Buprenorphine/samidorphan

Buprenorphine/samidorphan

Buprenorphine (top) + samidorphan (bottom)
Combination of
Buprenorphine Opioid modulator
Samidorphan Opioid antagonist
Clinical data
Legal status
Routes of
administration		 Sublingual
Identifiers
ATC code None

Buprenorphine/samidorphan (developmental code name ALKS-5461) is a combination drug formulation of buprenorphine and samidorphan acting as a κ-opioid receptor (KOR) antagonist which is under development by Alkermes as an adjunct to antidepressant therapy in treatment-resistant depression (TRD).[1][2] It is also under investigation by Alkermes as a treatment for cocaine dependence, which is being funded by a grant from the National Institute on Drug Abuse (NIDA).[3]

Clinical results with ALKS-5461 in Phase II have been described as "very encouraging", and researchers have stated that KOR antagonists including ALKS-5461 might work "extremely well for the treatment of major depression."[4][5] However, data from two of three core Phase III trials was recently released and revealed that ALKS-5461 was safe and well-tolerated but, disappointingly, failed to meet its primary efficacy endpoints, although some efficacy was observed.[6][7][8][9] The third and final core Phase III study is currently ongoing, with results expected sometime in 2016.[6][7][8][9]

History

Following very positive phase II trial results, ALKS-5461 was granted Fast Track Designation by the Food and Drug Administration (FDA) for TRD in October 2013.[10][11] During June and July 2014, three major phase III clinical trials were initiated in the United States to evaluate core efficacy for the use of ALKS-5461 as an adjunctive treatment for patients who have had an inadequate treatment response to antidepressant monotherapy with an agent such as a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).[1][2][12] Results of these trials are expected in 2016.[1][12] In addition to these trials, nine smaller supplementary studies will also be conducted, and will together conclude phase III research.[1] In January 2015, Alkermes announced positive results from FORWARD-1, the first completed phase III study.[13]

Alkermes has expressed its intent to submit a New Drug Application (NDA) to the FDA for the approval of adjunctive ALKS-5461 for the indication of TRD once phase III research has been completed.[1] Assuming positive phase III trial results and NDA acceptance, initial sales of ALKS-5461 are forecast for 2016, with $25 million in sales estimated for that year and $350 million in total sales anticipated by 2019.[14] Alkermes is looking to out-license ALKS-5461.[14]

In December 2015, Alkermes revealed that the development schedule of ALKS-5461 is still on-track and data from the first two phase III core efficacy studies was to be expected in quarter I 2016 while the data from the third and final core efficacy study is to be expected in mid-2016.[15] Negative results from the pivotal FORWARD-3 and FORWARD-4 studies were announced in late January 2016.[16] None of the dosages of ALKS-5461 (0.5 mg/day and 2 mg/day) met the FORWARD studies' primary endpoint, which was the change from baseline vs. placebo on the Montgomery–Åsberg Depression Rating Scale (MADRS). The FORWARD-5 study remains ongoing, and Alkermes will provide an update on the timing of study completion in the first quarter of 2016.

Pharmacology

ALKS-5461 is a combination (1:1) of buprenorphine, a moderate partial agonist of the μ-opioid receptor (MOR) and antagonist/very weak partial agonist of the κ-opioid receptor (KOR),[17][18][19] and samidorphan, a selective antagonist of the MOR.[20][21] The combination of these two drugs results in what is functionally a selective blockade of KORs with minimal or negligible effects on the MOR.[19][21]

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,[22] induce dysphoria and stress-like responses in both animals and humans,[23] as well as psychotomimetic effects in humans,[24][25] and are thought to be essential for the mediation of the dysphoric aspects of stress.[26] 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.[22][26][27] 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).[28] Accordingly, KOR antagonists show robust efficacy in animal models of depression, anxiety, anhedonia, drug addiction, and other stress-related behavioral and physiological abnormalities.[22][23][29][30] As such, there has been great interest in developing KOR antagonists for the treatment of these and other psychiatric conditions in humans.[22][29] Progress has been limited until recently however, due to difficulty in finding selective KOR antagonists with suitable drug profiles (e.g., good pharmacokinetic parameters, short-acting (non-"inactivating") KOR inhibition, lack of toxicity, etc.) for clinical development and use in humans.[23][29]

