A Phase 2a, Randomized, Double-blind, Placebo-controlled Pilot Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With a Major Depressive Episode Associated With Bipolar II Disorder

This is a randomized, double-blind, placebo-controlled pilot study aiming to evaluate the effects of NMRA-335140 on symptoms of major depression in adults with Bipolar (BP) II disorder. The study design consists of a Screening Period (up to 28 days), a 6-week Treatment Period (during which participants will receive either NMRA-335140 or placebo), and a 6-week Safety Follow-up Period.

Start Date13 May 2024

Sponsor / Collaborator

Neumora Therapeutics, Inc.

NCT06058039

/ RecruitingPhase 3

A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder

This randomized, double-blind, placebo-controlled, multicenter study will evaluate the effects of NMRA-335140 (formerly BTRX-335140) on symptoms of depression in participants with Major Depressive Disorder (MDD). The study design consists of a Screening Period (up to 35 days), and a 6-week Treatment Period (during which participants will receive either NMRA-335140 or placebo). At the completion of the 6-week Treatment Period, participants who complete the study, provide informed consent, and meet the eligibility criteria may enter an open-label extension study (NMRA-335140-501).

Start Date21 Dec 2023

Sponsor / Collaborator

Neumora Therapeutics, Inc.

NCT06058013

/ RecruitingPhase 3

A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder

This is a randomized, double-blind, placebo-controlled, multicenter study to evaluate the effects of NMRA-335140 (formerly BTRX-335140) on symptoms of depression in participants with Major Depressive Disorder (MDD). The study design consists of a Screening Period (up to 28 days), and a 6-week Treatment Period (during which participants will receive either NMRA-335140 or placebo). At the completion of the 6-week Treatment Period, participants who complete the study, provide informed consent, and meet the eligibility criteria may enter an open-label extension study (NMRA-335140-501).

Start Date20 Dec 2023

Sponsor / Collaborator

Neumora Therapeutics, Inc.

100 Clinical Results associated with Navacaprant

100 Translational Medicine associated with Navacaprant

100 Patents (Medical) associated with Navacaprant

Literatures (Medical) associated with Navacaprant

01 Oct 2024·JOURNAL OF AFFECTIVE DISORDERS

Preclinical and clinical efficacy of kappa opioid receptor antagonists for depression: A systematic review

Review

Author: Kwan, Angela T H ; Rosenblat, Joshua D ; Meshkat, Shakila ; Choi, Hayun ; Vasudeva, Shreya ; Ho, Roger ; Cao, Bing ; McIntyre, Roger S ; Teopiz, Kayla M ; Le, Gia Han ; Rhee, Taeho Greg ; Wong, Sabrina ; Phan, Lee

BACKGROUND:

Approximately 30 % of persons with Major Depressive Disorder (MDD) inadequately respond to conventional antidepressants. Kappa opioid receptor (KOR) antagonists, aticaprant and navacaprant, are in development as treatments for MDD. Herein, we aim to comprehensively evaluate the safety, efficacy and pharmacology of aticaprant and navacaprant for MDD.

METHODS:

We performed a systematic review of primary research investigating aticaprant and navacaprant on PubMed, OVID, and Scopus databases from inception to April 2024. Studies that reported on the pharmacological profile and/or safety and efficacy of aticaprant and navacaprant were included.

RESULTS:

Navacaprant monotherapy and aticaprant adjunctive therapy are in development for MDD. Navacaprant exhibits 300-fold selectivity for the KOR compared to the mu-opioid receptor, while aticaprant exhibits 30-fold selectivity. At clinically-relevant doses, navacaprant and aticaprant occupy 87-95 % and 73-94 % of KORs, respectively. Clinical trials of the foregoing agents (navacaprant as monotherapy and actiprant as adjunctive therapy) reported significant improvement in depressive symptoms and may clinically benefit measures of anhedonia. Both agents appear well-tolerated, with most adverse events mild and no known safety concerns.

LIMITATIONS:

Aticaprant and navacaprant treatment for MDD are in early stages of clinical trials and results from Phase 3 pivotal trials are not yet available.

CONCLUSIONS:

Kappa opioid receptor antagonists may serve as mechanistically-novel treatments for MDD and persons who inadequately respond to index conventional antidepressants. Anhedonia is debilitating and insufficiently treated with conventional antidepressants. Future research vistas should establish the efficacy and safety of KORAs in phase 3 studies in both acute and maintenance paradigms.

