Small Molecule · BI 409306

Osoresnontrine

DiscontinuedBoehringer Ingelheim

Oral, potent and selective phosphodiesterase 9A (PDE9A) inhibitor developed by Boehringer Ingelheim for cognitive impairment associated with schizophrenia, relapse prevention in schizophrenia, attenuated psychosis syndrome, and Alzheimer's disease. PDE9A selectively hydrolyses cGMP in brain regions related to cognition; inhibiting it was hypothesised to strengthen NMDA-receptor-dependent glutamatergic signalling, long-term potentiation and synaptic plasticity (IC50 65 nM at human PDE9A; increased brain cGMP, enhanced hippocampal LTP and rescued MK-801-induced memory deficits in rodents). The clinical program was uniformly negative: Phase 2 misses in cognitive impairment in schizophrenia (n=518, MCCB), in prodromal and mild Alzheimer's disease (pooled n=457, NTB), in schizophrenia relapse prevention (n=264, terminated during COVID-19), and no benefit in attenuated psychosis syndrome (n=50, terminated during COVID-19). Alzheimer's development was formally stopped in February 2018; the schizophrenia/psychosis franchise wound down after the 2021 trial terminations, with Boehringer's CNS focus moving to the GlyT1 inhibitor iclepertin. A cautionary read-across for the cGMP/glutamatergic pro-cognitive hypothesis in psychiatry.

Also known as: BI 409306, BI-409306, osoresnontrine, SUB 166499, 1189767-28-9, 6-(pyridin-2-ylmethyl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Data current as of

Key facts

Modality
Small molecule
Chemical class
pyrazolopyrimidinone, oxane, pyridine
Chemistry
Achiral
Mechanism
PDE9A inhibitor
Highest phase
Discontinued
Lead indication
Schizophrenia
Developer
Boehringer Ingelheim
Trials
4 tracked · 214 sites