It has been known for decades that buprenorphine binds to at high affinity and antagonizes the KOR.[31][32] In addition, there have been many reports over the years supporting the notion of the drug being effective in the management of depressive and anxious symptomatology, and two small clinical trials have shown it to produce remission even in depressive patients refractory to conventional antidepressants and electroconvulsive therapy.[22][33][34][35][36][37][38][39][40][41][42][43] However, buprenorphine has never previously been seriously pursued for mental health indications, presumably due to concerns about its liability for abuse and dependence (and the additional difficulty in gaining regulatory approval that would certainly come with that).[44] In conjunction with samidorphan, as in ALKS-5461, however, its potential for abuse and dependence has been shown to be effectively abolished.[15][45] As a result, it seems that ALKS-5461 may allow for buprenorphine to be employed safely and without restriction in the treatment of depression and other conditions that it has shown efficaciousness in but that it would otherwise very likely not be employed in.

Effectiveness

In phase I and phase II trials, augmentation of an SSRI or SNRI with ALKS-5461 demonstrated a rapid onset of action and substantial effectiveness in the adjunctive treatment of TRD.[46] Therapeutic responses were observed by day seven of treatment,[46] and 35–50% of patients achieved remission by the collective phase I and II trial endpoints.[2] In addition, a relatively small set of 32 patients but nonetheless high quality (i.e., double-blind, placebo-controlled, etc.) phase I/II trial showed a remarkable 100% of patients (32/32) experiencing a significant antidepressant response.[47]

Based on the above findings, compared to most currently available antidepressant monotherapies, which generally require several weeks of treatment for a significant therapeutic response to be seen and have significantly lower comparative response and remission rates (which are approximately 50–70% and 20–50%, respectively),[48][49] adjunctive ALKS-5461 could prove to be advantageous in many regards.[45][50] In addition, vilazodone (Viibryd), a relatively new antidepressant, was recently approved by the FDA with two positive phase III trials showing Montgomery–Åsberg Depression Rating Scale (MADRS) score decreases of 3.2 and 2.5 points in depressive symptomatology as verification of its effectiveness in major depressive disorder (MDD); in comparison, treatment with ALKS-5461 as an adjunct to an SSRI or SNRI in a phase II trial for TRD demonstrated MADRS score decreases of 5.3 and 8.7 points for a low-dose (2 mg/day) and a high-dose (8 mg/day) formulation of the drug, respectively.[45] These differences are approximately two- to three-fold higher than those of vilazodone monotherapy, suggesting that adjunctive ALKS-5461 could possess substantially greater effectiveness in comparison.[45]

On 21 January 2016, data from two of three core Phase III trials was released.[6][7][8][9] The two trials, which each studied the drug at dosages including 0.5 mg/day and 2 mg/day, failed to meet their primary efficacy endpoints.[6][7][8][9] However, there was a clear trend towards efficacy for 2 mg/day (but not 0.5 mg/day) on the primary endpoint of one of the trials (FORWARD-4), as well as statistically significant efficacy on the MADRS endpoint in post hoc analyses of that trial.[6][7][8][9] In addition, the placebo response was unusually high in the other trial (FORWARD-3), potentially confounding results.[51] Moreover, Phase II studies investigated ALKS-5461 at dosages of 2 mg/day and 8 mg/day (and notably not 0.5 mg/day) and found effectiveness with both dosages but significantly greater improvement with the 8 mg/day dose (5.3- and 8.7-point MADRS score decreases for 2 mg/day and 8 mg/day, respectively), suggesting that higher dosages of ALKS-5461 might demonstrate more marked effectiveness.[45] Alkermes has expressed that it fully intends to continue development and seek FDA approval for ALKS-5461, with the third of the core Phase III studies, FORWARD-5 (which is assessing dosages of 1 mg/day and 2 mg/day), yet-to-be-completed.[52] In addition, Alkermes may decide to investigate ALKS-5461 at a higher dosage again, such as 8 mg/day, in a Phase III trial.[53]

