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Last update 31 May 2025

Buprenorphine Hydrochloride/Samidorphan

Last update 31 May 2025

Overview

R&D Status

Clinical Result

Translational Medicine

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

ALKS 33/buprenorphine, Buprenorphine/ALKS-33, Buprenorphine/RDC 0313

+ [6]

Target

κ opioid receptor x μ opioid receptor

Action

antagonists, agonists

Mechanism

κ opioid receptor antagonists(Kappa opioid receptor antagonists), μ opioid receptor agonists(Mu opioid receptor agonists)

Therapeutic Areas

Nervous System DiseasesOther Diseases

Active Indication-

Inactive Indication

Originator Organization

Alkermes Plc

Active Organization-

Inactive Organization

Alkermes, Inc.

License Organization-

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC21H26N2O4

InChIKeyRYIDHLJADOKWFM-MAODMQOUSA-N

CAS Registry852626-89-2

View All Structures (2)

Clinical Trials associated with Buprenorphine Hydrochloride/Samidorphan

NCT03610048

/ TerminatedPhase 3

A Phase 3b Extension Study of Adjunctive ALKS 5461 in the Treatment of Refractory Major Depressive Disorder

This study will assess the long-term safety and tolerability of ALKS 5461 as an adjunctive treatment for refractory MDD.

Start Date09 Aug 2018

Sponsor / Collaborator

Alkermes, Inc.

NCT03188185

/ CompletedPhase 3

A Phase 3b Efficacy and Safety Study of Adjunctive ALKS 5461 in Treatment Refractory Major Depressive Disorder

This study will evaluate the efficacy, safety, and tolerability of adjunctive ALKS 5461 in adults who have treatment refractory MDD.

Start Date12 Jun 2017

Sponsor / Collaborator

Alkermes, Inc.

NCT02545439

/ CompletedPhase 1

A Phase 1 Study to Evaluate the Impact of CYP3A4 Induction on the Single Dose Pharmacokinetics of ALKS 5461

This study will evaluate the impact of CYP3A4 induction on the single-dose pharmacokinetics of ALKS 5461.

Start Date01 Jul 2015

Sponsor / Collaborator

Alkermes, Inc.

100 Clinical Results associated with Buprenorphine Hydrochloride/Samidorphan

100 Translational Medicine associated with Buprenorphine Hydrochloride/Samidorphan

100 Patents (Medical) associated with Buprenorphine Hydrochloride/Samidorphan

Literatures (Medical) associated with Buprenorphine Hydrochloride/Samidorphan

01 Dec 2019·Neuropsychopharmacology : official publication of the American College of NeuropsychopharmacologyQ1 · MEDICINE

Results from a long-term open-label extension study of adjunctive buprenorphine/samidorphan combination in patients with major depressive disorder

Q1 · MEDICINE

Article

Author: Yu, Miao ; Trivedi, Madhukar H ; Fava, Maurizio ; Claxton, Amy ; Martin, William ; Bodkin, J Alexander ; Thase, Michael E ; Pathak, Sanjeev ; Stanford, Arielle D ; Memisoglu, Asli

Buprenorphine/samidorphan (BUP/SAM; ALKS 5461) is an investigational opioid system modulator for the adjunctive treatment of patients with major depressive disorder (MDD), who did not respond adequately to prior antidepressant therapy (ADT). FORWARD-2, an open-label extension study, assessed long-term safety and tolerability of adjunctive BUP/SAM treatment in these patients. Patients from four short-term trials and de novo patients were enrolled; all had confirmed MDD and a current major depressive episode lasting 2-24 months. Patients were treated with an established ADT for ≥8 weeks before receiving sublingual, adjunctive BUP/SAM 2 mg/2 mg for up to 52 weeks. Safety (primary objective) was assessed via adverse events (AEs), the Columbia-Suicide Severity Rating Scale, and the Clinical Opiate Withdrawal Scale (COWS). Exploratory evaluation of efficacy was done using the Montgomery-Åsberg Depression Rating Scale (MADRS). Of 1485 patients, 50% completed the study and 11% discontinued due to AEs. AEs of nausea, headache, constipation, dizziness, and somnolence, each occurred in ≥10% of patients. There was no evidence of increased suicidal ideation or behavior. Euphoria-related AEs were uncommon (1.2%). Following abrupt BUP/SAM discontinuation, "drug withdrawal" AEs were infrequent (0.4%), and the incidence of COWS categorical worsening after abrupt drug discontinuation was low (6.5%). Improvements in mean MADRS scores were maintained until study end, suggesting durability of antidepressant effect in patients continuing treatment. BUP/SAM was generally well tolerated, with a low risk of abuse and an AE profile consistent with those seen in placebo-controlled studies. Withdrawal reports were uncommon and of limited clinical impact.