01 Oct 2024·NEUROPHARMACOLOGY

Navacaprant, a novel and selective kappa opioid receptor antagonist, has no agonist properties implicated in opioid-related abuse

Article

Author: Zeitz, Karla ; Van Orden, Lori Jean ; Morrison, Filomene G ; Wallace, Tanya L ; Kuijer, Eloise J ; Heal, David J ; Smith, Sharon L

Kappa opioid receptors (KORs) are implicated in the pathophysiology of various psychiatric and neurological disorders creating interest in targeting the KOR system for therapeutic purposes. Accordingly, navacaprant (NMRA-140) is a potent, selective KOR antagonist being evaluated as a treatment for major depressive disorder. In the present report, we have extended the pharmacological characterization of navacaprant by further demonstrating its selective KOR antagonist properties and confirming its lack of agonist activity at KORs and related targets involved in opioid-related abuse. Using CHO-K1 cells expressing human KOR, mu (MOR), or delta (DOR) opioid receptors, navacaprant demonstrated selective antagonist properties at KOR (IC₅₀ = 0.029 μM) versus MOR (IC₅₀ = 3.3 μM) and DOR (IC₅₀ > 10 μM) in vitro. In vivo, navacaprant (10-30 mg/kg, i.p.) dose-dependently abolished KOR-agonist induced analgesia in the mouse tail-flick assay. Additionally, navacaprant (10, 30 mg/kg, p.o.) significantly reduced KOR agonist-stimulated prolactin release in mice and rats, confirming KOR antagonism in vivo. Navacaprant showed no agonist activity at any opioid receptor subtype (EC₅₀ > 10 μM) in vitro and exhibited no analgesic effect in the tail-flick assays at doses ≤100 mg/kg, p.o. thereby confirming a lack of opioid receptor agonist activity in vivo. Importantly, navacaprant did not alter extracellular dopamine concentrations in the nucleus accumbens shell of freely-moving rats following doses ≤100 mg/kg, p.o., whereas morphine (10, 20 mg/kg, i.p.) significantly increased dopamine levels. These results demonstrate that navacaprant is a KOR-selective antagonist with no pharmacological properties implicated in opioid-related abuse.

01 Feb 2024·Anesthesiology

Opposing Effects on Descending Control of Nociception by µ and κ Opioid Receptors in the Anterior Cingulate Cortex

Article

Author: Roberts, Edward ; Neugebauer, Volker ; Navratilova, Edita ; Guerrero, Miguel ; Ji, Guangchen ; Porreca, Frank ; Rosen, Hugh ; Qu, Chaoling

Background:

The efficiency of descending pain modulation, commonly assessed with the conditioned pain modulation procedure, is diminished in patients with chronic pain. The authors hypothesized that the efficiency of pain modulation is controlled by cortical opioid circuits.

Methods:

This study evaluated the effects of µ opioid receptor activation in the anterior cingulate cortex on descending control of nociception, a preclinical correlate of conditioned pain modulation, in male Sprague-Dawley rats with spinal nerve ligation–induced chronic pain or in sham-operated controls. Additionally, the study explored the consequences of respective activation or inhibition of κ opioid receptor in the anterior cingulate cortex of naive rats or animals with neuropathic pain. Descending control of nociception was measured as the hind paw withdrawal response to noxious pressure (test stimulus) in the absence or presence of capsaicin injection in the forepaw (conditioning stimulus).

Results:

Descending control of nociception was diminished in the ipsilateral, but not contralateral, hind paw of rats with spinal nerve ligation. Bilateral administration of morphine in the anterior cingulate cortex had no effect in shams but restored diminished descending control of nociception without altering hypersensitivity in rats with neuropathic pain. Bilateral anterior cingulate cortex microinjection of κ opioid receptor antagonists, including nor-binaltorphimine and navacaprant, also re-established descending control of nociception in rats with neuropathic pain without altering hypersensitivity and with no effect in shams. Conversely, bilateral injection of a κ opioid receptor agonist, U69,593, in the anterior cingulate cortex of naive rats inhibited descending control of nociception without altering withdrawal thresholds.

Conclusions:

Anterior cingulate cortex κ opioid receptor activation therefore diminishes descending control of nociception both in naive animals and as an adaptive response to chronic pain, likely by enhancing net descending facilitation. Descending control of nociception can be restored by activation of μ opioid receptors in the anterior cingulate cortex, but also by κ opioid receptor antagonists, providing a nonaddictive alternative to opioid analgesics. Navacaprant is now in advanced clinical trials.

