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.
Colon cancer prevention currently relies on colonoscopy using white light to detect and remove polyps, but small and flat polyps are difficult to detect and frequently missed when using this ...technique. Fluorescence colonoscopy combined with a fluorescent probe specific for a polyp biomarker may improve polyp detection. Here we describe GE-137, a water-soluble probe consisting of a 26-amino acid cyclic peptide that binds the human tyrosine kinase c-Met conjugated to a fluorescent cyanine dye. Intravenous administration of GE-137 leads to its accumulation specifically in c-Met-expressing tumors in mice, and it is safe and well tolerated in humans. Fluorescence colonoscopy in patients receiving intravenous GE-137 enabled visualization of all neoplastic polyps that were visible with white light (38), as well as an additional nine polyps that were not visible with white light. This first-in-human pilot study shows that molecular imaging using an intravenous fluorescent agent specific for c-Met is feasible and safe, and that it may enable the detection of polyps missed by other techniques.
Aim
To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of the highly selective oral p38alpha/beta mitogen‐activated protein (MAP) kinase inhibitor Org 48,775‐0 in a ...first‐in‐human study.
Methods
In the single ascending dosing (SAD) study, an oral dose of Org 48,775‐0 (0.3‐600 mg) was evaluated in healthy males. In the multiple ascending dosing (MAD) study, levels of 30, 70 and 150 mg were dosed for six consecutive days, twice daily. Both studies were performed in a double‐blind, randomized, placebo‐controlled, cross‐over fashion and evaluated pharmacokinetics, pharmacodynamics (ex vivo inhibition of lipopolysaccharide LPS‐induced tumor necrosis factor (TNFα) release) and routine clinical and laboratory data. Pharmacokinetic and pharmacodynamic parameters of Org 48,775‐0 were compared between healthy males and postmenopausal females, and the effect of a standardized fat meal was evaluated.
Results
All adverse events observed in the SAD (16; dizziness and headache, diarrhoea and catheter‐related phlebitis) and MAD (43; mainly somnolence, dizziness, headache and nasopharyngitis) cohorts were mild, transient and completely reversible. Pharmacokinetics were linear up to single doses of 400 mg. Median Tmax ranged from 0.5 to 1.8 hours, geometric mean for T1/2 from 7.0 to 14.4 hours. Org 48,775‐0 doses equal to and greater than 30 mg significantly inhibited LPS‐induced TNFα release (42.3%; 95% CI = −65.2, −4.3) compared to placebo. In the MAD study, Org 48,775‐0 treatment inhibited LPS‐induced TNFα release during the entire steady‐state period. Levels of inhibition amounted 30‐75% for 30 mg, 53‐80% for 70 mg and 77‐92% for 150 mg Org 48,775‐0.
Conclusion
Org 48,775‐0 has the capacity to significantly inhibit MAP kinase activity in humans without safety concerns.
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.
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.
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.
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.
ISRCTN.org identifier: ISRCTN79036545 (retrospectively registered).
Aim
Cannabinoid receptor type 1 (CB1) antagonists show central side effects, whereas beneficial effects are most likely peripherally mediated. In this study, the peripherally selective CB1 antagonist ...TM38837 was studied in humans.
Methods
This was a double‐blind, randomized, placebo‐controlled, crossover study. On occasions 1–4, 24 healthy subjects received 5 × 4 mg THC with TM38837 100 mg, 500 mg or placebo, or placebos only. During occasion 5, subjects received placebo TM38837 + THC with rimonabant 60 mg or placebo in parallel groups. Blood collections and pharmacodynamic (PD) effects were assessed frequently. Pharmacokinetics (PK) and PD were quantified using population PK−PD modelling.
Results
The TM38837 plasma concentration profile was relatively flat compared with rimonabant. TM38837 showed an estimated terminal half‐life of 771 h. THC induced effects on VAS feeling high, body sway and heart rate were partly antagonized by rimonabant 60 mg −26.70% 90% confidence interval (CI) −40.9, −12.6%; −7.10%, (90%CI −18.1, 5.3%); −7.30%, (90% CI −11.5%, −3.0%) respectively and TM38837 500 mg −22.10% (90% CI −34.9, −9.4%); −12.20% (90% CI −21.6%, −1.7%); −8.90% (90% CI −12.8%, −5.1%) respectively. TM38837 100 mg had no measurable feeling high or body sway effects and limited heart rate effects.
Conclusions
Rimonabant showed larger effects than TM38837, but the heart rate effects were similar. TM38837 100 mg had no impact on CNS effects, suggesting that this dose does not penetrate the brain. This TM38837 dose is predicted to be at least equipotent to rimonabant with regard to metabolic disorders in rodent models. These results provide support for further development of TM38837 as a peripherally selective CB1 antagonist for indications such as metabolic disorders, with a reduced propensity for psychiatric side effects.
