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Further evidence that a drug-drug interaction may have been responsible for the reduction in seizure frequency was also pointed out to the NEJM based on other analyses. After being approached, NEJM replied in a response to the submitting team of clinical pharmacologists that the point of a possible drug-drug interaction had already been made by others, referring to the letter by Tang et al, and that they were not interested in publishing the manuscript. Surprisingly, GW Research Ltd and Devinsky et al were also involved in the initiation of a trial about possible drug-drug interactions between CBD and clobazam (NCT02565108),[14] that was noted in their study protocol, completed in 2016 but which is not in the public domain. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. [Extracted from the article]

Aim Subjects with increasing age are more sensitive to the effects of the anti-muscarinic agent scopolamine, which is used (among other indications) to induce temporary cognitive dysfunction in early phase drug studies with cognition enhancing compounds. The enhanced sensitivity has always been attributed to incipient cholinergic neuronal dysfunction, as a part of the normal aging process. The aim of the study was to correlate age-dependent pharmacodynamic neuro-physiologic effects of scopolamine after correcting for differences in individual exposure. Methods We applied a pharmacokinetic and pharmacodynamic modelling approach to describe individual exposure and neurocognitive effects of intravenous scopolamine administration in healthy subjects. Results A two-compartment linear kinetics model best described the plasma concentrations of scopolamine. The estimated scopolamine population mean apparent central and peripheral volume of distribution was 2.66 ± 1.050 l and 62.10 ± 10.100 l, respectively and the clearance was 1.09 ± 0.096 l min−1. Age was not related to a decrease of performance in the tests following scopolamine administration in older subjects. Only the saccadic peak velocity showed a positive correlation between age and sensitivity to scopolamine. Age was, however, correlated at baseline with an estimated slower reaction time while performing the cognitive tests and to higher global δ and frontal θ frequency bands measured with the surface EEG. Conclusions Most of the differences in response to scopolamine administration between young and older subjects could be explained by pharmacokinetic differences (lower clearance) and not to an enhanced sensitivity when corrected for exposure levels. [ABSTRACT FROM AUTHOR]

BACKGROUND: The objective of this paper is to discuss the sequential trial design and its advantages in clinical trials for ALS. The sequential trial design is an alternative to the classical trial design, which permits stopping a study as soon as a treatment effect can be significantly demonstrated or denied. METHODS: As an example of a sequential survival analysis, a recently completed clinical trial is described. A secondary outcome measure used in the same trial, the decline of the vital lung capacity, was re-analyzed sequentially, in order to illustrate the use of the sequential method for a non-survival variable. To compare the classical with the sequential trial design, the number of patients needed in trials aiming at survival effects ranging from 10% to 20% with a power of 80% or 90% was calculated for both designs. RESULTS: In the given examples the time needed to prove the null hypothesis in the survival analysis, and the number of patients needed to prove the null hypothesis in the analysis of the vital capacity is lower than would have been the case in a classical analysis. In 18 of 24 different situations, the chance is at least 90% that with a sequential trial design fewer patients are needed. CONCLUSIONS: We argue that, particularly for ALS trials, a sequential design may be superior to a classical trial design, as it most often requires fewer patients than classically designed trials of equal power, and more importantly may avoid unnecessary continuation. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Corneal confocal microscopy (CCM) detects small nerve fiber loss and correlates with skin biopsy findings in diabetic neuropathy. In chronic idiopathic axonal polyneuropathy (CIAP) this correlation is unknown. Therefore, we compared CCM and skin biopsy in patients with CIAP to healthy controls, patients with painful diabetic neuropathy (PDN) and diabetics without overt neuropathy (DM). Methods: Participants with CIAP and suspected small fiber neuropathy (n = 15), PDN (n = 16), DM (n = 15), and healthy controls (n = 16) underwent skin biopsy and CCM testing. Inter‐center intraclass correlation coefficients (ICC) were calculated for CCM parameters. Results: Compared with healthy controls, patients with CIAP and PDN had significantly fewer nerve fibers in the skin (IENFD: 5.7 ± 2.3, 3.0 ± 1.8, 3.9 ± 1.5 fibers/mm, all p <.05). Corneal nerve parameters in CIAP (fiber density 23.8 ± 4.9 no./mm2, branch density 16.0 ± 8.8 no./mm2, fiber length 13.1 ± 2.6 mm/mm2) were not different from healthy controls (24.0 ± 6.8 no./mm2, 22.1 ± 9.7 no./mm2, 13.5 ± 3.5 mm/mm2, all p >.05). In patients with PDN, corneal nerve fiber density (17.8 ± 5.7 no./mm2) and fiber length (10.5 ± 2.7 mm/mm2) were reduced compared with healthy controls (p <.05). CCM results did not correlate with IENFD in CIAP patients. Inter‐center ICC was 0.77 for fiber density and 0.87 for fiber length. Discussion: In contrast to patients with PDN, corneal nerve parameters were not decreased in patients with CIAP and small nerve fiber damage. Therefore, CCM is not a good biomarker for small nerve fiber loss in CIAP patients. [ABSTRACT FROM AUTHOR]

Aims: Phosphodiesterase 2 (PDE2) regulates intracellular cyclic adenosine monophosphate and guanosine monophosphate (cAMP/cGMP) levels, which contribute to processes crucial for learning and memory. BI 474121, a potent and selective PDE2 inhibitor, is in development for treating cognitive impairment associated with schizophrenia. Methods: The effects of BI 474121 on cGMP concentrations were first assessed in rat cerebrospinal fluid (CSF) to demonstrate central nervous system (CNS) and functional target engagement. Next, a Phase I study in healthy participants assessed the pharmacokinetics of BI 474121 in CSF vs. plasma, the pharmacodynamics of BI 474121 by measuring cGMP concentrations in the CSF, and the safety of BI 474121. Results: In rats, BI 474121 was associated with a dose‐dependent increase (71% at the highest dose tested [3.0 mg kg−1]) in cGMP levels in the CSF relative to vehicle (P < 0.001). In healthy participants, the maximum‐measured concentration CSF‐to‐plasma ratio for BI 474121 exposure was similar following single oral doses of BI 474121 2.5, 10, 20 and 40 mg (dose‐adjusted geometric mean: 8.96% overall). BI 474121 2.5–40 mg administration in healthy participants also increased cGMP levels in CSF (maximum exposure‐related change from baseline ratio, BI 474121: 1.44–2.20 vs. placebo: 1.26). The most common treatment‐emergent adverse event (AE) was mild‐to‐moderate post‐lumbar puncture syndrome, which resolved with standard treatment. No AEs of special interest were observed. Conclusions: BI 474121 crosses the blood–brain barrier to inhibit PDE2, supporting cGMP as a translational marker to monitor CNS target engagement. These findings promote further clinical development of BI 474121. ClinicalTrials.gov number (NCT04672954). [ABSTRACT FROM AUTHOR]

RIPK1 is a master regulator of inflammatory signaling and cell death and increased RIPK1 activity is observed in human diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). RIPK1 inhibition has been shown to protect against cell death in a range of preclinical cellular and animal models of diseases. SAR443060 (previously DNL747) is a selective, orally bioavailable, central nervous system (CNS)–penetrant, small‐molecule, reversible inhibitor of RIPK1. In three early‐stage clinical trials in healthy subjects and patients with AD or ALS (NCT03757325 and NCT03757351), SAR443060 distributed into the cerebrospinal fluid (CSF) after oral administration and demonstrated robust peripheral target engagement as measured by a reduction in phosphorylation of RIPK1 at serine 166 (pRIPK1) in human peripheral blood mononuclear cells compared to baseline. RIPK1 inhibition was generally safe and well‐tolerated in healthy volunteers and patients with AD or ALS. Taken together, the distribution into the CSF after oral administration, the peripheral proof‐of‐mechanism, and the safety profile of RIPK1 inhibition to date, suggest that therapeutic modulation of RIPK1 in the CNS is possible, conferring potential therapeutic promise for AD and ALS, as well as other neurodegenerative conditions. However, SAR443060 development was discontinued due to long‐term nonclinical toxicology findings, although these nonclinical toxicology signals were not observed in the short duration dosing in any of the three early‐stage clinical trials. The dose‐limiting toxicities observed for SAR443060 preclinically have not been reported for other RIPK1‐inhibitors, suggesting that these toxicities are compound‐specific (related to SAR443060) rather than RIPK1 pathway‐specific. [ABSTRACT FROM AUTHOR]

Dermal allyl isothiocyanate (AITC) administration and whole-body heat stress (WBHS) are two challenge models that are used to evaluate physiological mechanisms of vasodilation and pharmacological activity in humans. Their exact vasodilatory mechanisms in humans are not fully elucidated but are likely to be nitric oxide (NO)-mediated. This study aimed to evaluate whether there is overlap in the vasodilatory pathways of dermal AITC application and WBHS by combining the challenges. In this open-label interventional study, healthy volunteers underwent dermal administration of AITC twice: under basal conditions and during WBHS. Dermal blood flow (DBF) was non-invasively measured using laser speckle contrast imaging four times, once in each of the following situations: baseline, WBHS only, AITC only, and WBHS combined with AITC. A total of 12 male volunteers, aged 18– 61 years, participated in the study. Compared to baseline, following AITC application, their DBF increased by 63.43 AU (baseline: 32.55, 95% CI [17.78, 47.31] AU, AITC only: 95.97, 95% CI [81.21, 110.7] AU, p < 0.0001). During WBHS, the increase in DBF after AITC was 42.76 AU (WBHS only: 87.25, 95% CI [72.49, 102.0] AU, WBHS+AITC: 130.0, 95% CI [115.2, 144.8] AU, p < 0.0001). The combination of WBHS and AITC resulted in a lower DBF than the sum of the DBF responses to AITC and WBHS when applied separately (ED 20.67, 95% CI [− 3.532, 44.88], p = 0.0916). This might point towards the presence of an interaction in the vasodilatory mechanism of AITC application and WBHS, possibly indicating overlap in their NOS-driven vasodilatory pathways. [ABSTRACT FROM AUTHOR]

