page-title-main">Zyklophin</span> Chemical compound

Zyklophin is a semisynthetic peptide derived from dynorphin A and a highly selective antagonist of the κ-opioid receptor (KOR). It is systemically-active, displaying good metabolic stability and blood-brain-barrier penetration. Similarly to other KOR antagonists, it has been shown to block stress-induced reinstatement of cocaine-seeking in animals. The drug is currently experimental, and thus cannot be considered safe for consumption or usage.

<span class="mw-page-title-main">Buprenorphine/naloxone</span> Opioid treatment

Buprenorphine/naloxone, sold under the brand name Suboxone among others, is a fixed-dose combination medication that includes buprenorphine and naloxone. It is used to treat opioid use disorder, and reduces the mortality of opioid use disorder by 50%. It relieves cravings to use and withdrawal symptoms. Buprenorphine/­naloxone is available for use in two different forms, under the tongue or in the cheek.

Buprenorphine/naltrexone is an experimental combination drug formulation of buprenorphine, a μ-opioid receptor (MOR) weak partial agonist and κ-opioid receptor (KOR) antagonist, and naltrexone, a MOR and KOR silent antagonist, which is under investigation for the potential treatment of psychiatric disorders. The combination of the two drugs is thought to result in a selective blockade of the KOR and hence fewer MOR activation-related concerns such as euphoria and opioid dependence. It has been found to produce antidepressant-like effects in mice and has recently been found to be effective in the treatment of cocaine dependence in a large clinical trial.

<span class="mw-page-title-main">Dextromethorphan/bupropion</span> Antidepressant medication

Dextromethorphan/bupropion (DXM/BUP), sold under the brand name Auvelity, is a combination medication for the treatment of major depressive disorder (MDD). It contains an extended-release combination of dextromethorphan (DXM) and bupropion. The medication is modestly more effective in the treatment of depression than placebo or bupropion alone. It is taken as a tablet by mouth.

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