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Background Schizophrenia is a complex psychiatric disorder characterized by positive, negative, and cognitive symptoms. KarXT, a novel combination of xanomeline and trospium, offers potential therapeutic benefits for schizophrenia treatment by targeting muscarinic receptors and avoiding dopamine receptor blockade. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of KarXT. Methods PubMed, Scopus, Web of Science, and Cochrane databases were systematically searched for relevant randomized controlled trials (RCTs) up to October 2024. Studies involving adult patients with schizophrenia treated with KarXT were included. Furthermore, the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was used to assess evidence quality, and the risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool. Results Four studies with 690 participants were included. KarXT significantly reduced Positive and Negative Syndrome Scale (PANSS) total scores compared to placebo (mean difference (MD): -13.77, 95% confidence interval (CI) [-22.33 to -5.20], P-value = 0.002), with significant improvements in positive and negative subscale scores. It significantly increased the incidence of achieving ≥ 30% PANSS score reduction (risk ratio: 2.15, 95% CI [1.64 to 2.84], P  < 0.00001). Moreover, KarXT demonstrated a favorable safety profile, with side effects such as nausea and constipation being mild and transient. Notably, it was not significantly associated with weight gain or extrapyramidal symptoms, which are common with traditional antipsychotics. Conclusions KarXT’s distinct mechanism and tolerability highlight its potential to address unmet needs in schizophrenia treatment. Future studies should explore its long-term efficacy, delayed adverse effects, and comparative effectiveness against existing therapies. Clinical trial number Not applicable.

Describe xanomeline and trospium chloride efficacy and safety/tolerability for the treatment of schizophrenia using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH). Categorical data were extracted from the three 5-week, randomized, double blind, placebo controlled EMERGENT-1, EMERGENT-2, and EMERGENT-3 clinical trials of xanomeline/trospium in adults with schizophrenia experiencing acute psychosis. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S), and categorical response criteria. Safety and tolerability were assessed using rates of discontinuation and treatment-emergent adverse events (TEAEs). NNT, NNH, and LHH values were calculated for each individual study as well as pooled. In data from the acute EMERGENT trials, NNT estimates were significant for xanomeline/trospium vs placebo for the pre-specified treatment response threshold of ≥30% reduction from baseline in PANSS total score at Week 5 (NNT=5 [95% CI, 4-8]). NNT estimates for response thresholds of ≥20% and ≥40% reduction from baseline in PANSS total score and ≥1- and ≥2-point decrease from baseline in CGI-S score were <10, indicating a clinically relevant therapeutic benefit of xanomeline/trospium over placebo. Estimates of NNH vs placebo for the most common TEAEs were >10, with the exception of nausea and vomiting; however, rates of discontinuations due to TEAEs of nausea, dyspepsia, or vomiting were low (NNH=49 [95% CI, 28-182]). LHH indicated an overall benefit of xanomeline/trospium vs placebo for all assessed outcomes. In indirect comparisons based on published data from trials of available antipsychotics approved for schizophrenia, xanomeline/trospium exhibited comparable or more robust NNT estimates vs placebo and was the least likely agent to be associated with weight gain or somnolence/sedation. In the 5-week EMERGENT clinical trials, NNT, NNH, and LHH assessments demonstrated a favorable benefit-risk profile for xanomeline/trospium. ClinicalTrials.gov identifiers: NCT03697252, NCT04659161, NCT04738123.