Background: Noradrenergic signaling declines in Parkinson's disease (PD) following locus coeruleus neurodegeneration. Epidemiologic studies demonstrate that β-acting drugs slow PD progression. Objective: The primary objective was to compare the safety and effects of 3 β-adrenoceptor (β-AR) acting drugs on central nervous system (CNS) function after a single dose in healthy volunteers (HVs) and evaluate the effects of multiple doses of β-AR acting drugs in HVs and PD-patients. Methods: In Part A, HVs received single doses of 32 mg salbutamol, 160μg clenbuterol, 60 mg pindolol and placebo administered in a randomized, 4-way cross-over study. In Part B (randomized cross-over) and Part C (parallel, 2:1 randomized), placebo and/or clenbuterol (20μg on Day 1, 40μg on Day 2, 80μg on Days 3–7) were administered. CNS functions were assessed using the NeuroCart test battery, including pupillometry, adaptive tracking and recall tests. Results: Twenty-seven HVs and 12 PD-patients completed the study. Clenbuterol improved and pindolol reduced the adaptive tracking and immediate verbal recall performance. Clenbuterol and salbutamol increased and pindolol decreased pupil-to-iris ratios. Clenbuterol was selected for Parts B and C. In Part B, clenbuterol significantly increased performance in adaptive tracking with a tendency toward improved performance in immediate and delayed verbal recall. In Part C trends toward improved performance in immediate and delayed verbal recall were observed in PD-patients. Typical cardiovascular peripheral β2-AR effects were observed with clenbuterol. Conclusions: This study demonstrates the pro-cognitive effects of clenbuterol in HVs with similar trends in PD-patients. The mechanism of action is likely activation of β2-ARs in the CNS. Plain Language Summary: Aims and Purpose of the Research: This research aimed to explore how three different drugs affect brain function. These drugs are salbutamol, clenbuterol, and pindolol and work in the brain by stimulating specific brain cells that can improve aspects like memory and coordination. The main question was to see how safe these drugs were and how they impact the brain function after one dose in healthy people, and after multiple doses in both healthy people and those with Parkinson's disease. Background of the Research: Parkinson's disease is a condition where brain cells start to die, which affects different areas of the brain, including movement function, as well as memory and attention. This research matters because finding drugs that affect the brain function could improve the lives of people with Parkinson's disease. Methods and Research Design: The study was conducted in three parts. In the first part, healthy volunteers took one dose of each of the three drugs— salbutamol, clenbuterol, and pindolol— as well as a placebo (a harmless pill that has no effect). The researchers tested the participants' brain functions using various tasks including memory tests and eye response measurements. In the second and third part, healthy people and people with Parkinson's disease took the drug that performed best in healthy volunteers for seven days. Results and Importance: In the first part, a single dose of clenbuterol was safe and improved memory and attentions tasks in healthy people, and therefore was chosen for further testing in the second and third part. In these parts, multiple doses of clenbuterol were safe and helped improve memory and attention tasks in healthy people, with similar positive trends seen in people with Parkinson's disease. The study suggests that clenbuterol might help improve brain function by activating specific receptors in the brain. These results are important because they suggest that clenbuterol could be a potential treatment to help improve brain function in people with Parkinson's disease. However, more research is needed to fully understand its effects and to confirm these findings. [ABSTRACT FROM AUTHOR]

C–C Motif Chemokine Ligand 17 (CCL17) is a chemokine that binds and signals through the G‐protein coupled CC‐chemokine receptor 4 and has been implicated in the development of inflammatory and arthritic pain. GSK3858279 is a high‐affinity, first‐in‐class, monoclonal antibody, binding specifically to CCL17 and inhibiting downstream signaling. In this phase I, randomized, single‐center, double‐blind, placebo‐controlled, three‐period, incomplete‐block crossover study (NCT04114656), the analgesic effects and safety of intravenous GSK3858279 were assessed in a battery of evoked acute pain assessments on healthy, adult (aged ≥18 years), male participants. Participants were randomized 1:1 to receive either one placebo (0.9% w/v NaCl) dose followed by two GSK3858279 doses (PAA treatment sequence), or one GSK3858279 dose followed by two placebo doses (APP treatment sequence). The co‐primary end points were ultraviolet B heat pain detection threshold (°C), cold pressor time to pain tolerance threshold (PTT, sec), and electrical PTT (mA, single stimulus). Twenty‐one participants were enrolled (PAA = 11; APP = 10). Mean age (standard deviation) was 29.3 (7.9) years for PAA, 31.1 (7.7) years for APP. No significant differences were observed in the analgesic effect between GSK3858279 and placebo for any end point. Exposure to GSK3858279 was similar between Period 1 (APP sequence), and Periods 2 and 3 (PAA sequence), with some GSK3858279 carry‐over. Changes in serum CCL17 levels were consistent with the expected GSK3858279 activity. All drug‐related adverse events were mild in intensity and caused no discontinuations. The absence of an efficacy signal in this acute pain model does not preclude efficacy in chronic pain states. [ABSTRACT FROM AUTHOR]

Dynamic balance assessments such as walking adaptability may yield a more realistic prediction of drug‐induced falls compared with postural stability measurements, as falls often result from limited gait adjustments when walking. The Interactive Walkway (IWW) measures walking adaptability but sensitivity to medication effects is unknown. If proven sensitive and specific, IWW could serve as a biomarker for targeted fall‐risk assessments in early clinical drug development. In this three‐way crossover study, 18 healthy elderly (age: 65–80 years) subjects received 5 mg zolpidem, 10 mg suvorexant, or placebo in the morning. Assessments were performed pre‐dose and approximately hourly until 9 h post‐dose. IWW assessments included an 8‐meter walking test, goal‐directed stepping, obstacle‐avoidance, and tandem‐walking. Other pharmacodynamic measurements were the Timed‐Up‐and‐Go (TUG) test at a comfortable and fast pace, adaptive tracking, and body sway. A decline in performance was observed for zolpidem compared with placebo for 3 h post‐dose in IWW walking adaptability outcome measures, TUG, adaptive tracking, and body sway. For the IWW tasks, a decrease in walking speed (among others) was observed. IWW parameters were not affected by suvorexant compared with placebo at any timepoint. However, an increase of 9.8% (95%CI: 1.8%, 18.5%) in body sway was observed for suvorexant compared with placebo up to 3 h post‐dose. The IWW successfully quantified drug effects of two hypnotic drugs and distinguished between zolpidem and suvorexant regarding their effects on walking. As a biomarker, the IWW demonstrated sensitivity in assessing dynamic balance and potential fall risk in early phase clinical drug development. [ABSTRACT FROM AUTHOR]

Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal solution could offer a non‐invasive and user‐friendly alternative. This two‐part clinical study evaluated the safety, tolerability, pharmacokinetics (PK), and dose proportionality of a novel apomorphine hydrochloride oromucosal solution, as well as its relative bioavailability to subcutaneous apomorphine injection and apomorphine sublingual film. In part A of the study, 12 patients with PD received 2 mg oromucosal apomorphine (4% weight/volume) and 2 mg subcutaneous apomorphine in a randomized order, followed by 4 and 8 mg oromucosal apomorphine. In part B of the study, 13 patients with PD received 7 mg oromucosal apomorphine (7% weight/volume) and 30 mg sublingual apomorphine in a randomized order, followed by 14 mg oromucosal apomorphine. Washout between dose administrations in both study parts was at least 2 days. Safety, tolerability, and PK were assessed pre‐ and post‐dose. Both study parts showed that oromucosal apomorphine was generally well‐tolerated. Observed side effects were typical for apomorphine administration and included asymptomatic orthostatic hypotension, yawning, fatigue, and somnolence. Oromucosal apomorphine exposure increased with dose, although less than dose proportional. The mean (SD) maximum exposure reached with 14 mg oromucosal apomorphine was 753.0 (298.6) ng*min/mL (area under the plasma concentration–time curve from zero to infinity) and 8.0 (3.3) ng/mL (maximum plasma concentration). This was comparable to exposure reached after 2 mg subcutaneous apomorphine and approximately half of the exposure observed with 30 mg sublingual apomorphine. In summary, clinically relevant plasma concentrations could be reached in PD patients without tolerability issues. [ABSTRACT FROM AUTHOR]

With this study, we aim to test the hypothesis that the effect of cannabidiol on drop‐seizure frequency in patients with Lennox–Gastaut syndrome and Dravet syndrome could be attributed to a drug–drug interaction with clobazam. We performed clinical trial simulations for the effect of 20 mg/kg/day cannabidiol on drop‐seizure frequency in patients with Lennox–Gastaut syndrome. We assumed that patients taking 10 or 20 mg clobazam would have a 2‐ to 7‐fold increase in N‐desmethylclobazam exposure, whereas patients not taking clobazam would have a median reduction in drop‐seizure frequency and a variability in the percent reduction similar to the placebo group. The results show that the effect of cannabidiol on the median reduction in drop‐seizure frequency in patients with Lennox–Gastaut syndrome may be explained by a drug–drug interaction with clobazam. This may have important implications for the use of cannabidiol and its Food and Drug Administration registration. [ABSTRACT FROM AUTHOR]

It is arguable whether this study is a clear example of drug repurposing, since patients had comorbid insomnia in addition to the diagnosis of MDD, making it impossible to distinguish different drug mechanisms from overlapping disease mechanisms. During clinical trials, dosing that leads to an acceptable interval of plasma drug concentrations is partly determined by the drug's safety profile. [Extracted from the article]

