Buprenorphine (top) + samidorphan (bottom)
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). 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).
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." 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. The third and final core phase III study, FORWARD-5, has been completed, and it was announced on 20 October 2016 that ALKS-5461 met its primary efficacy endpoint in the study.
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. 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). Results of these trials are expected in 2016. In addition to these trials, nine smaller supplementary studies will also be conducted, and will together conclude phase III research. In January 2015, Alkermes announced positive results from FORWARD-1, the first completed phase III study.
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. 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. Alkermes is looking to out-license ALKS-5461.
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. Negative results from the pivotal FORWARD-3 and FORWARD-4 studies were announced in late January 2016. 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).
Failures of endpoint efficacy goals in FORWARD-3 and FORWARD-4 phase III clinical trials were analyzed and suggested to be unreliable based on a usually strong placebo effect. In addition, near-efficacious results were received using higher dosages only, indicating that ALKS-5641 will only be effective in higher than initially expected doses. No clinically relevant side effects were reported with the higher dosage trials.
On 20 October 2016, Alkermes announced that the third and final core phase III study (FORWARD-5) had been completed and that unlike in the prior two core phase III studies, ALKS-5461 had reached its primary efficacy endpoint in the study.
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); and (2) samidorphan, a preferential antagonist of the MOR (but also, to a slightly lesser extent, weak partial agonist of the KOR and DOR). The combination of these two drugs putatively results in what is functionally a blockade of KORs with negligible activation of MORs.
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, induce dysphoria and stress-like responses in both animals and humans, as well as psychotomimetic 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 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. 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). Accordingly, KOR antagonists show robust efficacy in animal models of depression, anxiety, anhedonia, drug addiction, and other stress-related behavioral and physiological abnormalities. As such, there has been great interest in developing KOR antagonists for the treatment of these and other psychiatric conditions in humans. 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.
It has been known since the 1980s that buprenorphine binds to at high affinity and antagonizes the KOR. 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. 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). In conjunction with samidorphan, as in ALKS-5461, however, its potential for abuse and dependence has been shown to be effectively abolished. 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.
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). However, a subsequent study found that the MOR may play an important role in the antidepressant-like effects of buprenorphine in animals.
Partial agonist activity
Buprenorphine is not actually a silent antagonist 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 Emax 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 Emax of 36%. According to Alkermes researchers:
In addition to its effects on μ-opioid receptors, buprenorphine has also been shown in vivo to block the action of κ-opioid agonists (21) and has been characterized in vitro to be a partial κ agonist with low intrinsic activity (19). The buprenorphine/samidorphan combination results in high affinity binding with net low intrinsic activity at both μ- and κ-opioid receptors. It is hypothesized that the combination serves to decrease or dampen opioid tone in regions of excess endogenous μ- and κ-opioid ligand activity and restore opioid tone in regions where such activity is impaired.
As such, ALKS-5461 may actually possess both antagonistic and agonistic potential at the KOR. However, as antagonism of the KOR seems to be responsible for the antidepressant effects of ALKS-5461, this property could in theory actually serve to limit the effectiveness of ALKS-5461 in the treatment of depression. This might explain the finding that a lower dose of ALKS-5461 (2 mg/2 mg) was more effective in the treatment of depression than a higher dose (8 mg/8 mg) (which failed to separate from placebo) in a phase II clinical trial, for instance. In light of the aforementioned, it is noteworthy that a silent antagonist of the KOR, CERC-501 (LY-2456302), which also happens to have far improved selectivity for the KOR (30-fold relative to other opioid receptors) relative to ALKS-5461, is in clinical development for the treatment of depression and cocaine dependence as well.
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. Therapeutic responses were observed by day seven of treatment, and 35–50% of patients achieved remission by the collective phase I and II trial endpoints. 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.
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), adjunctive ALKS-5461 could prove to be advantageous in many regards. 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. 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.
On 21 January 2016, data from two of three core Phase III trials was released. 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. 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. In addition, the placebo response was unusually high in the other trial (FORWARD-3), potentially confounding results. 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. 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. In addition, Alkermes may decide to investigate ALKS-5461 at a higher dosage again, such as 8 mg/day, in a Phase III trial.
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. These side effects are generally transient, being experienced commonly upon initiation of treatment but lessening or disappearing with continued use. The most common side effects observed in phase III trials thus far have been nausea, headache, dizziness, constipation, and dry mouth.
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. It has been postulated that the efficacy observed was due to KOR activation-mediated amelioration of hyperdopaminergia in the reward pathways. As such, similarly to other antidepressants, 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. Potentially in accordance, a case report of buprenorphine-induced hypomania exists. 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 possibly abolished, and hence ALKS-5461 may prove contraindicated in patients who require opioid analgesics for pain management.
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.
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