roluperidone (MIN-101) / Mitsubishi Tanabe, Minerva Neurosciences - LARVOL DELTA

Roluperidone monotherapy, a treatment for negative symptoms in schizophrenia. (PubMed, Int J Neuropsychopharmacol) - "The patients who were symptomatic stable for 3 or 6 months before antipsychotic drug withdrawal, showed a very low prevalence of psychotic symptoms worsening over 6 or 9 months trials duration. Focus: Treatment of primary negative symptoms in a subgroup of patients suffering from schizophrenia."

Journal • Monotherapy • CNS Disorders • Psychiatry • Schizophrenia

Unlocking the potential of lumateperone and novel anti-psychotics for schizophrenia. (PubMed, Bioimpacts) - "This review also focuses on a few more emerging antipsychotics like brexpiprazole, brilaroxazine, roluperidone, F17464, pimavanserin (ACP-103), xanomeline, BI 409306, BI 425809 and MK-8189 which are under different phase of clinical trials and might get approved soon. All the antipsychotic drugs covered did not show any other severe adverse effects except gastrointestinal issues and cardiometabolic risk factors. However, still rigorous clinical trials and modifications are needed to manage adverse effects, and we can expect a few antipsychotics to be on the market soon."

Journal • Review • Anesthesia • CNS Disorders • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder • Psychiatry • Schizophrenia

Third-Generation Antipsychotics: The Quest for the Key to Neurotrophism. (PubMed, Life (Basel)) - "While second-generation antipsychotics (SGAs) are associated with a better side effect profile than their predecessors, the emergence of third-generation antipsychotics (TGAs)-such as brexpiprazole, cariprazine, lurasidone, iloperidone, lumateperone, pimavanserin, and roluperidone-has prompted renewed interest in their potential neuroprotective and pro-cognitive effects. Although data remain limited and focused primarily on earlier SGAs, emerging findings suggest that some TGAs may exert positive effects on neuroplastic processes, including the modulation of brain-derived neurotrophic factors (BDNFs) and synaptic architecture. However, robust clinical data on their long-term effects and comparative efficacy are lacking; therefore, further research is necessary to validate their role in preventing neurodegenerative changes and improving cognitive outcomes in patients with psychiatric conditions."

Journal • Review • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia • BDNF

Fibroblast Growth Factor 23 (FGF-23) and Endothelial Cell Dysfunction (ECD) in the Dallas Heart Study Cohort (KIDNEY WEEK 2024) - "Funding: NIDDK Support; Veterans Affairs SupportCharacteristics Across FGF23 Quartiles Quartile 1 (6.2-28.3 pg/mL)Quartile 2 (28.3-36.4 pg/mL)Quartile 3 (36.4-45.2 pg/mL)Quartile 4 (45.3-2034 pg/mL)p-value for trendAge (years)43 (35, 52)42 (36, 50)44 (37, 52)45 (37, 52).1Diabetes (%)17 (6%)27 (9%)19 (6%)35 (12%).03BMI (kg/m2)27.3 (24-32)27.8 (24-32)28.8 (25-34)29.1 (25-34).003Estimated MDRD Glomerular Filtration Rate (mL/min)101 (90-118)99.5 (87-114)94.1 (81-111)91.1 (78-104)<.0001Serum Phosphate (mg/dL)3.1 (2.8-3.5)3.2 (2.8-3.5)3.1 (2.8-3.5)3.3 (2.9-3.7).001Serum Calcium (mg/dL)9.2 (9-9.5)9.2 (9-9.5)9.3 (9.1-9.5)9.3 (9-9.6).02Intact Parathyroid Hormone (pg/mL)35.6 (27-51)37 (27-50)35.3 (28-46)40.3 (29-57).03Total cholesterol (mg/dL)167 (147-196)175 (151-201)179 (154-203)191 (160-208).0001Electron Beam Computed Tomography Coronary Artery Calcification (Agatston)0 (0-2.6)0.5 (0-3.8)0.5 (0-8.8)1 (0-11.5).001Asymmetric Dimethylarginine (μmol/L)0.47 (0.4-0.53)0.47..."

IO biomarker • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Orthopedics • CD40LG • ENG • FGF23 • ICAM1 • SDC1 • VCAM1

Olanzapine added to roluperidone, in patients with schizophrenia and negative symptoms, a safety open-label trial (ECNP 2024) - "Conclusion . Results of this study suggest that the administration of olanzapine, a commonly used antipsychotic, in conjunction with roluperidone does not affect its safety or pharmacokinetics."

Clinical • CNS Disorders • Pain • Psychiatry • Schizophrenia

Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities. (PubMed, Med Res Rev) - "Notably, the sigma-2, 5-HT2A, and α1A receptor antagonist roluperidone, as well as a fixed-dose combination of the M1/4 receptor agonist KarXT, have been submitted for NDA applications. The dual agonist ulotaront, which targets TAAR1 and 5-HT1A receptors, and the GlyT1 inhibitor iclepertin have advanced into phase 3 clinical trials. Nevertheless, satisfactory therapeutic strategies for schizophrenia remain elusive. This review highlights current clinical endeavors in developing novel chemical small-molecule entities and fixed-dose combinations for the treatment of schizophrenia since 2017, thus facilitating the efficient development of the next generation of antipsychotics."

