Newron Pharmaceuticals (United States)

Introduction Treatment of schizophrenia remains a challenge despite the development of numerous antipsychotics (AP) (Pompili et al CNS NDDT 2017; 16 870-884). The various strategies to address patients’ unmet needs, such as AP polypharmacy or switching AP, do not seem to provide adequate benefit. A reason for this may reside in the similarity of mechanisms of action of most APs. However, the monoaminergic systems targeted by these drugs are not always disrupted in schizophrenia, as it is widely accepted that patients who fail to respond to AP have glutamatergic, but not dopaminergic dysfunctions (Moghaddam et al NPP 2012; 37 4-15). Evenamide normalizes excessive glutamate release without affecting its basal levels, and it does not interact with >150 CNS targets. It has been shown to be effective in animal models of psychosis as monotherapy and add-on to AP. Previous trials indicate that evenamide benefits patients with schizophrenia with inadequate response and have shown clinically important benefits lasting up to 1-year in TRS (Anand et al IJNPP 2023; 26 523-528). Objectives Study 008A, a phase 2/3 international, randomized, double-blind, placebo-controlled, 4-week trial, assessed the efficacy and safety of evenamide 30 mg bid as add-on in patients poorly responding to an SGA. Methods Outpatients with a diagnosis of schizophrenia, still symptomatic (PANSS 70-85; CGI-S 4-6) despite treatment with an SGA at a therapeutic dose (confirmed through plasma levels) for an adequate period, were enrolled. Efficacy was assessed on the PANSS, CGI-S, and LOF through the comparison of changes from baseline to Day 29 between evenamide and placebo groups using a MMRM analysis. Moreover, the proportion of patients reaching a clinically important improvement on the PANSS and CGI-C were compared between groups using a logistic regression model (chi-square test). Safety measures comprised: TEAEs, vital signs, labs, ECG/EEG, seizure checklist, physical/neurological/eye examinations, C-SSRS, ESRS-A, CDSS. Results 291 patients were randomized in the study in 11 countries (EU, Asia and LATAM), and 280 completed the study. The low attrition rate (<4%), and proportion of patients with TEAEs (~25% in both groups) indicate that evenamide was well tolerated. A statistically significant greater improvement was found on the PANSS total score and on the CGI-S in the evenamide compared to the placebo group. Furthermore, a significantly higher proportion of patients treated with evenamide, compared to those receiving placebo, experienced clinically meaningful benefit measured on the PANSS (≥20% improvement) and CGI-C (at least much improved). Conclusions This is the first randomized, placebo-controlled trial to demonstrate the clinical benefit of adding a NCE modulating glutamate in patients with schizophrenia who did not experience adequate response from treatment with a SGA. Disclosure of Interest R. Anand Consultant of: AbbVie, Acadia, BiolineRx, Domain, Enkam, Erydel, Forest, Janssen, Hoffman La Roche, Lundbeck, Noema, Ono, Pfizer, UCB, Shire, Sigma-Tau, Takeda, Teva, A. Turolla Employee of: Newron Pharmaceuticals SpA, G. Chinellato Employee of: Newron Pharmaceuticals SpA, R. Giuliani Employee of: Newron Pharmaceuticals SpA, F. Sansi Employee of: Newron Pharmaceuticals SpA, R. Hartman Consultant of: Newron Pharmaceuticals SpA.

