Serum ARGS-aggrecan in a phase 2 clinical trial targeting osteoarthritis.

OBJECTIVE: To monitor serum concentrations of the aggrecan ARGS neoepitope in a clinical trial of ADAMTS-5 inhibition as disease-modifying therapy of knee osteoarthritis, and to investigate relationships between reduction in ARGS and change in cartilage thickness, knee related pain and function. DESIGN: ROCCELLA trial participants received once-daily oral S201086 75, 150 or 300 mg, or placebo, for 52 weeks. Serum was collected at baseline, 4, 12, 28 and 52 weeks, and 2 weeks post treatment with ARGS measured by an in-house immunoassay. Change from baseline to week 52 in central medial femorotibial compartment cartilage thickness was measured by MRI, function and pain by WOMAC subscores. Associations between cumulative change in ARGS and change in cartilage thickness or WOMAC subscores were evaluated by linear regression. RESULTS: S201086 reduced serum levels of ARGS in a dose-dependent manner throughout the treatment period. Maximal reduction was at 4 weeks with a 58.5% [95% CI 60.8%, 56.2%] reduction of ARGS compared to baseline for 300 mg S201086. Two weeks post treatment, ARGS concentrations rebounded with a dose-dependent overshoot compared to baseline levels. Cumulative change of ARGS concentration from baseline to week 52 had no effect on change in cartilage thickness (slope -0.8x10-6 [-2.9x10-6, 1.3x10-6]) or change in WOMAC pain and function (slopes -30x10-6 [-64x10-6, 5.2x10-6] and -97x10-6 [-214x10-6, 20x10-6], respectively) at week 52. CONCLUSION: Systemic inhibition of ADAMTS-5 resulted in markedly reduced serum ARGS, but change in serum ARGS concentrations showed no association with the progression of cartilage thinning, or patient reported pain and function. CLINICALTRIALS: GOV: NCT03595618.

The design of a randomized, placebo-controlled, dose-ranging trial to investigate the efficacy and safety of the ADAMTS-5 inhibitor S201086/GLPG1972 in knee osteoarthritis.

Objective: This study aims to assess the efficacy of the anticatabolic 'a disintegrin and metalloproteinase with thrombospondin motif-5' (ADAMTS-5) inhibitor, S201086/GLPG1972, in slowing cartilage loss in participants with knee osteoarthritis (OA). Design: ROCCELLA (NCT03595618) is a randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, phase 2 trial. We plan to enrol a total of 852 participants with knee OA across 12 countries. Participants will be randomized 1:1:1:1 to receive 75, 150 or 300 â€‹mg S201086/GLPG1972, or placebo orally, once daily for 52 weeks. Eligible participants will be aged 40-75 years and have predominantly medial knee OA with centrally read Kellgren-Lawrence grade 2 or 3, OARSI atlas medial femorotibial joint space narrowing grade 1 or 2, and consistent moderate to severe baseline pain. The primary endpoint will be the change from baseline to week 52 in magnetic resonance imaging-assessed central medial femorotibial compartment cartilage thickness. Secondary endpoints will include other structural outcomes, and patient-reported outcomes, as well as safety and pharmacokinetic assessments. Study sites will be assessed for eligibility based on factors including imaging quality, and images will be centrally read and quality checked. Conclusions: Using strict inclusion criteria and leading imaging techniques with stringent quality controls, the ROCCELLA trial will evaluate the efficacy of S201086/GLPG1972 in slowing cartilage loss in participants with knee OA. The selected eligibility criteria should enrich for participants with OA who experience sufficient cartilage loss to allow detection of a substantial treatment effect.

A simple inclusion criteria combination increases the rate of cartilage loss in patients with knee osteoarthritis.