Mechanism of action#

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ⓘ

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—

Development timeline#

2016201820202022Phase 22 May 2018 — readout (missed) — Phase 2 CIAS trial negative: no significant difference between BI 409306 (any of four doses, 10-100 mg once daily) and placebo on MCCB composite score change at 12 weeks (1.2-2.8 vs 2.5), and no SCoRS benefit, in 518 randomized patients with schizophrenia.1 Feb 2018 — phase change — After the Alzheimer's Phase 2 trials missed their endpoints, Boehringer Ingelheim announced it was refocusing PDE9 inhibition brain research on schizophrenia (press release, February 2018) — the relapse-prevention trial NCT03351244 (started 2017-12-07) and the attenuated psychosis syndrome trial NCT03230097 (started 2017-09-29) became the program's remaining bets, despite the CIAS trial having already missed its own primary endpoint. Date carries month precision; the release's exact day is not stated on the archived page.15 Jan 2015 — phase change — 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.10 Nov 2014 — phase change — CIAS Phase 2 NCT02281773 (BI study 1289.6) started: randomized, double-blind, placebo-controlled, learn-and-confirm adaptive trial of BI 409306 10/25/50/100 mg once daily vs placebo for 12 weeks in 518 patients on stable antipsychotic treatment.Discontinued4 Apr 2022 — readout (missed) — Phase 2 relapse-prevention trial negative: incidence of first relapse over 28 weeks 48.2% on pooled BI 409306 vs 49.6% on placebo (pooled HR 0.910, 95% CI 0.468-1.770, p=0.78; 25 mg HR 1.097, 50 mg HR 0.910); no PANSS-positive or CGI-S benefit. Trial terminated early (n=264) citing COVID-19 disruption.7 Apr 2021 — Trial terminated — Phase 2 attenuated psychosis syndrome trial of BI 409306 terminated (COVID-19 disruption); no benefit on APS remission31 Mar 2021 — phase change — Both remaining Phase 2 trials were terminated citing 'disruption due to COVID-19' (NCT03351244 completed 2021-03-31; NCT03230097 completed 2021-04-07), and the posted results show the relapse-prevention primary endpoint was missed (pooled HR 0.910, p=0.78). No formal discontinuation announcement exists; discontinuation is inferred from the terminations, the absence of any new BI 409306 trial since, the compound's absence from Boehringer's subsequent pipeline communications, and BI's own 2024 Schizophr Res paper describing development in the past tense. Date is the relapse trial's CT.gov completion date, an approximation of an undisclosed internal decision.31 Mar 2021 — Trial terminated — Phase 2 schizophrenia relapse-prevention trial of BI 409306 terminated (COVID-19 disruption); primary endpoint missed1 Feb 2018 — readout (missed) — 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).
Phase change Readout Event UpcomingHover a marker for details.
DiscontinuedFeb 2018 – Apr 2022
  1. missedPhase 2 relapse-prevention trial negative: incidence of first relapse over 28 weeks 48.2% on pooled BI 409306 vs 49.6% on placebo (pooled HR 0.910, 95% CI 0.468-1.770, p=0.78; 25 mg HR 1.097, 50 mg HR 0.910); no PANSS-positive or CGI-S benefit. Trial terminated early (n=264) citing COVID-19 disruption.Schizophrenia
  2. Trial terminatedPhase 2 attenuated psychosis syndrome trial of BI 409306 terminated (COVID-19 disruption); no benefit on APS remission
  3. Both remaining Phase 2 trials were terminated citing 'disruption due to COVID-19' (NCT03351244 completed 2021-03-31; NCT03230097 completed 2021-04-07), and the posted results show the relapse-prevention primary endpoint was missed (pooled HR 0.910, p=0.78). No formal discontinuation announcement exists; discontinuation is inferred from the terminations, the absence of any new BI 409306 trial since, the compound's absence from Boehringer's subsequent pipeline communications, and BI's own 2024 Schizophr Res paper describing development in the past tense. Date is the relapse trial's CT.gov completion date, an approximation of an undisclosed internal decision.Schizophrenia
  4. Trial terminatedPhase 2 schizophrenia relapse-prevention trial of BI 409306 terminated (COVID-19 disruption); primary endpoint missedSchizophrenia
  5. 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).Alzheimer's disease↗
Phase 2Nov 2014 – May 2018
  1. missedPhase 2 CIAS trial negative: no significant difference between BI 409306 (any of four doses, 10-100 mg once daily) and placebo on MCCB composite score change at 12 weeks (1.2-2.8 vs 2.5), and no SCoRS benefit, in 518 randomized patients with schizophrenia.Schizophrenia↗
  2. After the Alzheimer's Phase 2 trials missed their endpoints, Boehringer Ingelheim announced it was refocusing PDE9 inhibition brain research on schizophrenia (press release, February 2018) — the relapse-prevention trial NCT03351244 (started 2017-12-07) and the attenuated psychosis syndrome trial NCT03230097 (started 2017-09-29) became the program's remaining bets, despite the CIAS trial having already missed its own primary endpoint. Date carries month precision; the release's exact day is not stated on the archived page.Schizophrenia↗
  3. 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.Alzheimer's disease
  4. CIAS Phase 2 NCT02281773 (BI study 1289.6) started: randomized, double-blind, placebo-controlled, learn-and-confirm adaptive trial of BI 409306 10/25/50/100 mg once daily vs placebo for 12 weeks in 518 patients on stable antipsychotic treatment.Schizophrenia

