Cholinergic Adverse Effects Research Articles

P19: Design of ADEPT-2, a phase 3, parallel group study to evaluate xanomeline and trospium as a treatment for psychosis associated with Alzheimer’s disease dementia

Background: Psychosis represents a major unmet medical need in patients with Alzheimer’s disease (AD) dementia. With no approved medications for AD dementia psychosis (ADP), current treatment relies on off-label uses of antipsychotics with limited efficacy and significant safety concerns. Xanomeline is an M1/M4 preferringmuscarinic receptor agonist that has previously been shown to have antipsychotic effects in subjects with AD (Bodick et al., 1997). While xanomeline had promising efficacy for potentially treating psychosis in AD, cholinergic adverse events limited further clinical development of xanomeline. Xanomeline and trospium is an investigational treatment that combines xanomeline with trospium, an FDA-approved non- specific muscarinic receptor antagonist. Unlike xanomeline, trospium does not measurably cross the blood-brain barrier, providing a mechanism to mitigate peripheral cholinergic effects of xanomeline while maintaining its muscarinic receptor agonist activities in the brain.Methods: ADEPT-2 trial is a phase 3, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and efficacy of xanomeline and trospium for the treatment of ADP. Subjects aged 55-90 years with moderate to severe psychosis associated with mild to severe AD dementia will be enrolled into the study. Eligible subjects will be randomized to receive either xanomeline and trospium or placebo in a double-blinded manner for 12 weeks and subjects who complete the study will be eligible to participate in a one-year, open-label safety extension study.Results: The primary efficacy endpoint of the study is change from baseline to end of Week 12 in the Neuropsychiatric Inventory-Clinical (NPI-C): Hallucinations and Delusions (H+D) score and the key secondary efficacy endpoint is change from baseline to end of Week 12 in the Cohen- Mansfield Agitation Inventory (CMAI). The safety endpoints include the evaluation of safety and tolerability of xanomeline and trospium compared with placebo in subjects with ADP. The study started in 2023 and will enroll approximately 360 subjects with psychosis associated with AD dementia.Conclusions: ADEPT-2 is designed to assess the safety and efficacy of xanomeline and trospium for the treatment of psychosis in patients with AD dementia. If ADEPT-2 is successful, xanomeline and trospium have the potential to be the first in a new class of pharmacologic treatment for AD psychosis based on muscarinic receptor agonism.

A golden age of muscarinic acetylcholine receptor modulation in neurological diseases.

Over the past 40 years, the muscarinic acetylcholine receptor family, particularly the M1-receptor and M4-receptor subtypes, have emerged as validated targets for the symptomatic treatment of neurological diseases such as schizophrenia and Alzheimer disease. However, despite considerable effort and investment, no drugs have yet gained clinical approval. This is largely attributable to cholinergic adverse effects that have halted the majority of programmes and resulted in a waning of interest in these G-protein-coupled receptor targets. Recently, this trend has been reversed. Driven by advances in structure-based drug design and an appreciation of the optimal pharmacological properties necessary to deliver clinical efficacy while minimizing adverse effects, a new generation of M1-receptor and M4-receptor orthosteric agonists and positive allosteric modulators are now entering the clinic. These agents offer the prospect of novel therapeutic solutions for 'hard to treat' neurological diseases, heralding a new era of muscarinic drug discovery.

Deepening insights into cholinergic agents for intraocular pressure reduction: systems genetics, molecular modeling, and in vivo perspectives.