Objectives: Selection of patients with KL radiographic grade 2 and 3 is widely used in clinical trials, but this approach could have some limitations. The purpose of this study performed on OsteoArthritis Initiative (OAI) data is to assess whether adding OARSI-JSN to KL grading could select a population with increased rate of cartilage loss. Indeed, KL is not compartment-specific and not uniformly graded amongst expert readers. OARSI-JSN is another established, compartment-specific grading scale that specifically captures the joint space narrowing from radiographs. Design: 1019 knee radiographs data from the progression cohort of the OAI public database were used. Cartilage loss measured with magnetic resonance imaging was evaluated using change over 1 year from baseline in cartilage thickness in the central Medial Tibio-Femoral Compartment (cMTFC) in the KL2-3 and KL2-3+JSN1-2 populations. Results: The mean cMTFC cartilage loss over one year was -0.135 â€‹± â€‹0.29 â€‹mm (median â€‹= â€‹-0.095 â€‹mm) in the KL2-3 population and -0.176 â€‹± â€‹0.29 â€‹mm (median â€‹= â€‹-0.140 â€‹mm) in the KL2-3 +JSN1-2 population. Conclusions: OARSI-JSN appears to be an effective inclusion criterion to be considered in combination with the KL grade in future clinical trials testing the structural efficacy of DMOADs in a time window of 1-year as it contributes to identify knees in whom the disease progresses rapidly.

A 24-week double-blind placebo-controlled study of the efficacy and safety of the AMPA modulator S47445 in patients with mild to moderate Alzheimer's disease and depressive symptoms.

INTRODUCTION: S47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors that may emerge as a favorable candidate for the symptomatic treatment of cognitive and depressive disorders in patients suffering from Alzheimer's disease (AD) of mild to moderate severity and with depressive symptoms. METHODS: For this double-blind, placebo-controlled 24-week phase II trial, 520 outpatients aged between 55 and 85 years, with probable AD at mild to moderate stages (a Mini-Mental State Examination score of 24-15 inclusive) and exhibiting depressive symptoms (Cornell Scale for Depression in Dementia [CSDD] ≥ 8) were recruited in twelve countries and randomized to 3 doses of S47445 (5-15-50 mg) or placebo. The primary end point was the change from baseline in the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score at week 24. Secondary measures included the Disability Assessment for Dementia, Mini-Mental State Examination, ADAS-Cog 13-item, CSDD, Clinical Global Impression of Change (Alzheimer's Disease Cooperative Study-CGIC), Neuropsychiatric Inventory (NPI), and safety criteria. RESULTS: Baseline characteristics were comparable between the 4 groups. After 24 weeks, no statistically significant treatment difference was demonstrated between S47445 (5, 15 or 50 mg/d) and placebo on cognition (ADAS-Cog), function (Disability Assessment for Dementia), or depressive symptoms (CSDD). An improvement on neuropsychiatric symptoms assessed by NPI was evidenced at the lower dose 5 mg/d (Δ -2.55, P = .023, post hoc analysis) compared to placebo. CSDD and total NPI scores improved in all groups including placebo. There were no specific and/or unexpected safety signals observed with any of the S47445 doses. DISCUSSION: S47445 administered for 24 weeks was safe and well tolerated by patients with mild to moderate AD; the compound did not show significant benefits over placebo on cognition, function, or depressive symptoms.

Protocols to Study Declarative Memory Formation in Mice and Humans:Optogenetics and Translational Behavioral Approaches.

