Delving into the Latest Updates on MK-1942 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

MK 1942

Target-

Action-

Mechanism-

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

Alzheimer DiseaseDepressive Disorder, Treatment-Resistant

Originator Organization

Merck Sharp & Dohme Corp.

Active Organization-

Inactive Organization

Merck Sharp & Dohme Corp.MSD KK (Tokyo)

License Organization-

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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The main purpose of this study is to assess the efficacy and safety of daily and intermittent dosing of MK-1942 compared to placebo among participants with Treatment-Resistant Depression (TRD) on a stable course of antidepressant therapy. The dual primary hypotheses of the study are that the daily MK-1942 treatment or intermittent MK-1942 treatment are superior to placebo in reducing Montgomery-Asberg Depression Rating Scale (MADRS) score.

Start Date20 May 2021

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

100 Clinical Results associated with MK-1942

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100 Translational Medicine associated with MK-1942

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100 Patents (Medical) associated with MK-1942

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3

Literatures (Medical) associated with MK-1942

01 Nov 2026·CNS DRUGS

Next-Generation Pharmacotherapies for Unipolar Mood Disorders: A Leading Article on Phase II/III Drug Development Across Diverse Mechanisms

Review

Author: Rhee, Taeho Greg ; King, Alana ; Hardy, Morgan ; Wilkinson, Samuel T

Despite the wide prevalence of mood disorders globally, there is a substantial unmet need for effective, mechanistically distinct treatments. Given that approximately 30% of individuals do not display adequate response to standard antidepressant therapies, the past 15 years have seen a shift away from traditional monoaminergic approaches toward glutamatergic and other novel mechanisms. Following the US Food and Drug Administration (FDA) approval of esketamine and brexanolone in 2019, industry investment in therapeutics with novel mechanisms for mood and anxiety disorders has expanded, catalyzing a new wave of innovative interventions. This review summarizes progress for unipolar mood disorders in four categories-glutamatergic/GABA modulators, ion channel modulators, psychedelics, and other potential therapeutic mechanisms-focusing on Phase II/III industry-sponsored US clinical trials active within the past 3 years. The drug names discussed are ALTO-100, ALTO-203, ALTO-207, ALTO-300, BHV-7000, BI-1569912, BPL-003, COMP360, DT120, ELE-101, GATE-251, GH001, GM-1020, GM-2505, HLP003, MK-1942, NBI-1065845, NBI-1070770, NV-5138, PIPE-307, SEP-363856, SPT-300, VLS-01, and XEN1101. The US Clinical Trials registry (clinicaltrials.gov), MEDLINE, conference proceedings, and company communications such as press releases were consulted to obtain up-to-date trial information and reported outcomes. Overall, the therapeutic landscape shows an expanding range of clinical compounds under active development; nonetheless, persistent challenges remain, including approaches to therapeutics where functional unblinding may occur, the ways in which to consider a novel conceptualization of occupancy-driven versus event-driven pharmacology, and the role of supporting psychotherapy.

01 Jul 2026·JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY

Phase 2 Clinical Trial of MK-1942, a Negative Allosteric Modulator of Metabotropic Glutamate Receptor 2, for Treatment-Resistant Depression

Article

Author: Bueters, Tjerk ; Thase, Michael E. ; Mukai, Yuki ; Targum, Steven D. ; Dupre, Nicole ; Egan, Michael F. ; Furtek, Christine ; Ceesay, Paulette ; Smith, Sean M. ; Merola, Aristide ; Sanacora, Gerard

Purpose::

To evaluate MK-1942, a negative allosteric modulator of mGluR2, for treatment-resistant depression using chronic and intermittent dosing.

Methods::

Randomized, double-blind, 4-week study of MK-1942 added to stable antidepressant therapy in adults with treatment-resistant depression (NCT04663321). Participants were randomized 2:1:2 to (1) daily MK-1942 titrated from 5 to 20 mg bid, (2) twice-weekly MK-1942 10 mg, or (3) placebo. The endpoints were Montgomery Asberg Depression Rating Scale (MADRS) scores at week 3 (daily MK-1942) and week 1 (twice-weekly MK-1942).