The prevalence of neurodegenerative diseases increases significantly with increasing age. Neurodegeneration is the progressive loss of function of neurons that eventually leads to cell death, which ...in turn leads to cognitive disfunction. Cognitive performance can therefore also be considered age dependent. The current study investigated if the NeuroCart can detect age related decline on drug-sensitive CNS-tests in healthy volunteers (HV), and whether there are interactions between the rates of decline and sex. This study also investigated if the NeuroCart was able to differentiate disease profiles of neurodegenerative diseases, compared to age-matched HV and if there is age related decline in patient groups.
This retrospective study encompassed 93 studies, performed at CHDR between 2005 and 2020 that included NeuroCart measurements, which resulted in data from 2729 subjects. Five NeuroCart tests were included in this analysis: smooth and saccadic eye movements, body sway, adaptive tracking, VVLT and N-back. Data from 84 healthy male and female volunteer studies, aged 16–90, were included. Nine studies were performed in patients with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) or vascular dementia (VaD). The data were analyzed with regression analyses on age by group, sex, sex by age, group by sex and group by sex by age. Least square means (LSMs) and 95% confidence intervals (CIs) were calculated for each group at the average age of the group, and at the average age of each of the other groups, and per sex.
Mean age and standard deviation (SD) for all groups was: HV 36.2 years (19.3), 68.3 CE years (8), PD 62.7 years (8.5), HD 51.4 years (9.8) and VaD 66.9 years (8.1). Performance on all NeuroCart tests decreased significantly each year in HV. Saccadic peak velocity (SPV) was increased in AD compared to age-matched HV (+26.28 degrees/s, p = 0.007), while SPV was decreased for PD and HD compared to age-matched HV (PD: −15.87 degrees/s, p = 0.038, HD: −22.52 degrees/s, p = 0.018). In HD patients SPV decreased faster with age compared to HV. On saccadic peak velocity the slopes between HD vs HV were significantly different, indicating a faster decline in performance on this task for HD patients compared to HV per age year. Smooth pursuit showed an overall significant difference between subject groups (p = 0.037. Significantly worse performance was found for AD (−12.87%, p ≤0.001), PD (−4.45%, p ≤0.001) and VaD (−5.69%, p = 0.005) compared to age-matched HV. Body sway significantly increased with age (p = 0.021). Postural stability was decreased for both PD and HD compared to age-matched HV (PD: +38.8%, p ≤0.001, HD: 154.9%, p ≤0.001). The adaptive tracking was significantly decreased with age (p ≤0.001). Adaptive tracking performance by AD (−7.54%, p ≤0.001), PD (−8.09%, p ≤0.001), HD (−5.19%, p ≤0.001) and VaD (−5.80%, p ≤0.001) was decreased compared to age-matched HV. Adaptive tracking in PD patients vs HV and in PD vs HD patients was significantly different, indicating a faster decline on this task per age year for PD patients compared to HV and HD. The VVLT delayed word recall showed an overall significant effect of subject group (p = 0.006. Correct delayed word recall was decreased for AD (−5.83 words, p ≤0.001), HD (−3.40 words, p ≤0.001) and VaD (−5.51 words, p ≤0.001) compared to age-matched HV.
This study showed that the NeuroCart can detect age-related decreases in performance in HV, which were not affected by sex. The NeuroCart was able to detect significant differences in performance between AD, PD, HD, VaD and age-matched HV. Disease durations were unknown, therefore this cross-sectional study was not able to show age-related decline after disease onset. This article shows the importance of investigating age-related decline on digitalized neurocognitive test batteries. Performance declines with age, which emphasizes the need to correct for age when including HV in clinical trials. Patients with different neurogenerative diseases have distinct performance patterns on the NeuroCart, which this should be considered when performing NeuroCart tasks in patients with AD, PD, HD and VaD.
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.
Abstract
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.
Rationale:
Assessment of the effects of medicines on the risks of car driving must be derived from laboratory tests, simulated driving or real on-road driving tests. Relevance of tests is determined ...by their sensitivity and predictive ability for the probability of accidents or damage. This cannot be determined directly, but methods should be able to at least detect the effects of a positive control in dosage known to be clearly associated with increased risk.
Objectives:
A driving simulator was evaluated in comparison with a battery of validated tests of CNS performance, the NeuroCart®. Alcohol in a concentration exactly at the legal limit (0.5 g L−1) and well above (1.0 g L−1) as well as alprazolam (1 mg) was used as positive control.
Methods:
This was a randomised, cross-over study using a double dummy blinded design in 24 healthy study subjects (12 M, 12 F) aged 20–43 years. Alcohol was infused intravenously using a validated clamping protocol to obtain concentrations of 0.5 g L−1 and on another occasion 1.0 g L−1. Alprazolam was given orally. Driving tests and lab tests were done at regular time intervals during a study day.
Results:
Alprazolam and alcohol significantly affected the main parameters of driving in the simulator and affected scores of safe driving and alprazolam increased the odds ratio of a virtual crash. Several laboratory measurements of psychomotor performance were affected by the reference substances as expected and correlated significantly with the driving performance
Conclusions:
The driving simulator can detect effects of reference substances at levels that are known to negatively affect driving.
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