NMD670 is a first-in-class inhibitor of skeletal muscle-specific chloride channel ClC-1, developed to improve muscle weakness and fatigue in neuromuscular diseases. Preclinical studies show that ClC-1 inhibition enhances muscle excitability, improving muscle contractility and strength. We describe the first-in-human administration of ClC-1 inhibitor NMD670. In this randomized, double-blind, placebo-controlled study we evaluated safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of NMD670 in healthy male and female subjects. Single-ascending doses were administered in a (partial) cross-over design; multiple-ascending doses were administered in a parallel design. Differences in pharmacokinetics between males/females and fed/fasted state were evaluated. Pharmacodynamic effects were evaluated using muscle velocity recovery cycles (MVRC), and analyzed using mixed effects modelling, with baseline as covariate. NMD670 was considered safe and well-tolerated. Symptoms of myotonia were observed at the highest dose levels. Moreover, NMD670 significantly increased the following MVRC parameters after a single dose of 1200mg compared to placebo: early supernormality (estimated difference (ED) 2.04; 95% confidence interval (CI) (0.379, 3.70); p=0.0242); early supernormality after 5 conditioning stimuli (ED 2.51; 95%CI (0.599, 4.41); p=0.0177; supernormality at 20 ms (ED 2.78; 95%CI (1.377, 4.181); p=0.0021. Importantly, the results of this study indicate pharmacological target engagement of NMD670 as ClC-1 inhibitor, at dose levels that were considered safe in healthy subjects. Firstly, because myotonia was an expected exaggerated on-target pharmacological effect. Secondly, because the effects on MVRC indicate increased muscle cell excitability. This study in healthy subjects indicates proof-of-mechanism and provides a solid base for translation to patients with neuromuscular diseases.

Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl-) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise. Here, we show that partial inhibition of ClC-1 with an orally bioavailable small molecule (NMD670) can restore muscle function in rat models of MG and in patients with MG. In severely affected MG rats, ClC-1 inhibition enhanced neuromuscular transmission, restored muscle function, and improved mobility after both single and prolonged administrations of NMD670. On this basis, NMD670 was progressed through nonclinical safety pharmacology and toxicology studies, leading to approval for testing in clinical studies. After successfully completing phase 1 single ascending dose in healthy volunteers, NMD670 was tested in patients with MG in a randomized, placebo-controlled, single-dose, three-way crossover clinical trial. The clinical trial evaluated safety, pharmacokinetics, and pharmacodynamics of NMD670 in 12 patients with mild MG. NMD670 had a favorable safety profile and led to clinically relevant improvements in the quantitative myasthenia gravis (QMG) total score. This translational study spanning from single muscle fiber recordings to patients provides proof of mechanism for ClC-1 inhibition as a potential therapeutic approach in MG and supports further development of NMD670.

Aims: To characterise the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of oxathridine, a first-in-class histamine-3 receptor partialagonist, in healthy male volunteers.Methods: A randomised, double-blind, placebo-controlled study including the NeuroCart, consisting of a battery of drug sensitive neurophysiological tests, was performed. Oxathridine was administered orally as an aqueous solution. After dosing, safety and NeuroCart tests (adaptive tracking [AT], body sway [BS], saccadic peak velocity [SPV], smooth pursuit [SP] eye movements, VAS according to Bond and Lader, VAS according to Bowdle [VAS B&L, Bowdle], pharmaco-electroencephalogram [pEEG], Sustained Attention to Response Task [SART]) were performed at set times.Results: Forty volunteers completed the study. Given doses were: 0.5, 2.5, 5, 0.25 and 1.5 mg. At 5 mg, unacceptable and unanticipated adverse events (AEs) of (orthostatic) hypotension and pseudo-hallucinations were reported. Statistically significant effects ([CI]; p-value) of 2.5 mg and 5 mg oxathridine were observed on AT ([-8.28,-1.60]; p = 0.0048), ([-8.10,-1.51]; p = 0.00530), BS ([0.6, 80.2]; p = 0.0455), ([5.9, 93.1]; p = 0.0205) and SPV ([-59.0,-15.9]; p = 0.0011), ([-43.9,-1.09]; p = 0.0399), respectively. Oxathridine 5 mg significantly increased all three VAS Bowdle subscale scores; VAS external ([0.183, 0.476]; p = <.0001), VAS internal ([0.127, 0.370]; p = 0.0001) and VAS feeling high ([0.263, 0.887]; p = 0.0006).Conclusion: NeuroCart tests indicated central nervous system (CNS) depressant effects. Oxathridine also unexpectedly caused pseudohallucinations. Although this led to the decision to stop further development of oxathridine, these observations suggest that the H3R system could be an interesting new target for the development of novel antipsychotics.