Declarative memory formation depends on the hippocampus and declines in aging. Two functions of the hippocampus, temporal binding and relational organization (Rawlins and Tsaltas, 1983; Eichenbaum et al., 1992 ; Cohen et al., 1997 ), are known to decline in aging (Leal and Yassa, 2015). However, in the literature distinct procedures have been used to study these two functions. Here, we describe the experimental procedures used to investigate how these two processes are related in the formation of declarative memory and how they are compromised in aging ( Sellami et al., 2017 ). First, we studied temporal binding using a one-trial learning procedure: trace fear conditioning. It is classical Pavlovian conditioning requiring temporal binding since a brief temporal gap separates the conditioned stimulus (CS) and unconditioned stimulus (US) presentations. We combined the trace fear condition procedure with an optogenetic approach, and we showed that the temporal binding relies on dorsal (d)CA1 activity over temporal gaps. Then, we studied the interaction between temporal binding and relational organization in declarative memory formation using a two-phase radial-maze task in mice and its virtual analog in humans. The behavioral procedure comprises an initial learning phase where subjects learned the constant rewarding /no rewarding valence of each arm, followed by a test phase where the reward contingencies among the arms remained unchanged but where the arms were recombined to assess flexibility, a cardinal property of declarative memory. We demonstrated that dCA1-dependent temporal binding is necessary for the development of a relational organization of memories that allows flexible declarative memory expression. Furthermore, in aging, the degradation of declarative memory is due to a reduction of temporal binding capacity that prevents relation organization.

Temporal binding function of dorsal CA1 is critical for declarative memory formation.

Temporal binding, the process that enables association between discontiguous stimuli in memory, and relational organization, a process that enables the flexibility of declarative memories, are both hippocampus-dependent and decline in aging. However, how these two processes are related in supporting declarative memory formation and how they are compromised in age-related memory loss remain hypothetical. We here identify a causal link between these two features of declarative memory: Temporal binding is a necessary condition for the relational organization of discontiguous events. We demonstrate that the formation of a relational memory is limited by the capability of temporal binding, which depends on dorsal (d)CA1 activity over time intervals and diminishes in aging. Conversely, relational representation is successful even in aged individuals when the demand on temporal binding is minimized, showing that relational/declarative memory per se is not impaired in aging. Thus, bridging temporal intervals by dCA1 activity is a critical foundation of relational representation, and a deterioration of this mechanism is responsible for the age-associated memory impairment.

Absence of psychostimulant effects of a supratherapeutic dose of tianeptine: a placebo-controlled study versus methylphenidate in young healthy volunteers.

OBJECTIVE: The primary objective of the present study was to assess the potential psychostimulant effect of a single oral supratherapeutic dose of tianeptine (75 mg in 1 shot) in young healthy volunteers compared with methylphenidate (40 mg) and placebo. METHOD: Eighteen healthy young male and female volunteers with no history of psychostimulant abuse completed this balanced, crossover, placebo-controlled study. Subjective and behavioral effects were assessed before treatment and 1, 2, 3, 4, and 8 hours after drug intake. Subjective effects of the drugs were recorded using self-questionnaire Addiction Research Center Inventory (ARCI 49). In addition, the Profile of Mood Scale, Visual Analog Scale, and attention/vigilance tests (choice reaction time and critical flicker fusion test) were used to evaluate mood state, subjective feeling, and sustained attention, respectively. RESULTS: Analysis on changes from baseline, from 1 to 8 hours, showed statistically significant differences between treatment groups for 2 of the 5 ARCI subscales: amphetamine and morphine benzedrine scales. A trend to significance was observed for Lysergic Acid Diethylamide scale. Indeed, although tianeptine did not significantly change any ARCI scores, methylphenidate significantly increased amphetamine and morphine benzedrine scores of the ARCI compared with placebo. No significant treatment effect was observed on the Profile of Mood Scale and the visual analog scale. Analyses of attention and vigilance tests showed a psychostimulant effect for methylphenidate on choice reaction time (decrease of recognition time) and critical flicker fusion test (higher frequency). CONCLUSIONS: A single administration of a supratherapeutic dose of tianeptine does not induce psychostimulant effect in young healthy volunteers in contrast to methylphenidate at a therapeutic dose. These findings suggest an absence of psychostimulant liability of tianeptine in a therapeutic situation.