Side effects

In the clinical trials conducted thus far, ALKS-5461 has been found to be generally well-tolerated, with the adverse effects seen including nausea, vomiting, headaches, sedation, and dizziness.[46][54] These side effects are generally transient, being experienced commonly upon initiation of treatment but lessening or disappearing with continued use.[46][54] The most common side effects observed in phase III trials thus far have been nausea, headache, dizziness, constipation, and dry mouth.[13][51]

Contraindications

A small clinical study found that pentazocine, a KOR agonist, was able to rapidly and substantially reduce symptoms of mania in individuals with bipolar disorder that were in the manic phase of the condition.[55] It has been postulated that the efficacy observed was due to KOR activation-mediated amelioration of hyperdopaminergia in the reward pathways.[55] As such, similarly to other antidepressants,[56] ALKS-5461 might be able to precipitate or worsen manic states in individuals with bipolar disorder or cause a switch from depressive state to manic state. Hence, caution might be warranted in the use of ALKS-5461 in people with bipolar illness.

Due to occupation and antagonism of the MOR by ALKS-5461, an anticipatable drug interaction between ALKS-5461 and opioid analgesics may exist in that the effects of the latter may be significantly reduced or even abolished, and hence ALKS-5461 may prove contraindicated in patients who require opioid analgesics for pain management.

Abuse potential

A phase III human abuse potential study found that all dosages of ALKS-5461 tested did not share the abuse potential of buprenorphine, and no difference in drug liking for ALKS-5461 was observed relative to placebo.[15]