Editor’s Perspective:

What We Already Know about This Topic:

What This Article Tells Us That Is New:

News (Medical) associated with Navacaprant

02 Jan 2025

·www.fiercebiotech.com

Neumora stumbles at start of phase 3 depression readout run, sending stock down 80%

Neumora Therapeutics’ stock fell more than 80% to below $2 in premarket trading.\n Neumora Therapeutics’ big bet on a new era of neuroscience has delivered an age-old result. The first of three late-stage readouts on Neumora’s lead drug candidate has ended in failure, wiping more than 80% off the value of the biotech.Arch Venture Partners set up Neumora in the belief advances in genomics and neurobiology had set the stage for a more targeted—and less risky—approach to neuroscience R&D. The VC shop rolled up several biotechs to create Neumora and led a syndicate that pumped an initial $500 million into the startup. A deal with Amgen, a second private round and an IPO added almost $500 million more to the coffers.This morning, investors learnt what their cash has delivered—and were unimpressed with the results. The biotech reported data from KOASTAL-1, the first of three phase 3 trials of navacaprant in major depressive disorder.Investigators randomized 383 people to receive the oral kappa opioid receptor antagonist or placebo. After six weeks of daily dosing, scores on a depression rating scale had fallen 12.5 points in the navacaprant cohort. The problem? Scores also fell 12.5 points in the placebo arm, causing the trial to miss its primary endpoint. The bad news was compounded by the failure of a key secondary endpoint that evaluated changes in the ability of patients to feel pleasure. Scores fell 5.8 points on the Snaith-Hamilton Pleasure Scale in people taking navacaprant versus a 5.5-point reduction in their counterparts on placebo.Even so, Neumora CEO Henry Gosebruch noted “encouraging trends in the data” in a statement about the readout. The trends include a disconnect between how navacaprant performed in men and women, with the results favoring navacaprant in the 105 female patients.On the depression scale, the navacaprant and placebo reductions were 14 and 11.4 points, respectively. The reductions on the pleasure scale were 7.2 points for navacaprant and 4.9 points for placebo. The flip side of that case for navacaprant is that placebo performed numerically better than navacaprant in men. Women made up a smaller portion of participants in KOASTAL-1 than in Neumora’s phase 2 trial.Neumora’s press release lacks an explanation for why navacaprant would perform better in women than in men. More details may emerge when Neumora presents at the J.P. Morgan Healthcare Conference later this month. For now, investors are taking little solace from Neumora’s talk of encouraging trends, driving the stock down more than 80% to below $2 in premarket trading.

Clinical ResultPhase 2Phase 3Clinical Trial FailureIPO

02 Jan 2025

·endpts.com

Neumora's major depression drug flunks first of three Phase 3 trials

Neuroscience drug developer Neumora Therapeutics released highly anticipated results from the first of three Phase 3 trials for its experimental major depression drug, saying Thursday that navacaprant was not statistically significant at improving patients’ depressive symptoms better than placebo in the late-stage KOASTAL-1 trial. Neumora is hoping to compete against Johnson & Johnson, which is also running Phase 3 studies for its experimental MDD drug, called aticaprant, and markets the esketamine spray Spravato. Both companies are developing kappa opioid receptor (KOR) antagonists, which are meant to hit upon the reward processing and dopamine pathways. The biotech’s stock price $NMRA fell 80% in Thursday morning trading in reaction to the news. In the 383-adult KOASTAL-1, navacaprant and placebo both led to a -12.5 change from baseline on the primary endpoint, the Montgomery-Asberg Depression Rating Scale (MADRS). “We are disappointed by the results from KOASTAL-1 as they were not consistent with the body of evidence supporting this mechanism in MDD,” Neumora head of R&D Rob Lenz said in a statement. “There is a lot to investigate from this study, in particular the contrast in drug and placebo responses in depressed mood and anhedonia in female participants compared to male participants.” Neumora CEO Henry Gosebruch said the company will share more details on its pipeline at the JP Morgan Healthcare Conference later this month. The first results for Neumora’s once-daily pill are a preview of more to come. The company is running two additional identical pivotal trials dubbed KOASTAL-2 and KOASTAL-3. Those trials are expected to read out in the first half of this year, the company has said. In their note from December, Stifel analysts said Neumora’s drug likely only needs to succeed in two of the trials. “The other two would likely have sufficient data for an NDA as the psychiatry division typically doesn’t penalize sponsors for a negative study,” the analysts wrote Dec. 16. If navacaprant makes it to market for major depression, the analysts predict almost $3 billion in peak worldwide revenues. The readout also marks a key moment for the KOR space. J&J is expected to release Phase 3 data for aticaprant this year. If either company is successful, it will open up a new treatment option in depression, a large market that has lacked effective new treatments and run into clinical or regulatory disappointments . The opportunity is so large that ARCH Venture Partners named Neumora the “ Really Big Neuroscience Company ” when it formed the startup. The company attracted key industry leaders to its management team, including Gosebruch , the former AbbVie strategy chief. It then went public in a $250 million IPO in September 2023. While Gosebruch was at AbbVie, the drug giant got a label expansion in depression for its drug Vraylar. In prior studies, navacaprant helped patients with moderate-to-severe MDD in a Phase 2 trial, but it didn’t hit statistical significance in the overall study population when factoring in mildly depressed patients. Neumora did not include mildly depressed patients in its Phase 3. BlackThorn Therapeutics, which designed the Phase 2 trial, was acquired by Neumora in 2020. Editor’s note: This story was updated to include stock price reaction.