Parasympathetic activation in the anterior eye segment regulates various physiological functions. This process, mediated by muscarinic acetylcholine receptors, also impacts intraocular pressure (IOP) through the trabecular meshwork. While FDA-approved M3 muscarinic receptor (M3R) agonists exist for IOP reduction, their systemic cholinergic adverse effects pose limitations in clinical use. Therefore, advancing our understanding of the cholinergic system in the anterior segment of the eye is crucial for developing additional IOP-reducing agents with improved safety profiles. Systems genetics analyses were utilized to explore correlations between IOP and the five major muscarinic receptor subtypes. Molecular docking and dynamics simulations were applied to human M3R homology model using a comprehensive set of human M3R ligands and 1,667 FDA-approved or investigational drugs. Lead compounds from the modeling studies were then tested for their IOP-lowering abilities in mice. Systems genetics analyses unveiled positive correlations in mRNA expressions among the five major muscarinic receptor subtypes, with a negative correlation observed only in M3R with IOP. Through modeling studies, rivastigmine and edrophonium emerged as the most optimally suited cholinergic drugs for reducing IOP via a potentially distinct mechanism from pilocarpine or physostigmine. Subsequent animal studies confirmed comparable IOP reductions among rivastigmine, edrophonium, and pilocarpine, with longer durations of action for rivastigmine and edrophonium. Mild cholinergic adverse effects were observed with pilocarpine and rivastigmine but absent with edrophonium. These findings advance ocular therapeutics, suggesting a more nuanced role of the parasympathetic system in the anterior eye segment for reducing IOP than previously thought.

Design of ADEPT‐2, a phase 3, parallel group study to evaluate KarXT [xanomeline‐trospium] as a treatment for psychosis associated with Alzheimer’s disease

AbstractBackgroundPsychosis represents a major unmet medical need in patients with Alzheimer’s disease (AD) dementia. With no approved medications for AD dementia psychosis (ADP), current treatment relies on off‐label uses of antipsychotics with limited efficacy and significant safety concerns. Xanomeline is an M1/M4 preferring muscarinic receptor agonist that has previously been shown to have antipsychotic effects in subjects with AD (Bodick et al., 1997). While xanomeline had promising efficacy for potentially treating psychosis in AD, cholinergic adverse events limited further clinical development of xanomeline. KarXT is an investigational treatment that combines xanomeline with trospium, an FDA‐approved non‐specific muscarinic receptor antagonist. Unlike xanomeline, trospium does not measurably cross the blood‐brain barrier, providing a mechanism to mitigate peripheral cholinergic effects of xanomeline while maintaining its muscarinic receptor agonist activities in the brain.MethodsADEPT‐2 trial is a phase 3, randomized, double‐blind, placebo‐controlled, parallel group study to evaluate the safety and efficacy of KarXT for the treatment of ADP. Subjects aged 55‐90 years with moderate to severe psychosis associated with mild to severe AD dementia will be enrolled into the study. Eligible subjects will be randomized to receive either KarXT or placebo in a double‐blinded manner for 14 weeks and subjects who complete the study will be eligible to participate in a one‐year, open‐label safety extension study.ResultsThe primary efficacy endpoint of the study is change from Randomization to End of Treatment in the Neuropsychiatric Inventory‐Clinical (NPI‐C): Hallucinations and Delusions (H+D) score and the key secondary efficacy endpoint is change from Randomization to End of Treatment in the Cohen‐Mansfield Agitation Inventory (CMAI). The safety endpoints include the evaluation of safety and tolerability of KarXT compared with placebo in subjects with ADP. The study is planned to start in 2023 and will enroll approximately 360 subjects with psychosis associated with AD dementia.ConclusionADEPT‐2 is designed to assess the safety and efficacy of KarXT for the treatment of psychosis in patients with AD dementia. If ADEPT‐2 is successful, KarXT has the potential to be the first in a new class of pharmacologic treatment for AD psychosis based on muscarinic receptor agonism.

Psychiatric Adverse Events of Acetylcholinesterase Inhibitors in Alzheimer's Disease and Parkinson's Dementia: Systematic Review and Meta-Analysis.

