Slide 1: Study 008A: Add-on treatment with evenamide in chronic schizophrenia
STUDY 008A: ADD-ON TREATMENT WITH EVENAMIDE IN PATIENTS WITH CHRONIC SCHIZOPHRENIA NOT RESPONDING ADEQUATELY TO THEIR CURRENT ANTIPSYCHOTIC Results of a potentially pivotal, phase 2/3, international, randomized, double-blind, placebo-controlled trial Ravi Anand, MD Anand Pharma Consulting (APC) Cons
Slide 2: Author Disclosures
AUTHOR DISCLOSURES Commercial Interest Relationship(s) Newron Pharmaceuticals SpA Chief Medical Officer, Consultant AbbVie, Acadia, BiolineRx, Domain, Enkam, Erydel, Forest, Janssen, Hoffman La Roche, Lundbeck, Noema, Consultant Ono, Pfizer, UCB, Sigma–Tau, Shire, Takeda, Teva
Slide 3: Evenamide – Efficacy in Psychiatric Animal Models
EVENAMIDE – EFFICACY IN PSYCHIATRIC ANIMAL MODELS • Evenamide is a voltage gated sodium channel (VGSC) modulator devoid of any interaction with any other CNS target (>130 tested), and it attenuates stimulated release of glutamate • It is active as a monotherapy and add–on to ineffective doses of fir
Slide 4: Evenamide as a monotherapy reverses PPI deficit induced by PCP or MK-801
EVENAMIDE AS A MONOTHERAPY REVERSES THE PPI DEFICIT INDUCED BY DYSREGULATION OF THE GLUTAMATE NEUROTRANSMISSION DUE TO PCP OR MK-801 ADMINISTRATION PPI DEFICIT INDUCED BY PCP PPI DEFICIT INDUCED BY MK-801 80 MK-801 (0.1 mg/kg, sc) 60 % PPI 40 *** * * 20 ### 0 ac 15 R 1 N -5 10 N icle Ve rol 5 ac 1 a
Slide 5: Evenamide as add-on in amphetamine-induced PPI deficit
EVENAMIDE AS ADD-ON IN AMPHETAMINE-INDUCED PPI DEFICIT Evenamide augments the effect of Typical and Atypical Antipsychotics in amphetamine-induced Pre-Pulse Inhibition (PPI) deficit evenamide 1.25 mg/kg po + haloperidol 0.05mg/kg ip evenamide 1.25 mg/kg po evenamide 0.62 mg/kg po + risperidone 0.05
Slide 6: Phase 2/3 completed and planned clinical studies with evenamide add-on
PHASE 2/3 COMPLETED AND PLANNED CLINICAL STUDIES WITH EVENAMIDE ADD-ON TREATMENT TO ANTIPSYCHOTICS Study 002 Study 014 - TRS Study 015 - TRS Study 008A Study 017 - TRS Phase 2 Phase 2 Phase 2 Phase 2/3 Phase 3 US; India India; Sri Lanka; Italy India; Sri Lanka; Italy EU; LATAM; Asia EU; US; LATAM; A
Slide 7: Studies 014/015 TRS – Long-term efficacy results up to 1-year
STUDIES 014/015 TRS – LONG–TERM EFFICACY RESULTS UP TO 1–YEAR OC; mITT N=156 • Progressive and sustained improvement up to 1–year of treatment with evenamide at all doses (7.5, 15 and 30 mg bid) • Benefits across all efficacy measures (PANSS total and subscales, CGI–S, CGI–C and LOF^) Mean change fr
Slide 8: Evenamide Study 008A
EVENAMIDE STUDY 008A EVENAMIDE IN PATIENTS WITH CHRONIC SCHIZOPHRENIA NOT RESPONDING ADEQUATELY TO SECOND-GENERATION ANTIPSYCHOTICS A Phase II/III, 4-week, international, randomized, double-blind, placebo-controlled, add-on study
Slide 9: Study 008A – Outpatient study in inadequately responding patients
STUDY 008A – OUTPATIENT STUDY IN INADEQUATELY RESPONDING PATIENTS WITH CHRONIC SCHIZOPHRENIA Day 29 Safety Day 0/1 Endpoint Follow up Day 8 Day 15 Day 22 (+ 30 days) 21-day Screening Period Antipsychotic plasma levels to confirm adherence RANDOMIZATION Evenamide (30 mg bid) Eligibility Process Place
Slide 10: Study 008A – Issues impacting on availability of results
