Mathematical Disease Progression Modeling in Type 2/3 Spinal Muscular Atrophy.

INTRODUCTION: We propose a mathematical model to empirically describe spinal muscular atrophy (SMA) progression assessed by the 3 domains of the motor function measure (MFM) scale. The model implements development and deterioration of muscle function. METHODS: Nonlinear mixed-effects modeling was applied to data from 2 observational studies and 1 prospective clinical efficacy study comprising 190 healthy participants and 277 patients with type 2/3 SMA. RESULTS: The model evidenced correlations between parameter estimates for different MFM domains. Slower development in MFM domain D1 (standing and transfers) was associated with faster deterioration for MFM domains D2 (proximal and axial motricity) and D3 (distal motor function). DISCUSSION: The model describes all individual data well, although sparseness and variability of observational data prevented numerically stable estimation of parameters. Treatment duration in clinical studies was too limited to determine a proper drug-effect model that could differentiate between symptomatic and disease modifying effects. Muscle Nerve 58: 528-535, 2018.

The effect of aleglitazar on the pharmacokinetics and pharmacodynamics of S- and R-warfarin in healthy male subjects.

: Aleglitazar acts through balanced activation of peroxisome proliferator-activated receptors α and γ; warfarin is a commonly prescribed anticoagulant. Given the extent of cardiovascular disease in patients with type 2 diabetes, cotreatment with aleglitazar and warfarin is likely in this population. This open-label, randomized, 2-period, crossover study in 12 healthy male subjects investigated the potential for drug-drug interactions between warfarin and aleglitazar (final data drawn from 11 white subjects). The primary objective was to investigate the effect of aleglitazar on the pharmacokinetic properties of S-warfarin and on the pharmacodynamics of the racemic mixture; the secondary objectives included the effect of aleglitazar on R-warfarin pharmacokinetics and of racemic warfarin on aleglitazar pharmacokinetics. Subjects were randomized to single-dose warfarin on day 1 or aleglitazar once daily (12 days) plus single-dose warfarin on day 6 followed by a 14-day washout period, then crossover. Coadministration of aleglitazar reduced S- and R-warfarin exposure (AUC0-∞) by 18% and 13%, respectively, but did not change its pharmacodynamic effects (prothrombin time and factor VII activity). After warfarin dosing, aleglitazar trough concentrations remained within the same range. These findings indicate that coadministration of aleglitazar and warfarin is unlikely to affect the efficacy or safety of either agent.

NfL concentration in CSF is a quantitative marker of the rate of neurodegeneration in aging and Huntington's disease: a semi-mechanistic model-based analysis.

The concentrations of neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and plasma have become key biomarkers of many neurodegenerative diseases, including Huntington's Disease (HD). However, the relationship between the dynamics of NfL concentrations in CSF and the time-course of neurodegeneration (whole brain atrophy) has not yet been described in a quantitative and mechanistic manner. Here, we present a novel semi-mechanistic model, which postulates that the amount of NfL entering the CSF corresponds to the amount of NfL released from damaged neurons, whose degeneration results in a decrease in brain volume. In mathematical terms, the model expresses the NfL concentration in CSF in terms of the NfL concentration in brain tissue, the rate of change of whole brain volume and the CSF flow rate. To test our model, we used a non-linear mixed effects approach to analyze NfL and brain volume data from the HD-CSF study, a 24-month prospective study of individuals with premanifest HD, manifest HD and healthy controls. The time-course of whole brain volume, obtained from MRI, was represented empirically by a 2nd order polynomial, from which its rate of change was computed. CSF flow rates in healthy and HD populations were taken from recent literature data. By estimating the NfL concentration in brain tissue, the model successfully described the time-course of the NfL concentration in CSF in both HD subjects and healthy controls. Furthermore, the model-derived estimate of NfL concentration in brain agreed well with recent direct experimental measurements. The consistency of our model with the NfL and brain volume data suggests that the NfL concentration in CSF reflects the rate, rather than the extent, of neurodegeneration and that the increase in NfL concentration over time is a measure of the accelerating rate of neurodegeneration associated with aging and HD. For HD subjects, the degree of acceleration was found to increase markedly with the number of CAG repeats on their HTT gene. The application of our semi-mechanistic NfL model to other neurodegenerative diseases is discussed.

Development of a population pharmacokinetic model to characterize the pharmacokinetics of intrathecally administered tominersen in cerebrospinal fluid and plasma.

Tominersen is an intrathecally administered antisense oligonucleotide targeting huntingtin mRNA which leads to a dose-dependent, reversible lowering of cerebrospinal fluid (CSF) mutant huntingtin protein concentration in individuals with Huntington's disease. Nonlinear mixed-effect population pharmacokinetic (PopPK) modeling was conducted to characterize the CSF and plasma pharmacokinetics (PK) of tominersen, and to identify and quantify the covariates that affect tominersen PKs. A total of 750 participants from five clinical studies with a dose range from 10 to 120 mg contributed CSF (n = 6302) and plasma (n = 5454) PK samples. CSF PK was adequately described by a three-compartment model with first-order transfer from CSF to plasma. Plasma PK was adequately described by a three-compartment model with first-order elimination from plasma. Baseline total CSF protein, age, and antidrug antibodies (ADAs) were the significant covariates for CSF clearance. Body weight was a significant covariate for clearances and volumes in plasma. ADAs and sex were significant covariates for plasma clearance. The developed PopPK model was able to describe tominersen PK in plasma and CSF after intrathecal administration across a range of dose levels, and relevant covariate relationships were identified. This model has been applied to guide dose selection for future clinical trials of tominersen in patients with Huntington's disease.