Aims: Dysfunction of nitric oxide‐soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate signalling is implicated in the pathophysiology of cognitive impairment. Zagociguat is a central nervous system (CNS) penetrant sGC stimulator designed to amplify nitric oxide–cyclic guanosine monophosphate signalling in the CNS. This article describes a phase 1b study evaluating the safety and pharmacodynamic effects of zagociguat. Methods: In this randomized crossover study, 24 healthy participants aged ≥65 years were planned to receive 15 mg zagociguat or placebo once daily for 2 15‐day periods separated by a 27‐day washout. Adverse events, vital signs, electrocardiograms and laboratory tests were conducted to assess safety. Pharmacokinetics of zagociguat were evaluated in blood and cerebrospinal fluid (CSF). Pharmacodynamic assessments included evaluation of cerebral blood flow, CNS tests, pharmaco‐electroencephalography, passive leg movement and biomarkers in blood, CSF and brain. Results: Twenty‐four participants were enrolled; 12 participants completed both treatment periods, while the other 12 participants completed only 1 treatment period. Zagociguat was well‐tolerated and penetrated the blood–brain barrier, with a CSF/free plasma concentration ratio of 0.45 (standard deviation 0.092) measured 5 h after the last dose of zagociguat on Day 15. Zagociguat induced modest decreases in blood pressure. No consistent effects of zagociguat on other pharmacodynamic parameters were detected. Conclusion: Zagociguat was well‐tolerated and induced modest blood pressure reductions consistent with other sGC stimulators. No clear pharmacodynamic effects of zagociguat were detected. Studies in participants with proven reduced cerebral blood flow or CNS function may be an avenue for further evaluation of the compound. [ABSTRACT FROM AUTHOR]

Drug development for mood disorders can greatly benefit from the development of robust, reliable, and objective biomarkers. The incorporation of smartphones and wearable devices in clinical trials provide a unique opportunity to monitor behavior in a non-invasive manner. The objective of this study is to identify the correlations between remotely monitored self-reported assessments and objectively measured activities with depression severity assessments often applied in clinical trials. 30 unipolar depressed patients and 29 age- and gender-matched healthy controls were enrolled in this study. Each participant's daily physiological, physical, and social activity were monitored using a smartphone-based application (CHDR MORE™) for 3 weeks continuously. Self-reported depression anxiety stress scale-21 (DASS-21) and positive and negative affect schedule (PANAS) were administered via smartphone weekly and daily respectively. The structured interview guide for the Hamilton depression scale and inventory of depressive symptomatology–clinical rated (SIGHD-IDSC) was administered in-clinic weekly. Nested cross-validated linear mixed-effects models were used to identify the correlation between the CHDR MORE™ features with the weekly in-clinic SIGHD-IDSC scores. The SIGHD-IDSC regression model demonstrated an explained variance (R2) of 0.80, and a Root Mean Square Error (RMSE) of ± 15 points. The SIGHD-IDSC total scores were positively correlated with the DASS and mean steps-per-minute, and negatively correlated with the travel duration. Unobtrusive, remotely monitored behavior and self-reported outcomes are correlated with depression severity. While these features cannot replace the SIGHD-IDSC for estimating depression severity, it can serve as a complementary approach for assessing depression and drug effects outside the clinic. [ABSTRACT FROM AUTHOR]

Highlights • We developed an EEG index sensitive to mecamylamine, for monitoring nicotinic cholinergic effects. • We demonstrate reversal of mecamylamine-induced EEG disturbances both with nicotine and galantamine. • The nicotinic acetylcholine receptor index could enable quantifying EEG effects of pro-cognitive cholinergic compounds. Abstract Objectives Cognitive impairment models are used in clinical studies aimed at proving pharmacology of drugs being developed for Alzheimer's disease and other cognitive disorders. Due to rising interest in nicotinic agonists, we aimed to establish a method to monitor neurophysiological effects of modulating the nicotinic cholinergic system. Methods In a four-way cross-over study, eyes-closed rest EEG was recorded in 28 healthy subjects receiving mecamylamine—a nicotinic acetylcholine receptor (nAChR) antagonist, which induces temporary cognitive dysfunction in healthy subjects—with co-administration of placebo, nicotine or galantamine. Results Using machine learning to optimally contrast the effects of 30 mg of mecamylamine and placebo on the brain, we developed a nAChR index that consists of 10 EEG biomarkers and shows high classification accuracy (∼95% non-cross-validated, ∼70% cross-validated). Importantly, using the nAChR index, we demonstrate reversal of mecamylamine-induced neurophysiological effects due to 16 mg of galantamine as well as administering 21 mg of nicotine transdermally. Conclusions Our findings indicate that the mecamylamine challenge model jointly with the nAChR index—a measure of the nicotinic EEG profile—could aid future proof-of-pharmacology studies to demonstrate effects of nicotinic cholinergic compounds. Significance This novel measure for quantifying nicotinic cholinergic effects on the EEG could serve as a useful tool in drug development of pro-cognitive compounds. [ABSTRACT FROM AUTHOR]

Soluble guanylate cyclase (sGC) and its product, cyclic guanosine monophosphate, play a role in learning and memory formation. Zagociguat (CY6463) is a novel stimulator of sGC being developed for the treatment of neurodegenerative disease. Single zagociguat doses of 0.3, 1, 3, 10, 20, 30, and 50 mg were administered once to healthy participants in a single‐ascending‐dose phase; then zagociguat 2, 5, 10, and 15 mg was administered q.d. for 14 days in a multiple‐ascending‐dose phase; and, finally, zagociguat 10 mg was administered once in both fed and fasted state in a food‐interaction phase. Safety of zagociguat was evaluated by monitoring treatment‐emergent adverse events, suicide risk, vital signs, electrocardiography, and laboratory tests. Pharmacokinetics of zagociguat were assessed through blood, urine, and cerebrospinal fluid sampling. Pharmacodynamic effects of zagociguat were evaluated with central nervous system (CNS) tests and pharmaco‐electroencephalography. Zagociguat was well‐tolerated across all doses evaluated. Zagociguat exposures increased in a dose‐proportional manner. Median time to maximum concentration ranged from 0.8 to 5 h and mean terminal half‐life from 52.8 to 67.1 h. CNS penetration of the compound was confirmed by cerebrospinal fluid sampling. Zagociguat induced up to 6.1 mmHg reduction in mean systolic and up to 7.5 mmHg reduction in mean diastolic blood pressure. No consistent pharmacodynamic (PD) effects on neurocognitive function were observed. Zagociguat was well‐tolerated, CNS‐penetrant, and demonstrated PD activity consistent with other sGC stimulators. The results of this study support further development of zagociguat. [ABSTRACT FROM AUTHOR]

Increased leucine‐rich repeat kinase 2 (LRRK2) kinase activity is an established risk factor for Parkinson's disease (PD), and several LRRK2 kinase inhibitors are in clinical development as potential novel disease‐modifying therapeutics. This biomarker characterization study explored within‐ and between‐subject variability of multiple LRRK2 pathway biomarkers (total LRRK2 [tLRRK2], phosphorylation of the serine 935 (Ser935) residue on LRRK2 [pS935], phosphorylation of Rab10 [pRab10], and total Rab10 [tRab10]) in different biological sources (whole blood, peripheral blood mononuclear cells [PBMCs], neutrophils) as candidate human target engagement and pharmacodynamic biomarkers for implementation in phase I/II pharmacological studies of LRRK2 inhibitors. PD patients with a LRRK2 mutation (n = 6), idiopathic PD patients (n = 6), and healthy matched control subjects (n = 10) were recruited for repeated blood and cerebrospinal fluid (CSF) sampling split over 2 days. Within‐subject variability (geometric coefficient of variation [CV], %) of these biomarkers was lowest in whole blood and neutrophils (range: 12.64%–51.32%) and considerably higher in PBMCs (range: 34.81%–273.88%). Between‐subject variability displayed a similar pattern, with relatively lower variability in neutrophils (range: 61.30%–66.26%) and whole blood (range: 44.94%–123.11%), and considerably higher variability in PBMCs (range: 189.60%–415.19%). Group‐level differences were observed with elevated mean pRab10 levels in neutrophils and a reduced mean pS935/tLRRK2 ratio in PBMCs in PD LRRK2‐mutation carriers compared to healthy controls. These findings suggest that the evaluated biomarkers and assays could be used to verify pharmacological mechanisms of action and help explore the dose–response of LRRK2 inhibitors in early‐phase clinical studies. In addition, comparable α‐synuclein aggregation in CSF was observed in LRRK2‐mutation carriers compared to idiopathic PD patients. [ABSTRACT FROM AUTHOR]

Background: Loss‐of‐function mutations in the GBA1 gene are one of the most common genetic risk factors for onset of Parkinson's disease and subsequent progression (GBA‐PD). GBA1 encodes the lysosomal enzyme glucocerebrosidase (GCase), a promising target for a possible first disease‐modifying therapy. LTI‐291 is an allosteric activator of GCase, which increases the activity of normal and mutant forms of GCase. Objectives: This first‐in‐patient study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of 28 daily doses of LTI‐291 in GBA‐PD. Methods: This was a randomized, double‐blind, placebo‐controlled trial in 40 GBA‐PD participants. Twenty‐eight consecutive daily doses of 10, 30, or 60 mg of LTI‐291 or placebo were administered (n = 10 per treatment allocation). Glycosphingolipid (glucosylceramide and lactosylceramide) levels were measured in peripheral blood mononuclear cells (PBMCs), plasma, and cerebrospinal fluid (CSF), and a test battery of neurocognitive tasks, the Movement Disorder Society‐Unified Parkinson's Disease Rating Scale and the Mini‐Mental State Exam, were performed. Results: LTI‐291 was generally well tolerated, no deaths or treatment‐related serious adverse events occurred, and no participants withdrew due to adverse events. Cmax, and AUC0–6 of LTI‐291 increased in a dose‐proportional manner, with free CSF concentrations equal to the free fraction in plasma. A treatment‐related transient increase in intracellular glucosylceramide (GluCer) in PBMCs was measured. Conclusion: These first‐in‐patient studies demonstrated that LTI‐291 was well tolerated when administered orally for 28 consecutive days to patients with GBA‐PD. Plasma and CSF concentrations that are considered pharmacologically active were reached (ie, sufficient to at least double GCase activity). Intracellular GluCer elevations were detected. Clinical benefit will be assessed in a larger long‐term trial in GBA‐PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Central nervous system (CNS) disorders benefit from ongoing monitoring to assess disease progression and treatment efficacy. Mobile health (mHealth) technologies offer a means for the remote and continuous symptom monitoring of patients. Machine Learning (ML) techniques can process and engineer mHealth data into a precise and multidimensional biomarker of disease activity. Objective: This narrative literature review aims to provide an overview of the current landscape of biomarker development using mHealth technologies and ML. Additionally, it proposes recommendations to ensure the accuracy, reliability, and interpretability of these biomarkers. Methods: This review extracted relevant publications from databases such as PubMed, IEEE, and CTTI. The ML methods employed across the selected publications were then extracted, aggregated, and reviewed. Results: This review synthesized and presented the diverse approaches of 66 publications that address creating mHealth-based biomarkers using ML. The reviewed publications provide a foundation for effective biomarker development and offer recommendations for creating representative, reproducible, and interpretable biomarkers for future clinical trials. Conclusion: mHealth-based and ML-derived biomarkers have great potential for the remote monitoring of CNS disorders. However, further research and standardization of study designs are needed to advance this field. With continued innovation, mHealth-based biomarkers hold promise for improving the monitoring of CNS disorders. [ABSTRACT FROM AUTHOR]

