Buprenorphine/samidorphan

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Buprenorphine/samidorphan
Buprenorphine (top) + samidorphan (bottom)
Combination of
BuprenorphineOpioid modulator
SamidorphanOpioid 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]

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

See also: Buprenorphine § Pharmacology, and Samidorphan § Pharmacology

Pharmacodynamics

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

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,

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

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

References

  1. ^
    S2CID 45232796
    .
  2. PMID 26724279
    .
  3. ^
    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. S2CID 8243410
    .
  8. PMID 18997874
    .
  9. ^
    PMID 25518754
    .
  10. 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
  12. ^
    S2CID 3230414
    .
  13. ^
    ISBN 978-0-12-420177-4
    .
  14. ^
    PMID 19282177
    .
  15. PMID 2856939
    .
  16. S2CID 43382591
    .
  17. ^
    PMID 19079072
    .
  18. ^
    ISBN 978-1-84973-365-6
    .
  19. S2CID 37512800
    .
  20. PMID 15369697
    .
  21. ^
    PMID 18184783
    .
  22. PMID 19782055
    .
  23. PMID 12843270
    .
  24. PMID 24690494
    .
  25. PMID 19497337
    .
  26. ^
    PMID 26979295
    .
  27. PMID 27818236
    .
  28. ^
    PMID 26869247
    .
  29. ^
    PMID 9262330
    .
  30. PMID 25178815
    .
  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.
  33. ^ Al Idrus A (16 April 2018). "Plot twist: FDA pivots on Alkermes' depression drug". FierceBiotech. Retrieved 2018-04-23.

Further reading

External links
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