Background Several randomized clinical trials (RCTs) have recently examined the efficacy and tolerability of muscarinic receptor agonists in schizophrenia. However, whether therapeutics targeting muscarinic receptors improve symptom management and reduce side effects remains systemically unexplored. Methods Embase, PubMed, and Web of Science were searched from inception until Jan 9, 2025. Altogether, the efficacy and safety outcomes of four RCTs (397 individuals in the muscarinic receptor agonists group, and 374 in the placebo control group) were meta-analyzed. To compare scores of positive and negative syndrome scale (PANSS), response rate, discontinuation rate, and adverse events with muscarinic receptor agonists vs. placebo in patients with schizophrenia, scale changes were pooled as mean difference (MD) for continuous outcomes and risk ratio (RR) for categorical outcomes. Results It revealed that muscarinic receptor agonists were superior to placebo in terms of decrease in the total PANSS score (MD, − 9.92; 95% CI, -12.46 to -7.37; I 2  = 0%), PANSS positive symptom subscore (MD, − 3.21; 95% CI, -4.02 to -2.40; I 2  = 0%), and PANSS negative symptom subscore (MD, -1.79; 95% CI, -2.47 to -1.11; I 2  = 48%). According to the study-defined response rate, the pooled muscarinic receptor agonists vs. placebo RR was 2.08 (95% CI, 1.59 to 2.72; I 2  = 0%). No significance was found in the discontinuation rate. Muscarinic receptor agonists were associated with a higher risk of nausea (RR = 4.61, 95% CI, 2.65 to 8.02; I 2  = 3%), and in particular, xanomeline-trospium was associated with risks of dyspepsia, vomiting, and constipation. Conclusions The findings highlighted an efficacy advantage with tolerated adverse event profiles for muscarinic receptor agonists in schizophrenia.

Keywords Overactive bladder, urinary incontinence, lower urinary tract symptoms, anticholinergic, antimuscarinic, beta-3 adrenergic agonist.

Rationale The M 1 /M 4 preferring muscarinic receptor agonist xanomeline demonstrated antipsychotic and procognitive effects in patients with Alzheimer’s disease or schizophrenia in prior studies, but further clinical development was limited by cholinergic adverse events (AEs). KarXT combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium with the goal of improving tolerability and is in clinical development for schizophrenia and other neuropsychiatric disorders. Objective Test the hypothesis that trospium can mitigate cholinergic AEs associated with xanomeline. Methods Healthy volunteers enrolled in this phase 1 (NCT02831231), single-site, 9-day, double-blind comparison of xanomeline alone ( n  = 33) versus KarXT ( n  = 35). Rates of five prespecified cholinergic AEs (nausea, vomiting, diarrhea, excessive sweating, salivary hypersecretion) were compared between treatment arms. Vital signs, electrocardiograms (ECGs), safety laboratory values, and pharmacokinetic (PK) analyses were assessed. A self-administered visual analog scale (VAS) and clinician-administered scales were employed. Results Compared with xanomeline alone, KarXT reduced composite incidences of the five a priori selected cholinergic AEs by 46% and each individual AE by ≥ 29%. There were no episodes of syncope in KarXT-treated subjects; two cases occurred in the xanomeline-alone arm. The rate of postural dizziness was 11.4% in the KarXT arm versus 27.2% with xanomeline alone. ECG, vital signs, and laboratory values were not meaningfully different between treatment arms. The VAS and clinician-administered scales tended to favor KarXT. PK analysis revealed that trospium did not affect xanomeline’s PK profile. Conclusions Trospium was effective in mitigating xanomeline-related cholinergic AEs. KarXT had an improved safety profile compared with xanomeline alone.

Background: Preclinical and some human data suggest allosteric modulation of the muscarinic [M.sub.1] receptor (CHRM1) is a promising approach for the treatment of schizophrenia. However, it is suggested there is a subgroup of participants with schizophrenia who have profound loss of cortical CHRM1 (MRDS). This raises the possibility that some participants with schizophrenia may not respond optimally to CHRM1 allosteric modulation. Here we describe a novel methodology to measure positive allosteric modulation of CHRM1 in human CNS and the measurement of that response in the cortex, hippocampus, and striatum from participants with MRDS, non-MRDS and controls. Methods: The cortex (Brodmann's area 6), hippocampus, and striatum from 40 participants with schizophrenia (20 MRDS and 20 non-MRDS) and 20 controls were used to measure benzyl quinolone carboxylic acid-mediated shift in acetylcholine displacement of [[.sup.3]H]N-methylscopolamine using a novel in situ radioligand binding with autoradiography methodology. Results: Compared with controls, participants with schizophrenia had lower levels of specific [[.sup.3]H]N-methylscopolamine binding in all CNS regions, whilst benzyl quinolone carboxylic acid-modulated binding was less in the striatum, Brodmann's area 6, dentate gyrus, and subiculum. When divided by subgroup, only in MRDS was there lower specific [[.sup.3]H]N-methylscopolamine binding and less benzyl quinolone carboxylic acid-modulated binding in all cortical and subcortical regions studied. Conclusions: In a subgroup of participants with schizophrenia, there is a widespread decreased responsiveness to a positive allosteric modulator at the CHRM1. This finding may have ramifications it positive allosteric modulators of the CHRM1 are used in clinical trials to treat schizophrenia as some participants may not have an optimal response. Keywords: schizophrenia, musccarinic M1 receptor, positive allosteric modulation, hippocampus, striatum

