Meret Martin-Facklam

Effect of Bitopertin, a Glycine Reuptake Inhibitor, on Negative Symptoms of Schizophrenia: A Randomized, Double-Blind, Proof-of-Concept Study

IMPORTANCE In schizophrenia, the severity of negative symptoms is a key predictor of long-term disability. Deficient signaling through the N-methyl-D-aspartate receptor is hypothesized to underlie many signs and symptoms associated with schizophrenia in particular negative symptoms. Glycine acts as an N-methyl-D-aspartate receptor coagonist. Blockade of the glycine transporter type 1 to inhibit glycine reuptake and elevate synaptic glycine concentrations represents an effective strategy to enhance N-methyl-D-aspartate receptor transmission. OBJECTIVE To determine the efficacy and safety of bitopertin (RG1678), a glycine reuptake inhibitor, in patients with schizophrenia and predominant negative symptoms who were stable while taking an antipsychotic treatment. DESIGN, SETTING, AND PARTICIPANTS This randomized, double-blind, placebo-controlled, phase 2 proof-of-concept trial involved 323 patients with schizophrenia and predominant negative symptoms across 66 sites worldwide. INTERVENTIONS Bitopertin (10, 30, or 60 mg/d) or placebo added to standard antipsychotic therapy for a treatment duration of 8 weeks. MAIN OUTCOMES AND MEASURES Change from baseline in the Positive and Negative Syndrome Scale negative factor score. RESULTS In the per-protocol population, 8 weeks of treatment with bitopertin was associated with a significant reduction of negative symptoms in the 10-mg/d (mean [SE] reduction in negative symptoms score, -25% [2%]; P = .049) and 30-mg/d (mean [SE], -25% [2%]; P = .03) bitopertin groups, a significantly higher response rate and a trend toward improved functioning in the 10-mg/d group when compared with placebo (mean [SE], -19% [2%]). Results reached trend-level significance in the intent-to-treat population. Estimates of bitopertin binding to glycine transporter type 1 showed that low to medium levels of occupancy yielded optimal efficacy in patients, consistent with findings in preclinical assays. CONCLUSIONS AND RELEVANCE Bitopertin-mediated glycine reuptake inhibition may represent a novel treatment option for schizophrenia, with the potential to address negative symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00616798.

Glycine Transporter Type 1 Occupancy by Bitopertin: a Positron Emission Tomography Study in Healthy Volunteers

Deficient N-methyl-D-aspartate (NMDA) receptor transmission is thought to underlie schizophrenia. An approach for normalizing glutamate neurotransmission by enhancing NMDA receptor transmission is to increase glycine availability by inhibiting the glycine transporter type 1 (GlyT1). This study investigated the relationship between the plasma concentration of the glycine reuptake inhibitor bitopertin (RG1678) and brain GlyT1 occupancy. Healthy male volunteers received up to 175 mg bitopertin once daily, for 10–12 days. Three positron emission tomography scans, preceded by a single intravenous infusion of ∼30 mCi [11C]RO5013853, were performed: at baseline, on the last day of bitopertin treatment, and 2 days after drug discontinuation. Eighteen subjects were enrolled. At baseline, regional volume of distribution (VT) values were highest in the pons, thalamus, and cerebellum (1.7–2.7 ml/cm3) and lowest in cortical areas (∼0.8 ml/cm3). VT values were reduced to a homogeneous level following administration of 175 mg bitopertin. Occupancy values derived by a two-tissue five-parameter (2T5P) model, a simplified reference tissue model (SRTM), and a pseudoreference tissue model (PRTM) were overall comparable. At steady state, the relationship between bitopertin plasma concentration and GlyT1 occupancy derived by the 2T5P model, SRTM, and PRTM exhibited an EC50 of ∼190, ∼200, and ∼130 ng/ml, respectively. Emax was ∼92% independently of the model used. Bitopertin plasma concentration was a reliable predictor of occupancy because the concentration–occupancy relationship was superimposable at steady state and 2 days after drug discontinuation. These data allow understanding of the concentration–occupancy–efficacy relationship of bitopertin and support dose selection of future molecules.

Characterization of [11C]RO5013853, a novel PET tracer for the glycine transporter type 1 (GlyT1) in humans.

