Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial

IMPORTANCE: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. OBJECTIVE: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. DESIGN, SETTING, AND PARTICIPANTS: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. INTERVENTIONS: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. MAIN OUTCOMES AND MEASURES: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). RESULTS: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2 to -2.2 × 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 × 10-5 SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4 to -5.6 × 10-5; P < .001), and high CSF t-tau (-7.2 × 10-4 SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3 to -9.5 × 10-5; P = .03). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02149160

No synergistic effect of subtherapeutic doses of donepezil and EVP-6124 in healthy elderly subjects in a scopolamine challenge model

Introduction: Donepezil is a widely used cholinesterase inhibitor in the management of Alzheimer's disease. Despite large-scaled evidence for its efficacy, elevated peripheral ACh levels often lead to side effects and are dose limiting. The present exploratory study is designed to determine the potentiation of the effects of donepezil by cotreatment with EVP-6124, an alpha-7 nicotinic agonist, to reduce scopolamine-induced cognitive deficits in healthy elderly subjects. Secondary objectives are to explore safety and pharmacokinetic and pharmacodynamics effects of EVP-6124 alone and in combination with donepezil compared to placebo. Methods: A phase I randomized, single-center, placebo-controlled, double-blind, five-way, partial crossover study was performed with donepezil 2.5, 5 mg or placebo combined with EVP-6124 0.3, 1, 2, 4 mg or placebo in three cohorts of healthy elderly subjects in a scopolamine (0.3 mg i.v.) challenge test. Safety, pharmacokinetic, and pharmacodynamics outcomes were assessed. Results: A total of 36 subjects completed the study. Donepezil pharmacokinetic parameters were similar with and without EVP-6124. Effective dose combinations were donepezil/EVP-6124(5/2 mg) and donepezil/EVP-6124 (5/0.3 mg) and showed improvements of the delayed recall of the Visual Verbal Learning Test (1.2; CI = 0.1–2.3) and reaction time during the two-back condition of the N-back (−42; CI = −77, −8), respectively. Overall, no marked reversal of scopolamine effects was observed. Discussion: This study shows no synergistic effect of subtherapeutic doses of donepezil and EVP-6124 in a scopolamine challenge model in healthy elderly subjects. Dosing of scopolamine and the combination of donepezil and EVP-6124 requires further study

False negatives in GBA1 sequencing due to polymerase dependent allelic imbalance

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 frequencie

Placebo Response and Practice Effects in Schizophrenia Cognition Trials

Patients' previous experience with performance-based cognitive tests in clinical trials for cognitive impairment associated with schizophrenia can create practice-related improvements. Placebo-controlled trials for cognitive impairment associated with schizophrenia are at risk for these practice effects, which can be difficult to distinguish from placebo effects. To conduct a systematic evaluation of the magnitude of practice effects on the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) in cognitive impairment associated with schizophrenia and to examine which demographic, clinical, and cognitive characteristics were associated with improvement in placebo conditions. A blinded review was conducted of data from 813 patients with schizophrenia who were treated with placebo in 12 randomized placebo-controlled clinical trials conducted mostly in outpatient clinics in North America, Europe, Asia, and Latin America from February 22, 2007, to March 1, 2014. A total of 779 patients provided data for the primary outcome measure at baseline and at least 1 follow-up. Seven trials had prebaseline assessments wherein the patients knew that they were not receiving treatment, allowing a comparison of practice and placebo effects in the same patients. Placebo compared with various experimental drug treatments. Composite score on the MCCB. Of the 813 patients in the study (260 women and 553 men; mean [SD] age, 41.2 [11.5] years), the mean MCCB composite score at baseline was 22.8 points below the normative mean, and the mean (SEM) total change in the MCCB during receipt of placebo was 1.8 (0.2) T-score points (95% CI, 1.40-2.18), equivalent to a change of 0.18 SD. Practice effects in the 7 studies in which there was a prebaseline assessment were essentially identical to the postbaseline placebo changes. Baseline factors associated with greater improvements in the MCCB during receipt of placebo included more depression/anxiety (F1,438 = 5.41; P = .02), more motivation (F1,272 = 4.63; P = .03), and less improvement from screening to baseline (F1,421 = 59.32; P < .001). Placebo effects were minimal and associated with the number of postbaseline assessments and several patient characteristics. Given that the patients performed 2.28 SDs below normative standards on average at baseline, a mean placebo-associated improvement of less than 0.2 SD provides evidence that ceiling effects do not occur in these trials. These minimal changes in the MCCB could not be responsible for effective active treatments failing to separate from placebo

A Large-Scale Full GBA1 Gene Screening in Parkinson's Disease in the Netherlands.

Background: The most common genetic risk factor for Parkinson's disease known is a damaging variant in the GBA1 gene. The entire GBA1 gene has rarely been studied in a large cohort from a single population. The objective of this study was to assess the entire GBA1 gene in Parkinson's disease from a single large population. Methods: The GBA1 gene was assessed in 3402 Dutch Parkinson's disease patients using next-generation sequencing. Frequencies were compared with Dutch controls (n = 655). Family history of Parkinson's disease was compared in carriers and noncarriers. Results: Fifteen percent of patients had a GBA1 nonsynonymous variant (including missense, frameshift, and recombinant alleles), compared with 6.4% of controls (OR, 2.6; P < 0.001). Eighteen novel variants were detected. Variants previously associated with Gaucher's disease were identified in 5.0% of patients compared with 1.5% of controls (OR, 3.4; P < 0.001). The rarely reported complex allele p.D140H + p.E326K appears to likely be a Dutch founder variant, found in 2.4% of patients and 0.9% of controls (OR, 2.7; P = 0.012). The number of first-degree relatives (excluding children) with Parkinson's disease was higher in p.D140H + p.E326K carriers (5.6%, 21 of 376) compared with p.E326K carriers (2.9%, 29 of 1014); OR, 2.0; P = 0.022, suggestive of a dose effect for different GBA1 variants. Conclusions: Dutch Parkinson's disease patients display one of the largest frequencies of GBA1 variants reported so far, consisting in large part of the mild p.E326K variant and the more severe Dutch p.D140H + p.E326K founder allele