Journal • Review • CNS Disorders • Psychiatry • Schizophrenia

Network intervention analysis indicates that roluperidone achieves its effect on negative symptoms of schizophrenia by targeting avolition. (PubMed, Eur Neuropsychopharmacol) - "These phase 3 findings replicated the phase 2b findings, indicating that from a network perspective, roluperidone achieves its effect by influencing the extent to which avolition drives other negative symptoms. These findings are relevant for understanding negative symptoms and how to treat them in neuropsychiatric disorders."

Journal • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

Emerging trends in antipsychotic and antidepressant drug development: Targeting nonmonoamine receptors and innovative mechanisms. (PubMed, PCN Rep) - "One noteworthy candidate is Ulotaront (SEP-363856), an agent acting as a TAAR1 agonist with 5-HT1A agonist activity, demonstrating promising outcomes in the treatment of schizophrenia, devoid of extrapyramidal symptoms or metabolic side-effects. Similarly, MIN-101 (Roluperidone) and KarXT are currently in development, with its focus on addressing the symptoms in schizophrenia. In the domain of antidepressants, novel therapeutic approaches have surfaced, such as Auvelity, a Food and Drug Administration (FDA)-approved NMDA receptor antagonist synergistically combined with Bupropion to enhance its effects. Another notable candidate is Zuranolone, operating as a GABA A receptor-positive allosteric modulator, showcasing efficacy in treating major depressive disorder (MDD) and postpartum depression. Additionally, TAK-653 (NBI-1065845) and MJI821 (Onfasprodil) have emerged as potential antidepressants targeting AMPA receptors and NMDA receptor 2B (NR2B) negative allosteric..."

Journal • Review • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Postpartum Depression • Psychiatry • Schizophrenia

Beyond dopamine: Novel strategies for schizophrenia treatment. (PubMed, Med Res Rev) - "We describe the versatility behind the cholinergic neurotransmission modulation through the activation of M1 and M4 receptors, exemplified by the prospective drug candidate KarXT. Our discussion extends to the innovative approach of activating TAAR1 receptors via ulotaront, along with the promising outcomes of iclepertin, a GlyT-1 inhibitor with the potential to become the first treatment option for cognitive impairment associated with schizophrenia. Finally, we evaluate the 5-HT2A antagonist paradigm, assessing two recently developed serotonergic agents, pimavanserin and roluperidone. We present the latest advancements in developing novel solutions to the complex challenges posed by schizophrenia, offering an additional perspective on the diverse investigated drug candidates."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Advancements in Non-Dopaminergic Treatments for Schizophrenia: A Systematic Review of Pipeline Developments. (PubMed, Pharmacopsychiatry) - "Compounds that function differently from existing antipsychotics may offer novel symptom-specific therapeutic strategies for patients with schizophrenia."

Journal • Review • CNS Disorders • Psychiatry • Schizophrenia

Minerva Neurosciences Receives Complete Response Letter from FDA for New Drug Application for Roluperidone for the Treatment of Negative Symptoms in Patients with Schizophrenia (GlobeNewswire) - "Minerva Neurosciences, Inc...announced today that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to the Company’s New Drug Application (NDA) for roluperidone for the treatment of negative symptoms in patients with schizophrenia."

NDA • CNS Disorders • Schizophrenia

A Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Co-Administration of Roluperidone and Olanzapine in Adult Subjects With Moderate to Severe Negative Symptoms of Schizophrenia (clinicaltrials.gov) - P1 | N=17 | Completed | Sponsor: Minerva Neurosciences | Recruiting ➔ Completed | Phase classification: P1b ➔ P1

Phase classification • Trial completion • CNS Disorders • Psychiatry • Schizophrenia

Avolition as a Treatment Target Across Neuropsychiatric Conditions: Characteristics, Determinants, Potential Treatment Strategies, and Perspectives Based on Lived Experience (ACNP 2023) - "Study Group Proposal With the announcement that the FDA has issued an IND for roluperidone, the possibility has emerged that there will be an FDA approved treatment for negative symptoms in schizophrenia...The study group will be broadly configured across disciplines, career stage, ACNP membership, and, of course, racial and gender characteristics. In-Person Presenter Attestation I Agree."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Depression • Mood Disorders • Psychiatry • Schizophrenia

A Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Co-Administration of Roluperidone and Olanzapine in Adult Subjects With Moderate to Severe Negative Symptoms of Schizophrenia (clinicaltrials.gov) - P1b | N=18 | Recruiting | Sponsor: Minerva Neurosciences

New P1 trial • CNS Disorders • Psychiatry • Schizophrenia

"$NERV FDA confirms acceptance of the filing of the NDA for roluperidone The application has been granted a standard review. PDUFA 02/26/24" (@BioStocks)

NDA • PDUFA date • Review

The Efficacy of Roluperidone on Negative Symptoms and Social Functioning: Are There Qualitatively Distinct Patterns of Treatment Response? (ASCP 2023) - "Goodness-of-fit indices frequently favored a quadratic model of change for negative symptoms in both studies, and social functioning in the Phase 3 trial. In Phase 2b, roluperidone treatment was a significant predictor of improved PANSS NSFS (slope=-0.269, p<0.001) but its effect on non-linear change was not significant (q=0.156, p=0.134). Treatment drove reductions in both the PANSS emotional expression (EXP) (slope = -0.289, p<0.001) and marginally in motivation and pleasure (MAP) items (slope = -0.164, p=0.067)."