BackgroundNumerous findings indicate reduced life-expectancy in patients with TRS, along with multiple morbidities, frequent hospitalizations, indigent status, and increasing costs of care for families and society [1]; no new treatment has emerged since clozapine approval in 1989 [2]. Despite its therapeutic promise, current experience indicates that less than 5% and 15% of TRS patients in the US, and in the EU respectively, receive clozapine [Global Data; 2017]. The vast majority of TRS patients are managed by off-label use of first and second-generation antipsychotics (APs) in conjunction with other psychopharmaceuticals, without showing efficacy [3]. Evenamide, a selective inhibitor of voltage-gated sodium channels, devoid of biological activity at >130 CNS targets, normalizes glutamate release [4,5,6,7] without affecting its basal levels. Preclinical experiments have indicated that it is likely to benefit patients responding inadequately or resistant to APs. Evenamide was evaluated as monotherapy or add-on to APs in animal models in which PPI was impaired using amphetamine, scopolamine, phencyclidine, MK-801, ketamine, or sleep deprivation. It demonstrated efficacy across a broad spectrum of experiments, including models of mania, depression, impulse control loss, and obsessive-compulsive behavior.Aims & ObjectivesTo present final, 1-year results of evenamide treatment in TRS patients unstable on their current AP. This data will demonstrate the unique benefits of glutamate modulation, when added to 5HT2/D2 modulators. It is likely that profound long-lasting efficacy of the combination, observed in shorter trials, will be demonstrated on efficacy variables used to assess patients with schizophrenia, as well as on key characteristics of TRS patients.MethodsThe selection criteria for the study require patients to meet standardized criteria for TRS: non-response to two APs, baseline PANSS total score 70-90 with predominant positive symptoms, at least two moderate core symptoms and functional deficits. Efficacy data (PANSS, CGI-S/C, and LOF) were analyzed using paired t-test to assess changes from baseline to endpoint (1-year) for each dose group and provide descriptive statistics for the responder analyses.ResultsThe high retention rate [82.5% after 6-month] and the low incidence of adverse dropouts [1.9%] indicate the good tolerability of evenamide. Interim analyses at 6-month (mITT=156) and 1-year for the first cohort of 100 patients, indicated that a large proportion of patients improve to an extent that they no longer meet the operational severity criteria for TRS; and a significant proportion can be considered ‘responders’ based on TRRIP definition (>=20% improvement on PANSS maintained for >=12 weeks [8]). Comparison of results available after 6-week, 6-month, and 1-year are likely to indicate a pattern of unique efficacy over time. Furthermore, increasing and long-lasting improvement was observed in all efficacy scales [9,10], with the largest improvement in the 15 and 30 mg bid dose groups. Full, 1-year results, available by the time of the Congress, will be presented demonstrating remarkable efficacy of evenamide at 1-year in TRS patients.DiscussionThis is the first international trial of evenamide add-on to any AP (except clozapine) in patients with TRS. Encouraging results of this study have expedited the conduct of a potentially pivotal, randomized, double-blind, placebo-controlled, 1-year, international study.

ABSTRACT A study was conducted to evaluate alternatives for transporting crude oil from the Bering Sea to the U.S. West Coast. Three scenarios, including all relevant environmental parameters, defined the northern, central and southern regions of the Bering Sea. The major force acting on most Arctic and sub Arctic offshore structures results from contact with sea ice. Ice strength, level ice characteristics, ice ridge characteristics, and other relevant ice parameters are defined. Ice forces on each of the structural configurations considered are determined and the selected offshore crude oil storage and loading system for each region are described. INTRODUCTION A major study, titled "Evaluation of Bering Sea Crude Oil Transportation Systems," was recently carried out by Han-Padron Associates for the U.S. Department of the Interior, Minerals Management Service, Alaska Region, to evaluate and compare the technology and costs associated with alternatives for transporting crude oil from the Bering Sea to the U.S. West Coast. There exist a large number of possible transportation alternatives that are generally categorized as either offshore loading systems or pipeline systems. However, both systems contain elements of pipelines, crude oil storage structures, tanker mooring and loading systems, and tankers. The optimum crude oil transportation system for a particular offshore oil field development scenario depends on the characteristics and details of that scenario. Therefore, three basic scenarios of environmental parameters were defined, representative of the northern, central and southern regions of the Bering Sea. These three locations, indicated in Figure 1, were selected because the extent of ice cover and size of ice features varies considerably from the northern to southern boundaries of the Bering Sea and it is the presence of ice that creates the most significant difference between the Bering Sea environment and the environments in which previous offshore oil field developments have taken place. The transportation system analyses were based upon environmental data available in the public domain. Additional environmental data exist but they are proprietary and were not available for the study. While the available data are quite extensive and are adequate for preliminary evaluation of alternative crude oil transportation systems, they are not sufficient to provide a sound basis for the final design of the transportation system elements. The cost of many of these elements is quite sensitive to specific site conditions and such conditions must be fully defined before a final design can be performed. In order to carry out the study, preliminary designs for many different types of structures were prepared. The major force acting on these structures results from contact with sea ice and the magnitude of the force depends on the configuration of the structure. Structure configurations considered included large and small diameter rigid vertical cylinders, with and without conical surfaces at the water line, small diameter articulated vertical cylinders, with and without conical surfaces at the waterline, and floating vessels with an ice-breaking configuration.