encenicline (EVP-6124) / Forum Pharmaceuticals, Mitsubishi Tanabe - LARVOL DELTA

Pharmacological and Mechanistic Interventions for Cognitive Impairment Associated With Schizophrenia: A Review of Registered Clinical Trials. (PubMed, Acta Psychiatr Scand) - "In this comprehensive overview of clinical trials on pro-cognitive agents in schizophrenia, we identify emerging opportunities but also acknowledge a lack of replicated evidence. Despite extensive attempts to address CIAS, it remains an undertreated domain, and future trials should explore better ways to treat this important condition."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Advancements in Non-Dopaminergic Treatments for Schizophrenia: A Systematic Review of Pipeline Developments. (PubMed, Pharmacopsychiatry) - "Compounds that function differently from existing antipsychotics may offer novel symptom-specific therapeutic strategies for patients with schizophrenia."

Journal • Review • CNS Disorders • Psychiatry • Schizophrenia

Meta-Analysis of Adjunctive Treatment Trials for Cognitive Deficits in Schizophrenia (SOBP 2024) - "For NMDAR-modulators, the largest significant effects were for luvadaxistat (d=0.44, p=0.01) and iclepertin (d=0.34, p=0.01). Published results for the alpha-7 encenicline (d=1.04, p<0.001) were highly significant, but results for the subsequent negative phase III studies are unavailable... These results highlight the potential efficacy of specific add-on mechanisms and encourage further clinical development. Overall effect sizes were similar across MoA, suggesting that significance for NMDAR modulators is presumably driven by the larger number of studies. Nevertheless, effect sizes were generally small, suggesting possible ceiling effects or the need for combined behavioral/pharmacological treatments."

Retrospective data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Characterizing the binding of TC-5619 and encenicline on the alpha7 nicotinic acetylcholine receptor using PET imaging in the pig. (PubMed, Front Neuroimaging) - "Of particular significance, our in vivo investigations demonstrate that TC-5619 achieves substantial α7-nAChR occupancy, effectively blocking approximately 40% of α7-nAChR binding, whereas encenicline exhibits more limited α7-nAChR occupancy. This study underscores the importance of preclinical PET imaging and target engagement analysis in informing clinical trial strategies, including dosing decisions."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Mental Retardation • Psychiatry • Schizophrenia

Molecular Docking Analysis at the Human α7-nAChR and Proliferative and Evoked-Calcium Changes in SH-SY5Y Cells by Imidacloprid and Acetamiprid Insecticides. (PubMed, Neurotox Res) - "Docking analysis showed that the binding of IMI and ACE occurred at the same aromatic cage that the specific α-7 nAChR agonist EVP-6124...Through the interaction with α-7nAChRs, IMI would demonstrate its high neurotoxic potential for humans. More research is needed for investigating the proliferative effects of IMI in neuroblastoma cells."

Journal • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor

[VIRTUAL] The Perils of Placebo: Developing Medications for Persons with Schizophrenia (ASCP 2021) - "In the past several years this has been observed with novel compounds such as pomaglumetad methionil, bitopertin, and encenicline...For example, asenapine was approved for the treatment of acute schizophrenia on the basis of 2 out of 4 placebo-controlled trials, where one of the studies considered 'positive' for asenapine was actually a Phase 2 study where the active control, risperidone, failed to demonstrate efficacy despite a therapeutic dose. Iloperidone was also approved for schizophrenia based on 2 out of 4 clinical trials, with disagreement between the US Food and Drug Administration and the manufacturer as to which studies were considered ‘positive’ for iloperidone...Be aware of the challenges in studying persons with schizophrenia in placebo-controlled trials 2. Understand some of the ways to increase the probability of differentiating study drug from placebo in clinical trials in persons with schizophrenia"

Clinical • CNS Disorders • Psychiatry • Schizophrenia

Aged rhesus monkeys: cognitive performance categorizations and preclinical drug testing. (PubMed, Neuropharmacology) - "Accordingly, the older subjects could be categorized as aged "cognitively-unimpaired" or aged "cognitively-impaired" with a third group (aged-other) falling in between. Finally, as a proof of principle, we demonstrated using the DMTP task that aged cognitively-impaired monkeys are sensitive to the pro-cognitive effects of a nicotinic acetylcholine receptor (nAChR) partial agonist, encenicline, suggesting that nAChR ligands remain viable as potential treatments for age-related disorders of cognition."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry

The Novel Antipsychotic Drug Cariprazine and Cognition Enhancing Drugs: Indications for Their Use as an Add-on Therapy in Schizophrenia. (PubMed, Curr Pharm Des) - "In clinical trials, patients with treatment-resistant forms of psychosis should be examined to know whether a combination therapy with clozapine and a novel antipsychotic drug can ameliorate the PANSS total score. In schizophrenia, long-acting injectable antipsychotic drugs are a safe and tolerable maintenance therapy. In further clinical studies, it should be investigated whether patients with treatment-resistant forms of psychoses can improve negative schizophrenic symptoms and cognitive functions by an add-on therapy with cognition enhancing drugs."