See also

References

  1. 1 2 3 4 5 Alkermes (2014). "Alkermes Announces Initiation of FORWARD-3 and FORWARD-4 Efficacy Studies in Pivotal Program for ALKS 5461 for Treatment of Major Depressive Disorder".
  2. 1 2 3 Alkermes (2014). "Alkermes Announces Advances With Its Late-Stage CNS Pipeline".
  3. ↑ Reuters (2012). "Alkermes Presents Positive Clinical Data of ALKS 5461 at 52nd Annual New Clinical Drug Evaluation Unit Meeting".
  4. ↑ Dale, Elena; Bang-Andersen, Benny; Sánchez, Connie (2015). "Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs". Biochemical Pharmacology 95 (2): 81–97. doi:10.1016/j.bcp.2015.03.011. ISSN 0006-2952. PMID 25813654.
  5. ↑ Dogra, Shalini; Yadav, Prem N. (2015). "Biased agonism at kappa opioid receptors: Implication in pain and mood disorders". European Journal of Pharmacology 763: 184–190. doi:10.1016/j.ejphar.2015.07.018. ISSN 0014-2999.
  6. 1 2 3 4 5 Anne Steele (21 January 2016). "Alkermes Depression Drug Disappoints in Trials". WSJ. Retrieved 21 January 2016.
  7. 1 2 3 4 5 Emma Court. "Alkermes shares plunge after drug misses trial goals". MarketWatch. Retrieved 21 January 2016.
  8. 1 2 3 4 5 Amrutha Penumudi (21 January 2016). "Alkermes depression drug fails in studies, shares plunge". Reuters. Retrieved 21 January 2016.
  9. 1 2 3 4 5 Rebecca Spalding (21 January 2016). "Alkermes Falls Most Since 2002 as Depression Drug Trials Fail". Bloomberg.com. Retrieved 21 January 2016.
  10. ↑ PR Newswire (2014). "ALKS-5461 (Major Depressive Disorder) - Forecast and Market Analysis to 2023".
  11. ↑ Business Wire (2013). "Alkermes Receives Fast Track Designation for ALKS 5461 for Major Depressive Disorder".
  12. 1 2 Digital Journal (2014). "Alkermes Announces Initiation of FORWARD-5 Clinical Study of ALKS 5461 For Treatment of Major Depressive Disorder".
  13. 1 2 Alkermes (2015). "Alkermes Announces Positive Results From Study of ALKS 5461 for Treatment of Major Depressive Disorder".
  14. 1 2 D'Souza P, Jago C (March 2014). "Spotlight on depression: a Pharma Matters report" (PDF). Drugs Today 50 (3): 251–67. doi:10.1358/dot.2014.50.3.2134450. PMID 24696870.
  15. 1 2 3 Business Wire (2015). "Alkermes Announces Achievement of Milestones for CNS Medicines in Proprietary Product and Pipeline Portfolio".
  16. ↑ "Alkermes PLC > Investor Relations > Press Release". phx.corporate-ir.net (Press release). Retrieved 2016-01-21.
  17. ↑ Kress HG (March 2009). "Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine". Eur J Pain 13 (3): 219–30. doi:10.1016/j.ejpain.2008.04.011. PMID 18567516.
  18. ↑ Lutfy K, Cowan A (October 2004). "Buprenorphine: a unique drug with complex pharmacology". Curr Neuropharmacol 2 (4): 395–402. doi:10.2174/1570159043359477. PMC 2581407. PMID 18997874.
  19. 1 2 Ehrich, Elliot; Turncliff, Ryan; Du, Yangchun; Leigh-Pemberton, Richard; Fernandez, Emilio; Jones, Reese; Fava, Maurizio (2014). "Evaluation of Opioid Modulation in Major Depressive Disorder". Neuropsychopharmacology. doi:10.1038/npp.2014.330. ISSN 0893-133X.
  20. ↑ 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
  21. 1 2 Rorick-Kehn LM, Witkin JM, Statnick MA; 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: 131–44. doi:10.1016/j.neuropharm.2013.09.021. PMID 24071566.
  22. 1 2 3 4 5 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.
  23. 1 2 3 Zoran Rankovic; Richard Hargreaves; Matilda Bingham (2012). Drug Discovery for Psychiatric Disorders. Royal Society of Chemistry. pp. 314–317. ISBN 978-1-84973-365-6.
  24. ↑ Pfeiffer A, Brantl V, Herz A, Emrich HM (August 1986). "Psychotomimesis mediated by kappa opiate receptors". Science 233 (4765): 774–6. doi:10.1126/science.3016896. PMID 3016896.
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  26. 1 2 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". J. Neurosci. 28 (2): 407–14. doi:10.1523/JNEUROSCI.4458-07.2008. PMC 2612708. PMID 18184783.
  27. ↑ Knoll AT, Carlezon WA (February 2010). "Dynorphin, stress, and depression". Brain Res. 1314: 56–73. doi:10.1016/j.brainres.2009.09.074. PMC 2819644. PMID 19782055.
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  29. 1 2 3 Urbano M, Guerrero M, Rosen H, Roberts E (May 2014). "Antagonists of the kappa opioid receptor". Bioorg. Med. Chem. Lett. 24 (9): 2021–32. doi:10.1016/j.bmcl.2014.03.040. PMID 24690494.
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  31. ↑ Su TP (January 1985). "Further demonstration of kappa opioid binding sites in the brain: evidence for heterogeneity". J. Pharmacol. Exp. Ther. 232 (1): 144–8. PMID 2856939.