01 Nov 2018·The Journal of pharmacology and experimental therapeuticsQ3 · MEDICINE

In Vitro Pharmacological Characterization of Buprenorphine, Samidorphan, and Combinations Being Developed as an Adjunctive Treatment of Major Depressive Disorder

Q3 · MEDICINE

Article

Author: Bidlack, Jean M ; Arnelle, Derrick ; Deaver, Daniel R ; Pin, Sokhom S ; Wonsey, Angela M ; Plotnikava, Margarita ; Namchuk, Mark N ; Knapp, Brian I ; Fern Toh, May

A combination of buprenorphine (BUP) and samidorphan (SAM) at a 1:1 (mg/mg) fixed-ratio dose is being investigated as an adjunctive treatment of major depressive disorder (BUP/SAM, ALKS 5461). Both [³H]BUP and [³H]SAM bound to the μ-, κ-, and δ-opioid receptors (MOR, KOR, and DOR, respectively) with K_d values of 3 nM or less. [³H]BUP dissociated from the MOR more slowly than [³H]SAM did. In the [³⁵S]GTPγS assay, BUP was a partial agonist at the MOR, KOR, and DOR. SAM was an antagonist at the MOR and a partial agonist at the KOR and DOR. The pharmacology of the combination of SAM and BUP was characterized at ratios like the molar ratios of both compounds at steady state in humans. In all assessments, SAM reduced the efficacy of BUP at the MOR without altering its potency. At the KOR, SAM had no significant effect on the activity of BUP. In bioluminescent resonance energy transfer assays, SAM, naltrexone, and naloxone were partial agonists when the MOR was coupled to the Gα _oB and Gα _z, and were antagonists when coupled to Gα _i At the KOR, SAM was a partial agonist activating Gα _oA and Gα _oB and a full agonist in stimulating Gα _z SAM inhibited BUP's recruitment of β-arrestin to the MOR, suggesting an attenuation of BUP's efficacy in activating G proteins correlated with an inhibition of β-arrestin recruitment. The collective data suggest that SAM attenuates the efficacy of BUP under all conditions tested at the MOR and DOR but had little effect on BUP activity at the KOR.

01 Jul 2018·The mental health clinician

Kappa opioid receptor antagonism: Are opioids the answer for treatment resistant depression?

Article

Author: Peckham, Alyssa M. ; De La Cruz, Austin ; Dufresne, Robert L.

Abstract:

Introduction::

Past trials of buprenorphine (BUP) in the treatment of major depressive disorder (MDD) have displayed favorable results, although its clinical utility was limited by the risk of abuse or physical dependence. By combining BUP with samidorphan (SAM), the euphoric high is negated by an opposing mechanism, which theoretically reduces addictive-like properties while allowing the antidepressant properties to remain. As such, the objective of this article is to analyze the results of BUP/SAM premarketing clinical trials as adjunctive treatment for treatment-resistant MDD.

Methods::

A comprehensive PubMed/MEDLINE search was conducted through November 9, 2017, using the following search terms: depression, samidorphan, buprenorphine, ALKS-5461. Additional data were obtained from Clinicaltrials.gov and resources included in the present study. All English-language clinical trials evaluating the combination of BUP/SAM in the treatment of MDD were included.

Results::

A few premarketing studies have evaluated the efficacy and safety of BUP/SAM combination as adjunctive treatment in patients with treatment-resistant MDD. The FORWARD-1 through FORWARD-5 trials concluded (1) the most effective dosing ratio of BUP/SAM to reduce abuse potential was 1:1; (2) statistically significant changes in scores from baseline on the Montgomery-Asberg Depression Rating Scale were noted for the 2 mg/2 mg dose compared with placebo; and (3) the most commonly reported adverse effects were nausea, dizziness, and fatigue.

Discussion::

Buprenorphine/samidorphan has shown favorable results for efficacy and tolerability in premarketing studies evaluating its use as adjunctive therapy for treatment-resistant MDD. Its novel mechanism targeting the opioid pathway may serve as a promising antidepressant devoid of abuse potential.