STUDY 008A – ISSUES IMPACTING ON AVAILABILITY OF RESULTS Entry in the screening period was terminated on 30 November 2023 Randomization was terminated on 28 December 2023 (LPI N=290) An Investigator in Argentina, contacted by the caregiver, informed that a patient, who was in screening, wanted to pa
Slide 11: Study 008A – Challenges in subject selection
STUDY 008A – CHALLENGES IN SUBJECT SELECTION Identifying patients on antipsychotic monotherapy (70% at most sites on antipsychotic polypharmacy) Non-compliance with background AP; results from AP plasma assessments during screening indicated: o No AP detected; o AP plasma levels do not reflect the d
Slide 12: Study 008A – Patient disposition
STUDY 008A – PATIENT DISPOSITION Baseline DAY 29 First dose Endpoint Screened Screen Failures Randomized Completed N = 428 137 (32%) N = 291* N = 280 (96%) *Final number Screening of 21 days 4–week of double–blind treatment Total Screen Failures* 137 (32.0%) Total Discontinued 11 Did not meet entry
Slide 13: Study 008A – Patient characteristics by region
STUDY 008A – PATIENT CHARACTERISTICS BY REGION Antipsychotic daily dose (mg) Demographic and disease characteristics Baseline values Randomized Risperidone Duration (% completers) Risperidone Age at PANSS dose Sex Age of illness CGI-S Region Use diagnosis * Total equivalent # (years) ^ Mean n (%) Me
Slide 14: Study 008A – Demographics of patients on most common antipsychotics
STUDY 008A – DEMOGRAPHIC CHARACTERISTICS OF PATIENTS CONCOMITANTLY TREATED WITH MOST COMMON ANTIPSYCHOTICS (>10%) Demographic and disease Baseline values Risperidone characteristics Patients Daily dose * dose equivalent # Duration of Antipsychotic Daily doses Age illness PANSS Total CGI-S score (yea
Slide 15: Experience gained during add-on international study in non-TRS patients
EXPERIENCE GAINED DURING PERFORMANCE OF AN ADD–ON INTERNATIONAL STUDY IN NON–TRS PATIENTS Risperidone is the most used background antipsychotic overall: the usage was higher in Asia The risperidone dose equivalents of background APs show some variability, with higher doses prescribed in Asia D
Slide 16: Glutamate modulation by evenamide as add-on to TRS patients
GLUTAMATE MODULATION BY EVENAMIDE AS AN ADD-ON TO TRS PATIENTS NOT RESPONDING TO CURRENT ANTIPSYCHOTICS IS ASSOCIATED WITH CLINICALLY IMPORTANT IMPROVEMENT ACROSS OUTCOME MEASURES Results from a pilot, phase II, 1-year, open-label trial in patients with treatment resistant schizophrenia (TRS) Ravi A
Slide 17: Author Disclosures
AUTHOR DISCLOSURES Commercial Interest Relationship(s) Newron Pharmaceuticals SpA Chief Medical Officer, Consultant AbbVie, Acadia, BiolineRx, Domain, Enkam, Erydel, Forest, Janssen, Hoffman La Roche, Lundbeck, Noema, Consultant Ono, Pfizer, UCB, Shire, Sigma-Tau, Takeda, Teva
Slide 18: Agenda
Evenamide Background AGENDA Study 014/015: Open-label 1-year results in patients with TRS Design of a potentially pivotal 1-year study in TRS
Slide 19: Evenamide Background
EVENAMIDE BACKGROUND
Slide 20: Evenamide – Mechanism of Action
EVENAMIDE – MECHANISM OF ACTION Evenamide is a highly selective inhibitor of voltage-gated sodium channels (VGSCs) Reduces excessive glutamate release without any effect on basal levels of glutamate Devoid of biological activity at >130 CNS targets [receptors, transporters, enzymes, channels (except
Slide 21: Evenamide – Efficacy in Psychiatric Animal Models
