irsenontrine (E2027) / Eisai - LARVOL DELTA

A novel selective phosphodiesterase 9 inhibitor, irsenontrine (E2027), enhances GluA1 phosphorylation in neurons and improves learning and memory via cyclic GMP elevation. (PubMed, Neuropharmacology) - "L-NAME downregulated cGMP in the CSF and hippocampus and impaired novel object recognition, but oral administration of irsenontrine clearly attenuated these phenotypes. These results indicate that irsenontrine improves learning and memory via the elevation of cGMP levels, and they strongly suggest that irsenontrine could be a novel therapeutic approach against cognitive dysfunction."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease

Drug Development. (PubMed, Alzheimers Dement) - "This global proteomics analyses in DLB clinical trial samples presents that, despite the small number of participants treated with E2027, there were changes in proteins related to the mechanism of action, as indicated by Pantothenate and CoA biosynthesis increase, which amongst others factors related to glutamate metabolism. In addition, multiple proteins and pathways were differentially affected between the DLB A- and A+ group, which could lead to improved understanding of differential clinical treatment response in DLB patients."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease

The Combination of E2027 (Irsenontrine) and Donepezil Hydrochloride Increases Supernatant Acetylcholine Concentrations in Human iPS-derived Neurons and Improves Memory Deficits in Rat Models (Neuroscience 2024) - "Donepezil HCl did not affect the cGMP-increasing effect of E2027 in rat CSF.E2027 promoted ACh release from human cholinergic neurons, and when combined with donepezil hydrochloride, ACh concentrations were increased in culture supernatants synergistically. This combination treatment also improved memory in rats."

Preclinical • Alzheimer's Disease • CNS Disorders • Dementia

The effects of the novel phosphodiesterase 9 (pde9) inhibitor E2027 (irsenontrine) on CSF proteomics profile in amyloid positive and amyloid negative Lewy Body Dementia (AAIC 2024) - "This global proteomics analyses in DLB clinical trial samples presents that, despite the small number of participants treated with E2027, there were changes in proteins related to the mechanism of action, as indicated by Pantothenate and CoA biosynthesis increase, which amongst others factors related to glutamate metabolism. In addition, multiple proteins and pathways were differentially affected between the DLB A- and A+ group, which could lead to improved understanding of differential clinical treatment response in DLB patients."

Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease

Insights into the management of Lewy body dementia: a scoping review. (PubMed, Ann Med Surg (Lond)) - "Donepezil, rivastigmine, memantine, and galantamine were the commonly used drugs for LBD. Together with that, levodopa, antipsychotics, armodafinil, piracetam, and traditional medications like yokukansan were also used, when indicated...Talking about recent advances in the treatment of LBD, various disease-modifying therapies like ambroxol, neflamapimod, irsenontrine, nilotinib, bosutinib, vodobatinib, clenbuterol, terazosin, elayta, fosgonimeton, and anle138b are emerging out...With the different pharmacological and nonpharmacological modalities we have for treatment of LBD, all of them offer symptomatic relief only. Being a degenerative disease, definite cure of the disease can only be possible with regenerative measures."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease

Results of a Phase 2/3 Placebo-Controlled, Double-Blind, Parallel-Group, Randomized Study to Evaluate the Efficacy and Safety of 12 Week Treatment with the Phosphodiesterase 9 (PDE9) inhibitor Irsenontrine (E2027) in Subjects With Dementia With Lewy Bodies (CTAD 2022) - "In the overall DLB population, 12 weeks treatment with irsenontrine 50 mg daily did not improve cognition relative to placebo. The suggestion of efficacy in the “pure” DLB subgroup, lacking AD co-pathology, generated the hypothesis that irsenontrine preferentially increases CSF cGMP in pure DLB relative to mixed DLB due to relative preservation of synapses (the site of action of PDE9 inhibition) in patients lacking amyloid co-pathology. This hypothesis is explored in the translational medicine Study 203."