Randomized, Double-Blind, Placebo-Controlled Trial of the mGlu2/3 Negative Allosteric Modulator Decoglurant in Partially Refractory Major Depressive Disorder.

OBJECTIVE: To assess putative antidepressant and procognitive effects of decoglurant, a selective metabotropic glutamate receptor type 2/3 (mGlu2/3) negative allosteric modulator, as adjunctive treatment to selective serotonin reuptake inhibitors and/or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) in patients with partially refractory major depressive disorder (MDD), diagnosed using DSM-IV-TR criteria. METHODS: This randomized, placebo-controlled, double-blind, multicenter phase 2 trial consisted of 4 weeks' screening, 6 weeks' treatment, and 8 weeks' follow-up between September 2011 and June 2014. Individuals with Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 25 and Clinical Global Impressions-Severity of Illness scale score ≥ 4, despite up to 2 adequate trials of an SSRI/SNRI and compliance confirmed by positive SSRI/SNRI blood levels, were randomized to decoglurant 5 mg (n = 101), 15 mg (n = 102), or 30 mg (n = 55) daily or placebo (n = 99) as adjunct to ongoing treatment with 1 SSRI/SNRI. An adaptive design was used with an interim analysis after 30 patients in each group had received 6 weeks' treatment. The primary outcome variable was change in MADRS total score from baseline to end of treatment. Primary assessments were performed by fully blinded centralized raters. RESULTS: Of 357 participants, 310 completed 6 weeks' treatment. At 6 weeks, no significant differences between any active treatment arm and placebo in reducing MADRS total score or response or remission rates were observed. Decoglurant exerted no significant effects on Cambridge Neuropsychological Test Automated Battery cognitive accuracy and cognitive speed composite scores or on secondary measures of mood and functioning. A relatively high placebo response was observed, which may have constrained the ability to detect treatment effects. No deaths occurred; few patients reported serious adverse events. CONCLUSIONS: Decoglurant was well tolerated overall but did not exert any antidepressant or procognitive effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01457677.

Subcutaneous Bioavailability of Taspoglutide at 3 Different Injection Sites in Healthy Overweight/Obese Subjects.

PURPOSE: Taspoglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist that has >90% homology with the endogenous GLP-1 while retaining equivalent potency. Once-weekly subcutaneous injections with taspoglutide demonstrated meaningful antihyperglycemic and weight loss effects in patients with type 2 diabetes. The present study was performed to compare the relative bioavailability of taspoglutide injected subcutaneously in the abdomen, upper arm, and thigh. METHODS: Healthy overweight/obese subjects were randomized in an open-label, 3-way crossover study. A single 20-mg dose of taspoglutide was injected subcutaneously on 3 occasions in the abdomen, upper arm, or thigh. Each injection was separated by a 12-week washout period. Blood was sampled up to 12 weeks for the pharmacokinetic evaluation of taspoglutide. FINDINGS: Sixty subjects were randomized into the study (mean age, 45.5 years; body weight, 97.6 kg; and body mass index, 31.4 kg/m(2)). AUClast values (geometric mean) for subcutaneous injections in the abdomen, upper arm, and thigh were 44.2, 61.2, and 50.0 ng·h/mL, respectively. The geometric mean ratio (relative bioavailability) for the upper arm versus the abdomen was 1.41 (90% CI: 1.22-1.62) and for the thigh versus the abdomen was 1.13 (90% CI: 0.98-1.31). Corresponding Cmax values for subcutaneous injections in the abdomen, upper arm, and thigh were 0.268, 0.382, and 0.341 ng/mL, respectively, and the geometric mean ratio for the upper arm versus the abdomen was 1.43 (90% CI: 1.24-1.64) and for the thigh versus the abdomen was 1.27 (90% CI: 1.10-1.46). Decreases in taspoglutide exposure were observed with each subsequent period. AUClast values (geometric mean across injections sites) for periods 1, 2, and 3 were 97.2, 42.6, and 31.5 ng·h/mL, respectively. The geometric mean ratio for period 2 versus 1 was 0.44 (90% CI: 0.38-0.50) and for period 3 versus 1 was 0.32 (90% CI: 0.27-0.37). Analysis of pharmacokinetic data after first injection only (period 1) showed comparable AUClast across the 3 injection sites and lower initial Cmax after injection into the abdomen compared with the other 2 injection sites. Overall, taspoglutide was well tolerated by most subjects in all 3 injection sites, with a lower incidence of nausea and vomiting when injected in the abdomen. IMPLICATIONS: Regardless of a pronounced period effect, relative bioavailability of taspoglutide was different across injection sites, with the lowest exposure and incidence of nausea and vomiting seen after administration in the abdomen. In the absence of comparable bioavailability, taspoglutide was recommended to be injected into the abdomen.