EVENAMIDE – EFFICACY IN PSYCHIATRIC ANIMAL MODELS Evenamide is active as a monotherapy and add-on to ineffective doses of first-or-second generation antipsychotics, attenuating abnormal behaviours in different animal models Monotherapy Add-On Information Processing Deficit - Pre-Pulse Inhibition (PP
Slide 22: Ketamine-induced deterioration of PPI rescued by clozapine and evenamide
KETAMINE-INDUCED DETERIORATION OF PPI IS RESCUED BY COMBINATION OF INEFFECTIVE DOSES OF CLOZAPINE AND EVENAMIDE 80 Impairment “Full reversal” P<0.001 60 ^^^ *** Evenamide FGAs/SGAs %PPI Average 40 *** *** ns ns Combination of ineffective doses of evenamide with 20 1 antipsychotics (APs) was associat
Slide 23: Evenamide Study 014/015 pilot, Phase 2, open-label results in TRS
EVENAMIDE STUDY 014/015 PILOT, PHASE 2, OPEN-LABEL RESULTS WITH EVENAMIDE IN PATIENTS WITH TREATMENT-RESISTANT SCHIZOPHRENIA (TRS)
Slide 24: Study 014/015 – Key Features
STUDY 014/015 – KEY FEATURES Six-week, open-label, randomized, rater-blinded, parallel group study, option to enter extension up to 1 year to evaluate tolerability and preliminary efficacy of adjunctive 7.5, 15, 30 mg BID PHASE II Patients with confirmed treatment resistant schizophrenia (TRS) non-r
Slide 25: Study 014/015 – Patient disposition by study and duration
STUDY 014/015 – PATIENT DISPOSITION BY STUDY AND DURATION Randomized Completed Entered extension Completed Completed N = 161* N = 153 (95%) N = 144 (89%) N = 132 (82%) N = 121 (75%) 7.5/15/30 mg bid N=50/60/51 Discontinued Did not enter Discontinued Discontinued * One patient not dosed N=8 extension
Slide 26: Demographics, baseline and disease characteristics – safety population
DEMOGRAPHICS, BASELINE AND DISEASE CHARACTERISTICS – SAFETY POPULATION Total Characteristic Statistics N=160 Age (years) mean (SD) 37.7 (9.71) Sex (% of males) n (%) 111 (69.4) Race Asian population n (%) 157 (98.1) White n (%) 3 (1.9) Duration of illness (years) mean (SD) 6.8 (3.1) Duration of curr
Slide 27: Background most commonly prescribed antipsychotic medications
BACKGROUND MOST COMMONLY PRESCRIBED CURRENT ANTIPSYCHOTIC MEDICATIONS – SAFETY POPULATION N=160 Daily dose n (%) of patients Total Antipsychotic Mode AP class Statistics N=160 N=160 [min-max] in mg 8 SGAs n (%) 144 (90.0) Risperidone 88 (55.0) [2-12] 20 FGAs n (%) 16 (10.0) Olanzapine 42 (26.3) [10-
Slide 28: Study 014/015 Safety and efficacy results at 1-year
STUDY 014/015 SAFETY AND EFFICACY RESULTS AT 1-YEAR
Slide 29: Summary of treatment-emergent adverse events at 1 year
SUMMARY OF TREATMENT-EMERGENT ADVERSE EVENTS (TEAES) AT 1 YEAR SAFETY POPULATION N=160 7.5 mg bid 15 mg bid 30 mg bid Total Number of subjects with N=50 N=60 N=50 N=160 At least one TEAE 23 (46.0%) 18 (30.0%) 24 (48.0%) 65 (40.6%) At least one Serious TEAE* 0 1 (2.0%) 1 (2.0%) 2 (1.3%) At least one
Slide 30: Most common TEAE by preferred term
MOST COMMON (≥2.5%) TEAE BY PREFERRED TERM – SAFETY POPULATION N=160 7.5 mg bid 15 mg bid 30 mg bid Total Preferred Term N=50 N=60 N=50 N=160 Medication error 0 0 7 (14.0%) 7 (4.3%) (investigator mistake in dispensing kit) * Blood creatine phosphokinase increased 2 (4.0%) 2 (3.3%) 2 (4.0%) 6 (3.8%)
Slide 31: Long-term up to 1-year efficacy results (PANSS)
LONG-TERM UP TO 1-YEAR EFFICACY RESULTS; mITT N=156 PANSS mean change from baseline (SD) PANSS Responder Analysis % change from baseline n (%) of patients with ≥20% improvement from baseline # LOCF OC 79.5 (5.04) 58 * (48.3) 70.2 48 -9.3 (7.14) * (36.6) -11.6% 67.1 * -12.4 (7.98) 64.9 24 -15.6% -14.