The U.S. Food and Drug Administration (FDA) has authorized 50 new drugs in 2024, which matches the average figure for recent years (2018–2023). The approval of 13 monoclonal antibodies (mAbs) sets a new record, with these molecules accounting for more than 25% of all drugs authorized this year. Three proteins have been added to the list of biologics, and with the inclusion of four TIDES (two oligonucleotides and two peptides), only one in three approved drugs this year is a small molecule. As of 2023, no antibody-drug conjugates (ADCs) have reached the market this year. Two deuterated drugs have been approved, bringing the total approvals for this class of compounds to four. This year saw the authorization of two more PEGylated drugs—both peptides—highlighting a renewed interest in this strategy for extending drug half-life, despite the setback caused by the withdrawal of peginesatide from the market in 2014 due to adverse side effects. N-aromatic heterocycles and fluorine atoms are present in two-thirds of all the small molecules approved this year. Herein, the 50 new drugs authorized by the FDA in 2024 are analyzed exclusively on the basis of their chemical structure. They are classified as the following: biologics (antibodies, proteins), TIDES (oligonucleotides and peptides), combined drugs, natural products, F-containing molecules, nitrogen aromatic heterocycles, aromatic compounds, and other small molecules.

Overactive bladder (OAB) is a symptom complex that includes urinary urgency, frequency, urgency incontinence, and nocturia. It is highly prevalent, affecting up to 12% of the adult population, and can significantly impact quality of life. The diagnosis of OAB is made by history, physical examination, and a urinalysis to rule out underlying infection or other concerning potential etiologies. The need for additional testing is based on the initial evaluation findings, and is recommended in cases of underlying urinary tract infection, microscopic hematuria, obstructive voiding symptoms, and symptoms refractory to previous treatments. Initial management includes behavioral modification with attention to total daily fluid intake, avoidance of bladder irritants, treatment of constipation, weight loss, timed voiding, urge-suppression techniques, and pelvic floor physical therapy. Options for oral medications include antimuscarinic agents and β adrenergic agents, and can be used following or in conjunction with behavioral treatment. For patients refractory to behavioral therapy and oral medications, consideration should be given to referral to a specialist (eg, a urologist or urogynecologist) for discussion of more advanced therapies such as sacral neuromodulation, percutaneous tibial nerve stimulation, and intradetrusor injection of onabotulinumtoxinA. These more advanced treatments have favorable efficacy compared with oral agents in randomized trials, although each has a unique risk/benefit profile and shared decision-making with the individual patient is crucial. Here, we review pertinent considerations in the clinical evaluation and management of OAB in women.

During the 2010s, overall generic dispensing rates rose well into the 80%-plus range (up from 50%-plus roughly a decade prior), relegating drug cost control to intensive harvesting of savings from a small number of products or intensive reduction in dispensing rates for generics from pharmacies. SCRUTINY INTENSIFIES ON PBMS' BUSINESS PRACTICES AND BENEFIT TO THE MARKETPLACE In the summer of 2022, the Federal Trade Commission (FTC) launched an investigation into PBM practices,1 largely owing to these potential misalignments with purchasers and functional and efficient markets (thus the FTC on the inquiry's lead). The other half of the population entitled to government sponsored insurance will find local and national legislators and administrators demanding access to data to ensure their constituency doesn't wake up to see articles exposing gross excesses in economic rents from taxpayers.5 COMMUNITY PHARMACY SUSTAINABILITY AND SURVIVAL HANGS IN THE BALANCE Meanwhile, nearly 2500 pharmacies have closed in 2024 alone, with thousands more on the brink of closure due to paltry reimbursement and contract terms with PBMs.