Journal • CNS Disorders • Psychiatry • Schizophrenia

[VIRTUAL] Rats with long learning experience showed resistance to the impairing effect of MK-801 in several cognitive assays (ECNP 2020) - "In the present study we investigated the memory and learning disrupting effect of MK-801, an NMDA receptor antagonist, and intended to subsequently test a nicotinic α7 receptor partial agonist compound, EVP-6124, for a putative cognitive enhancing effect. In conclusion, animals with a long and rich history of learning experience and problem solving showed resistance to the cognitive impairing effects of MK-801. This finding highlights the importance of the cognitive status of the experimental subjects in studies used for prediction of clinical efficacy."

Preclinical • Ataxia • CNS Disorders • Cognitive Disorders

Quantitative assessment of oligomeric amyloid beta peptide binding to alpha7 nicotinic receptor. (PubMed, Br J Pharmacol) - "Our TR-FRET Aβ binding assay demonstrates for the first time the specific binding of Aβ to α7nAChR, which will be a crucial tool for the development, testing and selection of a novel generation of AD drug candidates targeting Aβ/α7nAChR complexes with high specificity and lesser side effects compared to currently approved α7nAChR drugs."

Journal • Alzheimer's Disease • CNS Disorders • Dementia

Two Global Phase III Trials of Encenicline for Cognitive Impairment in Chronic Schizophrenia Patients: Red Flags and Lessons Learned (SIRS 2019) - "These include: 1) the importance of accounting for/mitigating non-adherence to treatment, 2) multiple repeated MCCB testing sessions did not plateau learning effects and 3) subjects with greater change in Outcome scores from screening to baseline also showed aberrant changes from baseline to week 26 compared to subjects with smaller changes prior to baseline, inherently reducing signal:noise ratio. Results of additional post-hoc analyses will be discussed to guide and inform the future development of CIAS clinical trials."

Clinical • P3 data • CNS Disorders • Schizophrenia

Normalizing effects of EVP-6124, an alpha-7 nicotinic partial agonist, on event-related potentials and cognition: A proof of concept, randomized trial in patients with schizophrenia (J Psychiatr Pract) - P1, N=21; NCT01556763; Sponsor: EnVivo Pharmaceuticals; "EVP-6124 was well tolerated and showed positive, and in some cases, dose-dependent effects on several EEG responses...Mismatch Negativity and P300 potentials. Positive effects were also found in performance on cognitive tests that measured non-verbal learning, memory, and executive function."

P1 data • Schizophrenia

Effect of circadian rhythm on cognition testing in a Phase 2b mild/moderate Alzheimer’s disease (AD) study (CTAD 2015) - P2b, N=409; NCT01073228; Sponsor: FORUM Pharmaceuticals Inc; "The 1.8 mg/d Encenicline group [n=100 vs n=104 placebo] showed the largest treatment effect on the ADAS-Cog-13 [cohen’s d ES at 6 months vs placebo of d=0.39, p=0.019 after multiplicity correction]....Patients in the 1.8 mg Encenicline treatment group whose ADAS-Cog-13 at 6 months was administrated at the same time of day (+ one hour) (n= 46, 1.8 mg Encenicline, n=40, placebo) at 6 months as compared to baseline had a treatment effect of d=0.5, p=0.039 vs those who did not: d=0.16, p=0.708 (n=37, 1.8 mg Encenicline, n=48, placebo)."

P2b data • Alzheimer's Disease

Forum Pharmaceuticals: Regulatory Update (Forum Pharmaceuticals) - Anticipated top-line data from P3 trials (NCT01714661, NCT01716975) for cognitive impairment in schizophrenia in H1 2016

Anticipated P3 data: top line • Schizophrenia

Forum Pharmaceuticals: Needham Healthcare Conference (Forum Pharmaceuticals) - "Encenicline is Generally Well-Tolerated"; "Alzheimer's Disease; Phase 2b"; "AEs predominantly GI (mild constipation and nausea); "~2X AE frequency in add-on patients vs. de novo"; "Two GI SAEs 'possibly drug related'; SAEs more frequent overall in add-on group"

P2b data • Alzheimer's Disease

Forum Pharmaceuticals: Needham Healthcare Conference (Forum Pharmaceuticals) - Anticipated P3 top-line data for Alzheimer's disease in Q1 2017 