Slide 32: Long-term up to 1-year efficacy results (CGI-S)
LONG-TERM – UP TO 1-YEAR EFFICACY RESULTS; mITT N=156 CGI-S Responder Analysis CGI-S mean change from baseline (SD) n (%) of patients with ≥2 categories of improvement LOCF OC 4.5 (0.58) * * * 3.8 34 3.6 3.5 -0.7 (0.71) (28.3) -0.9 (0.65) -1.0 (0.74) 21 16 (16.0) (10.5) Baseline Week-6 6-Month 1-Yea
Slide 33: Long-term up to 1-year efficacy results (CGI-C, LOF)
LONG-TERM – UP TO 1-YEAR EFFICACY RESULTS; mITT N=156 CGI-C Responder Analysis LOF# mean change from baseline (SD) n (%) of patients rated at least “much improved” LOCF OC * 20.1 53 17.9 +2.2 (3.21) (44.2) (4.05) 43 38 (32.8) (25.0) Week-6 6-Month 1-Year Baseline 1-Year N=152 N=131 N=120 # Strauss-C
Slide 34: Patients no longer meeting severity criteria for TRS
PATIENTS NO LONGER MEETING SEVERITY CRITERIA FOR TRS Selection criteria for severity of symptoms: 1 PANSS total score ≥ 70 2 CGI-S of moderately ill to severely ill (score 4-6) Total score ≥ 20 on the combined total of the PANSS symptom items: P1 (Delusions), P2 (Conceptual 3 Disorganization), P3 (H
Slide 35: Patients no longer meeting severity criteria for TRS (mITT; OC)
PATIENTS NO LONGER MEETING SEVERITY CRITERIA FOR TRS (mITT; OC) Week-6 6-Month 1-Year Severity Criteria Stats N=152 N=131 N=120 1. PANSS < 70 n (%) 72 (47.3) 84 (64.1) 84 (70.0) 2. CGI-S < 4 n (%) 52 (34.2) 66 (50.4) 76 (63.3) 3. Core items* < 20 n (%) 60 (39.4) 76 (58.0) 80 (66.7) 4. Score ≥ 4 in m
Slide 36: Criteria for remission in patients with schizophrenia
CRITERIA FOR REMISSION IN PATIENTS WITH SCHIZOPHRENIA ORIGINAL REQUIREMENTS PROPOSED ADAPTATIONS Lieberman et al., 1993 Score ≤3 on SADS-C+PD* items: suspiciousness, severity of SADS Impaired understandability replaced with delusions, hallucinations, impaired understandability, PANSS P2 concep
Slide 37: Proportion of patients meeting proposed remission criteria
STUDY 014/015 – PROPORTION OF PATIENTS WHO MEET PROPOSED REMISSION CRITERIA FROM LITERATURE (mITT) n (%) of patients meeting Maintenance Method Criteria remission criteria requirement N=156 P1, P2, P3, P6, G5 ≤ 3 Lieberman et al, 1993 CGI-S «mildly ill»; 8 weeks 43 (27.6%) CGI-C «much improved» Andr
Slide 38: Long-term treatment with evenamide: key observations
LONG-TERM TREATMENT WITH EVENAMIDE: KEY OBSERVATIONS Well-tolerated: only three (3) adverse dropouts (i.e. flu-like symptoms, somnolence, insomnia) No pattern of laboratory, ECG, vital signs abnormalities, no complaints of EPS, sedation, weight gain, sexual dysfunction, and endocrine abnormalities N
Slide 39: Phase 3, placebo-controlled, 1-year study in patients with TRS
PHASE 3, PLACEBO-CONTROLLED, 1-YEAR STUDY IN PATIENTS WITH TRS A Phase III, 52-week, prospective, randomized, double-blind, placebo-controlled, Key Selection Criteria parallel-group, multi-center study, with a primary efficacy endpoint at 12 weeks, to determine the efficacy, safety, and tolerability
Slide 40: Thank you
Thank you ky