The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia. While these drugs are known to induce classic cholinergic adverse events such as diarrhea, their potential to cause psychiatric adverse events has yet to be thoroughly examined. We sought to determine the risk of psychiatric adverse events associated with the use of AChEIs through a systematic review and meta-analysis of double-blind randomized controlled trials involving patients with Alzheimer's dementia and Parkinson's dementia. A total of 48 trials encompassing 22,845 patients were included in our analysis. Anorexia was the most commonly reported psychiatric adverse event, followed by agitation, insomnia, and depression. Individuals exposed to AChEIs had a greater risk of experiencing appetite disorders, insomnia, or depression compared with those who received placebo (anorexia: odds ratio [OR] 2.93, 95% confidence interval [CI] 2.29-3.75; p < 0.00001; decreased appetite: OR 1.93, 95% CI 1.33-2.82; p=0.0006; insomnia: OR 1.55, 95% CI 1.25-1.93; p < 0.0001; and depression: OR 1.59, 95% CI 1.23-2.06, p=0.0004). Appetite disorders were also more frequent with high-dose versus low-dose therapy. A subgroup analysis revealed that the risk of insomnia was higher for donepezil than for galantamine. Our findings suggest that AChEI therapy may negatively impact psychological health, and careful monitoring of new psychiatric symptoms is warranted. Lowering the dose may resolve some psychiatric adverse events, as may switching to galantamine in the case of insomnia. The study was pre-registered on PROSPERO (CRD42021258376).

Xanomeline-Trospium and Muscarinic Involvement in Schizophrenia.

Schizophrenia is a severe mental illness that has its onset in late adolescence or early adulthood and is associated with significant dysfunction across multiple domains. The pathogenesis of schizophrenia remains unknown, but physiologic understanding of the illness has been driven by the dopamine hypothesis. However, acetylcholine (ACh) clearly plays a role with mixed results regarding effect on psychosis. Selective muscarinic M1 and M4 agonists, such as xanomeline, originally developed to aid in cognitive loss with Alzheimer's, showed promise in proof-of-concept study in 20 patients with schizophrenia. Unfortunately, tolerability problems made muscarinic agonists impractical in either condition. However, coadministration of trospium, a lipophobic, non-selective muscarinic antagonist previously used for the treatment of overactive bladder, with xanomeline resulted in a significant reduction of cholinergic adverse effects. A recent randomized, placebo-controlled study of the antipsychotic effects of this combination in 182 patients with acute psychosis revealed improved tolerability with 80% of subjects staying to the end of the 5 weeks study. At the end of the trial, the treatment group saw a -17.4 change in the positive and negative symptom scale (PANSS) score from baseline compared to a -5.9 change in the placebo arm (P < 0.001). Furthermore, the negative symptom subscore, was also superior in the active arm (P < 0.001). These early studies are exciting because they suggest that the cholinergic system may be recruited to treat a severe and disabling disorder with suboptimal treatment options. Xanomeline-trospium combination is currently in phase III studies.

Evidence of trospium’s ability to mitigate cholinergic adverse events related to xanomeline: phase 1 study results

RationaleThe M1/M4 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.ObjectiveTest the hypothesis that trospium can mitigate cholinergic AEs associated with xanomeline.MethodsHealthy 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.ResultsCompared 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.ConclusionsTrospium was effective in mitigating xanomeline-related cholinergic AEs. KarXT had an improved safety profile compared with xanomeline alone.

Opportunities and challenges for the development of M1 muscarinic receptor positive allosteric modulators in the treatment for neurocognitive deficits.

Targeting allosteric sites of M1 muscarinic acetylcholine receptors (M1 receptors) is a promising strategy to treat neurocognitive disorders, such as Alzheimer's disease and schizophrenia. Indeed, the last two decades have seen an impressive body of work focussing on the design and development of positive allosteric modulators (PAMs) for the M1 receptor. This has led to the identification of a structurally diverse range of highly selective M1 PAMs. In preclinical models, M1 PAMs have shown rescue of cognitive deficits and improvement of endpoints predictive of symptom domains of schizophrenia. Yet, to date only a few M1 PAMs have reached early-stage clinical trials, with many of them failing to progress further due to on-target mediated cholinergic adverse effects that have plagued the development of this class of ligand. This review covers the recent preclinical and clinical studies in the field of M1 receptor drug discovery for the treatment of Alzheimer's disease and schizophrenia, with a specific focus on M1 PAM, highlighting both the undoubted potential but also key challenges for the successful translation of M1 PAMs from bench-side to bedside. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.

