Newron presents encouraging detailed results of its Phase IIa study with Evenamide in patients with schizophrenia

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.

About schizophrenia

Schizophrenia is a long-term mental health condition that causes a range of different psychological symptoms. It is one of the most common serious mental health conditions. About 1 in 100 people will experience schizophrenia in their lifetime, with many continuing to lead normal lives. Schizophrenia is most often diagnosed betweenthe ages of 15 and 35. Men and women are affected equally. There is no single test for schizophrenia. It is most often diagnosed after an assessment by a mental health care professional, such as a psychiatrist. It is important to diagnose schizophrenia as early as possible, as the chances of recovery improve the earlier it is treated. Schizophrenia is often described in terms of positive and negative (or deficit) symptoms. Positive symptoms are those that most individuals do not normally experience but are present in people with schizophrenia. They can include delusions, disordered thoughts and speech, and tactile, auditory, visual, olfactory and gustatory hallucinations, typically regarded as manifestations of psychosis. Hallucinations are also typically related to the content of the delusional theme. Positive symptoms generally respond well to medication. Negative symptoms are deficits of normal emotional responses or of other thought processes, and are less responsive to medication.

About Evenamide (NW-3509)

Evenamide is an orally available new chemical entity that specifically targets voltage-gated sodium channels. The compound modulates sustained repetitive firing, without inducing impairment of normal neuronal excitability. Evenamide normalizes glutamate release induced by aberrant sodium channel activity. The potential benefits of the compound have been demonstrated in numerous preclinical models predictive of efficacy in psychiatric diseases, including models of psychosis such as amphetamine-induced hyperactivity, sensorimotor gating and information processing deficits (pre-pulse inhibition impairment induced by different stimuli), mania and depression. Efficacy of Evenamide has also been demonstrated in models of aggression and compulsive behavior, as well as in short- and long-term memory tests. Sub-threshold doses of the compound increased the activity of inactive doses of both typical and atypical antipsychotics in models of schizophrenia, psychosis and mania. Moreover, given its neuronal stabilization properties, Evenamide may reduce relapses and prevent or treat episodes of psychosis due to established super-sensitivity psychosis (SSP) induced by antipsychotics. As it is devoid of the risk of drug-induced movement disorders or weight gain, Evenamide can be given in combination for extended periods of time.

About Newron Pharmaceuticals

Newron (SIX: NWRN) is a biopharmaceutical company focused on the development of novel therapies for patients with diseases of the Central Nervous System (CNS) and pain. The Company is headquartered in Bresso near Milan, Italy. Xadago®(safinamide) has received marketing authorization for the treatment of Parkinson's disease in the European Union, Switzerland and the USA, and is commercialized by Newron's Partner Zambon. US WorldMeds holds the commercialization rights in the USA. Meiji Seika has the rights to develop and commercialize the compound in Japan and other key Asian territories. In addition to Xadago® for Parkinson's disease, Newron has a strong pipeline of promising treatments for rare disease patients at various stages of clinical development, including sarizotan for patients with Rett syndrome and ralfinamide for patients with specific rare pain indications. Newron is also developing Evenamide as the potential first add-on therapy for the treatment of patients with positive symptoms of schizophrenia. www.newron.com

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