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.

Aging is accompanied by a gradual decline in both muscle mass and strength over time, which can eventually lead to pathologies, such as frailty and sarcopenia. While these two conditions are well characterized, further investigation of the early biological signs present in pre-frail elderly is still needed to help identify strategies for preventative therapeutic intervention. The goal of the present clinical study was to evaluate the level of mitochondrial (dys)function in a well-defined population of pre-frail elderly (>60 years of age). Pre-frail elderly were compared with an age-matched population of active elderly. Muscle mitochondrial function was assessed in vivo using phosphorus magnetic resonance spectroscopy (31P-MRS) and a comprehensive set of biological biomarkers were measured ex vivo in vastus lateralis muscle biopsies. In pre-frail subjects, phosphocreatine recovery was impaired and mitochondrial respiratory complex protein and activity levels were significantly lower when compared with active elderly. Analysis of microarray data showed that mitochondrial genes were also significantly down-regulated in muscle of pre-frail compared to active elderly. These results show that mitochondrial impairment is a hallmark of pre-frailty development and the onset of decline in muscle function in the elderly.

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.

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.

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.

This review provides tools to consider the inclusion of healthy volunteers (HVs) in first-in-human (FIH) oncology clinical trials with small molecules, including targeted and immunomodulatory agents, a strategy that was not envisioned with classic chemotherapy. To enable an FIH oncology trial in HVs compared to cancer patients (CPs), a robust nonclinical package must be generated, which includes toxicokinetic and pharmacokinetic studies, as well as more extensive safety pharmacology, toxicology and genotoxicity studies. This strategy could provide an early clinical characterization of the pharmacokinetic parameters and clinical safety profile in the absence of comorbidities and concomitant medication. It also avoids the ethical issue of administrating subtherapeutic doses to CPs, and could potentially help to accelerate the timelines of clinical drug development for patient care. That being said, stakeholders involved in these studies need to proceed with caution, fully understand the regulatory guidance and thoroughly evaluate the benefits and risks. This paper serves to address the regulatory guidance and other considerations needed when using healthy volunteers in early oncology trials.

The cholinergic system and M1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M1 receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia's including Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects.

A variant in the GBA1 gene is one of the most common genetic risk factors to develop Parkinson's disease (PD). Here the serendipitous finding is reported of a polymerase dependent allelic imbalance when using next generation sequencing, potentially resulting in false-negative results when the allele frequency falls below the variant calling threshold (by default commonly at 30%). The full GBA1 gene was sequenced using next generation sequencing on saliva derived DNA from PD patients. Four polymerase chain reaction conditions were varied in twelve samples, to investigate the effect on allelic imbalance: (1) the primers (n = 4); (2) the polymerase enzymes (n = 2); (3) the primer annealing temperature (Ta) specified for the used polymerase; and (4) the amount of DNA input. Initially, 1295 samples were sequenced using Q5 High-Fidelity DNA Polymerase. 112 samples (8.6%) had an exonic variant and an additional 104 samples (8.0%) had an exonic variant that did not pass the variant frequency calling threshold of 30%. After changing the polymerase to TaKaRa LA Taq DNA Polymerase Hot-Start Version: RR042B, all samples had an allele frequency passing the calling threshold. Allele frequency was unaffected by a change in primer, annealing temperature or amount of DNA input. Sequencing of the GBA1 gene using next generation sequencing might be susceptible to a polymerase specific allelic imbalance, which can result in a large amount of flase-negative results. This was resolved in our case by changing the polymerase. Regions displaying low variant calling frequencies in GBA1 sequencing output in previous and future studies might warrant additional scrutiny.

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.

Monitoring effects of disease or therapeutic intervention on brain function is increasingly important for clinical trials, albeit hampered by inter-individual variability and subtle effects. Here, we apply complementary biomarker algorithms to electroencephalography (EEG) recordings to capture the brain's multi-faceted signature of disease or pharmacological intervention and use machine learning to improve classification performance. Using data from healthy subjects receiving scopolamine we developed an index of the muscarinic acetylcholine receptor antagonist (mAChR) consisting of 14 EEG biomarkers. This mAChR index yielded higher classification performance than any single EEG biomarker with cross-validated accuracy, sensitivity, specificity and precision ranging from 88-92%. The mAChR index also discriminated healthy elderly from patients with Alzheimer's disease (AD); however, an index optimized for AD pathophysiology provided a better classification. We conclude that integrating multiple EEG biomarkers can enhance the accuracy of identifying disease or drug interventions, which is essential for clinical trials.

No abstract available