The novel M4 PAM PET tracer [11C] MK‐6884: a novel biomarker for measuring target engagement of muscarinic M4 positive allosteric modulators (PAMs) as well as cholinergic tone in patients with Alzheimer’s disease

AbstractBackgroundThe muscarinic acetylcholine receptor 4 (M4) has attracted attention as a target for treating neuropsychiatric symptoms, such as agitation and aggression, associated with Alzheimer’s disease. We have developed novel selective, potent, and in vivo suitable M4 positive allosteric modulators (PAMs) and demonstrated robust pharmacology in preclinical models predictive of antipsychotic and pro‐cognitive effects. Importantly, we have also shown that these selective M4 PAMs produce greater therapeutic margins for cholinergic adverse effects compared to less selective muscarinic receptor agonists.MethodsTo enable translation in the clinic, we set out to discover an M4 PAM PET tracer suitable for measuring central receptor occupancy (RO).Result[11C]MK‐6884 binds with high affinity and selectivity to the allosteric site on the M4 receptor that our other M4 PAMs bind. The affinity of [11C]MK‐6884 was found to be influenced by the concentration of orthosteric agonist in vitro and in vivo, consistent with the high cooperativity of the molecule in vitro. PET studies successfully determined the target engagement of PAMs to enable modeling the relationship between drug plasma exposure, RO, and pharmacodynamic activity. Donepezil increased the tracer binding potential of [11C]MK‐6884 in rhesus and healthy human subjects, confirming in vivo the influence of cholinergic tone on [11C]MK‐6884 binding that was observed in vitro. Consistent with a presumed cortical deficit in synaptic acetylcholine, [11C]MK‐6884 PET studies in AD patients showed lower cortical binding potential compared to healthy elderly participants, as well as notable cortical heterogeneity and bilateral asymmetry of M4 receptor binding in AD patients. Striatal binding potential was unchanged in these different populations.ConclusionOur findings demonstrate that the M4 PAM PET tracer [11C]MK‐6884 is a useful tool for determining target engagement of M4 PAMs, as well serving as a unique probe to study changes in cholinergic neurotransmission in neurodegenerative disease. The Enigma Biomedical Group has an exclusive license agreement with Merck &amp; Co., Inc., for the global development and commercialization of MK‐6884. This allows Enigma and its partner, Cerveau Technologies Inc. to provide biomarkers to industry and academia to accelerate research in the field of neurodegenerative and neuropsychiatric diseases.

Investigating Drivers for M1 Muscarinic Acetylcholine Receptor‐Mediated Adverse Events by M1 Positive Allosteric Modulators