Clinical • P2/3 data • Alzheimer's Disease • CNS Disorders • Dementia • Hypotension • Lewy Body Disease • Psychiatry • Plasma Aβ42

THE EFFECTS OF THE NOVEL PHOSPHODIESTERASE 9 (PDE9) INHIBITOR E2027 (IRSENONTRINE) ON CSF CGMP, ADDITIONAL CSF AND PLASMA BIOMARKERS, AND CLINICAL OUTCOMES IN AMYLOID POSITIVE AND AMYLOID NEGATIVE PATIENTS WITH DEMENTIA WITH LEWY BODIES (DLB) AND PARKINSON’S DISEASE DEMENTIA (PDD). (CTAD 2022) - "Irsenontrine was safe and well-tolerated in LBD and achieved robust pharmacodynamic responses in all subgroups regardless of amyloid status. The results did not support a differential pharmacodynamic effect of irsenontrine with regards to presence or absence of amyloid copathology within DLB or PDD patients."

Biomarker • Clinical • Clinical data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease • CSF Aβ42 • GFAP • Plasma Aβ42

Phase 1 Single Ascending and Multiple Ascending Dose Studies of Phosphodiesterase-9 Inhibitor E2027: Confirmation of Target Engagement and Selection of Phase 2 Dose in Dementia With Lewy Bodies Trial. (PubMed, Alzheimer Dis Assoc Disord) - "S.E2027 was well-tolerated following single and multiple administration. E2027 achieved maximal and sustained target engagement at 50 mg QD, the dose selected for the phase 2 clinical trial."

Clinical • Journal • P1 data • P2 data • Alzheimer's Disease • Back Pain • CNS Disorders • Dementia • Lewy Body Disease • Musculoskeletal Pain • Pain

E2027 Cardiac Safety Evaluation With Concentration-Response Modeling of ECG Data to Inform Dose Selection in Studies in Patients With Dementia With Lewy Bodies. (PubMed, Alzheimer Dis Assoc Disord) - "This pooled post hoc analysis evaluating cardiac safety of E2027 demonstrated that clinically concerning QTcF prolongation and related cardiac complications are highly unlikely with proposed E2027 doses planned for phase 2."

Clinical • Journal • Alzheimer's Disease • Atrial Fibrillation • Cardiovascular • CNS Disorders • Dementia • Lewy Body Disease

A Study of E2027 in Participants With Dementia With Lewy Bodies (DLB) or Parkinson's Disease Dementia (PDD) With or Without Amyloid Copathology (clinicaltrials.gov) - P2 | N=34 | Completed | Sponsor: Eisai Inc. | Active, not recruiting ➔ Completed

Trial completion • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease

A Study of E2027 in Participants With Dementia With Lewy Bodies (DLB) or Parkinson's Disease Dementia (PDD) With or Without Amyloid Copathology (clinicaltrials.gov) - P2; N=32; Active, not recruiting; Sponsor: Eisai Inc.; Recruiting ➔ Active, not recruiting; Trial completion date: Sep 2021 ➔ Jan 2022; Trial primary completion date: Sep 2021 ➔ Jan 2022

Clinical • Enrollment closed • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease

A Study of E2027 in Participants With Dementia With Lewy Bodies (DLB) or Parkinson's Disease Dementia (PDD) With or Without Amyloid Copathology (clinicaltrials.gov) - P2; N=32; Recruiting; Sponsor: Eisai Inc.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease

Study To Evaluate the Efficacy, Safety and Tolerability of E2027 in Participants With Dementia With Lewy Bodies (clinicaltrials.gov) - P2; N=320; Completed; Sponsor: Eisai Inc.; N=206 ➔ 320

Enrollment change • Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease

Eisai Alzheimer's Disease Pipeline Research to be Presented at Virtual AD/PD™ 2021, Including Lecanemab (BAN2401) Data (PRNewswire) - "Eisai...announced today the presentation of data and information from the company's robust Alzheimer's disease (AD) pipeline, including lecanemab (BAN2401)….At AD/PD™ 2021 Virtual Conference, the 15th International Conference on Alzheimer's and Parkinson's Diseases, March 9 - 14, 2021."

Biomarker • P3 data • Preclinical • Alzheimer's Disease • Amyloidosis • CNS Disorders • Lewy Body Disease

A Study of E2027 in Participants With Dementia With Lewy Bodies (DLB) or Parkinson's Disease Dementia (PDD) With or Without Amyloid Copathology (clinicaltrials.gov) - P2; N=32; Not yet recruiting; Sponsor: Eisai Inc.

