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Dr. Bob is Robert Hsiung, MD,
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Posted by PeterMartin on November 16, 2024, at 11:20:15
Anyone aware of this drug? Could be available in 2025 if all goes well. Anhedonia is very common (me!) But most drugs don't help much. From a chat w chatgpt:
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Kappa opioid receptor (KOR) agonists are not currently under study for the treatment of depression, bipolar disorder, or anhedonia. In fact, KOR agonists have been associated with inducing dysphoria and depressive-like symptoms, making them unsuitable for treating these conditions. Instead, research has focused on KOR antagonists, which block the receptor's activity and have shown promise in alleviating symptoms of depression and anhedonia.For instance, aticaprant, a selective KOR antagonist, has been investigated for its potential to treat major depressive disorder (MDD) and anhedonia. Clinical studies have demonstrated that aticaprant can ameliorate anhedonic behavior in patients with MDD, suggesting its utility in addressing this core symptom of depression.
CDA SRSimilarly, navacaprant, another KOR antagonist, is currently in Phase 3 clinical trials as a monotherapy for MDD. Preliminary data indicate that navacaprant may improve depressive symptoms without significant side effects, highlighting its potential as a novel treatment option.
PSYCHIATRIC TIMESIn summary, while KOR agonists are not being pursued for the treatment of depression, bipolar disorder, or anhedonia due to their adverse effects, KOR antagonists like aticaprant and navacaprant are under active investigation and have shown encouraging results in clinical studies.
Sorry that's what I meant. Can you give me the latest on navacaprant? Has an nda been submitted? Is there a chance it'll be available in 2025? Does it affect typical neurotransmitters like serotonin as well or just KOR?
ChatGPT said:
ChatGPT
Navacaprant is a selective kappa opioid receptor (KOR) antagonist currently under development for the treatment of major depressive disorder (MDD). As of November 14, 2024, the drug is in Phase 3 clinical trials, with the pivotal KOASTAL Program underway to evaluate its safety and efficacy.
NEUMORANew Drug Application (NDA) Status: An NDA for navacaprant has not yet been submitted. The ongoing Phase 3 studies are expected to support an NDA submission to the U.S. Food and Drug Administration (FDA) in 2025.
NEUMORAPotential Availability: If the Phase 3 trials are successful and the FDA approves the NDA, navacaprant could become available as a treatment option for MDD in 2025.
Mechanism of Action: Navacaprant functions as a selective KOR antagonist, modulating the dopamine and reward processing pathways, which are crucial in regulating mood, cognition, reward, and behavior. While its primary action is on the KOR system, this modulation indirectly influences neurotransmitters like dopamine. There is no evidence to suggest that navacaprant directly affects serotonin levels.
NEUMORAIn summary, navacaprant is progressing through Phase 3 clinical trials, with an anticipated NDA submission in 2025. Its mechanism of action involves selective antagonism of KOR, primarily affecting dopamine pathways without direct modulation of serotonin.
What's the history of this drug? When was it first discovered? Drug company? Has it been tried for other drugs? Any failed trials? Have the results for phase 2?
ChatGPT said:
ChatGPT
Navacaprant, also known by its developmental code NMRA-140, is a selective kappa opioid receptor (KOR) antagonist currently under development for the treatment of major depressive disorder (MDD).Discovery and Development: Navacaprant was discovered at Scripps Research in the laboratories of Dr. Edward Roberts and Dr. Hugh Rosen. The compound was initially developed by BlackThorn Therapeutics, which initiated its clinical evaluation. In 2021, Neumora Therapeutics acquired BlackThorn Therapeutics and continued the development of navacaprant.
SCRIPPS RESEARCH INSTITUTEClinical Trials:
Phase 2 Trials: Navacaprant underwent a Phase 2 clinical trial (NCT04221230) initiated by BlackThorn Therapeutics prior to its acquisition by Neumora. This double-blind, placebo-controlled, randomized, multicenter trial evaluated once-daily navacaprant monotherapy compared to placebo in patients with MDD. The results demonstrated significant and clinically meaningful improvements in depressive symptoms, particularly in reducing anhedoniathe inability to experience pleasure.
NEUMORA
EUROPEAN PHARMACEUTICAL REVIEWPhase 3 Trials: Following the positive Phase 2 results, Neumora Therapeutics initiated the KOASTAL Program, a series of Phase 3 clinical trials to further assess the safety and efficacy of navacaprant in MDD. Topline data from the KOASTAL-1 study are expected in the fourth quarter of 2024, with additional studies (KOASTAL-2 and KOASTAL-3) anticipated to report results in the first half of 2025.
YAHOO FINANCEOther Indications: Beyond MDD, navacaprant is being investigated for its potential in treating bipolar depression. A Phase 2 clinical trial was initiated in May 2024 to evaluate its safety and efficacy in individuals with depression associated with bipolar II disorder. Topline data from this trial are expected in the second half of 2025.
GLOBENEWSWIRESafety Profile: Navacaprant has demonstrated a favorable safety profile in clinical trials, with no significant side effects such as weight gain or sexual dysfunction, which are commonly associated with other antidepressant treatments.
MARKETWATCHIn summary, navacaprant is a promising KOR antagonist initially discovered at Scripps Research and developed by BlackThorn Therapeutics, now under the development of Neumora Therapeutics. It has shown positive results in Phase 2 trials for MDD and is currently undergoing Phase 3 trials, with potential applications in bipolar depression also being explored.
So it actually blocks opiod receptors?
ChatGPT said:
ChatGPT
Yes, kappa opioid receptor (KOR) antagonists like navacaprant indeed work by blocking kappa opioid receptors, but it's important to understand their specific action in the broader opioid receptor family:Opioid Receptor Families:
Mu opioid receptors (MOR): Associated with pain relief and euphoria (targeted by drugs like morphine and oxycodone).
Delta opioid receptors (DOR): Less well-understood, but involved in mood and neuroprotection.
Kappa opioid receptors (KOR): Play a role in stress, dysphoria (a state of unease or dissatisfaction), and reward system regulation.
What KOR Antagonists Do:
Block Stress-Induced Dysphoria: KORs are activated during stress, contributing to feelings of dysphoria and withdrawal from rewarding behaviors. Blocking them can reverse these effects, promoting a more positive emotional state and restoring reward system function.
Modulate Dopamine Release: KOR antagonists indirectly increase dopamine activity in key brain areas like the nucleus accumbens, which is critical for experiencing pleasure and motivation.
No Classic Opioid Effects: Unlike mu opioid receptor (MOR) agonists (e.g., morphine or fentanyl), KOR antagonists do not produce euphoria, pain relief, or the risk of addiction. Their action is more specific to alleviating negative mood states and enhancing reward sensitivity.
Why This Is Unique:
Addressing Mood and Motivation: KOR antagonists are designed to counteract the dysregulation of the opioid and dopamine systems often seen in depression and anhedonia.
Not an Opioid Drug in the Traditional Sense: While KOR antagonists act on opioid receptors, they do not involve addictive properties or the severe side effects of opioid drugs targeting MORs.
Safety Considerations:
Because KOR antagonists only block (not activate) kappa receptors and do not interact significantly with mu or delta receptors, they sidestep the risks typically associated with opioid medications, such as respiratory depression or dependency.In summary, these drugs do block opioid receptorsbut only kappa receptorsresulting in a completely different, targeted therapeutic effect focused on improving mood, motivation, and reward sensitivity.
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