IntroductionTargeting the allosteric site of the M1 muscarinic acetylcholine receptor (M1 mAChR) is a promising strategy to develop selective drugs to treat cognitive disorders. By binding to the allosteric site, positive allosteric modulators of the M1 mAChRs (M1 PAMs) can enhance the binding (α) and/or the efficacy (β) of the endogenous ligand acetylcholine (ACh) (Fig 1), therefore improving impaired cholinergic transmission that is evident in Alzheimer’s disease and Schizophrenia. In addition, M1 PAMs may also display direct allosteric agonism (tB) (Fig 1). To date, many highly selective M1 PAMs with diverse structures have been developed, unfortunately, the majority of them still caused M1‐mediated cholinergic adverse effects (AEs), including gastrointestinal (GI) disturbances, salivation, increased heart rate and convulsions. This results from the ability of the M1 mAChR to interact with multiple intracellular partners, leading to different functional outcomes, both the beneficial (i.e, improved cognition), and the detrimental (i.e, GI AEs) effects. Excitingly, M1 PAMs can bias the M1 mAChR towards specific signalling outcomes versus others, a phenomenon called biased modulation. However, to date, it is unknown which intracellular partner is the most predominant in M1 PAM activity, and how this may drive the preclinically observed AEs.AimTo determine the role(s) Gα protein(s) and β‐arrestins exert on the allosteric activity of 5 structurally distinct M1 PAMs and link these to their reported AEs.MethodsThe M1 PAMs including BQCA, MK7622, PF06767832, MIPS1780 which showed AEs in in vivo studies, and VU0486846 without observed AEs, were assessed against ACh, in parental or CRISPR HEK293A cells with deletion of specific G proteins or β‐arrestins (ΔGαq/11, ΔGα12/13or Δβ‐arrestin 1/2) expressing the human M1 mAChR. [3H]‐NMS binding assays were performed to determine the binding affinity of ACh (KA), and of the 5 M1 PAMs (KB) and their binding cooperativity (α) with ACh. IP1 accumulation and b‐arrestin 2 recruitment were performed to quantify the efficacy (τB) of the M1 PAMs and their functional cooperativity (αβ) with ACh.ResultsΔGαq/11, ΔGα12/13 or Δb‐arrestin 1/2 significantly reduced the binding affinity of ACh, and for 3 M1‐PAMs, MK7622, PF06767832 and MIPS1780. Interestingly, all these deletions significantly increased the binding cooperativity of these M1‐PAMs with ACh. Unsurprisingly, ΔGαq/11 completely abolished IP1 responses from both orthosteric and allosteric ligands. Notably, ΔGα12/13 or Δβ‐arrestin 1/2 both increased ACh efficacy (τA). While ΔG12/13 caused no change in efficacy of tested PAMs but increased functional cooperativity of PF06767832 and MIPS1780 with ACh, Δβ‐arrestin 1/2 affected the functional properties (τB and αβ) of MK7622 in IP1 pathway. In β‐arrestin 2 pathway, ΔGαq/11 increased MIPS1780 efficacy and ΔGα12/13 increased functional cooperativity of BQCA.ConclusionGαq/11, Gα12/13 and b‐arrestin 1/2 influence binding affinity and functional properties for both ACh and M1 PAMs. These transductors affect M1 PAMs with observed AEs more than the M1 PAM without AEs, VU0486846, and thus playing a potential role in driving AEs.

Effects of Body Weight on the Safety of High-Dose Donepezil in Alzheimer’s Disease: Post hoc Analysis of a Multicenter, Randomized, Open-Label, Parallel Design, Three-Arm Clinical Trial

Background: Donepezil 23 mg is considered for Alzheimer’s disease (AD) to optimize cognitive benefits; however, increased adverse events (AEs) can negatively influence drug adherence. We investigated whether body weight (BW) differs based on the presence of AEs, and which baseline factors were relevant to the safety of high-dose donepezil. Methods: This study was a post hoc analysis of a multicenter randomized trial between 2014 and 2016. We included patients with moderate to severe AD treated with 10 mg/day of donepezil, and the daily dose was escalated to 23 mg with/without dose titration. Dose titration indicates 15 mg/day of donepezil before escalation or 10 mg and 23 mg/day on alternate days before escalation during the first 4 weeks. The patients were divided into 2 groups based on occurrence of AEs of special interest (AESIs) to compare baseline characteristics. We also assessed relationships between BW and AESIs. Results: Among the 160 participants in the safety population, the baseline BWs differed between the AESI (+) (n = 67) and AESI (−) (n = 93) groups. Baseline BW was inversely correlated with the occurrence of AESIs (p = 0.020), and this relationship was prominent in the no-dose titration group (p = 0.009) but absent in the dose-titration groups (p > 0.05). Conclusions: BW is the most important factor that correlated with cholinergic AEs. Hence, stepwise dose titration should be considered, particularly in patients with low BW, to minimize the inverse relationship between BW and the occurrence of AEs (“Clinicaltrials.gov” No. NCT02550665 registered on September 15, 2015).