We characterize a novel radioligand for the glycine transporter type 1 (GlyT1), [(11)C]RO5013853, in humans. Ten healthy male volunteers, 23-60 years of age, were enrolled in this PET study; seven subjects participated in the evaluation of test-retest reliability and three subjects in whole body dosimetry. Subjects were administered intravenous bolus injections of approximately 1100 MBq (30 mCi) [(11)C]RO5013853 with a high specific activity of about 481 GBq (13 Ci)/μmol. Standard compartmental model analysis with arterial plasma input function, and an alternative noninvasive analysis method which was evaluated and validated by occupancy studies in both baboons and humans, were performed. Mean parameter estimates of the volumes of distribution (VT) obtained by a 2-tissue 5-parameter model were higher in the cerebellum, pons, and thalamus (1.99 to 2.59 mL/mL), and lower in the putamen, caudate, and cortical areas (0.86 to 1.13 mL/mL), with estimates showing less than 10% difference between test and retest scans. Tracer retention was effectively blocked by the specific glycine reuptake inhibitor (GRI), bitopertin (RG1678). [(11)C]RO5013853 was safe and well tolerated. Human dosimetry studies showed that the effective dose was approximately 0.0033 mSv/MBq, with the liver receiving the highest absorbed dose. In conclusion, quantitative dynamic PET of the human brain after intravenous injection of [(11)C]RO5013853 attains reliable measurements of GlyT1 binding in accordance with the expected transporter distribution in the human brain. [(11)C]RO5013853 is a radioligand suitable for further clinical PET studies. Full characterization of a novel radiotracer for GlyT1 in humans is provided. The tracer has subsequently been used to assess receptor occupancy in healthy volunteers and to estimate occupancy at doses associated with best efficacy in a clinical trial with schizophrenic patients with predominantly negative symptoms.

Clinical Drug–Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib

The efficacy and safety of alectinib, a central nervous system–active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK‐positive (ALK+) non–small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time‐dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed‐sequence studies evaluating drug–drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is coadministered with CYP3A inhibitors or inducers or for coadministered CYP3A substrates.

Evaluation of the effects of bitopertin (RG1678) on cardiac repolarization: a thorough corrected QT study in healthy male volunteers.

BACKGROUND Bitopertin (RG1678) is a selective glycine reuptake inhibitor currently in Phase III development for the treatment of schizophrenia. Thorough QT studies to assess the effects of candidate drugs on cardiac repolarization and proarrhythmic potential are required by regulatory authorities and are a common part of the drug development process. A clinically relevant effect on QT interval is suspected if prolongation of the corrected QT interval (QTc) is ∼5 milliseconds or more, evidenced by an upper 1-sided 95% CI for the mean effect on the QTc of at least 10 milliseconds. OBJECTIVE The goal of this study was to investigate the effect of bitopertin on the QTc interval in healthy male volunteers. METHODS This was a multiple-dose, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study using bitopertin 30 mg (n = 56) or bitopertin 175 mg (n = 56) once daily for 10 days plus placebo on day 11, moxifloxacin 400 mg on day 1 plus placebo once daily for 10 days (n = 29), or placebo once daily for 10 days plus moxifloxacin 400 mg on day 11 (n = 28). Continuous Holter ECGs were obtained on days -1, 1, 10, and 11, and the placebo-corrected mean change from time-matched baseline in the QT interval calculated by using Fridericias formula (QTcF) on day 10 was the primary end point. Pharmacokinetic parameters of bitopertin were determined on day 10 by using HPLC-MS/MS methods to obtain bitopertin plasma drug concentrations. Adverse events were recorded throughout the study. RESULTS A total of 169 predominantly white, healthy male volunteers (mean age, 31.8 years; range, 19-59 years) were randomized to treatment; 162 completed the study. The mean change in placebo-corrected QTcF from baseline to day 10 of bitopertin ranged from -2.8 to 3.9 milliseconds. The upper bound of the 1-sided 95% CI was <10 milliseconds at all time points with both doses. There was no relation between bitopertin concentrations and changes in QTcF or other ECG variables. Assay sensitivity was confirmed by a placebo-corrected mean change from time-matched baseline in QTcF of 10.6 milliseconds (lower bound of the 1-sided 98.3% CI, 6.9 milliseconds) 4 hours after moxifloxacin administration. Peak bitopertin plasma concentrations were achieved ∼4 hours after dosing. The terminal elimination t(½) was ∼53 hours. No safety or tolerability concerns were noted with bitopertin at either dose. Dizziness, nausea, and blurred vision were more common in the bitopertin 175-mg group compared with the bitopertin 30-mg or placebo groups. CONCLUSION Multiple dosing with bitopertin 30 mg or 175 mg did not affect QTcF in these healthy male volunteers. ClinicalTrials.gov identifier: NCT01613040.

Effect of Food and Esomeprazole on the Pharmacokinetics of Alectinib, a Highly Selective ALK Inhibitor, in Healthy Subjects

Alectinib, an anaplastic lymphoma kinase (ALK) inhibitor, is approved for treatment of patients with ALK+ non–small cell lung cancer who have progressed, on or are intolerant to, crizotinib. This study assessed the effect of a high‐fat meal and the proton pump inhibitor, esomeprazole, on the pharmacokinetics (PK) of alectinib. This was an open‐label, 2‐group study in healthy subjects. In group 1 (n = 18), subjects were randomly assigned to a 2‐treatment (A, fasted conditions; B, following a high‐fat meal), 2‐sequence (AB or BA) crossover assessment, separated by a 10‐day washout. In group 2 (n = 24), subjects were enrolled in a 2‐period, fixed‐sequence crossover assessment to evaluate the effect of esomeprazole. PK parameters were evaluated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Administration of alectinib following a high‐fat meal substantially increased the combined exposure of alectinib and M4 to 331% (90%CI, 279%–393%) and 311% (90%CI, 273%–355%) for Cmax and AUC0–∞, respectively, versus fasted conditions. Coadministration of esomeprazole had no clinically relevant effect on the combined exposure of alectinib and M4. Alectinib should be administered under fed conditions to maximize its bioavailability, whereas no restrictions are required with antisecretory agents.