DRUG FOCUS: S 18986: A positive allosteric modulator of AMPA-type glutamate receptors pharmacological profile of a novel cognitive enhancer.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) type glutamate receptors are critical for synaptic plasticity and induction of long-term potentiation (LTP), considered as one of the synaptic mechanisms underlying learning and memory. Positive allosteric modulators of AMPA receptors could provide a therapeutic approach to the treatment of cognitive disorders resulting from aging and/or neurodegenerative diseases, such as Alzheimer disease (AD). Several AMPA potentiators have been described in the last decade, but for the moment their clinical efficacy has not been demonstrated due to the complexity of the target, AMPA receptors, and the difficulty in studying cognition in animals and humans. A better understanding of the mechanism of action of this type of drug remains an important issue, if knowledge of these compounds is to be increased and if this novel therapeutic approach is to be an interesting research area. Among the AMPA potentiators, S 18986 is emerging as a new selective positive allosteric modulator of AMPA-type glutamate receptors. S 18986, as with other positive AMPA receptor modulators, increased induction and maintenance of LTP in the hippocampus as well as the expression of brain-derived neurotrophic factor (BDNF) both in vitro and in vivo. Its cognitive-enhancing properties have been demonstrated in various behavioral models (procedural, spatial, "episodic," working, and relational/declarative memory) in young-adult and aged rodents. It is interesting to note that memory-enhancing effects appeared more robust in middle-aged animals compared with aged ones and in "episodic" and spatial memory tasks. From these results, S 18986 is expected to treat memory deficits associated with early cerebral aging and neurological diseases in elderly people.

The AMPA modulator S 18986 improves declarative and working memory performances in aged mice.

The aim of this study was to further characterize the memory-enhancing profile of S 18986 a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. S 18986 was studied in two mouse models of age-related memory deficits, using radial maze paradigms involving long-term/declarative memory and short-term/working memory. Aged mice exhibited severe deficits when compared with their younger counterparts in the two behavioural tests. S 18986 at the dose of 0.1 mg/kg selectively improved aged mouse performance in the test of long-term/declarative memory flexibility and exerted a beneficial effect on short-term retention of successive arm-visits in the short-term/working memory test. This study confirms the memory-enhancing properties of S 18986 and, in line with emerging data on multiple AMPA modulators, highlights the relevance of targeting AMPA receptors in the development of new memory enhancers.

Neuropharmacokinetics of a new alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) modulator, S18986 [(S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide], in the rat.

The aim of our study was to determine the neuropharmacokinetics of S18986 [(S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide], a new positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type receptors, in the rat. We focused on its blood-brain barrier (BBB) uptake and on its brain intra- and extracellular fluid (bICF-bECF) partitioning. BBB transport of S18986 was measured using the in situ brain perfusion technique. bECF concentrations were determined by microdialysis in the two effector areas, i.e., frontal cortex (FC) and dorsal hippocampus (DH), and blood samples were collected simultaneously through a femoral catheter. Cerebrospinal fluid and brain tissue concentrations were determined using a conventional pharmacokinetic approach. Using all the experimental data, pharmacokinetic modeling was applied to describe the S18986 blood-brain disposition. The brain uptake clearance of S18986 was found to be high, about 20 mul s(-1) g(-1). Terminal half-lives were similar in plasma and brain, at around 1 h. Experimental and predicted blood and brain concentrations were a good fit with the pharmacokinetic model, which assumed first-order rate constants at each interface. Ratios of bECF to the unbound plasma area under the curve (AUC) were 0.24 in FC and 0.25 in DH, whereas ratios of bICF/plasma AUC were 1 in FC and 1.5 in DH. We conclude that despite the ratio of bECF/plasma AUC below 1, there is nevertheless an elevated BBB uptake of S18986. This can be explained by the S18986 nonhomogenous bECF/bICF partitioning, since S18986 mainly distributes into hippocampal bICF. This illustrates the importance of taking bECF/bICF partitioning into account when interpreting the neuropharmacokinetics of a drug.