Safety, pharmacokinetics and quantitative EEG modulation of TAK-071, a novel muscarinic M1 receptor positive allosteric modulator, in healthy subjects.

AimsTAK‐071 is a muscarinic M1 receptor positive allosteric modulator designed to have low cooperativity with acetylcholine. This was a first‐in‐human study to evaluate the safety, pharmacokinetics, and pharmacodynamics of TAK‐071.MethodsTAK‐071 was administered as single and multiple doses in a randomized, double‐blind, placebo‐controlled, parallel‐group design in healthy volunteers alone and in combination with donepezil. Laboratory, electrocardiogram (ECG) and electroencephalogram (EEG) evaluations were performed. Cerebrospinal fluid and blood samples were taken to evaluate the pharmacokinetics (PK), relative bioavailability and food effect.ResultsTAK‐071 was safe and well tolerated, and no deaths or serious adverse events occurred. TAK‐071 demonstrated a long mean (% coefficient of variation) half‐life of 46.3 (25.2%) to 60.5 (51.5%) hours and excellent brain penetration following oral dosing. Coadministration with donepezil had no impact on the PK of either drug. There was no food effect on systemic exposure. Quantitative EEG analysis revealed that TAK‐071 40‐80 mg increased power in the 7‐9 Hz range in the posterior electrode group with eyes open and 120‐160 mg doses increased power in the 16‐18 Hz range and reduced power in the 2‐4 Hz range in central‐posterior areas with eyes open and eyes closed. Functional connectivity was significantly reduced after TAK‐071 at high doses and was enhanced with coadministration of donepezil under the eyes‐closed condition.ConclusionsPK and safety profiles of TAK‐071 were favorable, including those exceeding expected pharmacologically active doses based on preclinical data. When administered without donepezil TAK‐071 was largely free of cholinergic adverse effects. Further clinical evaluation of TAK‐071 is warranted.

Galantamine nanoparticles outperform oral galantamine in an Alzheimer's rat model: pharmacokinetics and pharmacodynamics.

Aim: Galantamine is an acetylcholinesterase inhibitor frequently used in Alzheimer's disease management. Its cholinergic adverse effects and rapid elimination limit its therapeutic outcomes. We investigated the pharmacodynamics and pharmacokinetics of 2-week intranasal galantamine-bound chitosan nanoparticles (G-NP) treatment in scopolamine-induced Alzheimer's disease rat model. Materials & methods: Behavioral, neurobiochemical and histopathological changes were assessed and compared with oral and nasal solutions. Brain uptake and pharmacokinetics were determined using a novel validated LC/MS assay. Results: G-NP enhanced spatial memory, exploring behavior and cholinergic transmission in rats. Beta-amyloid deposition and Notch signaling were suppressed and the histopathological degeneration was restored. G-NP potentiated galantamine brain delivery and delayed its elimination. Conclusion: G-NP hold promising therapeutic potentials and brain targeting, outperforming conventional galantamine therapy.

Safety, pharmacokinetics and exploratory pro-cognitive effects of HTL0018318, a selective M1 receptor agonist, in healthy younger adult and elderly subjects: a multiple ascending dose study