Background: Molecules related to glucocerebrosidase (GCase) are potential biomarkers for development of compounds targeting GBA1‐associated Parkinson's disease (GBA‐PD). Objectives: Assessing variability of various glycosphingolipids (GSLs) in plasma, peripheral blood mononuclear cells (PBMCs), and cerebrospinal fluid (CSF) across GBA‐PD, idiopathic PD (iPD), and healthy volunteers (HVs). Methods: Data from five studies were combined. Variability was assessed of glucosylceramide (various isoforms), lactosylceramide (various isoforms), glucosylsphingosine, galactosylsphingosine, GCase activity (using fluorescent 4‐methylumbeliferryl‐β‐glucoside), and GCase protein (using enzyme‐linked immunosorbent assay) in plasma, PBMCs, and CSF if available, in GBA‐PD, iPD, and HVs. GSLs in leukocyte subtypes were compared in HVs. Principal component analysis was used to explore global patterns in GSLs, clinical characteristics (Movement Disorder Society – Unified Parkinson's Disease Rating Scale Part 3 [MDS‐UPDRS‐3], Mini‐Mental State Examination [MMSE], GBA1 mutation type), and participant status (GBA‐PD, iPD, HVs). Results: Within‐subject between‐day variability ranged from 5.8% to 44.5% and was generally lower in plasma than in PBMCs. Extracellular glucosylceramide levels (plasma) were slightly higher in GBA‐PD compared with both iPD and HVs, while intracellular levels were comparable. GSLs in the different matrices (plasma, PBMCs, CSF) did not correlate. Both lactosylceramide and glucosylsphingosine were more abundant in granulocytes compared with monocytes and lymphocytes. Absolute levels of GSL isoforms differed greatly. GBA1 mutation types could not be differentiated based on GSL data. Conclusions: Glucosylceramide can stably be measured over days in both plasma and PBMCs and may be used as a biomarker in clinical trials targeting GBA‐PD. Glucosylsphingosine and lactosylceramide are stable in plasma but are strongly affected by leukocyte subtypes in PBMCs. GBA‐PD could be differentiated from iPD and HVs, primarily based on glucosylceramide levels in plasma. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Leucine‐rich repeat kinase 2 (LRRK2) inhibition is a promising therapeutic approach for the treatment of Parkinson's disease (PD). Objective: The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the potent, selective, CNS‐penetrant LRRK2 inhibitor BIIB122 (DNL151) in healthy participants and patients with PD. Methods: Two randomized, double‐blind, placebo‐controlled studies were completed. The phase 1 study (DNLI‐C‐0001) evaluated single and multiple doses of BIIB122 for up to 28 days in healthy participants. The phase 1b study (DNLI‐C‐0003) evaluated BIIB122 for 28 days in patients with mild to moderate PD. The primary objectives were to investigate the safety, tolerability, and plasma pharmacokinetics of BIIB122. Pharmacodynamic outcomes included peripheral and central target inhibition and lysosomal pathway engagement biomarkers. Results: A total of 186/184 healthy participants (146/145 BIIB122, 40/39 placebo) and 36/36 patients (26/26 BIIB122, 10/10 placebo) were randomized/treated in the phase 1 and phase 1b studies, respectively. In both studies, BIIB122 was generally well tolerated; no serious adverse events were reported, and the majority of treatment‐emergent adverse events were mild. BIIB122 cerebrospinal fluid/unbound plasma concentration ratio was ~1 (range, 0.7–1.8). Dose‐dependent median reductions from baseline were observed in whole‐blood phosphorylated serine 935 LRRK2 (≤98%), peripheral blood mononuclear cell phosphorylated threonine 73 pRab10 (≤93%), cerebrospinal fluid total LRRK2 (≤50%), and urine bis (monoacylglycerol) phosphate (≤74%). Conclusions: At generally safe and well‐tolerated doses, BIIB122 achieved substantial peripheral LRRK2 kinase inhibition and modulation of lysosomal pathways downstream of LRRK2, with evidence of CNS distribution and target inhibition. These studies support continued investigation of LRRK2 inhibition with BIIB122 for the treatment of PD. © 2023 Denali Therapeutics Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Introduction: Drivers should be aware of possible impairing effects of alcohol, medicinal substance, or fatigue on driving performance. Such effects are assessed in clinical trials, including a driving task or related psychomotor tasks. However, a choice between predicting tasks must be made. Here, we compare driving performance with on-the-road driving, simulator driving, and psychomotor tasks using the effect of sleep deprivation. Method: This two-way cross over study included 24 healthy men with a minimum driving experience of 3000km per year. Psychomotor tasks, simulated driving, and on-the-road driving were assessed in the morning and the afternoon after a well-rested night and in the morning after a sleep-deprived night. Driving behaviour was examined by calculating the Standard Deviation of Lateral Position (SDLP). Results: SDLP increased after sleep deprivation for simulated (10cm, 95%CI:6.7–13.3) and on-the-road driving (2.8cm, 95%CI:1.9–3.7). The psychomotor test battery detected effects of sleep deprivation in almost all tasks. Correlation between on-the-road tests and simulator SDLP after a well-rested night (0.63, p <.001) was not present after a night of sleep deprivation (0.31, p =.18). Regarding the effect of sleep deprivation on the psychomotor test battery, only adaptive tracking correlated with the SDLP of the driving simulator (-0.50, p =.02). Other significant correlations were related to subjective VAS scores. Discussion: The lack of apparent correlations and difference in sensitivity of performance of the psychomotor tasks, simulated driving and, on-the-road driving indicates that the tasks may not be interchangeable and may assess different aspects of driving behaviour. [ABSTRACT FROM AUTHOR]

Low muscle quality and a sedentary lifestyle are indicators for a slow recovery after a total knee arthroplasty (TKA). Mitochondrial function is an important part of muscle quality and a key driver of sarcopenia. However, it is not known whether it relates to recovery. In this pilot study, we monitored activity after TKA using a wrist mounted activity tracker and assessed the relation of mitochondrial function on the rate of recovery after TKA. Additionally, we compared the increase in activity as a way to measure recovery to traditional outcome measures. Patients were studied 2 weeks before TKA and up to 6 months after. Activity was monitored continuously. Baseline mitochondrial function (citrate synthase and complex [CP] 1–5 abundance of the electron transport chain) was determined on muscle tissue taken during TKA. Traditional outcome measures (Knee Injury and Osteoarthritis Outcome Score [KOOS], timed up‐and‐go [TUG] completion time, grip, and quadriceps strength) were performed 2 weeks before, 6 weeks after, and 6 months after TKA. Using a multivariate regression model with various clinical baseline parameters, the following were significantly related to recovery: CP5 abundance, grip strength, and activity (regression weights 0.13, 0.02, and 2.89, respectively). During recovery, activity correlated to the KOOS‐activities of daily living (ADL) score (r = 0.55, p = 0.009) and TUG completion time (r = −0.61, p = 0.001). Mitochondrial function seems to be related to recovery, but so are activity and grip strength, all indicators of sarcopenia. Using activity trackers before and after TKA might give the surgeon valuable information on the expected recovery and the opportunity to intervene if recovery is low. [ABSTRACT FROM AUTHOR]

Aim: We assessed whether total sleep deprivation (TSD) in combination with pain tests yields a reliable method to assess altered pain thresholds, which subsequently may be used to investigate (novel) analgesics in healthy subjects. Methods: This was a two‐part randomized crossover study in 24 healthy men and 24 women. Subjects were randomized 1:1 to first complete a day of nonsleep‐deprived nociceptive threshold testing, followed directly by a TSD night and morning of sleep‐deprived testing, or first complete the TSD night and morning sleep‐deprived testing, returning 7 days later for a day of nonsleep‐deprived testing. A validated pain test battery (heat, pressure, electrical burst and stair, cold pressor pain test and conditioned pain modulation [CPM] paradigm) and sleep questionnaires were performed. Results: Subjects were significantly sleepier after TSD as measured using sleepiness questionnaires. Cold pressor pain tolerance (PTT, estimate of difference [ED] −10.8%, 95% CI −17.5 to −3.6%), CPM PTT (ED −0.69 mA, 95% CI −1.36 to −0.03 mA), pressure PTT (ED −11.2%, 95% CI −17.5% to −4.3%) and heat pain detection thresholds (ED ‐0.74 °C, 95% CI −1.34 to −0.14 °C) were significantly decreased after TSD compared to the baseline morning assessment in the combined analysis (men + women). Heat hyperalgesia was primarily driven by an effect of TSD in men, whereas cold and pressure hyperalgesia was primarily driven by the effects of TSD observed in women. Conclusions: TSD induced sex‐dependent hyperalgesia on cold, heat and pressure pain, and CPM response. These results suggest that the TSD model may be suitable to evaluate (novel) analgesics in early‐phase drug studies. [ABSTRACT FROM AUTHOR]

