Buprenorphine/samidorphan (developmental code name ALKS-5461) is a combination formulation of

buprenorphine Buprenorphine, sold under the brand name Subutex among others, 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 (intravenous a ...

and

samidorphan Samidorphan (, ) is an opioid antagonist that in the form of olanzapine/samidorphan (sold as Lybalvi) is used in the treatment of schizophrenia and bipolar disorder. Samidorphan reduces the weight gain associated with olanzapine. Samidorphan is t ...

which is under development as an add on to

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

s in

treatment-resistant depression Treatment-resistant depression (TRD) is often defined as major depressive disorder in which an affected person does not respond adequately to at least two different antidepressant medications at an adequate dose and for an adequate duration. Inad ...

(TRD). ALKS-5461 failed to meet its primary efficacy endpoints in two trials from 2016. On the basis of a third study that did meet its primary endpoints, Alkermes initiated a rolling

New Drug Application The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial ...

with the FDA. In November 2018, an FDA panel voted against recommending approval, finding that evidence was insufficient. As such, approval of the medication was rejected in 2019. It is a

κ-opioid receptor 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 re ...

(KOR)

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.Alkermes.

Pharmacology

Pharmacodynamics

ALKS-5461 is a (1:1 ratio) combination of: (1) buprenorphine, a weak

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of the

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...

(MOR),

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.κ-opioid receptor 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 re ...

(KOR), and, to a lesser extent, antagonist of the

δ-opioid receptor The δ-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 alpha subunit, Gi/G0 and has enkephalins as it ...

(DOR) and weak partial agonist of the

nociceptin receptor The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the ''OPRL1'' (opioid receptor-like 1) gene. The nociceptin recepto ...

(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).Almarsson, O., Deaver, D., Turncliff, R., Wentland, M., & Ehrich, E. (2010). Discovery and early development of ALKS-33, an opioid modulator for treatment of reward disorders. Abstracts Of Papers Of The American Chemical Society, 240 The combination of these two drugs putatively results in what is functionally a blockade of KORs with negligible activation of MORs.

κ-Opioid receptor antagonism

It has been known since the 1980s that buprenorphine binds to at high

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

and antagonizes the KOR. Through activation of the KOR,

dynorphin 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 ...

opioid peptide Opioid peptides or opiate peptides are peptides that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Such peptides may be produced by the body itself, for example endorphins. The effects of these p ...

s that are the

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

s of the KOR and that can, in many regards, be figuratively thought of as functional inverses of the

morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...

-like,

euphoric Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and danci ...

and

stress Stress may refer to: Science and medicine * Stress (biology), an organism's response to a stressor such as an environmental condition * Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phra ...

-inhibiting

endorphin Endorphins (contracted from endogenous morphine) are peptides produced in the brain that block the perception of pain and increase feelings of wellbeing. They are produced and stored in the pituitary gland of the brain. Endorphins are endogeno ...

s, induce

dysphoria Dysphoria (; ) is a profound state of unease or dissatisfaction. It is the semantic opposite of euphoria. In a psychiatric context, dysphoria may accompany depression, anxiety, or agitation. In psychiatry Intense states of distress and uneas ...

and stress-like responses in both animals and humans, as well as

psychotomimetic A drug with psychotomimetic (also known as psychomimetic or psychotogenic) actions mimics the symptoms of psychosis, including delusions and/or delirium, as opposed to only hallucinations. Psychotomimesis is the onset of psychotic symptoms followi ...

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 Neuroplasticity, also known as neural plasticity or just plasticity, is the ability of neural networks in the brain to change through neurogenesis, growth and reorganization. Neuroplasticity refers to the brain's ability to reorganize and rewir ...

evoked by

chronic stress Chronic stress is the physiological or psychological response induced by a long-term internal or external stressor. The stressor, either physically present or recollected, will produce the same effect and trigger a chronic stress response. There ...

that lead to the development of depressive and

anxiety disorder Anxiety disorders are a group of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal functions are significantly impaired. Anxiety may cause phys ...

s, increased drug-seeking behavior, and dysregulation of the hypothalamic-pituitary-adrenal (HPA)

axis An axis (: axes) may refer to: Mathematics *A specific line (often a directed line) that plays an important role in some contexts. In particular: ** Coordinate axis of a coordinate system *** ''x''-axis, ''y''-axis, ''z''-axis, common names ...

. In support of this, in

knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

lacking the

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

s encoding the KOR and/or

prodynorphin Prodynorphin, also known as proenkephalin B, is an opioid polypeptide hormone involved with chemical signal transduction and cell communication. The gene for prodynorphin is expressed in the endometrium and the striatum, and its gene map locus is 2 ...

(the endogenous

precursor Precursor or Precursors may refer to: *Precursor (religion), a forerunner, predecessor ** The Precursor, John the Baptist Science and technology * Precursor (bird), hypothesized genus of fossil birds that was composed of fossilized parts of unre ...

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 Conditioned place preference (CPP) is a form of Pavlovian conditioning used to measure the motivational effects of objects or experiences. This motivation comes from the pleasurable aspect of the experience, so that the brain can be reminded of th ...

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 Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

anhedonia Anhedonia is a diverse array of deficits in hedonic function, including reduced motivation or ability to experience pleasure. While earlier definitions emphasized the inability to experience pleasure, anhedonia is currently used by researcher ...

drug addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...

, and other stress-related

behavior Behavior (American English) or behaviour (British English) is the range of actions of Individual, individuals, organisms, systems or Artificial intelligence, artificial entities in some environment. These systems can include other systems or or ...

al and

physiological Physiology (; ) is the science, scientific study of function (biology), functions and mechanism (biology), mechanisms in a life, living system. As a branches of science, subdiscipline of biology, physiology focuses on how organisms, organ syst ...

abnormalities. A mouse study found that

knockout A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, Muay Thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, ...

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. Buprenorphine is not a

silent antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of recep ...

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 E_max 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 E_max 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.

History

ALKS-5461 was granted Fast Track Designation by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) for treatment-resistant depression in October 2013. During June and July 2014, three phase III

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s were initiated in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

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

for ALKS-5461 to the FDA. On 31 January 2018, Alkermes submitted a New Drug Application for ALKS-5461 to the FDA for the adjunctive treatment of major depressive disorder. 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. 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. The main reason cited was insufficient evidence of effectiveness. The panel voted in favor of adequate safety having been demonstrated.

References

External links

* {{DEFAULTSORT:Buprenorphine samidorphan Antidepressants Combination psychiatric drugs Delta-opioid receptor antagonists Drug rehabilitation Morphinans 4,5-Epoxymorphinans Kappa-opioid receptor antagonists Mu-opioid receptor antagonists Nociceptin receptor agonists Nociceptin receptor antagonists Semisynthetic opioids Synthetic opioids