BackgroundThe cholinergic system and M1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M1 receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia’s including Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects.MethodsThis randomised, double blind, placebo-controlled study was performed, investigating oral doses of 15–35 mg/day HTL0018318 or placebo in 7 cohorts of healthy younger adult (n = 36; 3 cohorts) and elderly (n = 50; 4 cohorts) subjects. Safety, tolerability and pharmacokinetic measurements were performed. Pharmacodynamics were assessed using a battery of neurocognitive tasks and electrophysiological biomarkers of synaptic and cognitive functions.ResultsHTL0018318 was generally well-tolerated in multiple doses up to 35 mg/day and were associated with mild or moderate cholinergic adverse events. There were modest increases in blood pressure and pulse rate when compared to placebo-treated subjects, with tendency for the blood pressure increase to attenuate with repeated dosing. There were no clinically significant observations or changes in blood and urine laboratory measures of safety or abnormalities in the ECGs and 24-h Holter assessments. HTL0018318 plasma exposure was dose-proportional over the range 15–35 mg. Maximum plasma concentrations were achieved after 1–2 h. The apparent terminal half-life of HTL0018318 was 16.1 h (± 4.61) in younger adult subjects and 14.3 h (± 2.78) in elderly subjects at steady state. HTL0018318 over the 10 days of treatment had significant effects on tests of short-term (working) memory (n-back) and learning (Milner maze) with moderate to large effect sizes.ConclusionMultiple doses of HTL0018138 showed well-characterised pharmacokinetics and were safe and generally well-tolerated in the dose range studied. Pro-cognitive effects on short-term memory and learning were demonstrated across the dose range. These data provide encouraging data in support of the development of HTL0018138 for cognitive dysfunction in AD and DLB.Trial registrationNetherlands Trial Register identifier NTR5781. Registered on 22 March 2016.

Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia

BackgroundThe muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor–blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown.MethodsIn this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline–trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression–Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2.ResultsA total of 182 patients were enrolled, with 90 assigned to receive xanomeline–trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline–trospium group and 96.6 in the placebo group. The change from baseline to week 5 was −17.4 points with xanomeline–trospium and −5.9 points with placebo (least-squares mean difference, −11.6 points; 95% confidence interval, −16.1 to −7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline–trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline–trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups.ConclusionsIn a 5-week trial, xanomeline–trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline–trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.)

Biased M1-muscarinic-receptor-mutant mice inform the design of next-generation drugs.

Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer's disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) represent a potential alternate therapeutic target; however, drug discovery programs focused on this G protein-coupled receptor (GPCR) have failed, largely due to cholinergic adverse responses. Employing novel chemogenetic and phosphorylation-deficient, G protein-biased, mouse models, paired with a toolbox of probe molecules, we establish previously unappreciated pharmacologically targetable M1 mAChR neurological processes, including anxiety-like behaviors and hyper-locomotion. By mapping the upstream signaling pathways regulating these responses, we determine the importance of receptor phosphorylation-dependent signaling in driving clinically relevant outcomes and in controlling adverse effects including 'epileptic-like' seizures. We conclude that M1 mAChR ligands that promote receptor phosphorylation-dependent signaling would protect against cholinergic adverse effects in addition to driving beneficial responses such as learning and memory and anxiolytic behavior relevant for the treatment of AD.

Safety and tolerability of donepezil 23\u2009mg with or without intermediate dose titration in patients with Alzheimer\u2019s disease taking donepezil 10\u2009mg: a multicenter, randomized, open-label, parallel-design, three-arm, prospective trial

BackgroundHigh-dose donepezil is currently prescribed for patients with Alzheimer’s disease (AD) who showed poor or waning response to a lower dose at the risk of increasing cholinergic side effects. However, the adverse events (AEs) depending on the method of dose escalation have not been clarified yet. This study aimed to find out whether dose titration before escalating to donepezil 23 mg is preferred. We investigated safety and tolerability of donepezil 23 mg during the first 12 weeks of dose escalation in patients with moderate to severe AD.MethodsThis study was a 12-week, multicenter, randomized, open-label prospective trial. We included patients with moderate to severe AD who were treated with a stable dose of donepezil 10 mg/day. Patients were randomized into 3 groups according to the dose escalation method: 15 mg of donepezil for 4 weeks before escalating to 23 mg (group 1), 10 mg and 23 mg on alternate days for 4 weeks prior to escalation (group 2), and direct escalation to 23 mg (group 3). Safety analyses included incidence, severity, timing of AEs, relationship to the study drug, and premature study discontinuation due to AEs between the groups.ResultsAmong 175 enrolled, 110 patients completed the study. Baseline characteristics were similar among the groups. Using safety population (N = 160), cholinergic gastrointestinal symptoms including anorexia and nausea were the most common AEs and titration groups showed significantly fewer cases of nausea as compared with those in no-titration group.ConclusionsIn this study, dose titration before escalating to donepezil 23 mg/day showed better safety in terms of cholinergic AEs. We suggest that dose titration during the first 4 weeks can be recommended for patients with moderate to severe AD.Trial registrationClinicaltrials.gov, NCT02550665. Retrospectively registered on 15 Sep 2015.

