Newron Presents Results of Its Phase IIa Study with Evenamide in Patients with Schizophrenia

Newron Pharmaceuticals S.p.A., a biopharmaceutical company focused on the development of novel therapies for patients with diseases of the central nervous system (CNS) and pain, today presented detailed results of a Phase IIa study with its unique sodium channel blocker, Evenamide (NW-3509), in patients with schizophrenia. The new chemical entity is orally available and specifically targets voltage-gated sodium channels by a unique mechanism of action.

The results were presented at the 16th International Congress on Schizophrenia Research, 24-28 March 2017, in San Diego.

Ravi Anand, M.D., Newron’s Chief Medical Officer, stated: “Evenamide uniquely combines voltage-gated sodium channel blockade with attenuation of glutamate release. The results of this first study in patients with schizophrenia confirm preclinical data, which indicated that Evenamide might provide significant evidence of efficacy as an add-on to the most commonly prescribed atypical antipsychotics in patients with chronic schizophrenia, without effect on any of the over 130 neurotransmitters, enzymes, or transporters targeted by most antipsychotics.”

Dr. Anand continued: “The patients in this study, who were showing signs of worsening symptoms of psychosis while on doses of antipsychotics they had responded to in the recent past, benefited on all efficacy measures evaluated. The onset of improvement occurred early in treatment. Evenamide was not associated with any increase in extrapyramidal, sexual, endocrine, cardiac, laboratory or metabolic side effects caused by the use of antipsychotics. The addition of Evenamide to patients showing a worsening of their symptoms while on their current atypical antipsychotic was not only well-tolerated, but showed a consistent pattern of benefit on all efficacy measures assessed. These preliminary results warrant further investigation in larger and longer trials in patients with more severe symptoms.”

The four-week, Phase IIa, double-blind, placebo-controlled, randomized, multi-national study was designed to investigate the tolerability, safety and preliminary evidence of efficacy of Evenamide as an add-on treatment in 89 patients with a DSM-5 diagnosis of schizophrenia. Patients included in the study were primarily male (86%) and 19 to 60 years of age, with a mean baseline PANSS total score of 62.9 ± 7.4, and were experiencing break-through psychotic symptoms while on stable and adequate doses of risperidone (mean dose: 4.2 ± 2.0 mg/day; n=70) or aripiprazole (mean dose: 19.7 ± 7.0 mg/day; n=19), the atypical antipsychotics to which they had responded previously. The study was conducted in two U.S (n=61) and three Indian (n=28) study centers, and enrolled patients with schizophrenia with a mean duration of illness of approximately 18 years and an average of three hospitalizations. Patients were randomized to receive twice daily Evenamide (15-25 mg) or placebo, in addition to their current antipsychotic.

The study protocol, including doses and study design, was finalized with FDA input and guidance, and received approval from the Drug Controller General of India (DCGI), as well as the institutional review board (IRB) at each center.

The results of the study indicate that patients treated with Evenamide showed improvement on the symptoms of schizophrenia assessed by the Positive and Negative Syndrome Scale (PANSS). The mean (SD) change from baseline at Day 28 for the PANSS total score was greater for Evenamide [-5.1 (9.67)] than for placebo [-3.7 (9.65)]. For the PANSS Positive Symptoms sub-scale, a statistically significant/near significant improvement from baseline (mean baseline score: 14.8 ± 2.8) to Day 28 for Evenamide, compared to placebo [LS mean difference (SE)], was noted in the ANCOVA-LOCF [-1.28 (0.632), p=0.046], ANCOVA-OC [-1.48 (0.641), p=0.024], and MMRM [-1.19 (0.643), p=0.068] analyses. Numerically greater improvement with Evenamide was also observed for patients’ functioning, assessed by the Strauss-Carpenter Level of Functioning scale, and severity of illness (Clinical Global Impression of Severity), compared to their standard antipsychotic alone. In addition, a global assessment of change from baseline in the patient’s overall condition (Clinical Global Impression of Change), performed by a clinician, showed a greater proportion of Evenamide-treated patients rated as improved (54%), compared to placebo (36%). An additional analysis demonstrated that the proportion of patients who showed improvement on the PANSS Positive sub-scale at Day 28 was significantly greater (p=0.0043; Fisher’s exact chi-square test) for the Evenamide group (74.5%) compared to the placebo group (43.6%).

Evenamide in the range of 15-25 mg bid (30-50 mg/day) was well tolerated. The most frequent (>5% of patients in any group) adverse events (AEs) (Evenamide vs. placebo) were somnolence [8 (16.0%) vs. 5 (12.8%)], insomnia [5 (10.0% vs. 1 (2.6%)], overdose [3 (6.0%) vs. 1 (2.6%)], dry mouth [3 (6.0%) vs. 2 (5.1%)], headache [3 (6.0%) vs 0], and cold sweat/hyperhidrosis [2 (4.0%) vs. 0]. The incidence of ‘respiratory, thoracic and mediastinal disorders’ was higher for placebo [1 (2.0%) vs. 3 (7.7%)]. Most AEs were of mild severity [Evenamide, 58 of 69 (84%); placebo, 30 of 34 (88%)]; 9 of 69 (13%) AEs for Evenamide and 4 of 34 (12%) for placebo were assessed as moderate.

Two patients in the Evenamide group discontinued treatment due to AEs: seizure (n=1) and atrial fibrillation (n=1). The proportions of patients with clinically notable abnormalities in vital signs or laboratory values were very low and were similar in the Evenamide and placebo groups. The proportion of patients with clinically significant ECG abnormalities was low and similar between groups, and there was no evidence of effects on QTc. Assessment of extrapyramidal symptoms (EPS) using the Extrapyramidal Symptoms Rating Scale did not reveal any treatment-emergent EPS with Evenamide treatment.