Results::

The study was terminated following asymptomatic elevations in liver function tests. At termination, ~70% of the planned enrolment was achieved (MK-1942 daily N=40, MK-1942 twice-weekly N=19, placebo N=40). No significant efficacy differences from placebo were seen for either MK-1942 group. The difference in mean change-from-baseline MADRS score for daily MK-1942 vs placebo directionally favored placebo at Week 3 (3.3 [95% CI: −1.4, 8.0]) and all other time points. The difference between twice-weekly MK-1942 and placebo directionally favored placebo at week 1 (1.9 [95% CI: −2.7, 6.4]) but not at later time points (eg, week 4, −1.5 [95% CI: −8.0, 4.9]). Interestingly, at every time point, the difference between twice-weekly and daily MK-1942 directionally favored the twice-weekly group. Discontinuations due to an adverse event were more common with MK-1942 than placebo (daily=10.0%, twice-weekly=15.8%, placebo=2.5%), and dizziness was the most common adverse event (daily=25.0%, twice-weekly=31.6%, placebo=7.5%).

Conclusions::

Although interpretation of the findings is limited by the early termination of the trial, MK-1942 was not effective in treatment-resistant depression.

JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY

The Randomization Effect in a Double-Blind Placebo-Controlled Depression Study

Article

Author: Sanacora, Gerard ; Ceesay, Paulette ; Merola, Aristide ; Targum, Steven D. ; Thase, Michael E. ; Lines, Christopher

Background::

Double-blind, placebo-controlled trials are often affected by higher-than-anticipated placebo responses that may contribute to study failure. It is common to observe symptomatic improvement immediately after randomization regardless of treatment allocation.

Methods::

This post hoc analysis examined the early randomization effect in a recent 4-week double-blind, placebo-controlled study that examined a novel presynaptic mGluR2 inhibitor, MK-1942, in a daily or twice-weekly dosing strategy versus placebo as an adjunctive treatment in acutely depressed participants with major depressive disorder who had not adequately responded to antidepressant treatment.

Results::

The original study failed to meet its primary endpoints, but a post hoc analysis revealed an early randomization effect that may have impeded signal detection. Over 60% of the overall Montgomery Asberg Depression Rating Scale (MADRS) score improvement observed in the placebo group occurred within the first week of this 4-week study, and >20% of placebo-assigned participants met criteria as treatment responders within 1 week after randomization. Using week 1 as an alternative (“revised”) baseline, the percentage of placebo responders at week 4 was reduced from 48.6% to 31.4%. Cohen standardized effect size favoring the twice-weekly MK-1942 dosing over placebo improved from -0.33 (original baseline) to -0.54 at week 4 by applying the revised baseline.

Conclusions::

These post hoc results suggest an early randomization effect may complicate the interpretation of studies that examine treatment effects of drugs in development. Masking the timing of randomization with blinded, placebo-lead-in designs may warrant consideration for depression studies, particularly for rapid-acting antidepressants.

2

News (Medical) associated with MK-1942

26 Oct 2023

·www.fiercebiotech.com

While stacking on deals, Merck hopes internal ADC work will see the clinic in the 'next couple years'

Merck has bet tens of billions of dollars on antibody-drug conjugates in the last year through a couple of partnerships. Much of the fervor around Merck & Co.’s work with antibody-drug conjugates has centered on partnerships, namely the most recent $4 billion collaboration announced last week with Daiichi Sankyo. But that’s not precluding the company from building its own internal capabilities, Head of Merck Research Labs Dean Li, M.D., Ph.D., said Thursday on the company’s latest earnings call. “We have built and we continue to build that expertise within the company, and we hope to see those internal programs peering its clinical head in the next couple years,” he said. Li’s comments further illuminate Merck’s level of investment in the class which was the talk of the town in Madrid during the recent European Society for Medical Oncology Annual Congress. Merck’s collaboration with Daiichi follows a biobucks-laden deal with Kelun Biotech announced in December 2022 worth more than $9.3 billion in total. But Merck has been disciplined even as it's stacked on the deals. Kelun revealed earlier this week that Merck recently axed two preclinical candidates. Li said that the data generated from the existing collaborations, in addition to others that are in combination with Keytruda, have built “a wall of data” informing where the field is headed. He noted that there will be improvements and changes to antibody structure that can impact tissue targeting in addition to the linkers between the antibody and payload. Li also suggested that there could be advancements in the kinds of payloads attached to the antibody, with just two types of chemotherapies currently used. Merck has made ADCs a focal point of its future oncology strategy, but that hasn’t stopped the company from investing heavily in other therapeutic areas, namely the cardiometabolic and immunology space. Merck CEO Rob Davis said the company’s confidence that it will reach at least $10 billion in revenue from its cardiovascular franchise is “higher today” than it was when the goal was first announced in April 2022. That bullishness is thanks to sotatercept, which is under review by regulators as a treatment for pulmonary arterial hypertension. Elsewhere, Merck is making cuts. The company has discontinued a couple of phase 2 trials testing MK-1942 for mild-to-moderate Alzheimer’s disease and major depressive disorder. The company says that the decision followed an unblinded review of the data indicating that the med was “potentially associated with observations of liver toxicity.” “This review was triggered by the identification of abnormalities in liver function tests for several study participants,” according to a statement provided by Merck. No related serious side effects were reported.