Clinical • New P2 trial • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease

[VIRTUAL] EFFECT OF E2027, A NOVEL PHOSPHODIESTERASE-9 INHIBITOR, ON COGNITIVE FUNCTION AND HIPPOCAMPAL CYCLIC GMP IN TG2576 MOUSE MODEL OF ALZHEIMER’S DISEASE. (ADPD 2021) - "Amyloid deposition in aged Tg2576 mice is associated with reduced cGMP and impaired contextual fear conditioning, which are improved by E2027."

Preclinical • Alzheimer's Disease • Anesthesia • CNS Disorders • Cognitive Disorders

Study To Evaluate the Efficacy, Safety and Tolerability of E2027 in Participants With Dementia With Lewy Bodies (clinicaltrials.gov) - P2; N=206; Completed; Sponsor: Eisai Inc.; Active, not recruiting ➔ Completed; Trial completion date: Jul 2025 ➔ Apr 2020; Trial primary completion date: Jul 2025 ➔ Apr 2020

Clinical • Trial completion • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Dementia • Lewy Body Disease

Study To Evaluate the Efficacy, Safety and Tolerability of E2027 in Participants With Dementia With Lewy Bodies (clinicaltrials.gov) - P2; N=206; Active, not recruiting; Sponsor: Eisai Inc.; Recruiting ➔ Active, not recruiting; Trial completion date: Nov 2023 ➔ Jul 2025; Trial primary completion date: May 2020 ➔ Jul 2025

Clinical • Enrollment closed • Trial completion date • Trial primary completion date

Study To Evaluate the Efficacy, Safety and Tolerability of E2027 in Participants With Dementia With Lewy Bodies (clinicaltrials.gov) - P2; N=182; Recruiting; Sponsor: Eisai Inc.; Trial completion date: Mar 2020 ➔ Nov 2023

Clinical • Trial completion date

A Study to Determine the Metabolism and Elimination of [14C]E2027 in Healthy Male Participants (clinicaltrials.gov) - P1; N=8; Completed; Sponsor: Eisai Inc.; Active, not recruiting ➔ Completed

Clinical • Trial completion

A Study to Determine the Metabolism and Elimination of [14C]E2027 in Healthy Male Participants (clinicaltrials.gov) - P1; N=8; Active, not recruiting; Sponsor: Eisai Inc.; Not yet recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

A Study to Determine the Metabolism and Elimination of [14C]E2027 in Healthy Male Participants (clinicaltrials.gov) - P1; N=8; Not yet recruiting; Sponsor: Eisai Inc.

Clinical • New P1 trial

Pharmacological Management of Dementia with Lewy Bodies. (PubMed, Drugs Aging) - "...This review discusses the three cholinesterase inhibitors that have been shown to be effective in managing the cognitive and behavioral symptoms of DLB: rivastigmine, galantamine and donepezil...A recent phase 2 clinical trial showed the benefit of zonisamide when it is added as an adjunct to levodopa for treating DLB parkinsonism. While atypical antipsychotic drugs may not always be helpful as monotherapy in managing the agitation associated with DLB, low doses of valproic acid can be effective when added as an adjunct to drugs like quetiapine. Pimavanserin may prove to be a useful treatment for psychosis in DLB patients, but like other antipsychotic drugs that are used in dementia patients, there is a small increased risk of mortality. RBD, which is a common core clinical feature of DLB, can be managed with either melatonin or clonazepam. Two agents targeting alpha-synuclein (NPT200-11 and ambroxol) currently hold promise as disease-modifying therapies for DLB, but..."

Journal • Review

CONCENTRATION RESPONSE MODELING OF ECG DATA FOR E2027 TO INFORM DOSE SELECTION FOR PHASE 2 DEMENTIA IN LEWY BODY STUDY (ADPD 2019) - "Clinically significant QTcF prolongation is not expected at concentrations of the E2027 phase 2 dose (ie, 50mg QD)."

P2 data

Eisai to present latest research on Alzheimer’s disease / dementia pipeline at the 14th International Conference on Alzheimer’s & Parkinson’s diseases (Eisai Press Release) - "Eisai Co...announced today that a total of seven presentations highlighting the latest data on its Alzheimer’s disease / dementia pipeline, including anti-amyloid beta (Aβ) protofibril antibody BAN2401 and oral beta amyloid cleaving enzyme (BACE) inhibitor elenbecestat will be given at the 14th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD) from March 26 to 31 in Lisbon, Portugal."

P2 data • P3 data • PK/PD data