Propofol is a commonly used agent in total intravenous anesthesia (TIVA). However, the link between its pharmacokinetics and pharmacodynamics has not been fully characterized in children yet. Our aim was to determine the quantitative relationship between the venous plasma concentration and bispectral index (BIS) effect in a heterogeneous group of pediatric patients undergoing various surgical procedures (ASA status I–III).Nine male and nine female patients were anesthetized with propofol–fentanyl TIVA. Sparse venous samples for propofol concentrations assay and dense BIS measurements were collected during and after the end of infusion. Nonlinear mixed-effect modeling in NONMEM was used for data analysis.A three-compartment model was linked with a classical Emax model through a biophase compartment to describe the available data. All clearance and volume terms were allometrically scaled to account for the body mass difference among the patients under study. A typical patient had their PK parameters observed within the range of literature values for children. The pharmacodynamic parameters were highly variable. The EC50 of 2.80 mg/L and the biophase distribution rate constant of 3.33 min−1 were found for a typical patient.The BIS values in children are highly correlated with the propofol effect compartment concentrations according to the classical Emax concentration–response relationship. Children had slightly lower sensitivity to propofol and slightly higher clearance, as compared with the adult data available in literature. The intra-patient variations in the BIS require the anesthesiologist's attention in using BIS values alone to evaluate the depth of anesthesia in children.

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 similar to 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. (c) 2023 Denali Therapeutics Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

0.71-0.76;p<0.001).Remission rate was 1.6 times higher for patients with OUD when taking suboxone compared to patients not on suboxone (29.0% vs. 18.3%;RR 1.59; 95% CI 1.56-1.62;p<0.001).After propensity matching, the effect on mortality was less, but still statistically significant (RR 0.91; 95% CI 0.87-0.95;p<001) and the remission rate was similar (29.0%vs 19.3%; RR 1.51; 95% CI 1.47-1.54;p<0.001).Conclusions: Suboxone showed significantly reduced mortality and increased remission rates for patients with opioid use disorder and should be used as a primary treatment.Understanding treatment options like Suboxone can mitigate the impact of opioid use disorder.

With expanding liberalization of cannabis laws across the US, emergency department (ED) visits related to acute cannabinoid intoxication (ACI) continue to increase. The clinical effects of ACI can include neuropsychiatric symptoms (eg, panic attacks, psychosis), tachycardia, and hypotension, which are mediated primarily through the cannabinoid type 1 (CB1) receptor. ANEB-001 is a CB1 receptor antagonist under development as an antidote to ACI. Conducting studies in the ED setting, where intoxicated patients cannot give consent, or giving extremely high cannabinoid doses to healthy volunteers presents ethical limitations. We conducted a clinical study in healthy subjects to assess the potential of ANEB-001 to reverse the effects of low to moderate doses of delta-9- tetrahydrocannabinol (THC). The aim of the current analysis was to develop a population model based on the pharmacokinetic (PK) and pharmacodynamic (PD) data from that study, in order to predict efficacious doses of ANEB-001 for reversing ACI in the ED setting.