Phase 3Phase 2Clinical ResultAcquisitionIPO

02 Jan 2025

·www.biopharmadive.com

Neumora plummets on depression drug data

Neumora Therapeutics, a well-funded biotechnology company, lost more than 80% of its value Thursday because its most advanced drug failed a major test.After seeing positive signs in a smaller study in 2023, Neumora pushed the drug into a trio of late-stage clinical trials to evaluate it as a treatment for the most common type of depression. The company just released data from the first of those trials, which found the drug no better than a placebo at alleviating depression.The KOASTAL-1 study had a main treatment period of six weeks and enrolled 383 adults with moderate-to-severe MDD, or major depressive disorder. Researchers assigned half of the participants to Neumoras drug, navacaprant,and half to a placebo. Both of those groups performed the same, with each experiencing an average decrease of 12.5 points on a 60-point scale that measures depression symptoms.Rob Lenz, head of Neumoras research and development, said the company is disappointed by the results since they are not consistent with the body of evidence that suggests drugs like navacaprant could be useful against MDD. Navacaprant is designed to spur the release of dopamine one of the so-called happy hormones by inhibiting a type of protein known as kappa opioid receptors. Johnson & Johnson and AbbVie are also working on depression drugs that target these receptors.Neumoras results did somewhat differ based on sex. Women had greater responses to the drug, showing a 14-point average decrease versus a 10.6-point decrease among men. Conversely, men had a greater response to the placebo. There is a lot to investigate from this study, Lenz said, particularly the contrasts between men and women.Neumora plans to provide more updates on the navacaprant development program later this month, at the industrys bellwether event, the annual J.P. Morgan Healthcare Conference. The trial outcome is not what we expected, but there are encouraging trends in the data that we are analyzing, said Henry Gosebruch, the former chief strategy officer at AbbVie who took over as Neumoras CEO in 2023.Investors, though, appear to have lost confidence in the program. Neumoras share price, which hovered around $11 on Tuesday, was down to just over $2 Thursday morning.We believe that today's readout represents a worst-case scenario for the program, wrote Brian Abrahams, an analyst at the investment firm RBC Capital Markets, in a note to clients.Abrahams acknowledged that the placebo responses in KOASTAL-1 were larger than what had been seen in prior studies. However, Neumora went to great lengths to structure the trial so that placebo effects would be low and it would have an optimal shot at success. As such, the RBC team is inclined to believe the outcome of the study reflects the true drug effect (or lack thereof) rather than any particular conduct issues.Both Abrahams and Paul Matteis, an analyst at Stifel, are skeptical that the differences seen among men and women in the trial will translate to any meaningful for the drugs development. [A]fter what looks like a clear failure, it's hard for us to have conviction, Matteis wrote in his own note to clients.Neumora had $342 million in cash by the end of September, which, according to Gosebruch, should keep it operational into the middle of 2026.The Massachusetts-based biotech was founded in 2019 and launched two years later, armed with half a billion dollars in funding. Neumoras backers include Amgen as well as prominent life sciences investors like Arch Venture Partners, Polaris Partners, Invus, F-Prime Capital and Alexandria Venture Investments.The company raised $250 million in an initial public offering in Sept. 2023, and shares peaked at about $20 apiece several months later. '

Clinical ResultClinical Study

100 Deals associated with Navacaprant

External Link

KEGG	Wiki	ATC	Drug Bank
-	Navacaprant	-	DB16068

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder, Major	Phase 3	US	Neumora Therapeutics, Inc.	20 Sep 2023
Depressive Disorder	Phase 2	-	Neumora Therapeutics, Inc.	14 May 2024
Bipolar II disorder	Phase 2	US	Neumora Therapeutics, Inc.	13 May 2024

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT06029426 (KOASTAL-1, GlobeNewswire) Manual	Phase 3	Depressive Disorder, Major	383	Navacaprant	hapxodebei(ipgogmcrpj) = bolesnvohp aahkapjfny (qysunujlnw ) Not Met View more	Negative	02 Jan 2025
				Placebo	hapxodebei(ipgogmcrpj) = fqdvaydkwy aahkapjfny (qysunujlnw ) Not Met View more
NCT04221230 (BusinessWire) Manual	Phase 2	Depressive Disorder, Major	171	navacaprant	clmmfwvvoh(daaxvgffhd): difference = -1.7, P-Value = 0.121 View more	Positive	18 Jul 2023
				placebo

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