Phase 2ADC

25 Oct 2023

·firstwordpharma.com

Liver toxicity ends mid-stage studies of Merck & Co. drug for Alzheimer’s, depression

Merck & Co. has terminated two Phase II studies of the experimental drug MK-1942 after liver abnormalities were seen in a number of patients. The company confirmed the news to FirstWord on Wednesday, with the halted trials first disclosed on ClinicalTrials.gov.One study was investigating the small molecule in nearly 100 patients with difficult-to-treat major depressive disorder (MDD) on a stable course of antidepressant therapy. Subjects were randomised to daily dosing with MK-1942, intermittent treatment with the drug or placebo.The second trial was evaluating MK-1942 as a potential adjunct treatment in around 100 patients with mild-to-moderate Alzheimer’s disease. Participants were randomised to receive one of two twice-daily doses of the drug or placebo.According to Merck, the decision to halt the studies followed an unblinded review of data suggesting that MK-1942 was potentially associated with observations of liver toxicity. The review had been triggered by the identification of abnormalities in liver function tests for several study participants. However, the company noted that no related serious adverse events were reported.

Phase 2Clinical Trial Failure

100 Deals associated with MK-1942

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Phase 2	United States	Merck Sharp & Dohme Corp.	02 Dec 2022
Alzheimer Disease	Phase 2	Japan	Merck Sharp & Dohme Corp.	02 Dec 2022
Alzheimer Disease	Phase 2	Argentina	Merck Sharp & Dohme Corp.	02 Dec 2022
Alzheimer Disease	Phase 2	Australia	Merck Sharp & Dohme Corp.	02 Dec 2022
Alzheimer Disease	Phase 2	Canada	Merck Sharp & Dohme Corp.	02 Dec 2022
Alzheimer Disease	Phase 2	Colombia	Merck Sharp & Dohme Corp.	02 Dec 2022
Alzheimer Disease	Phase 2	Italy	Merck Sharp & Dohme Corp.	02 Dec 2022
Alzheimer Disease	Phase 2	New Zealand	Merck Sharp & Dohme Corp.	02 Dec 2022
Alzheimer Disease	Phase 2	South Korea	Merck Sharp & Dohme Corp.	02 Dec 2022
Alzheimer Disease	Phase 2	Spain	Merck Sharp & Dohme Corp.	02 Dec 2022

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04663321 (Pubmed \| J Clin Psychopharmacol)	Phase 2	Depressive Disorder, Treatment-Resistant	99	daily MK-1942 titrated from 5 to 20 mg bid added to stable antidepressant therapy	auzatctelz(zdfobpbnuk) = hnyemnokfy cxjftvnfal (vwporalhmk ) View more	Negative	19 Mar 2026
				MK-1942 10 mg twice weekly added to stable antidepressant therapy	auzatctelz(zdfobpbnuk) = ofsmnphbwc cxjftvnfal (vwporalhmk ) View more
NCT05602727 (MK-1942-008, CTgov)	Phase 2	Alzheimer Disease	99	MK-1942 (MK-1942 5 mg)	inlsptaelp(qcrbbvhfqp) = qeqkrgphho urtvqregus (xrivgjjovf, frchjklznn - wejjsudcey) View more	-	15 Oct 2024
				MK-1942 (MK-1942 15 mg)	inlsptaelp(qcrbbvhfqp) = jzgupoijxd urtvqregus (xrivgjjovf, xdgbfrliwd - djmxbpzpzs) View more
NCT04663321 (MK-1942-006, CTgov)	Phase 2	Depressive Disorder, Treatment-Resistant	99	Placebo+MK-1942 (MK-1942 Daily Dose Group)	czozsqihox(yfmefbovei) = pkbyvjelwl wwfuilnlbm (neidcigrhg, nlncqvasgy - pcbrzozjbw) View more	-	19 Sep 2024
				Placebo+MK-1942 (MK-1942 Intermittent Dose Group)	czozsqihox(yfmefbovei) = clamwpxnom wwfuilnlbm (neidcigrhg, dxvmqkmpbo - snedkqwcqu) View more