Clinical • CNS Disorders • Psychiatry • Schizophrenia

Long-term outcomes from a multicenter randomized controlled trial on hypothermic oxygenated machine perfusion in human liver transplantation. (ESA 2023) - P=N/A | "End-ischemic HOPE was performed for a median of 145 min101-203 and total cold preservation time was 495 min465-593 in both groups...CONCLUSION HOPE was associated with reduced late-onset morbidity and improved long-term allograft survival in ECD-DBD liver transplantation. Larger trials specifically powered to assess long-term graft and patient survival are warranted."

Clinical • Cardiovascular • Hepatology • Reperfusion Injury • Transplantation

Latent Growth Modeling of the Efficacy of Roluperidone on Negative Symptoms and Social Functioning (SIRS 2023) - "Financial Relationships Details Commercial Interest Type of Financial Interest Minerva Neurosciences Inc. Consultant 3"

Clinical • CNS Disorders • Schizophrenia

Long-term effects of Roluperidone on negative symptoms of schizophrenia. (PubMed, Schizophr Res) - "Roluperidone was well tolerated with no meaningful changes in vital signs, laboratory values, weight gain, metabolic indices, or extrapyramidal symptoms. Results of 2 open-label extension trials support roluperidone as a treatment of negative symptoms and social functioning deficits in patients with moderate to severe negative symptoms of schizophrenia."

Journal • CNS Disorders • Psychiatry • Schizophrenia

The Future of Schizophrenia Psychopharmacotherapy: More Antipsychotic Atypicality? Guess So! (PubMed, Psychopharmacol Bull) - "In this regard, authors brief on five agents that sound pretty promising and might usher in a new sparkle in the psychopharmacotherapy of schizophrenia. This paper is a sequel for authors' previous article on future of schizophrenia psychopharmacotherapy."

Journal • Review • CNS Disorders • Psychiatry • Schizophrenia

Minerva Neurosciences Announces Update on its New Drug Application (NDA) for Roluperidone for the Treatment of Negative Symptoms in Schizophrenia (GlobeNewswire) - "Minerva Neurosciences, Inc...announced that, following the Type A meeting held on November 30, 2022, the Food and Drug Administration (FDA) has confirmed that the refuse to file letter dated October 14, 2022 remains in effect in respect of the Company’s New Drug Application (NDA) for roluperidone for the treatment of negative symptoms in patients with schizophrenia."

FDA event • CNS Disorders • Schizophrenia

A Phase 3 Trial of Roluperidone, a Drug for the Treatment of Negative Symptoms in Schizophrenia (EPA 2022) - No abstract available

P3 data • CNS Disorders • Psychiatry • Schizophrenia

A Phase 3 Trial of Roluperidone, a Drug for the Treatment of Negative Symptoms in Schizophrenia. (SIRS 2022) - "NSFS scores were lower (better) on roluperidone 64 mg compared to placebo for the modified Intent-to-Treat population (p≤ 0.044) but not for the Intent-to-Treat population (p≤ 0.064). PSP total score was statistically significantly superior on roluperidone 64 mg than on placebo ( p≤ 0.021). During the 40 week of open-label drug administration negative symptoms, daily functioning, and total PANSS scores continued to improve while positive symptoms remained stable, and < 12% of the patients experienced symptom relapses during the whole 52-week study duration."

P3 data • CNS Disorders • Schizophrenia

Efficacy and Safety of Roluperidone for the Treatment of Negative Symptoms of Schizophrenia. (PubMed, Schizophr Bull) - P3 | "Results of this trial confirm the potential of roluperidone as a treatment of negative symptoms and improving everyday functioning in patients with schizophrenia. Study registration: Eudra-CT: 2017-003333-29; NCT03397134."

Journal • CNS Disorders • Psychiatry • Schizophrenia

Roluperidone (MIN-101) Causes Brain Region-Specific Neurotransmitter Release, Increased Brain Activity and Functional Network Connectivity in the Rat Brain Related to Negative Symptoms in Schizophrenia (Neuroscience 2021) - "In resting state functional connectivity analysis, MIN101 significantly increased network connectivity over time. Our studies demonstrate that MIN-101 modulates hippocampal and cortical-striatal circuitry in naïve rats, which has been linked to negative symptoms in SCZ."

Preclinical • CNS Disorders • Psychiatry • Schizophrenia • MRI