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Buprenorphine (top) + samidorphan (bottom)
Combination of
BuprenorphineOpioid modulator
SamidorphanOpioid antagonist
Clinical data
Other namesALKS-5461
Routes of
Legal status
Legal status
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]

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.



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[edit]

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]


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[edit]


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  2. ^ Machado-Vieira R, Henter ID, Zarate CA (May 2017). "New targets for rapid antidepressant action". Progress in Neurobiology. 152: 21–37. doi:10.1016/j.pneurobio.2015.12.001. PMC 4919246. PMID 26724279.
  3. ^ a b Steele A (21 January 2016). "Alkermes Depression Drug Disappoints in Trials". WSJ. Retrieved 21 January 2016.
  4. ^ a b Taylor P (August 21, 2017). "Will third trial be the charm for Alkermes' depression drug?". FierceBiotech.
  5. ^ a b c d Al Idrus A (2 November 2018). "FDA panel slams Alkermes' opioid-based depression drug". Fierce Biotech.
  6. ^ "FDA declines to approve Alkermes opioid-based depression drug". Reuters. 1 February 2019. Retrieved 4 February 2019.
  7. ^ Kress HG (March 2009). "Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine". European Journal of Pain. 13 (3): 219–230. doi:10.1016/j.ejpain.2008.04.011. PMID 18567516. S2CID 8243410.
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  9. ^ a b Ehrich E, Turncliff R, Du Y, Leigh-Pemberton R, Fernandez E, Jones R, Fava M (May 2015). "Evaluation of opioid modulation in major depressive disorder". Neuropsychopharmacology. 40 (6): 1448–1455. doi:10.1038/npp.2014.330. PMC 4397403. PMID 25518754.
  10. ^ Khroyan TV, Wu J, Polgar WE, Cami-Kobeci G, Fotaki N, Husbands SM, Toll L (January 2015). "BU08073 a buprenorphine analogue with partial agonist activity at μ-receptors in vitro but long-lasting opioid antagonist activity in vivo in mice". British Journal of Pharmacology. 172 (2): 668–680. doi:10.1111/bph.12796. PMC 4292977. PMID 24903063.
  11. ^ 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
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  15. ^ Su TP (January 1985). "Further demonstration of kappa opioid binding sites in the brain: evidence for heterogeneity". The Journal of Pharmacology and Experimental Therapeutics. 232 (1): 144–148. PMID 2856939.
  16. ^ Leander JD (September 1987). "Buprenorphine has potent kappa opioid receptor antagonist activity". Neuropharmacology. 26 (9): 1445–1447. doi:10.1016/0028-3908(87)90112-2. PMID 2823167. S2CID 43382591.
  17. ^ a b c Shippenberg TS (January 2009). "The dynorphin/kappa opioid receptor system: a new target for the treatment of addiction and affective disorders?". Neuropsychopharmacology. 34 (1): 247. doi:10.1038/npp.2008.165. PMID 19079072.
  18. ^ a b Rankovic Z, Hargreaves R, Bingham M (2012). Drug Discovery for Psychiatric Disorders. Royal Society of Chemistry. pp. 314–317. ISBN 978-1-84973-365-6.
  19. ^ Pfeiffer A, Brantl V, Herz A, Emrich HM (August 1986). "Psychotomimesis mediated by kappa opiate receptors". Science. 233 (4765): 774–776. Bibcode:1986Sci...233..774P. doi:10.1126/science.3016896. PMID 3016896. S2CID 37512800.
  20. ^ Yan F, Roth BL (October 2004). "Salvinorin A: a novel and highly selective kappa-opioid receptor agonist". Life Sciences. 75 (22): 2615–2619. doi:10.1016/j.lfs.2004.07.008. PMID 15369697.
  21. ^ a b Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C (January 2008). "The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system". The Journal of Neuroscience. 28 (2): 407–414. doi:10.1523/JNEUROSCI.4458-07.2008. PMC 2612708. PMID 18184783.
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  23. ^ McLaughlin JP, Marton-Popovici M, Chavkin C (July 2003). "Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses". The Journal of Neuroscience. 23 (13): 5674–5683. doi:10.1523/JNEUROSCI.23-13-05674.2003. PMC 2104777. PMID 12843270.
  24. ^ Urbano M, Guerrero M, Rosen H, Roberts E (May 2014). "Antagonists of the kappa opioid receptor". Bioorganic & Medicinal Chemistry Letters. 24 (9): 2021–2032. doi:10.1016/j.bmcl.2014.03.040. PMID 24690494.
  25. ^ Carlezon WA, Béguin C, Knoll AT, Cohen BM (September 2009). "Kappa-opioid ligands in the study and treatment of mood disorders". Pharmacology & Therapeutics. 123 (3): 334–343. doi:10.1016/j.pharmthera.2009.05.008. PMC 2740476. PMID 19497337.
  26. ^ a b Falcon E, Browne CA, Leon RM, Fleites VC, Sweeney R, Kirby LG, Lucki I (August 2016). "Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors". Neuropsychopharmacology. 41 (9): 2344–2351. doi:10.1038/npp.2016.38. PMC 4946065. PMID 26979295.
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  28. ^ a b Fava M, Memisoglu A, Thase ME, Bodkin JA, Trivedi MH, de Somer M, et al. (May 2016). "Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial". The American Journal of Psychiatry. 173 (5): 499–508. doi:10.1176/appi.ajp.2015.15070921. PMID 26869247.
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  31. ^ "Alkermes Receives Fast Track Designation for ALKS 5461 for Major Depressive Disorder". Business Wire. 2013.
  32. ^ "Alkermes Submits New Drug Application To U.S. FDA For ALKS 5461 For The Adjunctive Treatment Of Major Depressive Disorder". Alkermes PLC (Press release). January 31, 2018 – via prnewswire.
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