Aims Human evoked pain models can be used to determine the efficacy of new and existing analgesics and to aid in the identification of new targets. Aspects of neuropathic pain can be simulated by inducing hyperalgesia resulting from provoked sensitization. The present literature review aimed to provide insight into the sensitivity of different hyperalgesia and allodynia models of pharmacological treatment. Methods A literature search was performed to identify randomized, double-blind, placebo-controlled studies that included human hyperalgesia pain models and investigated the pharmacodynamic effects of different classes of drugs. Results Three hyperalgesia models [ultraviolet B (UVB) irradiation, capsaicin and thermode burn] have been used extensively. Assessment of hyperalgesia/allodynia and pharmacological effect are measured using challenge tests, which generally comprise thermal (heat/cold) or mechanical stimulation (pin-prick, stroking or impact). The UVB model was sensitive to the antihyperalgesic effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. The capsaicin model was partially sensitive to opioids. The burn model did not detect any antihyperalgesic effects when NSAIDs or local anaesthetics were administered but responded to the effects of N-methyl D-aspartate (NMDA) receptor antagonists by moderately reducing mechanical hyperalgesia. Conclusions Based on pharmacological sensitivity, the UVB model adequately reflects inflammatory pain and was sensitive to NSAIDs and opioids. Findings from the capsaicin and burn models raised questions about the translatability of these models to the treatment of neuropathic pain. There is a need for a reproducible and predictive model of neuropathic pain, either in healthy subjects or in patients. [ABSTRACT FROM AUTHOR]

Measuring muscle velocity recovery cycles (MVRCs) is a method to obtain information on muscle cell excitability, independent of neuromuscular transmission. The goal was to validate MVRC as a pharmacodynamic (PD) biomarker for drugs targeting muscle excitability. As proof‐of‐concept, sensitivity of MVRC to detect effects of mexiletine, a voltage‐gated sodium channel (Nav) blocker, was assessed. In a randomized, double‐blind, two‐way crossover study, effects of a single pharmacologically active oral dose of 333 mg mexiletine was compared to placebo in 15 healthy male subjects. MVRC was performed predose, and 3‐ and 5‐h postdose using QTrac. Effects of mexiletine versus placebo were calculated using a mixed effects model with baseline as covariate. Mexiletine had significant effects on MVRC when compared to placebo. Early supernormality after five conditioning stimuli was decreased by mexiletine (estimated difference −2.78% [95% confidence interval: −4.16, −1.40]; p value = 0.0003). Moreover, mexiletine decreased the difference in late supernormality after five versus one conditioning stimuli (5XLSN; ED −1.46% [−2.26, −0.65]; p = 0.001). These results indicate that mexiletine decreases the percentage increase in velocity of the muscle fiber action potential after five conditioning stimuli, at long and short interstimulus intervals, which corresponds to a decrease in muscle membrane excitability. This is in line with the pharmacological activity of mexiletine, which leads to use‐dependent NaV1.4 blockade affecting muscle membrane potentials. This study shows that effects of mexiletine can be detected using MVRC in healthy subjects, thereby indicating that MVRC can be used as a tool to demonstrate PD effects of drugs targeting muscle excitability in early phase drug development. [ABSTRACT FROM AUTHOR]

Background: Movement Disorder Society–Unified Parkinson's Rating Scale Part III (MDS‐UPDRS III) is the gold standard for assessing medication effects in patients with Parkinson's disease (PD). However, short and rater‐independent measurements would be ideal for future trials. Objectives: To assess the ability of 3 different finger tapping tasks to detect levodopa/carbidopa‐induced changes over time and to determine their correlation and compare their discriminatory power with MDS‐UPDRS III. Methods: This was a randomized, double‐blind, crossover study in 20 patients with PD receiving levodopa/carbidopa and placebo capsules after overnight medication withdrawal. Pre‐ and up to 3.5 hours postdose, MDS‐UPDRS III and tapping tasks were performed. Tasks included 2 touchscreen‐based alternate finger tapping tasks (index finger versus index–middle finger tapping) and a thumb–index finger task using a goniometer. Results: In the alternate index finger tapping task, levodopa/carbidopa compared with placebo resulted in significantly faster (total taps: 12.5 [95% confidence interval, CI, 6.7–18.2]) and less accurate tapping (total spatial error: 240 mm [95% CI, 123–357 mm]) with improved rhythm (intertap interval standard deviation [SD], −16.3% [95% CI, −29.9% to 0.0%]). In the thumb–index finger task, tapping was significantly faster (mean opening velocity, 151 degree/s [64–237 degree/s]), with a higher mean amplitude (8.4 degrees [3.7–13.0 degrees]) and improved rhythm (intertap interval SD, −46.4% [95% CI, −63.7% to −20.9%]). The speed‐related endpoints showed a moderate‐to‐strong correlation with the MDS‐UPDRS III (r = 0.45–0.70). The effect sizes of total taps and spatial error in the alternate index finger tapping task and opening velocity in the thumb–index finger task were comparable with the MDS‐UPDRS III. In contrast, the MDS‐UPDRS III performed better than the alternate index–middle finger task. Conclusion: The alternate index finger and the thumb–index finger tapping tasks provide short, rater‐independent measurements that are sensitive to levodopa/carbidopa effects with a similar effect size as the MDS‐UPDRS III. [ABSTRACT FROM AUTHOR]

Background: This study investigated plasma biomarkers for neuroinflammation associated with Alzheimer's disease (AD) in subjects with preclinical AD compared to healthy elderly. How these biomarkers behave in patients with AD, compared to healthy elderly is well known, but determining these in subjects with preclinical AD is not and will add information related to the onset of AD. When found to be different in preclinical AD, these inflammatory biomarkers may be used to select preclinical AD subjects who are most likely to develop AD, to participate in clinical trials with new disease-modifying drugs. Methods: Healthy elderly (n= 50; age 71.9; MMSE >24) and subjects with preclinical AD (n=50; age 73.4; MMSE >24) defined by CSF Aβ1-42 levels < 1000 pg/mL were included. Four neuroinflammatory biomarkers were determined in plasma, GFAP, YKL-40, MCP-1, and eotaxin-1. Differences in biomarker outcomes were compared using ANCOVA. Subject characteristics age, gender, and APOE ε4 status were reported per group and were covariates in the ANCOVA. Least square means were calculated for all 4 inflammatory biomarkers using both the Aβ+/Aβ− cutoff and Ptau/Aβ1-42 ratio. Results: The mean (standard deviation, SD) age of the subjects (n=100) was 72.6 (4.6) years old with 62 male and 38 female subjects. Mean (SD) overall MMSE score was 28.7 (0.49) and 32 subjects were APOE ε4 carriers. The number of subjects in the different APOE ε4 status categories differed significantly between the Aβ+ and Aβ− groups. Plasma GFAP concentration was significantly higher in the Aβ+ group compared to the Aβ− group with significant covariates age and sex, variables that also correlated significantly with GFAP. Conclusion: GFAP was significantly higher in subjects with preclinical AD compared to healthy elderly which agrees with previous studies. When defining preclinical AD based on the Ptau181/Aβ1-42 ratio, YKL-40 was also significantly different between groups. This could indicate that GFAP and YKL-40 are more sensitive markers of the inflammatory process in response to the Aβ misfolding and aggregation that is ongoing as indicated by the lowered Aβ1-42 levels in the CSF. Characterizing subjects with preclinical AD using neuroinflammatory biomarkers is important for subject selection in new disease-modifying clinical trials. Trial registration: ISRCTN.org identifier: ISRCTN79036545 (retrospectively registered). [ABSTRACT FROM AUTHOR]

Altered motor neuron excitability in patients with amyotrophic lateral sclerosis (ALS) has been suggested to be an early pathophysiological mechanism associated with motor neuron death. Compounds that affect membrane excitability may therefore have disease‐modifying effects. Through which mechanism(s), these compounds modulate membrane excitability is mostly provided by preclinical studies, yet remains challenging to verify in clinical studies. Here, we investigated how retigabine affects human myelinated motor axons by applying computational modeling to interpret the complex excitability changes in a recent trial involving 18 ALS patients. Compared to baseline, the post‐dose excitability differences were modeled well by a hyperpolarizing shift of the half‐activation potential of slow potassium (K+)‐channels (till 2 mV). These findings verify that retigabine targets slow K+‐channel gating and highlight the usefulness of computational models. Further developments of this approach may facilitate the identification of early target engagement and ultimately aid selecting responders leading to more personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Background: α‐Synuclein (αSyn) is believed to play a central role in Parkinson's disease (PD) neuropathology and is considered a target for disease modification. UB‐312 is a synthetic αSyn peptide conjugated to a T helper peptide and is expected to induce antibodies specifically against oligomeric and fibrillar αSyn, making UB‐312 a potential immunotherapeutic for synucleopathies. Objective: To investigate the safety, tolerability, and immunogenicity of UB‐312 vaccination in healthy participants and to determine a safe and immunologically optimal dose for the first‐in‐patient study. Methods: Fifty eligible healthy participants were enrolled in a 44‐week, randomized, placebo‐controlled, double‐blind study. Participants in seven cohorts were randomized to three intramuscular UB‐312 or placebo injections at weeks 1, 5, and 13 (doses ranging between 40 and 2000 μg). Safety and tolerability were assessed by adverse events, clinical laboratory, vital signs, electrocardiograms, and neurological and physical examinations. Immunogenicity was assessed by measuring serum and cerebrospinal fluid (CSF) anti‐αSyn antibody concentrations. Results: Twenty‐three participants received all three vaccinations of UB‐312. Most adverse events were mild, transient, and self‐resolving. Common treatment‐emergent adverse events included headache, nasopharyngitis, vaccination‐site pain, lumbar puncture‐site pain, and fatigue. UB‐312 induced dose‐ and time‐dependent antibody production. Antibodies were detectable in serum and CSF of all participants receiving the 300/300/300 μg UB‐312 dose regimen. The average CSF/serum ratio was 0.2%. Conclusions: UB‐312 was generally safe, well tolerated, and induced anti‐αSyn antibodies in serum and CSF of healthy participants. The 100 and 300 μg doses are selected for further evaluation in participants with PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Aims: The purpose of this study was to investigate pharmacodynamic effects of drugs targeting cortical excitability using transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG) in healthy subjects, to further develop TMS outcomes as biomarkers for proof‐of‐mechanism in early‐phase clinical drug development. Antiepileptic drugs presumably modulate cortical excitability. Therefore, we studied effects of levetiracetam, valproic acid and lorazepam on cortical excitability in a double‐blind, placebo‐controlled, 4‐way cross‐over study. Methods: In 16 healthy male subjects, single‐ and paired‐pulse TMS‐EMG–EEG measurements were performed predose and 1.5, 7 and 24 hours postdose. Treatment effects on motor‐evoked potential, short and long intracortical inhibition and TMS‐evoked potential amplitudes, were analysed using a mixed model ANCOVA and cluster‐based permutation analysis. Results: We show that motor‐evoked potential amplitudes decreased after administration of levetiracetam (estimated difference [ED] −378.4 μV; 95%CI: −644.3, −112.5 μV; P <.01), valproic acid (ED −268.8 μV; 95%CI: −532.9, −4.6 μV; P =.047) and lorazepam (ED −330.7 μV; 95%CI: −595.6, −65.8 μV; P =.02) when compared with placebo. Long intracortical inhibition was enhanced by levetiracetam (ED −60.3%; 95%CI: −87.1%, −33.5%; P <.001) and lorazepam (ED −68.2%; 95%CI: −94.7%, −41.7%; P <.001) at a 50‐ms interstimulus interval. Levetiracetam increased TMS‐evoked potential component N45 (P =.004) in a central cluster and decreased N100 (P <.001) in a contralateral cluster. Conclusion: This study shows that levetiracetam, valproic acid and lorazepam decrease cortical excitability, which can be detected using TMS‐EMG–EEG in healthy subjects. These findings provide support for the use of TMS excitability measures as biomarkers to demonstrate pharmacodynamic effects of drugs that influence cortical excitability. [ABSTRACT FROM AUTHOR]