News (Medical) associated with Buprenorphine Hydrochloride/Samidorphan

20 Jul 2023

·www.outsourcing-pharma.com

Neumora’s depression treatment hits phase 3 after nailing phase 2

The company announced the successful completion of a meeting with the U.S. Food and Drug Administration (FDA) following the phase 2 study of its lead candidate drug navacaprant for the treatment of major depressive disorder (MDD). The company expects to launch its first phase 3 trial of the candidate drug later this year. MDD is a chronic condition that often comes with symptoms including low mood and anhedonia. Only a minority of MDD patients respond to first-line antidepressants, which can cause side effects including weight gain and insomnia. Navacaprant is an oral small molecule drug designed to tackle the condition by blocking proteins called kappa opioid receptors (KORs) and modulating the action of dopamine in the brain. The phase 2 trial of once-daily navacaprant was originally launched by BlackThorn Therapeutics in patients with mild-to-moderate MDD. Neumora acquired BlackThorn when it was launched in 2021 and later added patients with moderate-to-severe MDD to the trial plan. Among the 100 patients in the moderate-to-severe MDD population, navacaprant significantly improved symptoms of depression over eight weeks, measured using the 17-item Hamilton Rating Scale for Depression (HAMD-17). The drug also significantly improved feelings of anhedonia, which was measured using a metric known as the Snaith-Hamilton Pleasure Scale (SHAPS). Among the total population of 171 patients, which also included those with mild-moderate MDD, navacaprant significantly reduced depression symptoms after 4 weeks but failed to meet BlackThorn’s original primary endpoint of beating the placebo after 8 weeks. Nonetheless, the drug did significantly improve anhedonia at both time points. googletag.cmd.push(function () { googletag.display('text-ad1'); }); Neumora also reported promising a safety signal from the candidate drug, with the majority of the emergent adverse events being mild to moderate and none classed as severe. “Major depressive disorder remains one of the most prevalent psychiatric disorders and is associated with high rates of morbidity and functional impairment,” stated Roger McIntyre, professor of psychiatry and pharmacology, University of Toronto, Canada, in Neumora’s public release . “Anhedonia, the inability to experience pleasure or joy, impacts a majority of MDD patients and is a complex and challenging symptom that often remains untreated by current antidepressants. A growing body of research suggests that anhedonia is also a core risk factor for suicidal ideation, demonstrating the importance of studying and identifying new treatments that could improve care for impacted patients.” Going forward, Neumora plans to launch its first phase 3 trial of navacaprant in adult patients with moderate-to-severe MDD in the U.S. in the third quarter of 2023. A second phase 3 study is expected in the fourth quarter of this year, and a third is planned in early 2024. If it proceeds to plan, the company expects to apply for FDA approval in 2025. Neumora is developing navacaprant for the treatment of other neuropsychiatric disorders in phase 2. The firm is also developing a pipeline of other candidates for the treatment of neuropsychiatric disorders and neurodegenerative diseases such as agitation in Alzheimer’s disease. The KOR system is a target for many other companies seeking to treat MDD and other mental health disorders. Alkermes’ drug candidate ALKS 5461 was shot down for the treatment of MDD by the FDA in 2019. One current example is Johnson & Johnson, which is developing a candidate called aticaprant in a phase 3 trial for the treatment of MDD and anhedo