Objective: DNL343 is being investigated as a potential therapeutic agent for Amyotrophic Lateral Sclerosis (ALS). Background: ALS is a fatal neurodegenerative disease with TDP-43 inclusion pathology in 95% of patients. Chronic activation of the integrated stress response (ISR) may contribute to ALS by blocking translation, altering RNA and endosomal trafficking, and increasing formation of TDP-43-containing stress granules. DNL343 is a small molecule that activates a key ISR regulator, eIF2B, which inhibits ISR stress granule formation in cellular models and promotes neuroprotection in animal models. Design/Methods: The safety, pharmacokinetics (PK) and pharmacodynamics (PD) of DNL343 were evaluated in a Phase 1 randomized, placebo-controlled trial (RCT) in healthy volunteers (NCT04268784) and a 28-day Phase 1b RCT in ALS participants (NCT05006352), with an ongoing 18-month open label extension (OLE). ISR inhibition was evaluated by measuring CHAC1 gene expression and ATF4 protein in stimulated peripheral blood mononuclear cells (PBMCs). Results: In the Phase 1 study, ninety-five healthy participants were randomized (n=48 SAD, n=47 MAD). DNL343 was generally safe and well-tolerated with no serious adverse events (SAEs) or discontinuations related to study drug. DNL343 plasma concentrations were dose-dependent, with a plasma half-life of 38–46 hours and CSF-to-unbound plasma concentration ratio of 0.66–0.92. DNL343 attenuated two ISR biomarkers across the dosing period and at trough 24-hours after the last dose (CHAC1 [66–94%] and ATF4 [50–73%]) in all MAD cohorts. Safety, pharmacokinetics and ISR pharmacodynamics from the 28-day Phase 1b study in ALS participants will be presented. Conclusions: DNL343 is generally safe and well-tolerated at doses that demonstrate robust inhibition of ISR through CHAC1 and ATF4 inhibition. The pharmacokinetic profile supports once daily oral dosing and there is extensive CSF distribution. Data from these early-stage studies in HV and ALS patients support further development of DNL343 as a potential therapeutic for the treatment of ALS. Disclosure: Dr. Sun has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Sun has stock in Denali Therapeutics. Dr. Tsai has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Tsai has stock in Denali Therapeutics. Dr. Yulyaningsih has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Yulyaningsih has stock in Denali Therapeutics. Dr. Yulyaningsih has stock in 23 & ME. Dr. Yulyaningsih has stock in Ardelyx. Dr. Yulyaningsih has stock in Amylyx. Dr. Fanok has received personal compensation for serving as an employee of Denali Therapeutics . An immediate family member of Dr. Fanok has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Cincor Pharma. Dr. Fanok has stock in Denali Therapeutics. Mr. Vissers has received personal compensation for serving as an employee of Centre for Human Drug Research. Dr. Heuberger has received personal compensation for serving as an employee of Centre for Human Drug Research. Dr. Flores has nothing to disclose. Fen Huang has nothing to disclose. Dr. Kane has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Kane has stock in Denali Therapeutics. Dr. Cohen has received personal compensation for serving as an employee of Denali. Dr. Cohen has stock in Denali. Dr. Dhuria has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Dhuria has stock in Denali Thereapeutics. Dr. Fang has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Fang has stock in Denali therapeutics. Dr. Estrada has stock in Denali Therapeutics . Dr. Osipov has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Osipov has stock in Denali Therapeutics. Dr. Osipov has received intellectual property interests from a discovery or technology relating to health care. Mr. Willman-Yoswa has received personal compensation for serving as an employee of Denali Therapeutics. Mr. Maciuca has received personal compensation for serving as an employee of Denali Therapeutics. Mr. Maciuca has received stock or an ownership interest from Denali Therapeutics. Ms. Dobbins has received personal compensation for serving as an employee of Denali Therapeutics. Ms. Dobbins has stock in Denali Therapeutics. Miss Chau has received personal compensation for serving as an employee of Denali Therapeutics. Miss Chau has stock in Denali Therapeutics. Timothy Earr has received personal compensation for serving as an employee of Denali Therapeutics. Timothy Earr has stock in Denali Therapeutics. Ms. Nguyen has received personal compensation for serving as an employee of DENALI THERAPEUTICS. Ms. Nguyen has stock in Denali Therapeutics. Mrs. Lopez has nothing to disclose. Kimberly Scearce-Levie has received personal compensation for serving as an employee of Denali Therapeutics. Kimberly Scearce-Levie has stock in Denali Therapeutics. Mr. Bunte has nothing to disclose. Dr. Van den Berg has nothing to disclose. Carole Ho has nothing to disclose. Geert-Jan Groeneveld has nothing to disclose. Dr. Troyer has received personal compensation for serving as an employee of Denali Therapeutics Inc. Dr. Troyer has stock in Denali Therapeutics Inc. Dr. Troyer has stock in Merck & Co., Inc. Dr. Troyer has stock in Eli Lilly.

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.

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 (Na-v) 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 Na(V)1.4 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.