Aims: Cholinesterase inhibitors (CEIs) have been shown to improve cognitive functioning in Alzheimer's disease (AD) patients, but are associated with multiple side effects and only 20–40% of the patients clinically improve. In this study, we aimed to investigate the acute pharmacodynamic (PD) effects of administration of a single dose of galantamine on central nervous system (CNS) functioning in mild to moderate AD patients and its potential to predict long‐term treatment response. Methods: This study consisted of a challenge and treatment phase. In the challenge phase, a single dose of 16 mg galantamine was administered to 50 mild to moderate AD patients in a double‐blind, placebo‐controlled cross‐over fashion. Acute PD effects were monitored up to 5 hours after administration with use of the NeuroCart CNS test battery and safety and pharmacokinetics were assessed. In the treatment phase, patients were treated with open‐label galantamine according to regular clinical care. After 6 months of galantamine treatment, patients were categorized as either responder or as non‐responder based on their minimental state examination (MMSE), neuropsychiatric inventory (NPI) and disability assessment in dementia (DAD) scores. An analysis of covariance was performed to study the difference in acute PD effects during the challenge phase between responders and non‐responders. Results: A single dose of galantamine significantly reduced saccadic reaction time (−0.0099; 95% CI = −0.0195, −0.0003; P =.0430), absolute frontal EEG parameters in alpha (−14.9; 95% CI = −21.0, −8.3; P =.0002), beta (−12.6; 95% CI = −19.4, −5.3; P =.0019) and theta (−17.9; 95% CI = −25.0, −10.0; P =.0001) frequencies. Relative frontal (−1.669; 95% CI = −2.999, −0.339; P =.0156) and occipital (−1.856; 95% CI = −3.339, −0.372; P =.0166) EEG power in theta frequency and relative occipital EEG power in the gamma frequency (1.316; 95% CI = 0.158, 2.475; P =.0273) also increased significantly compared to placebo. Acute decreases of absolute frontal alpha (−20.4; 95% CI = −31.6, −7.47; P =.0046), beta (−15.7; 95% CI = −28.3, −0.93; P =.0390) and theta (−25.9; 95% CI = −38.4, −10.9; P =.0024) EEG parameters and of relative frontal theta power (−3.27%; 95% CI = −5.96, −0.58; P =.0187) on EEG significantly distinguished responders (n = 11) from non‐responders (n = 32) after 6 months. Conclusions: This study demonstrates that acute PD effects after single dose of galantamine are correlated with long‐term treatment effects and that patients who demonstrate a reduction in EEG power in the alpha and theta frequency after a single administration of galantamine 16 mg will most likely respond to treatment. [ABSTRACT FROM AUTHOR]

Background: Inhalation of apomorphine could be a faster‐acting and more user‐friendly alternative to subcutaneous injection for treating off periods in Parkinson's disease (PD). Objective: The aim of this study was to compare the safety and pharmacokinetics of inhaled apomorphine (AZ‐009) with subcutaneous apomorphine (APO‐go PEN) in healthy volunteers (HVs) and to examine the safety, pharmacokinetics, and efficacy of AZ‐009 in patients with PD. Methods: In part A of this study, eight HVs received 1 mg AZ‐009 and 2 mg subcutaneous apomorphine in a randomized crossover manner. In the subsequent single ascending dose parts in HVs (part B, n = 16) and patients with PD (part C, n = 25), participants were randomized to placebo or AZ‐009 up to 4 mg. In patients, after medication withdrawal, Movement Disorder Society‐Unified Parkinson's Disease Rating Scale part III and on/off states were assessed predose and postdose. Results: AZ‐009 was rapidly absorbed with peak plasma concentrations at 2 minutes, as compared to 30 minutes for subcutaneous apomorphine. Adverse events for AZ‐009 were comparable to subcutaneous apomorphine, except for mild and transient throat irritation. Adverse events limited AZ‐009 dose escalation in HVs to 3 mg. Patients tolerated up to 4 mg. In patients with PD, 2, 3, and 4 mg AZ‐009 reduced mean Movement Disorder Society‐Unified Parkinson's Disease Rating Scale part III score (standard deviation) by 10.7 (13.6), 12.8 (7.9), and 10.3 (3.7) points, respectively, compared to 4.8 (4.9) after placebo at 10 minutes postdose. The percentage of patients achieving full on within 45 minutes postdose increased dose dependently: 0% (placebo), 17% (2 mg), 50% (3 mg), and 83% (4 mg). Conclusions: AZ‐009 appears to be a rapid‐acting and reasonably well‐tolerated formulation for treating off periods. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Introduction: Apomorphine is used to treat OFF periods in Parkinson's disease (PD) patients. AZ-009 is a novel apomorphine formulation that delivers a thermally-generated aerosol to the deep lung via inhalation with a single breath.Methods: Part A was a randomized, placebo-controlled, double-blind study investigating the safety and pharmacokinetics of multiple ascending doses of AZ-009. PD patients (n = 24) received placebo or 2, 3 or 4 mg AZ-009 once daily for 5 days, followed by three times daily for 2 days with 2 h between doses. Part B was a double-blind crossover study in 8 PD patients who experience OFF periods. During an OFF state, patients received 4 mg AZ-009 and placebo on two consecutive days in a randomized order. MDS-UPDRS III and ON/OFF state were assessed pre- and post-dose.Results: Three times daily dosing with 2, 3 and 4 mg AZ-009 was relatively well tolerated with no apparent accumulation or changes in safety profile. Mild and transient throat irritation and cough were reported most often. AZ-009 was rapidly absorbed with median Tmax between 1 and 2 min. When corrected for placebo response, the maximum effect of 4 mg AZ-009 based on MDS-UPDRS III scores was observed at 10 and 30 min post-dose with mean (SD) reductions of 6.8 (9.4) and 6.1 (9.1) points respectively. Whereas 0% of patients turned ON after placebo, 50% turned ON 10 min after 4 mg AZ-009 treatment.Conclusion: AZ-009 is rapidly systemically absorbed and safe to dose three times daily. AZ-009 could provide a faster-acting and easier to use formulation than currently available therapies. [ABSTRACT FROM AUTHOR]

Selective inhibition of certain voltage‐gated sodium channels (Navs), such as Nav1.8, is of primary interest for pharmacological pain research and widely studied as a pharmacological target due to its contribution to repetitive firing, neuronal excitability, and pain chronification. VX‐128 is a highly potent and selective Nav1.8 inhibitor that was being developed as a treatment for pain. We evaluated the safety, tolerability, and pharmacokinetics of VX‐128 in healthy subjects in a single‐ and multiple‐ascending dose (MAD) first‐in‐human study. Pharmacodynamics were evaluated in the MAD part using a battery of evoked pain tests. Overall, single doses of VX‐128 up to 300 mg were well‐tolerated, although adverse effect (AE) incidence was higher in subjects receiving VX‐128 (41.7%) compared with placebo (25.0%). After multiple dosing of up to 10 days, skin rash events were observed at all dose levels (up to 100 mg once daily [q.d.]), in five of 26 (19.2%) subjects, including one subject receiving VX‐128 (100 mg q.d.) who had a serious AE of angioedema. A trend in pain tolerance were observed for cold pressor‐ and pressure pain, which was dose‐dependent for the latter. VX‐128 was rapidly absorbed (median time to maximum plasma concentration between 1 and 2 h) with a half‐life of ~80 h at 10 mg q.d., and approximately two‐fold accumulation ratio after 10 and 30 mg q.d. Although VX‐128, when given in a multiple dose fashion, resulted in early study termination due to tolerability issues, effects were observed on multiple pain tests that may support further investigation of Nav1.8 inhibitors as pain treatments. [ABSTRACT FROM AUTHOR]

Recently, Verberk et al showed that plasma A 42/A 40 ratio has potential to identify Alzheimer pathological changes in subjects with subjective memory decline.[1] Furthermore, the inclusion of age and APOE 4 carriership in their multivariate model improved the likelihood of identification. Based on these results, Verberk and colleagues postulated that plasma A 42/A 40 ratio could be a potential prescreener to identify the earliest Alzheimer disease (AD) pathological changes in individuals with subjective memory decline. [Extracted from the article]

