BI 409306 · program

Osoresnontrine for Alzheimer's disease

DiscontinuedDiscontinuedBoehringer Ingelheim

Indications for BI 409306: Schizophrenia · Discontinued Alzheimer's disease · Discontinued

BI 409306 (osoresnontrine), a selective PDE9A inhibitor, as a symptomatic (pro-cognitive) treatment for prodromal and mild Alzheimer's disease. Two multicentre, double-blind, randomised, placebo-controlled Phase 2 proof-of-concept trials ran in parallel across North America and Europe: NCT02240693 (study 1289.5, n=128, monotherapy in prodromal AD, patients not recently on cholinesterase inhibitors/memantine) and NCT02337907 (study 1289.7, n=329, add-on to donepezil in mild AD), each testing four oral doses of 10-50 mg daily vs placebo over 12 weeks with change from baseline in Neuropsychological Test Battery (NTB) total z-score as the primary endpoint. The prespecified pooled primary analysis (n=457 randomized, 93.4% completed) showed no significant NTB change vs placebo, with the same picture in each study individually and no indication of benefit on any secondary endpoint (CDR-SB, ADAS-Cog11, ADCS-MCI-ADL/ADCS-ADL). BI 409306 was well tolerated. In February 2018 Boehringer Ingelheim announced the trials had not met their efficacy endpoints and that further AD trials would not be pursued, refocusing PDE9 research on schizophrenia — where the compound subsequently also failed.

Data current as of

Development timeline

DiscontinuedFeb 2018 – Apr 2021
  1. Trial terminatedPhase 2 attenuated psychosis syndrome trial of BI 409306 terminated (COVID-19 disruption); no benefit on APS remission
  2. missedBoth Phase 2 Alzheimer's trials of BI 409306 missed their efficacy endpoints; Boehringer Ingelheim announced further AD development would not be pursued (pooled prespecified primary analysis, n=457: no significant change vs placebo in NTB total z-score at week 12, and no secondary-endpoint signal).↗
Phase 2Jan 2015
  1. Phase 2 proof-of-concept program started: NCT02240693 (monotherapy, prodromal AD, n=128) started 2015-01-15 and its sister add-on trial NCT02337907 (mild AD on donepezil, n=329) started 2015-01-21; four oral doses 10-50 mg daily vs placebo, 12 weeks, primary endpoint NTB total z-score.

Readouts

  • 2018-02-01ReportedTopline datamissedNCT02337907

    Both Phase 2 Alzheimer's trials of BI 409306 missed their efficacy endpoints; Boehringer Ingelheim announced further AD development would not be pursued (pooled prespecified primary analysis, n=457: no significant change vs placebo in NTB total z-score at week 12, and no secondary-endpoint signal). ↗

Clinical trials in Alzheimer's disease

NCT023379071289.7Phase 2Completedn=329

A Multi-centre, Double-blind, Parallel-group, Randomised Controlled Study of BI 409306 as Add-on to Donepezil in Mild Alzheimer's Disease

Started Jan 2015· Primary completion Sept 2017· 📍 60 sites across 11 countries (United States, Germany, Poland, Portugal)

NCT022406931289.5Phase 2Completedn=128

Alzheimer Disease Proof of Concept Study With BI 409306 Versus Placebo (monotherapy, prodromal/mild AD)

Started Jan 2015· Primary completion Sept 2017· 📍 52 sites across 12 countries (Poland, United States, Germany, Canada)

Formulations

FormulationRouteRegimenPharmacokinetics
BI 409306 oral tablet (10-100 mg)
Alzheimer's disease Phase 2s (NCT02240693 prodromal AD monotherapy; NCT02337907 mild AD add-on to donepezil): four oral doses of 10-50 mg daily for 12 weeks, randomized 1:1:1:1:2 vs placebo. Cognitive impairment in schizophrenia (NCT02281773): 10, 25, 50 or 100 mg once daily.
OralOnce daily—

Mechanism of action (compound-wide)

Potent and selective inhibitor of phosphodiesterase 9A (PDE9A), the cGMP-specific phosphodiesterase with the highest affinity for cGMP among the PDE family, expressed in cognition-relevant brain regions. Mean IC50 65 nM at human PDE9A and 168 nM at rat PDE9A in enzyme assays. In rodents, BI 409306 increased cGMP in prefrontal cortex and CSF, attenuated the MK-801-induced striatal cGMP reduction, enhanced hippocampal long-term potentiation ex vivo under both weak and strong tetanic stimulation, reversed MK-801-induced working-memory deficits (T-maze) and improved long-term object-recognition memory. The therapeutic hypothesis — amplifying NMDA-receptor-dependent cGMP signalling to restore synaptic plasticity and cognition in schizophrenia and Alzheimer's disease — was not borne out in any Phase 2 trial.

TargetActionAffinity
PDE9AprimaryPDE9AInhibitorIC50 65 nMⓘ

← Full BI 409306 compound page (identity, identifiers, all indications)

Sources

  1. Boehringer Ingelheim refocuses PDE9 inhibition brain research on schizophrenia following results from Phase II Alzheimer's trials (February 2018) — Boehringer Ingelheim
  2. Froelich L, et al. Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer's disease. Alzheimers Res Ther. 2019;11(1):18 — Alzheimer's Research & Therapy (BMC/Springer Nature) / PubMed
  3. NCT02240693 (1289.5) — Alzheimer Disease Proof of Concept Study With BI 409306 Versus Placebo; completed, n=128, results posted 2018-11-28 — ClinicalTrials.gov (U.S. National Library of Medicine)
  4. NCT02337907 (1289.7) — BI 409306 as add-on to donepezil in mild Alzheimer's disease; completed, n=329, results posted 2018-11-14 — ClinicalTrials.gov (U.S. National Library of Medicine)
  5. NCT03230097 (1289.32) — Phase II 52-week study of BI 409306 in attenuated psychosis syndrome; terminated (COVID-19 disruption), n=50, results posted 2022-06-29 — ClinicalTrials.gov (U.S. National Library of Medicine)
  6. Rosenbrock H, et al. The Novel Phosphodiesterase 9A Inhibitor BI 409306 Increases Cyclic Guanosine Monophosphate Levels in the Brain, Promotes Synaptic Plasticity, and Enhances Memory Function in Rodents. J Pharmacol Exp Ther. 2019;371(3):633-641 — Journal of Pharmacology and Experimental Therapeutics (ASPET) / PubMed