VU6007477, a Novel M1 PAM Based on a Pyrrolo[2,3-b]pyridine Carboxamide Core Devoid of Cholinergic Adverse Events.

Herein, we report the chemical optimization of a new series of M1 positive allosteric modulators (PAMs) based on a novel pyrrolo[2,3-b]pyridine core, developed via scaffold hopping and iterative parallel synthesis. The vast majority of analogs in this series proved to display robust cholinergic seizure activity. However, by removal of the secondary hydroxyl group, VU6007477 resulted with good rat M1 PAM potency (EC50 = 230 nM, 93% ACh max), minimal M1 agonist activity (agonist EC50 > 10 μM), good CNS penetration (rat brain/plasma K p = 0.28, K p,uu = 0.32; mouse K p = 0.16, K p,uu = 0.18), and no cholinergic adverse events (AEs, e.g., seizures). This work demonstrates that within a chemical series prone to robust M1 ago-PAM activity, SAR can result, which affords pure M1 PAMs, devoid of cholinergic toxicity/seizure liability.

A Novel M1 PAM VU0486846 Exerts Efficacy in Cognition Models without Displaying Agonist Activity or Cholinergic Toxicity.

Selective activation of the M1 subtype of muscarinic acetylcholine receptor, via positive allosteric modulation (PAM), is an exciting strategy to improve cognition in schizophrenia and Alzheimer's disease patients. However, highly potent M1 ago-PAMs, such as MK-7622, PF-06764427, and PF-06827443, can engender excessive activation of M1, leading to agonist actions in the prefrontal cortex (PFC) that impair cognitive function, induce behavioral convulsions, and result in other classic cholinergic adverse events (AEs). Here, we report a fundamentally new and highly selective M1 PAM, VU0486846. VU0486846 possesses only weak agonist activity in M1-expressing cell lines with high receptor reserve and is devoid of agonist actions in the PFC, unlike previously reported ago-PAMs MK-7622, PF-06764427, and PF-06827443. Moreover, VU0486846 shows no interaction with antagonist binding at the orthosteric acetylcholine (ACh) site (e.g., neither bitopic nor displaying negative cooperativity with [3H]-NMS binding at the orthosteric site), no seizure liability at high brain exposures, and no cholinergic AEs. However, as opposed to ago-PAMs, VU0486846 produces robust efficacy in the novel object recognition model of cognitive function. Importantly, we show for the first time that an M1 PAM can reverse the cognitive deficits induced by atypical antipsychotics, such as risperidone. These findings further strengthen the argument that compounds with modest in vitro M1 PAM activity (EC50 > 100 nM) and pure-PAM activity in native tissues display robust procognitive efficacy without AEs mediated by excessive activation of M1. Overall, the combination of compound assessment with recombinant in vitro assays (mindful of receptor reserve), native tissue systems (PFC), and phenotypic screens (behavioral convulsions) is essential to fully understand and evaluate lead compounds and enhance success in clinical development.

Design and Synthesis of γ- and δ-Lactam M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity.

Recent data demonstrated that activation of the muscarinic M1 receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M2 and M3 activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M1 PAMs that address this hypothesis. The lead molecule from this series, compound 1 (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M1-selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity. These findings provide preliminary evidence that positive allosteric modulation of M1 is sufficient to elicit cholinergic AEs.