The majority of disease modifying therapies for multiple sclerosis (MS) reduce inflammation, but do no't target remyelination. Development of remyelinating therapies will benefit from a method to quantify myelin kinetics in patients with MS. We labeled myelin in vivo with deuterium, and modeled kinetics of myelin breakdown products β‐galactosylceramide (β‐GalC) and N‐Octadecanoyl‐sulfatide (NO‐Sulf). Five patients with MS received 120 ml 70% D2O daily for 70 days and were compared with six healthy subjects who previously received the same procedure. Mass spectrometry and compartmental modeling were used to quantify the turnover rate of β‐GalC and NO‐Sulf in cerebrospinal fluid (CSF). Turnover rate constants of the fractions of β‐GalC and NO‐Sulf with non‐negligible turnover were 0.00186 and 0.00714, respectively, in both healthy subjects and patients with MS. The turnover half‐life of β‐GalC and NO‐Sulf was calculated as 373 days and 96.5 days, respectively. The effect of MS on the NO‐Sulf (49.4% lower fraction with non‐negligible turnover) was more pronounced compared to the effect on β‐GalC turnover (18.3% lower fraction with non‐negligible turnover). Kinetics of myelin breakdown products in the CSF are different in patients with MS compared with healthy subjects. This may be caused by slower myelin production in these patients, by a higher level of degradation of a more stable component of myelin, or, most likely, by a combination of these two processes. Labeling myelin breakdown products is a useful method that can be used to quantify myelin turnover in patients with progressive MS and can therefore be used in proof‐of‐concept studies with remyelination therapies. [ABSTRACT FROM AUTHOR]

Sleep deprivation has been shown to increase pain intensity and decrease pain thresholds in healthy subjects. In chronic pain patients, sleep impairment often worsens the perceived pain intensity. This increased pain perception is the result of altered nociceptive processing. We recently developed a method to quantify and monitor altered nociceptive processing by simultaneous tracking of psychophysical detection thresholds and recording of evoked cortical potentials during intra-epidermal electric stimulation. In this study, we assessed the sensitivity of nociceptive detection thresholds and evoked potentials to altered nociceptive processing after sleep deprivation in an exploratory study with 24 healthy male and 24 healthy female subjects. In each subject, we tracked nociceptive detection thresholds and recorded central evoked potentials in response to 180 single- and 180 double-pulse intra-epidermal electric stimuli. Results showed that the detection thresholds for single- and double-pulse stimuli and the average central evoked potential for single-pulse stimuli were significantly decreased after sleep deprivation. When analyzed separated by sex, these effects were only significant in the male population. Multivariate analysis showed that the decrease of central evoked potential was associated with a decrease of task-related evoked activity. Measurement repetition led to a decrease of the detection threshold to double-pulse stimuli in the mixed and the female population, but did not significantly affect any other outcome measures. These results suggest that simultaneous tracking of psychophysical detection thresholds and evoked potentials is a useful method to observe altered nociceptive processing after sleep deprivation, but is also sensitive to sex differences and measurement repetition. [ABSTRACT FROM AUTHOR]

Background: Opioid-induced respiratory depression driven by ligand binding to mu-opioid receptors is a leading cause of opioid-related fatalities. Buprenorphine, a partial agonist, binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects. The authors examined whether sustained buprenorphine plasma concentrations similar to those achieved with some extended-release injections used to treat opioid use disorder could reduce the frequency and magnitude of fentanyl-induced respiratory depression. Methods: In this two-period crossover, single-centre study, 14 healthy volunteers (single-blind, randomized) and eight opioid-tolerant patients taking daily opioid doses ≥90 mg oral morphine equivalents (open-label) received continuous intravenous buprenorphine or placebo for 360 minutes, targeting buprenorphine plasma concentrations of 0.2 or 0.5 ng/mL in healthy volunteers and 1.0, 2.0 or 5.0 ng/mL in opioid-tolerant patients. Upon reaching target concentrations, participants received up to four escalating intravenous doses of fentanyl. The primary endpoint was change in isohypercapnic minute ventilation (VE). Additionally, occurrence of apnea was recorded. Results: Fentanyl-induced changes in VE were smaller at higher buprenorphine plasma concentrations. In healthy volunteers, at target buprenorphine concentration of 0.5 ng/mL, the first and second fentanyl boluses reduced VE by [LSmean (95% CI)] 26% (13–40%) and 47% (37–59%) compared to 51% (38–64%) and 79% (69–89%) during placebo infusion (p = 0.001 and <.001, respectively). Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection. In opioid-tolerant patients, fentanyl reduced VE up to 49% (21–76%) during buprenorphine infusion (all concentration groups combined) versus up to 100% (68–132%) during placebo infusion (p = 0.006). In opioid-tolerant patients, the risk of experiencing apnea requiring verbal stimulation following fentanyl boluses was lower with buprenorphine than with placebo (odds ratio: 0.07; 95% CI: 0.0 to 0.3; p = 0.001). Interpretation: Results from this proof-of-principle study provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids like fentanyl. [ABSTRACT FROM AUTHOR]

Aim: Dual enkephalinase inhibitors (DENKIs) are involved in the regulation of nociception via opioid receptors. The novel compound STR‐324 belongs to the DENKI pharmacological class. This first‐in‐human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of STR‐324 in healthy male participants. Methods: This was a randomised, double‐blind, placebo‐controlled ascending dosing study in two parts: in part 1, 30 participants received 0.004‐11.475 mg h−1 of STR‐324 or placebo (ratio 4:1) by 4 h intravenous infusion in a two‐group, partial crossover design with four treatment periods separated by 1 month wash‐out, and in part 2, 48 participants divided into three groups received either the active drug (1.25‐11.25 mg h−1) or placebo (ratio 3:1) by 48 h intravenous infusion. Safety and tolerability parameters, pharmacokinetics and pharmacodynamic effects on neurocognitive and neurophysiological tasks and on a nociceptive test battery were evaluated. Results: No clinically relevant changes in safety parameters were observed. All treatment‐emergent adverse events were mild and transient. The pharmacokinetics of STR‐324 could not be determined due to most concentrations being below quantifiable limits. STR‐324 metabolite concentrations were measurable, showing dose proportionality of Cmax and AUCinf with an estimated t1/2 of 0.2‐0.5 h. Significant changes in pharmacodynamic parameters were observed, but these were not consistent or dose‐dependent. Conclusion: STR‐324 displayed favourable safety and tolerability profiles at all doses up to 11.475 mg h−1. Although pharmacokinetic characterisation of STR‐324 was limited, dose proportionality could be assumed based on major metabolite data assayed as proxy. No clear effects on nociceptive thresholds or other pharmacodynamic measures were observed. Trial registry: EudraCT (2014‐002402‐21) and toetsingonline.nl (63085). [ABSTRACT FROM AUTHOR]

Relevant regulations cited from ICH-GCP R2 5.18.1: "The purposes of trial monitoring are that: ... (b) The reported trial data are accurate, complete, and verifiable from source documents." Relevant regulations cited from ICH-GCP R2 4.8.6: "The language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical and should be understandable to the subject ...." ICH-GCP-R2 CHAPTER 5. Keywords: bureaucracy; clinical trials; drug development; regulation EN bureaucracy clinical trials drug development regulation 4552 4559 8 12/22/21 20211201 NES 211201 INTRODUCTION The International Conference on Harmonization-Good Clinical Practice (ICH-GCP)1 guidelines are implemented worldwide, to ensure the well-being of trial participants and the quality of trials. ICH-GCP-R2: 5.18 Monitoring Trial monitoring for the sake of trial monitoring, not related to integrity of the outcome or participant safety. [Extracted from the article]

Aims: HTL0009936 is a selective M1 muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 administered by continuous IV infusion at steady state were investigated in elderly subjects with below average cognitive functioning (BACF). Methods: Part A was a four‐treatment open label sequential study in healthy elderly investigating 10–83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five‐treatment randomized, double‐blind, placebo and physostigmine controlled cross‐over study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests. Results: Pharmacokinetics of HTL0009936 showed dose‐proportional increases in exposure with a mean half‐life of 2.4 hours. HTL0009936 was well‐tolerated with transient dose‐related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99–10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18–7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine. Conclusions: HTL0009936 showed well‐characterized pharmacokinetics and single doses were safe and generally well‐tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement. [ABSTRACT FROM AUTHOR]

Selective M1 muscarinic acetylcholine receptor (mAChR) agonists are being developed as symptomatic treatment for neurodegenerative and neuropsychiatric disorders that lead to cognitive dysfunction. Demonstrating cognition‐enhancing effects in early‐phase clinical development in healthy subjects is difficult. A challenge with the M1 mAChR antagonist biperiden could be used to demonstrate procognitive and pharmacological effects of selective M1 mAChR agonists. The aim of this study was to develop such a model. To this end, 12 healthy elderly subjects participated in a randomized, placebo‐controlled, 3‐way crossover study investigating tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of 2 and 4 mg biperiden. Repeated PD assessments were performed using neurocognitive tasks and electrophysiological measurements. A population PK‐PD model was developed. Four milligrams of biperiden showed significant impairment of sustained attention (−2.1 percentage point in adaptive tracking [95%CI, −3.043 to −1.148], verbal memory (2‐3 fewer words recalled [95%CI, −5.9 to −0.2]) and working memory (up to a 50‐millisecond increase in the n‐back task reaction time [95%CI, 21.854‐77.882]) compared with placebo. The PK data were best fitted by a 2‐compartment model and showed high interoccasion and intersubject variability. Population PK‐PD analysis quantified significant concentration‐effect relationships for the n‐back reaction time, n‐back accuracy, and adaptive tracking. In conclusion, biperiden caused M1 mAChR‐related dose‐ and concentration‐dependent temporary declines in cognitive functioning. Therefore a biperiden pharmacological challenge model can be used for proof‐of‐pharmacology studies and to demonstrate cognition‐enhancing effects of new cholinergic compounds that are being developed. [ABSTRACT FROM AUTHOR]

