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

Abstract

The primary endpoint of cognitive function improvement was not met. BI 409306 was well-tolerated, with an acceptable safety profile.

The Novel Phosphodiesterase 9A Inhibitor BI 409306 Increases Cyclic Guanosine Monophosphate Levels in the Brain, Promotes Synaptic Plasticity, and Enhances Memory Function in Rodents

“…The effects of BI 409306 on cognition have also been explored in a double-blind, randomized phase II study (NCT02281773) comparing BI 409306 at doses up to 100 mg and placebo in patients with schizophrenia. No significant differences were observed on a range of cognitive outcomes, and the primary endpoints were not met after 12 weeks of treatment (Brown et al, 2019). Two double-blind, randomized phase II studies (NCT02240693 and NCT02337907) have also been conducted in 128 and 329 patients with prodromal and mild Alzheimer's disease, respectively.…”

“…This may indicate that the effects of BI 409306 in patients require further investigation. For example, BI 409306 may have beneficial effects on cognition when administered at a higher dose, over a longer treatment period, or in patients with different stages of schizophrenia or Alzheimer's disease (Brown et al, 2019;Frölich et al, 2019). Alternatively, it may be that drugs enhancing synaptic plasticity are more effective in the treatment of other indications, or that the effects of such drugs observed in the rodent models used in the present study translate poorly to cognitive improvement in patients with schizophrenia and Alzheimer's disease.…”

“…In addition, a dose-dependent increase in cGMP levels in cerebrospinal fluid (CSF) of healthy volunteers has been demonstrated following a single oral administration of the PDE9A inhibitor BI 409306 (Boland et al, 2017). BI 409306 is a novel, potent, and selective PDE9A inhibitor in clinical development (Moschetti et al, 2016;Boland et al, 2017;Brown et al, 2019;Frölich et al, 2019). The current study aimed to assess the in vitro potency and selectivity of BI 409306 and to evaluate its functional target engagement in vivo through measurements of cGMP levels in brain tissue and CSF.…”

cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development

“…However, in clinical trials PF-04447943, a PDE9 inhibitor from Pfizer, had no effect on cognition in patients with mild to moderate AD. Boehringer Ingelheim also investigated their PDE9 inhibitor BI 409306 as a cognition enhancer in phase 2 clinical trials for both AD and schizophrenia (NCT02337907 and NCT02281773; Frölich et al 2019;Brown et al 2019). In 2018, Boehringer Ingelheim announced that efficacy endpoints in AD were not met and that beneficial effects in schizophrenia were also not found.…”

Using EEG-Guided Basket and Umbrella Trials in Psychiatry: A Precision Medicine Approach for Cognitive Impairment in Schizophrenia

“…The above analyses confirmed that the neurocognitive impairments in SZ appear to be a core disease component, reliably able to be measured and directly-linked to the symptoms and functional outcomes. Despite this advance, decades of clinical trials testing the effectiveness of currently approved antipsychotic medications and other novel therapeutics as putative pro-cognitive agents have failed to improve cognitive symptoms in SZ in any durable, meaningful way ( 17 , 18 ). The development of novel pro-cognitive treatment strategies is therefore of paramount importance but remains a critical unmet need ( 19 ).…”