Effect of the Wetting Agent Sodium Lauryl Sulfate on the Pharmacokinetics of Alectinib: Results From a Bioequivalence Study in Healthy Subjects.

The anaplastic lymphoma kinase (ALK) inhibitor alectinib is an effective treatment for ALK‐positive non‐small‐cell lung cancer. This bioequivalence study evaluated the in vivo performance of test 3 formulations with the reduced wetting agent sodium lauryl sulfate (SLS) content. This randomized, 4‐period, 4‐sequence, crossover study compared alectinib (600 mg) as 25%, 12.5%, and 3% SLS hard capsule formulations with the reference 50% SLS clinical formulation in healthy subjects under fasted conditions (n = 49), and following a high‐fat meal (n = 48). Geometric mean ratios and 90% confidence intervals (CIs) for Cmax, AUC0–last, and AUC0–∞ of alectinib, its major active metabolite, M4, and alectinib plus M4 were determined for the test formulations versus the reference formulation. Bioequivalence was concluded if the 90%CIs were within the 80% to 125% boundaries. The 25% SLS formulation demonstrated bioequivalence to the reference 50% SLS formulation for Cmax, AUC0–last, and AUC0–∞ of alectinib, M4, and alectinib plus M4 under both fasted and fed conditions. Further reductions in SLS content (12.5% and 3% SLS) did not meet the bioequivalence criteria. Cross‐group comparisons showed an approximately 3‐fold positive food effect. Reducing SLS to 25% resulted in a formulation that is bioequivalent to the current 50% SLS formulation used in alectinib pivotal trials.

Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti–α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial

Importance Aggregated &agr;-synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of &agr;-synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of &agr;-synuclein, potentially resulting in neuronal protection and slowing disease progression. Objective To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD. Design, Setting, and Participants Multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose trial at 8 US study centers from July 2014 to September 2016. Eligible participants were aged 40 to 80 years with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3). Interventions Participants were enrolled into 6 ascending-dose cohorts and randomly assigned to receive PRX002 (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg) or placebo. Participants received 3 intravenous infusions every 4 weeks of PRX002 or placebo and were monitored during a 24-week observational period. Main Outcomes and Measures Safety and tolerability assessments included physical and neurological examinations, laboratory tests, vital signs, and adverse events. Pharmacokinetic parameters included maximum PRX002 concentration, area under the curve, and half-life. Results Of the 80 participants, most were white (97.5%; n = 78) and male (80%; n = 64); median (SD) age was 58 (8.4) years. PRX002 was generally safe and well tolerated; no serious or severe PRX002-related treatment-emergent adverse events (TEAEs) were reported. The TEAEs experienced by at least 5% of patients receiving PRX002, irrespective of relatedness to study drug, were constipation (9.1%; n = 5), infusion reaction (7.3%; n = 4), diarrhea (5.5%; n = 3), headache (5.5%; n = 3), peripheral edema (5.5%; n = 3), post–lumbar puncture syndrome (5.5%; n = 3), and upper respiratory tract infection (5.5%; n = 3). No antidrug antibodies were detected. Serum PRX002 levels increased in an approximately dose-proportional manner; mean terminal elimination half-life was similar across all doses (10.2 days). Rapid dose- and time-dependent mean reductions from baseline vs placebo in free serum &agr;-synuclein levels of up to 97% were seen after a single infusion at the highest dose (F78,284 = 1.66; P = .002), with similar reductions after 2 additional infusions. Mean cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts. Conclusions and Relevance Single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral &agr;-synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated &agr;-synuclein in the brain. Findings support the design of an ongoing phase 2 clinical study (NCT03100149). Trial Registration ClinicalTrials.gov Identifier: NCT02157714

Large-Scale Continuous Mobility Monitoring of Parkinson’s Disease Patients Using Smartphones

Smartphone-based assessments have been considered a potential solution for continuously monitoring gait and mobility in mild to moderate Parkinson’s disease (PD) patients. Forty-four PD patients from cohorts 4 to 6 of the Multiple Ascending Dose (MAD) study of PRX002/RG7935 and thirty-five age- and gender-matched healthy individuals (i.e. healthy controls - HC) in a separate study performed smartphone-based assessments for up to 24 weeks and up to 6 weeks, respectively. The assessments included “active gait tests”, where all participants were asked to walk for 30 s with at least one 180\(^\circ \) turn, and “passive monitoring”, in which subjects carried the smartphone in a pocket or fanny pack as part of their daily routine. In total, over 6,600 active gait tests and over 30,000 h of passive monitoring data were collected. A mobility analysis indicates that patients with PD are less mobile than HCs, as manifested in time spent in gait-related activities, number of turns and sit-to-stand transitions, and power per step. It supports the potential use of smartphones for continuous mobility monitoring in future clinical practice and drug development.