Aims: A mutation in the GBA1 gene is the most common genetic risk factor for developing Parkinson's disease. GBA1 encodes the lysosomal enzyme glucosylceramidase beta (glucocerebrosidase, GCase) and mutations decrease enzyme activity. LTI‐291 is an allosteric modulator of GCase, enhancing its activity. These first‐in‐human studies evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of LTI‐291 in healthy volunteers. Methods: In the single ascending dose (SAD) study, 40 healthy volunteers were randomly assigned to LTI‐291 (n = 8 per dose level) or placebo (n = 2 per dose level). Single doses of 3, 10, 30 and 90 mg LTI‐291 were investigated. In the multiple ascending dose (MAD) study, 40 healthy middle‐aged or elderly volunteers were randomly assigned to LTI‐291 (n = 8 per dose level) or placebo (n = 2 per dose level). Fourteen consecutive daily doses of 3, 10, 30 and 60 mg LTI‐291 or placebo were administered. In both the SAD and MAD studies, glycosphingolipid levels were measured and a test battery of neurocognitive tasks was performed. Results: LTI‐291 was generally well tolerated and no deaths or treatment‐related SAEs occurred and no subject withdrew from a study due to AEs. Cmax, AUC0–24 and AUC0‐inf increased in a dose proportional manner. The median half‐life was 28.0 hours after multiple dosing. No dose‐dependent glycosphingolipid changes occurred. No neurocognitive adverse effects were detected. Conclusions: These first‐in‐human studies demonstrated that LTI‐291 was well tolerated when given orally once daily for 14 consecutive days. This supports the continued clinical development and the exploration of LTI‐291 effects in a GBA1‐mutated Parkinson population. [ABSTRACT FROM AUTHOR]

Introduction: HTL0018318 is a selective muscarinic M1 receptor partial agonist under development for the symptomatic treatment of dementias, including Alzheimer's disease. Clinically, HTL0018318 would likely be used alone or in conjunction with cholinesterase inhibitors (e.g. donepezil). Objective: We investigated the safety, tolerability, and pharmacokinetics of HTL0018318 given alone and in combination with donepezil. Methods: This was a randomized, double-blind, placebo-controlled trial in 42 (to deliver 36 with combination treatment) healthy elderly subjects investigating the effects of oral HTL0018318 15 and 25 mg given alone and combined with donepezil 10 mg at steady state on adverse events (AEs), vital signs, saliva production, sleep quality, pulmonary function, subjective feelings, and pharmacokinetics. Results: AEs were reported by lower percentages of subjects after HTL0018318 alone than after donepezil alone. There was no increase in the percentage of subjects reporting AEs after co-administration than after donepezil alone. Supine systolic blood pressure was 1.6 mmHg (95% confidence interval [CI] −3.1 to −0.1) lower after HTL0018318 alone than after combination treatment. This was comparable with results from placebo alone: 1.7 mmHg (95% CI −3.2 to 0.2) lower than with combination treatment. Supine pulse rate was 3.3 bpm (95% CI 1.5–5.1) higher after HTL0018318 alone than with co-administration. HTL0018318 and donepezil did not meaningfully affect each other's pharmacokinetics. Conclusion: HTL0018318 was well tolerated when given alone and in combination with donepezil. HTL0018318 and donepezil do not demonstrate pharmacokinetic or pharmacodynamic interactions, indicating that HTL0018318 can be safely administered in combination with donepezil. Clinical trial registration: Netherlands Trial register identifier NL5915, registered on 28 October 2016. [ABSTRACT FROM AUTHOR]

Objective To evaluate the analgesic potential, safety, tolerability, and pharmacokinetics of VX-150, a pro-drug of a highly selective NaV1.8 inhibitor, in healthy subjects. Design This was a randomized, double-blind, placebo-controlled, crossover study in healthy subjects. Subjects Twenty healthy male subjects with an age of 18–55 years, inclusive, were enrolled. Eligibility was based on general fitness, absence of current or previous medical conditions that could compromise subject safety, and a training assessment of pain tolerance across pain tests to exclude highly tolerant individuals whose tolerance could compromise the ability to detect analgesic responses. All dosed subjects completed the study. Methods Subjects were randomized 1:1 to one of two sequences receiving a single VX-150 dose and subsequently placebo, or vice versa, with at least 7 days between dosing. A battery of pain tests (pressure, electrical stair, [capsaicin-induced] heat, and cold pressor) was administered before dosing and repetitively up to 10 h after dosing, with blood sampling up to 24 h after dosing. Safety was monitored throughout the study. Data were analyzed with a repeated-measures mixed-effects model. Results VX-150 induced analgesia in a variety of evoked pain tests, without affecting subject safety. Significant effects were reported for the cold pressor and heat pain thresholds. Maximum median concentration for the active moiety was 4.30 µg/mL at 4 h after dosing. Conclusion Results of this proof-of-mechanism study are supportive of the potential of VX-150, a highly selective NaV1.8 channel inhibitor, to treat various pain indications. [ABSTRACT FROM AUTHOR]

Background: In the current study, we aimed to develop an algorithm based on biomarkers obtained through non- or minimally invasive procedures to identify healthy elderly subjects who have an increased risk of abnormal cerebrospinal fluid (CSF) amyloid beta42 (Aβ) levels consistent with the presence of Alzheimer's disease (AD) pathology. The use of the algorithm may help to identify subjects with preclinical AD who are eligible for potential participation in trials with disease modifying compounds being developed for AD. Due to this pre-selection, fewer lumbar punctures will be needed, decreasing overall burden for study subjects and costs. Methods: Healthy elderly subjects (n = 200; age 65–70 (N = 100) and age > 70 (N = 100)) with an MMSE > 24 were recruited. An automated central nervous system test battery was used for cognitive profiling. CSF Aβ1-42 concentrations, plasma Aβ1-40, Aβ1-42, neurofilament light, and total Tau concentrations were measured. Aβ1-42/1-40 ratio was calculated for plasma. The neuroinflammation biomarker YKL-40 and APOE ε4 status were determined in plasma. Different mathematical models were evaluated on their sensitivity, specificity, and positive predictive value. A logistic regression algorithm described the data best. Data were analyzed using a 5-fold cross validation logistic regression classifier. Results: Two hundred healthy elderly subjects were enrolled in this study. Data of 154 subjects were used for the per protocol analysis. The average age of the 154 subjects was 72.1 (65–86) years. Twenty-four (27.3%) were Aβ positive for AD (age 65–83). The results of the logistic regression classifier showed that predictive features for Aβ positivity/negativity in CSF consist of sex, 7 CNS tests, and 1 plasma-based assay. The model achieved a sensitivity of 70.82% (± 4.35) and a specificity of 89.25% (± 4.35) with respect to identifying abnormal CSF in healthy elderly subjects. The receiver operating characteristic curve showed an AUC of 65% (± 0.10). Conclusion: This algorithm would allow for a 70% reduction of lumbar punctures needed to identify subjects with abnormal CSF Aβ levels consistent with AD. The use of this algorithm can be expected to lower overall subject burden and costs of identifying subjects with preclinical AD and therefore of total study costs. Trial registration: ISRCTN.org identifier: ISRCTN79036545 (retrospectively registered). [ABSTRACT FROM AUTHOR]

Aims: HTL0018318 is a selective M1 receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other dementias. We investigated safety, tolerability, pharmacokinetics and exploratory pharmacodynamics (PD) of HTL0018318 following single ascending doses. Methods: This randomized, double‐blind, placebo‐controlled study in 40 healthy younger adult and 57 healthy elderly subjects, investigated oral doses of 1–35 mg HTL0018318. Pharmacodynamic assessments were performed using a battery of neurocognitive tasks and electrophysiological measurements. Cerebrospinal fluid concentrations of HTL0018318 and food effects on pharmacokinetics of HTL0018318 were investigated in an open label and partial cross‐over design in 14 healthy subjects. Results: Pharmacokinetics of HTL0018318 were well‐characterized showing dose proportional increases in exposure from 1–35 mg. Single doses of HTL0018318 were associated with mild dose‐related adverse events of low incidence in both younger adult and elderly subjects. The most frequently reported cholinergic AEs included hyperhidrosis and increases in blood pressure up to 10.3 mmHg in younger adults (95% CI [4.2–16.3], 35‐mg dose) and up to 11.9 mmHg in elderly subjects (95% CI [4.9–18.9], 15‐mg dose). There were no statistically significant effects on cognitive function but the study was not powered to detect small to moderate effect sizes of clinical relevance. Conclusion: HTL0018318 showed well‐characterized pharmacokinetics and following single doses were generally well tolerated in the dose range studied. These provide encouraging data in support of the development for HTL0018318 for Alzheimer's disease and other dementias. [ABSTRACT FROM AUTHOR]

Aims: Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. Toxic accumulation of misfolded mutant huntingtin protein induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. We evaluated the safety, pharmacokinetics and pharmacodynamics of SBT‐020, a novel compound to improve mitochondrial function, in a 2‐part study in early stage HD patients. Methods: Part 1 consisted of 7‐day multiple ascending dose study to select the highest tolerable dose for Part 2, a 28‐day multiple dose study. Mitochondrial function was measured in the visual cortex and calf muscle, using phosphorous magnetic resonance spectroscopy, and in circulating peripheral blood mononuclear cells. Results: Treatment‐emergent adverse events were mild and more present in the SBT‐020 group. Injection site reactions occurred in 91% in Part 1 and 97% in Part 2. Mitochondrial function in calf muscle, peripheral blood mononuclear cells or visual cortex was not changed overall due to treatment with SBT‐020. In a posthoc analysis, patients with a higher degree of mitochondrial dysfunction (below the median [∆Ψm < 3412 and τPCr > 42.5 s]) showed more improvement than patients with a relatively lower level of mitochondrial dysfunction. Conclusion: SBT‐020 was safe at all doses, but no significant differences in any of the pharmacodynamic measurements between the treatment groups and placebo group could be demonstrated. The data suggest that the better than expected mitochondrial function in our patient population at baseline might explain the lack of effect of SBT‐020. [ABSTRACT FROM AUTHOR]