Phase 3Phase 2Clinical Result

08 Oct 2020

·www.biospace.com

FDA Raises Concern Over Opioid Abuse Related to Alkermes’ Schizophrenia Drug

The assessment does point to a path for approval, however FDA staff do raise some concerns about the fact that the drug’s makeup includes an opioid antagonist. Shares of Alkermes climbed more than 6% Wednesday after the U.S. Food and Drug Administration (FDA) released its assessment of the company’s schizophrenia and bipolar drug ahead of an advisory committee meeting scheduled for Friday. The assessment points to a path for approval, however FDA staff members did raise some concerns about the fact that the drug’s makeup includes an opioid antagonist. Ireland-based Alkermes is aiming for approval of ALKS 3831 (olanzapine/samidorphan), a once-daily oral antipsychotic drug candidate for the treatment of adults with schizophrenia and for the treatment of adults with bipolar I disorder. The drug is a combination of samidorphan, an opioid antagonist that is a new molecular entity and Eli Lilly’s Zyprexa. Alkermes paired well-established schizophrenia medication, initially approved in 1996, with the opioid antagonist as a means of controlling weight gain and other side effects that have been commonly established to the Eli Lilly drug. Weight gain is a concern for patients taking second-generation antipsychotics like Zyprexa due to its relationship to metabolic syndrome. In its briefing documents for the advisory committee, the FDA notes potential safety risks from the inclusion of samidorphan that must be considered by members. Specifically, the FDA pointed to withdrawal concerns for people who have an opioid dependency and concerns over a reduced painkilling effect in patients who are already taking opioids. There is also a concern for potential opioid overdose if patients attempt to take more opioids than normal in order to overcome these issues. Alkermes said it could address these concerns in the labeling for the drug if approved. The company also noted that it could create a communication plan that would alert potential prescribing doctors about the safety concerns. The advisory panel will meet Friday to discuss the issue and recommend whether or not the FDA should approve the drug for patients. The decision of the advisory committee is not binding to the final regulatory decision. Alkermes submitted its New Drug Application for ALKS 3831 last fall. The NDA included data from the ENLIGHTEN clinical development program in patients with schizophrenia, as well as pharmacokinetic bridging data comparing ALKS 3831 and Zyprexa. The ENLIGHTEN-1 study evaluated the antipsychotic efficacy of ALKS 3831 compared to placebo over four weeks, and the ENLIGHTEN-2 study assessed weight gain with ALKS 3831 compared to olanzapine over six months. The Phase III ENLIGHTEN-2 study met its primary endpoints of a lower mean percent weight gain from baseline at six months compared to those receiving olanzapine, and a lower proportion of patients who gained 10% or more of their baseline body weight at six months compared to the cohort receiving olanzapine. Early last year, Alkermes was stunned when the FDA rejected ALKS-5461, a treatment for major depressive disorder. The company went through a tumultuous period to get that medication to the FDA. In April 2018, the FDA accepted Alkermes New Drug Application (NDA) for ALKS 5461 , only weeks after the regulatory agency rejected the NDA .

NDAPhase 3Clinical ResultDrug Approval

04 Feb 2019

·www.biospace.com

FDA Rejects Alkermes’ Opioid Modulator Treatment for Depression

Almost three months to the day after an FDA advisory committee overwhelmingly rejected Alkermes’ major depressive disorder treatment, ALKS-5461, the company received word that the regulatory agency will not approve the medication. Almost three months to the day after a U.S. Food and Drug Administration (FDA) advisory committee overwhelmingly rejected Alkermes ’ major depressive disorder (MDD) treatment, ALKS-5461, the company received word that the regulatory agency will not approve the medication. Late Friday, the FDA issued a Complete Response Letter to Ireland-based Alkermes that informed the company it cannot approve the therapeutics without additional clinical data. The FDA said that data is required in order to “provide substantial evidence of effectiveness of ALKS-5461 for the adjunctive treatment of MDD,” Alkermes said in a brief statement. The company said it plans to meet with the FDA to discuss the CRL and lay out the potential “next steps” for ALKS-5461. Alkermes said the meeting with the FDA will determine whether or not there is a “viable path forward” for its ALKS-5461 program. ALKS-5461 was being developed for the treatment of major depressive disorder in patients with an inadequate response to standard antidepressant therapies. An estimated 16.2 million people in the U.S. suffered from MDD in 2016, the majority of whom may not adequately respond to initial antidepressant therapy, Alkermes noted. The Complete Response Letter caps off a tumultuous year for the depression treatment. In April 2018, the FDA accepted Alkermes’ New Drug Application (NDA) for ALKS 5461 , only weeks after the regulatory agency rejected the NDA . The FDA initially refused the NDA for ALKS-5461 due to a lack of “insufficient evidence of overall effectiveness for the proposed indication.” As BioSpace reported last year, in its Refusal to File letter, the FDA said Alkermes would likely have to initiate additional clinical trials in order to support a resubmission. However, when the FDA did its about-face on the NDA, Alkermes said it did not submit any additional data to the FDA as was initially suggested by the regulatory agency. But, then in November, the advisory committee voted against the benefit-risk pro the medication. In overwhelming votes, the committee questioned its efficacy and whether or not it actually provided any real benefit for patients. With the advisory committee rejection, as well as some of the difficulties Alkermes had during clinical testing, it’s not totally surprising that the FDA rejected ALKS-5461, an oral medicine that acts as an opioid system modulator. Prior to the November rejection by the FDA advisory committee, BioSpace highlighted some of the difficulties the drug has facing approval , including criticism over the methods used to report data from its Phase III FORWARD-5 trial that was used to support the New Drug Application. While that trial was billed as a success, two of its three late-stage clinical trials studying ALKS 5461 in depression failed to meet their primary endpoints. Alkermes has certainly defended the efficacy of its asset. The company noted in the announcement regarding its rejection that throughout the clinical development program, ALKS 5461 demonstrated a consistent pro antidepressant activity, safety and tolerability in the adjunctive treatment of MDD. Shares of Alkermes closed Friday at $33.06. After the company announced the CRL, shares fell about 4.8 percent in after-market trading.