The creation of WADA contributed to harmonization of anti‐doping and changed doping behavior and prevalence in the past 22 years. However, the system has developed important deficiencies and limitations that are causing harm to sports, athletes and society. These issues are related to the lack of evidence for most substances on the Prohibited List for performance or negative health effects, a lack of transparency and accountability of governance and decision‐making by WADA and the extension of anti‐doping policies outside the field of professional sports. This article tries to identify these deficiencies and limitations and presents a plea for more science, better governance and more education. This should lead to a discussion for reform among stakeholders, which should cover support of a new Prohibited List by actual research and evidence and introduce better governance with accountable control bodies and regulation. Finally, comprehensive education for all stakeholders will be the basis of all future positive improvements.

Selective voltage gated sodium channel blockers are of growing interest as treatment for pain. For drug development of such compounds, it would be critical to have a biomarker that can be used for proof-of-mechanism. We aimed to evaluate whether drug-induced changes in sodium conductance can be detected using nerve excitability threshold tracking in 18 healthy subjects. In a randomized, double-blind, three-way crossover study, effects of single doses of mexiletine and lacosamide were compared to placebo. On each study visit, motor- and sensory nerve excitability measurements of the median nerve were performed (pre-dose; 2- and 5-hours post-dose). Stimulation was guided by QTRAC-S. Treatment effects were calculated using an ANCOVA, with baseline as covariate. Mexiletine and lacosamide had significant effects on a multitude of motor- and sensory nerve excitability parameters. In motor nerves, TEd 40-60ms was significantly decreased when compared to placebo, with an estimated difference -1.37% (95%CI:-2.20,-0.55;p=0.002) after mexiletine and -1.27% (95%CI:-2.0968,-0.4430; p=0.004) after lacosamide. Moreover, mexiletine and lacosamide significantly increased superexcitability in motor nerves, with an estimated difference of 1.74% (95%CI:0.61,2.87; p=0.004) and 1.47% (95%CI:0.34, 2.60;p=0.013), respectively. The strength-duration time constant decreased after lacosamide in both motor nerves -0.03ms (95%CI:-0.06,-0.01;p=0.005) and sensory nerves -0.08ms (95%CI:-0.12,-0.05;p<0.001). Mexiletine and lacosamide significantly decrease excitability of motor and sensory nerves, in line with the mechanism of action. This study shows that threshold tracking can be an effective biomarker in pharmacological studies. The method would therefore be a valuable tool in drug development, to help identifying target engagement in healthy subjects.

Selective voltage‐gated sodium channel blockers are of growing interest as treatment for pain. For drug development of such compounds, it would be critical to have a biomarker that can be used for proof‐of‐mechanism. We aimed to evaluate whether drug‐induced changes in sodium conductance can be detected in the peripheral nerve excitability profile in 18 healthy subjects. In a randomized, double‐blind, 3‐way crossover study, effects of single oral doses of 333 mg mexiletine and 300 mg lacosamide were compared with placebo. On each study visit, motor and sensory nerve excitability measurements of the median nerve were performed (predose; and 3 and 6 hours postdose) using Qtrac. Treatment effects were calculated using an analysis of covariance (ANCOVA) with baseline as covariate. Mexiletine and lacosamide had significant effects on multiple motor and sensory nerve excitability variables. Depolarizing threshold electrotonus (TEd40 (40–60 ms)) decreased by mexiletine (estimated difference (ED) −1.37% (95% confidence interval (CI): −2.20, −0.547; P = 0.002) and lacosamide (ED −1.27%, 95% CI: −2.10, −0.443; P = 0.004) in motor nerves. Moreover, mexiletine and lacosamide decreased superexcitability (less negative) in motor nerves (ED 1.74%, 95% CI: 0.615, 2.87; P = 0.004, and ED 1.47%, 95% CI: 0.341, 2.60; P = 0.013, respectively). Strength‐duration time constant decreased after lacosamide in motor‐ (ED −0.0342 ms, 95% CI: −0.0571, −0.0112; P = 0.005) and sensory nerves (ED −0.0778 ms, 95% CI: −0.116, −0.0399; P < 0.001). Mexiletine and lacosamide significantly decrease excitability of motor and sensory nerves, in line with their suggested mechanism of action. Results of this study indicate that nerve excitability threshold tracking can be an effective pharmacodynamic biomarker. The method could be a valuable tool in clinical drug development.

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.