P.3.F.022 Evenamide (Formerly NW-3509) Targets New Mechanisms, and Represents a New Approach to the Management of Untreated Symptoms in Schizophrenia Faravelli1, R
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P.3.f.022 Evenamide (formerly NW-3509) targets new mechanisms, and represents a new approach to the management of untreated symptoms in schizophrenia Faravelli1, R. Anand2, E. Forrest3. 1, 3 NEWRON Pharmaceuticals SPA, Bresso - Milan, Italy. 2 APC, AG, St. Moritz, Switzerland. Introduction Three large, independent (non-commercial), randomized clinical trials comparing first- and second-generation antipsychotics performed in the US, UK, and Europe have indicated no clinically meaningful differences in the effectiveness of first (FGA) vs second generation (SGA) antipsychotics. The CATIE study (US) [1] showed high rates of discontinuation due to unsatisfactory response for all antipsychotics tested, the CUTLASS (UK) [2] second study found no meaningful differences in Quality of life, or patient preference for FGA vs SGA, while the EUFEST (EU) [3] study found that although discontinuations were higher for haloperidol, there was no difference in symptom reduction between FGA and SGA in patients with first episode psychosis. Clozapine outperformed other second-generation drugs in the CATIE and CUTLASS studies where it was tested. These results raise numerous questions relating to the neurochemical changes needed to provide meaningful benefit to patients with schizophrenia. All currently available FGA and SGA, except clozapine, act through minor variations of monoaminergic modulation, therefore their therapeutic effects are similar. These observations and increasing evidence that hippocampal hyperactivity, glutamatergic abnormalities, and aberrant electrical connectivity are involved in the dysregulation of excitatory and inhibitory circuits in the pathophysiology of schizophrenia, suggest that multiple neurochemical systems need to be modulated to produce meaningful therapeutic benefit in schizophrenics. Evenamide (NW-3509), a derivative of a new chemical class unrelated to any existing CNS active drug, is a voltage-gated sodium channel inhibitor that does not bind, inhibit or interact with over 130 receptors, enzymes, or transporters that are usually involved in CNS activity. It’s sodium channel blockade leads to inhibition of glutamate release, and may reduce cortical and hippocampal hyper-excitability. Evenamide monotherapy has demonstrated activity in numerous animal models of psychosis and other CNS conditions, however, by combining its selective blockade of sodium channels, glutamate inhibition, and reduction of neuronal hyper-excitability with ineffective doses of SGA and FGA and their inhibition of multiple CNS receptors is associated with a broader spectrum of activity and may offer a new therapeutic promise to patients [4]. Evenamide background Evenamide effects on Negative Symptoms Social Interaction deficit model Methods: Rats treated for five days with the NMDA antagonist PCP (4 mg/kg day) display a deficit in social interaction expressed as reduced time of interaction between two rats Selectively blocks VGSCs in High frequency firing Low frequency firing when placed in the same cage. The PCP-induced social interaction deficit in the rat a voltage-and use-dependent Control represents a model of negative symptoms relevant to associality in schizophrenia manner (Ki = 0.4 µM) and NW-3509 Results: modulates sustained 1µM repetitive firing without Monotherapy: Evenamide is effective in attenuating the social interaction 1400 deficit in PCP-impaired rats (MED = 1 mg/kg po) inducing impairment of the Saline (n=18) ) 1200 normal neuronal excitability NW-3509A 5 mg/kg ip (n=8) PCP+ PCP+ NW-3509 mean Ari 0.003 1000 NW-3509A 2.5 mg/kg ip (n=6) PCP- mg/kg 1 mg/kg induced 800 (MED) basal deficit 600 Inhibits stimulated *** 400 glutamate release without of (% Glu modifying the basal levels 200 *** veratridine 0 -60 -30 0 30 60 90 120 150 Time, min No other targets / mechanisms identified Information processing deficits # p<0.05 vs water-saline *p<0.05 vs water- PCP. Pre-pulse inhibition (PPI) disrupted by Evenamide was shown amphetamine - NMDA antagonists (MK- Add-on: combination of inactive doses of evenamide and aripiprazole to be active in a wide 801, PCP) - stress (sleep deprivation) reverses the PCP-induced social interaction deficit range of psychiatric Psychosis & Mania animal models in Water – saline (n=11) NW-3509 NW-3509 Mean Amph and 140 Water – PCP 4 mpk/day (n=10) dose plasma concentration monotherapy and add- Amph/CDZ induced hyperactivity Aripiprazole 0.003 mpk - PCP 4 mpk/day (n=10) (mg/kg po) at the time of test (15 120 NW-3509 0.5 mpk - PCP 4 mpk/day (n=10) on to antipsychotics NW-3509 0.5 mpk – Ari 0.003 mpk - PCP 4 mpk/day (n= 10) min after Cognitive impairment 100 * administration) Novel object recognition: scopolamine 80 # (ng/ml) impairment and 24 hr natural forgetting 60 1 19.13 40 monotherapy Impulsivity and Mood Symptoms active Resident Intruder test (Impulsivity) -Tail suspension test (Depression) - (sec) Time Interaction 20 # p<0.05 vs water-saline *p<0.05 vs water- PCP 0.5 9.19 Marble burying test (Obsessive Compulsive Disorders) 0 add-on active Clinical overview The tolerability and pharmacokinetics of Evenamide (NW3509A) have been evaluated in a first in man phase I single dose study in the US. Single oral doses of placebo,1, 2, 5, 10, 20 and 30 mg of NW-3509A were administered to 9 (3-placebo; 6-NW-3509A) healthy male subjects at each dose level (total of 54 subjects). All doses were well tolerated, and without adverse changes in laboratory results, ECGs, vital signs, or Holter recordings. The most frequent AEs were somnolence, headache, and orthostatic tachycardia. The Tmax was 1.5 to 2.0 hours post-dose, half-life (t1/2) ranged from 1.1 to 4.7 hours and did not change with dose. Cmax and AUC(0-t) increased approx. proportionately with increasing dose -Cmax (2.08- 93ng/ml) and AUC (6.71-350ng/ml/hour) from 1 to 30mg. Higher doses (>30mg) were not evaluated as single doses of 10, 20, and 30 mg were associated with Cmax values significantly higher than 20 ng/ml, i.e. exceeding effective exposures in preclinical models. Evenamide is currently in a Phase II, 4-week, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, pharmacokinetics of single and multiple doses, and preliminary evidence of efficacy of a dose range (15 mg-20mg-25mg BID) of NW-3509 or placebo, in the US and India, in 90 schizophrenic patients currently on risperidone (2 mg/day or higher) or aripiprazole (10 mg/day or higher) who are still symptomatic, despite at least 4 weeks of treatment at a stable dose. Conclusions Evenamide is being evaluated in a Phase II trial as add-on treatment to 5HT2/D2 blocking References antipsychotics in schizophrenic patients. 1. Lieberman JA et al N Engl J Med 2005;353:1209-23. Due to its different mechanism of action, Evenamide may add to or synergize with other 2. Jones PB et al. Arch Gen Psychiatry antipsychotics to bring about a combined therapeutic effect on glutamate release, and 2006; 63: 1079– 87 dopaminergic and serotoninergic systems, modulating these major neurotransmitter systems that 3. Boter H et al. Schizophr Res. 2009 have been associated with schizophrenia symptoms. Dec;115(2-3):97-103. 4. Large et al Psychopharmacology Evenamide may improve efficacy of current antipsychotics, and may benefit domains of symptoms 2005, 181:415-436 that are currently not managed effectively by available treatments.