Phase 3NDA

100 Deals associated with Buprenorphine Hydrochloride/Samidorphan

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Major depressive disorder, moderate (MDD)	Phase 3	United States	Alkermes, Inc.	09 Aug 2018
Major depressive disorder, moderate (MDD)	Phase 3	Australia	Alkermes, Inc.	09 Aug 2018
Major depressive disorder, moderate (MDD)	Phase 3	Puerto Rico	Alkermes, Inc.	09 Aug 2018
Depressive Disorder, Major	Phase 3	United States	Alkermes, Inc.	01 Feb 2014
Depressive Disorder, Major	Phase 3	Canada	Alkermes, Inc.	01 Feb 2014
Cocaine-Related Disorders	Phase 1	United States	Alkermes, Inc.	01 Aug 2011

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03610048 (CTgov)	Phase 3	Major depressive disorder, moderate (MDD) \| Depressive Disorder, Major	175	ALKS 5461	caffccmqys = abfeukoukg iicpkzfljx (unegljspbb, ofoqaddzlh - cokymigbti) View more	-	16 Jul 2021
NCT03188185 (CTgov)	Phase 3	Depressive Disorder, Major	278	placebo (S1: Placebo)	wzwthperlj(kueulqtlle) = xbbvtipndf hrmykidfqa (qvbdjyknvs, 0.70) View more	-	15 Mar 2021
				ALKS 5461 (S1: ALKS 5461 2mg/2mg)	wzwthperlj(kueulqtlle) = weplnixnes hrmykidfqa (qvbdjyknvs, 1.12) View more
NCT02218008 (FORWARD-5, Pubmed) Manual	Phase 3	Depressive Disorder, Major Adjuvant	-	buprenorphine/samidorphan	lzpgazxopm(jeqowplfeq): difference = -1.9, P-Value = 0.026 View more	Positive	01 Jul 2020
				Placebo
NCT01500200 (CTgov)	Phase 2	Depressive Disorder, Major	142	Placebo (Placebo S1)	zsrqaadodh(bxdwrmxduy) = hqaxjmdzri vtlwujtjgw (vhtunyytlf, 0.6) View more	-	21 May 2019
				ALKS (ALKS 5461 2mg/2mg S1)	zsrqaadodh(bxdwrmxduy) = atbfvubnau vtlwujtjgw (vhtunyytlf, 1.5) View more
NCT02158546 (FORWARD-3, Pubmed \| Neuropsychiatr Dis Treat) Manual	Phase 3	Depressive Disorder, Major Adjuvant	-	Buprenorphine/samidorphan	tzzupuiqov(ludrzqqory) = tjcvjhryfz lzhuuexlyw (ntytccvsgu, 0.67) View more	Positive	04 Apr 2019
				Placebo	tzzupuiqov(ludrzqqory) = obxitvrukh lzhuuexlyw (ntytccvsgu, 0.66) View more
NCT02158533 (FORWARD-4, CTgov)	Phase 3	Depressive Disorder, Major	385	Placebo (Placebo S1)	rgzilhwmdl(zocbzduwyy) = aseqpnvbgj jotrpooiqy (mingbxhziu, 0.67) View more	-	27 Mar 2019
				ALKS 5461 (ALKS 5461 0.5mg/0.5mg S1)	rgzilhwmdl(zocbzduwyy) = jhgonkoeyb jotrpooiqy (mingbxhziu, 1.49) View more
NCT02085135 (CTgov)	Phase 3	Depressive Disorder, Major	66	ALKS 5461 (1-Week Titration)	bwgpeezaad = qsfnlpmzke qjlujrxfoy (ubzlmzuoyv, xgvpdrznyl - vzflgormyj) View more	-	27 Mar 2019
				ALKS 5461 (2-Week Titration)	bwgpeezaad = mfkdljjsdv qjlujrxfoy (ubzlmzuoyv, asgbltnryz - ntasqgqmdh) View more
NCT02141399 (CTgov)	Phase 3	Depressive Disorder, Major	1,485	ALKS 5461	qupousdpvg = xxusihryfq oscrgjlyxq (mcmelckabz, tvqhfzcqjy - acfdcvaynp) View more	-	14 Dec 2018

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