Anticipated P3 data: top line • Alzheimer's Disease

EVP-6124, an alpha-7 nicotinic partial agonist, produces positive effects on cognition, clinical function, and negative symptoms in patients with chronic schizophrenia on stable antipsychotic therapy (ACNP 2011) - P2b, N=319; The OCI plus Trails 2 and 4 suggested that 0.3 mg of EVP-6124, vs. pbo, was associated with improvement in general cognitive function (p=0.034) and that this improvement was due mainly to the beneficial effects of the drug on visual learning, visual attention, and social cognition; EVP-6124 treatment of subjects with stable schizophrenia resulted in improved cognition and clinical function, and decreased negative symptoms

P2 data • Schizophrenia

Forum Pharmaceuticals: Needham Healthcare Conference (Forum Pharmaceuticals) - Anticipated compound exclusivity in US until 2030

Patent expiry • Alzheimer's Disease

Nicotinic alpha7 treatments for improving cognitive symptoms - Proof of concept and further developments and the EVP-6124-009 study group (ECNP 2013) - Presentation time: 15:45-16:10; Oct 07, 2013; Monday; Abstract #S.13.04; P2b, N=319; NCT00968851; Sponsor: EnVivo; “OCI...significantly different between treatment groups (p=0.05); with greater improvement in the 0.3mg dose compared to placebo (p=0.009)....These results support further confirmatory studies and the initiation of confirmatory phase 3 program has been initiated.”

Anticipated new P3 trial • P2 data • Schizophrenia

In light of two major failed trials, FORUM Pharma closes its doors this week (BioSpace) - "It’s official—Waltham, Massachusetts-based FORUM Pharmaceuticals will be shuttering its doors this week before the Fourth of July holiday. The company had been hammered by two major failed trials. In September 2015, the U.S. Food and Drug Administration (FDA) advised the company to halt its clinical trials of encenicline for Alzheimer’s disease as the result of serious gastrointestinal side effects. Another trial in cognitive impairment in schizophrenia (CIS) was also placed on a clinical hold, which was lifted in November."

Commercial • Discontinued • Alzheimer's Disease

Forum Pharmaceuticals: Needham Healthcare Conference (Forum Pharmaceuticals) - Anticipated submission of supplemental NDA for Alzheimers disease in 2017; Anticipated approval for Alzheimers disease in 2018; Anticipated launch for Alzheimers disease in 2018

Anticipated launch • Anticipated sNDA • Alzheimer's Disease

EnVivo confirms EVP-6124 mechanism of action (Drug Discovery & Development) - EnVivo has demonstrated that EVP-6124 is a potent & highly selective agonist of alpha-7 neuronal nicotinic acetylcholine receptors in brain & treatment with EVP-6124, both alone& in combination with donepezil, restored memory loss & improved memory function in preclinical models; The company expects to report data from a multicenter, multinational, double-blind, placebo-controlled P2b study of EVP-6124 in Alzheimer’s disease in H1 2012

Anticipated P2b data • MOA • Alzheimer's Disease • Schizophrenia

EnVivo Pharmaceuticals presents additional EVP-6124 phase 2b clinical trial results at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting (EnVivo Pharmaceuticals) - P2b, N=409; EnVivo presented PK/PD data along with previously reported results from its P2b trial of EVP-6124 in patients with Alzheimer’s disease; New data demonstrate a relationship (p=0.003) between EVP-6124 plasma concentrations and probability of improvement in cognition, measured by ADAS-Cog-13; In new data EVP-6124 met both trial’s primary endpoints, with positive effects on cognition (p=0.0189), measured by ADAS-Cog-13 and clinical function (p=0.0253), measured by CDR-SB; Company is planning to advance EVP-6124 into P3 trial (schizophrenia) in this fall and another P3 trial (Alzheimer’s disease) in 2013

Anticipated trial initiation date • P2b data • Alzheimer's Disease • Schizophrenia

Study of the Safety and Clinical Effects of 2 Doses of EVP-6124 in Subjects With Alzheimer's Disease Who Complete Study EVP-6124-024 or EVP-6124-025 (clinicaltrials.gov) - P3; N=348; Terminated; Sponsor: FORUM Pharmaceuticals Inc; N=1000 ➔ 348; Suspended ➔ Terminated

Enrollment change • Trial termination • Alzheimer's Disease • Biosimilar

A randomized, double-blind, placebo-controlled, 24-week, phase 2b outcomes study of 3 different doses of encenicline or placebo in subjects with mild to moderate probable Alzheimer’s disease (AAN 2015) - Presentation time: Thursday, April 23, 2015 - 2:00 pm; Abstract #P7.100; P2b, N=409; "Encenicline reported the most significant procognitive effects (ADAS-Cog-13) in the 1.8mg group compared with placebo (P<0.05). Secondary measures of cognition and function supported these primary outcomes. De novo subjects reported somewhat greater cognitive improvement (P<0.05) than add-on subjects...46% of subjects experienced a treatment-emergent adverse event(TEAE) (0.27mg, 42.3%; 0.9mg, 48.5%; 1.8mg, 53.0%; placebo, 40.4%)."

P2b data • Alzheimer's Disease