Osoresnontrine for Schizophrenia#

DiscontinuedDiscontinuedSchizophrenia indication →

BI 409306 (osoresnontrine), a selective PDE9A inhibitor, for schizophrenia — first as adjunctive treatment of cognitive impairment associated with schizophrenia (CIAS), then repositioned to relapse prevention. The CIAS Phase 2 (NCT02281773, n=518, learn-and-confirm adaptive design) was negative: no significant difference vs placebo on MCCB composite change at 12 weeks (BI 409306 1.2-2.8 vs placebo 2.5) and no SCoRS benefit; adverse events were dose-dependent. Boehringer Ingelheim nonetheless refocused its PDE9 program on schizophrenia in February 2018 after the Alzheimer's Phase 2s failed, launching a 28-week adjunctive relapse-prevention Phase 2 (NCT03351244, n=264) and a 52-week attenuated psychosis syndrome Phase 2 (NCT03230097, n=50 of 300 planned). Both were terminated in March 2021 citing COVID-19 disruption, and both were negative on their primary endpoints (relapse prevention: pooled HR 0.910, 95% CI 0.468-1.770, p=0.78; first-relapse incidence 48.2% pooled vs 49.6% placebo). No new BI 409306 trial has been registered since, the compound is absent from Boehringer's subsequent CNS communications (which centre on iclepertin), and BI's own 2024 publication describes the program in the past tense — treated here as discontinued. A post-hoc adherence analysis suggested a possible relapse-risk reduction in medication-adherent subgroups (HR ~0.49-0.51), hypothesis-generating only.

Readouts

  • 2022-04-04ReportedFull resultsmissedNCT03351244

    Phase 2 relapse-prevention trial negative: incidence of first relapse over 28 weeks 48.2% on pooled BI 409306 vs 49.6% on placebo (pooled HR 0.910, 95% CI 0.468-1.770, p=0.78; 25 mg HR 1.097, 50 mg HR 0.910); no PANSS-positive or CGI-S benefit. Trial terminated early (n=264) citing COVID-19 disruption.

  • 2018-05-02ReportedFull resultsmissedNCT02281773

    Phase 2 CIAS trial negative: no significant difference between BI 409306 (any of four doses, 10-100 mg once daily) and placebo on MCCB composite score change at 12 weeks (1.2-2.8 vs 2.5), and no SCoRS benefit, in 518 randomized patients with schizophrenia. ↗

Osoresnontrine for Alzheimer's disease#

DiscontinuedDiscontinuedAlzheimer's disease indication →

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.

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#

NCT033512441289-0049Phase 2Discontinuedn=264

A Phase II Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Orally Administered BI 409306 During a 28-week Treatment Period as Adjunctive Therapy to Antipsychotic Treatment for the Prevention of Relapse in Patients With Schizophrenia

Started Dec 2017· Primary completion Mar 2021· 59 sites across 7 countries

United StatesJapanCanadaFrance

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 StatesGermanyPolandPortugal

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

PolandUnited StatesGermanyCanada

NCT022817731289.6Phase 2Completedn=518

A Phase II Randomised, Double-blinded, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Four Orally Administered Doses of BI 409306 During a 12-week Treatment Period in Patients With Schizophrenia (Cognitive Impairment)

Started Nov 2014· Primary completion May 2016· 43 sites across 5 countries

United StatesJapanTaiwanGermany

Sources#

  1. Boehringer Ingelheim refocuses PDE9 inhibition brain research on schizophrenia following results from Phase II Alzheimer's trials (February 2018) — Boehringer Ingelheim
  2. Brown D, et al. Evaluation of the Efficacy, Safety, and Tolerability of BI 409306, a Novel Phosphodiesterase 9 Inhibitor, in Cognitive Impairment in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled, Phase II Trial. Schizophr Bull. 2019;45(2):350-359 — Schizophrenia Bulletin (Oxford University Press) / PubMed
  3. 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
  4. 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)
  5. NCT02281773 (1289.6) — Phase II study of four oral doses of BI 409306 over 12 weeks in patients with schizophrenia (cognitive impairment); completed, n=518, results posted 2017-10-19 — ClinicalTrials.gov (U.S. National Library of Medicine)
  6. 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)
  7. 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)
  8. NCT03351244 (1289-0049) — Phase II 28-week adjunctive relapse-prevention study of BI 409306 in schizophrenia; terminated (COVID-19 disruption), n=264, results posted 2022-04-04 — ClinicalTrials.gov (U.S. National Library of Medicine)
  9. 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