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 rollingNew 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 aκ-opioid receptor (KOR)antagonist and is being developed byAlkermes.
ALKS-5461 is a (1:1 ratio) combination of: (1) buprenorphine, a weakpartial agonist of theμ-opioid receptor (MOR),antagonist/very weak partial agonist of theκ-opioid receptor (KOR), and, to a lesser extent, antagonist of theδ-opioid receptor (DOR) and weak partial agonist of thenociceptin receptor (NOP);[7][8][9][10] and (2) samidorphan, a preferentialantagonist 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]
A mouse study found thatknockout 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 asilent 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 anEmax 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 KORin 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 grantedFast Track Designation by theFood and Drug Administration (FDA) for treatment-resistant depression in October 2013.[31] During June and July 2014, threephase IIIclinical trials were initiated in theUnited 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 aNew 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]
^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
^abRorick-Kehn LM, Witkin JM, Statnick MA, Eberle EL, McKinzie JH, Kahl SD, et al. (February 2014). "LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders".Neuropharmacology.77:131–144.doi:10.1016/j.neuropharm.2013.09.021.PMID24071566.S2CID3230414.
^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.doi:10.1016/S0022-3565(25)20058-1.PMID2856939.
^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.PMID24690494.
^abZhu J, Luo LY, Li JG, Chen C, Liu-Chen LY (August 1997). "Activation of the cloned human kappa opioid receptor by agonists enhances [35S]GTPgammaS binding to membranes: determination of potencies and efficacies of ligands".The Journal of Pharmacology and Experimental Therapeutics.282 (2):676–684.doi:10.1016/S0022-3565(24)36877-6.PMID9262330.