  32. ↑ Leander JD (September 1987). "Buprenorphine has potent kappa opioid receptor antagonist activity". Neuropharmacology 26 (9): 1445–7. doi:10.1016/0028-3908(87)90112-2. PMID 2823167.
  33. ↑ Emrich HM, Vogt P, Herz A, Kissling W (September 1982). "Antidepressant effects of buprenorphine". Lancet 2 (8300): 709. doi:10.1016/s0140-6736(82)90727-9. PMID 6126640.
  34. ↑ Emrich HM, Vogt P, Herz A (1982). "Possible antidepressive effects of opioids: action of buprenorphine". Ann. N. Y. Acad. Sci. 398: 108–12. doi:10.1111/j.1749-6632.1982.tb39483.x. PMID 6760767.
  35. ↑ Emrich HM (1984). "Endorphins in psychiatry". Psychiatr Dev 2 (2): 97–114. PMID 6091098.
  36. ↑ Mongan L, Callaway E (December 1990). "Buprenorphine responders". Biol. Psychiatry 28 (12): 1078–80. doi:10.1016/0006-3223(90)90619-d. PMID 2289007.
  37. ↑ Kosten TR, Morgan C, Kosten TA (1990). "Depressive symptoms during buprenorphine treatment of opioid abusers". J Subst Abuse Treat 7 (1): 51–4. doi:10.1016/0740-5472(90)90035-o. PMID 2313769.
  38. ↑ Bodkin JA, Zornberg GL, Lukas SE, Cole JO (February 1995). "Buprenorphine treatment of refractory depression". J Clin Psychopharmacol 15 (1): 49–57. doi:10.1097/00004714-199502000-00008. PMID 7714228.
  39. ↑ Dean AJ, Bell J, Christie MJ, Mattick RP (December 2004). "Depressive symptoms during buprenorphine vs. methadone maintenance: findings from a randomised, controlled trial in opioid dependence". Eur. Psychiatry 19 (8): 510–3. doi:10.1016/j.eurpsy.2004.09.002. PMID 15589713.
  40. ↑ Gerra G, Leonardi C, D'Amore A; et al. (March 2006). "Buprenorphine treatment outcome in dually diagnosed heroin dependent patients: A retrospective study". Prog. Neuropsychopharmacol. Biol. Psychiatry 30 (2): 265–72. doi:10.1016/j.pnpbp.2005.10.007. PMID 16309810.
  41. ↑ Nyhuis PW, Gastpar M (2005). "Opiate treatment in ECT-resistant depression". Pharmacopsychiatry 38 (5). doi:10.1055/s-2005-918797.
  42. ↑ Nyhuis PW, Specka M, Gastpar M (2006). "Does the antidepressive response to opiate treatment describe a subtype of depression?". European Neuropsychopharmacology 16 (S16): S309. doi:10.1016/S0924-977X(06)70328-5.
  43. ↑ Nyhuis PW, Gastpar M, Scherbaum N (October 2008). "Opiate treatment in depression refractory to antidepressants and electroconvulsive therapy". J Clin Psychopharmacol 28 (5): 593–5. doi:10.1097/JCP.0b013e31818638a4. PMID 18794671.
  44. ↑ Van’t Veer, Ashlee; Carlezon, William A. (2013). "Role of kappa-opioid receptors in stress and anxiety-related behavior". Psychopharmacology 229 (3): 435–452. doi:10.1007/s00213-013-3195-5. ISSN 0033-3158.
  45. 1 2 3 4 5 Xconomy (2013). "Alkermes Unveils Full Mid-Stage Data On Depression Drug".
  46. 1 2 3 4 Alkermes (2013). "Alkermes Presents Positive Results from Phase 2 Clinical Study of ALKS 5461 in Major Depressive Disorder at 53rd Annual NCDEU Meeting".
  47. ↑ Fox News (2012). "Non-addictive, 'heroin-like' medicine may soon crush major depression".
  48. ↑ Ferrier IN (1999). "Treatment of major depression: is improvement enough?". J Clin Psychiatry. 60 Suppl 6: 10–4. PMID 10235119.
  49. ↑ McIntyre RS, O'Donovan C (March 2004). "The human cost of not achieving full remission in depression". Can J Psychiatry 49 (3 Suppl 1): 10S–16S. PMID 15147032.
  50. ↑ Xconomy (2013). "Alkermes Stock Climbs on Positive Trial for Depression Drug".
  51. 1 2 StreetInsider (21 January 2016). "Alkermes' (ALKS) Two Phase 3 Studies of ALKS 5461 in MDD Failed to Meet Primary Efficacy Endpoint". Retrieved 30 January 2016.
  52. ↑ 24/7 Wall St. (21 January 2016). ""Why Alkermes Top-Line Results Might Not Be as Bad as Once Thought"". Retrieved 30 January 2016.
  53. ↑ Daniel Chancellor (22 January 2016). "Alkermes is unlikely to resuscitate ALKS 5461 and must instead redefine its strategy". Datamonitor Healthcare. Retrieved 30 January 2016.
  54. 1 2 "Abstracts of Poster Presentations: CNS Summit 2013". 2013.
  55. 1 2 Chartoff, Elena H.; Mavrikaki, Maria (2015). "Sex Differences in Kappa Opioid Receptor Function and Their Potential Impact on Addiction". Frontiers in Neuroscience 9. doi:10.3389/fnins.2015.00466. ISSN 1662-453X.
  56. ↑ McInerney, Shane J.; Kennedy, Sidney H. (2014). "Review of Evidence for Use of Antidepressants in Bipolar Depression". The Primary Care Companion For CNS Disorders. doi:10.4088/PCC.14r01653. ISSN 2155-7780.

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