S190. Prevention of Relapse in Schizophrenia: A Phase II Study Evaluating Efficacy, Safety, and Tolerability of Oral BI 409306

Sand, Michael; Brown, David G.; Walling, David; Daniels, Kristen; McGinniss, Jennifer

doi:10.1016/j.biopsych.2018.02.1082

Cited by 2 publications

(7 citation statements)

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“…In the present study, the observed plasma exposure of BI 409306 1 mg/kg was in the range that would be expected for human participants after a 50 mg dose, based on exposure levels observed in previous clinical studies in healthy volunteers and patients with schizophrenia [7,8,29]. This dose is used in the ongoing clinical trials on prevention of relapse in schizophrenia [10] and early intervention in patients with APS [35], further supporting the relevance of our findings to patients. BI 409306 reversed MIA-induced social interaction deficits in adulthood in a similar manner when administered alone or in combination with risperidone, an established treatment for psychosis [22].…”

Section: Discussionsupporting

confidence: 88%

“…In addition, BI 409306 treatment could provide improvements alone and in combination with established treatments for psychosis acting on the dopaminergic and serotoninergic systems. These novel data support the ongoing development of BI 409306 for the prevention of relapse in patients with schizophrenia [10] and as an early intervention in patients with APS [35].…”

Section: Discussionsupporting

confidence: 61%

“…Given that BI 409306 and risperidone act on distinct targets and neurotransmitter systems, the combination of these two treatments may have resulted in further improvements that could not be detected in the social interaction and Amph-induced hyperlocomotion tasks due to ceiling effects. This will be explored further in the ongoing Phase II trial (NCT03351244), which will determine the benefit of BI 409306 as add-on therapy to standard care and establish whether combining treatments that act on different molecular targets is advantageous for the prevention of relapse in patients with schizophrenia [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…Maternal immune activation (MIA) is an established experimental approach based on immune-mediated disruption of neurodevelopment in the offspring to induce brain and behavioral dysfunctions [9,10]. Based on evidence highlighting a link between prenatal exposure to infectious or noninfectious MIA and neuropsychiatric disorders in the offspring [11], MIA approaches are commonly used to study the developmental trajectory of schizophrenia and other neurodevelopmental disorders [9][10][11][12]. In a commonly used MIA model, pregnant mouse dams are exposed to the viral mimic, polyriboinosinic-polyribocytidilic acid (poly[I:C]), a synthetic analog of double-stranded RNA that binds to transmembrane toll-like receptor 3, triggering an innate immune response [9].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Symptomatic and preventive effects of the novel phosphodiesterase-9 inhibitor BI 409306 in an immune-mediated model of neurodevelopmental disorders

Scarborough

Mattei

Dorner-Ciossek

et al. 2021

Neuropsychopharmacol.

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BI 409306, a phosphodiesterase-9 inhibitor under development for treatment of schizophrenia and attenuated psychosis syndrome (APS), promotes synaptic plasticity and cognition. Here, we explored the effects of BI 409306 treatment in the polyriboinosinic-polyribocytidilic acid (poly[I:C])-based mouse model of maternal immune activation (MIA), which is relevant to schizophrenia and APS. In Study 1, adult offspring received BI 409306 0.2, 0.5, or 1 mg/kg or vehicle to establish an active dose. In Study 2, adult offspring received BI 409306 1 mg/kg and/or risperidone 0.025 mg/kg, risperidone 0.05 mg/kg, or vehicle, to evaluate BI 409306 as add-on to standard therapy for schizophrenia. In Study 3, offspring received BI 409306 1 mg/kg during adolescence only, or continually into adulthood to evaluate preventive effects of BI 409306. We found that BI 409306 significantly mitigated MIA-induced social interaction deficits and amphetamine-induced hyperlocomotion, but not prepulse inhibition impairments, in a dose-dependent manner (Study 1). Furthermore, BI 409306 1 mg/kg alone or in combination with risperidone 0.025 mg/kg significantly reversed social interaction deficits and attenuated amphetamine-induced hyperlocomotion in MIA offspring (Study 2). Finally, we revealed that BI 409306 1 mg/kg treatment restricted to adolescence prevented adult deficits in social interaction, whereas continued treatment into adulthood also significantly reduced amphetamine-induced hyperlocomotion (Study 3). Taken together, our findings suggest that symptomatic treatment with BI 409306 can restore social interaction deficits and dopaminergic dysfunctions in a MIA model of neurodevelopmental disruption, lending preclinical support to current clinical trials of BI 409306 in patients with schizophrenia. Moreover, BI 409306 given during adolescence has preventive effects on adult social interaction deficits in this model, supporting its use in people with APS.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Symptomatic and preventive effects of the novel phosphodiesterase-9 inhibitor BI 409306 in an immune-mediated model of neurodevelopmental disorders

Scarborough

Mattei

Dorner-Ciossek

et al. 2021

Neuropsychopharmacol.

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The effect of BI 409306 on heart rate in healthy volunteers: a randomised, double-blind, placebo-controlled, crossover study

Müller

Sand

Wunderlich

et al. 2022

Eur J Clin Pharmacol

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Purpose The potent, selective phosphodiesterase-9A inhibitor BI 409306 may be beneficial for patients with attenuated psychosis syndrome and could prevent relapse in patients with schizophrenia. Transient BI 409306-dependent increases in heart rate (HR) demonstrated previously necessitated cardiac safety characterisation. We evaluated cardiac effects of BI 409306 in healthy volunteers during rest and exercise. Methods In this double-blind, three-way crossover study, volunteers received placebo, BI 409306 50 mg or 200 mg in randomised order (same treatment on Days 1 [resting] and 3 [exercise]). Cardiopulmonary exercise testing was performed twice post treatment on Day 3 of each period. BI 409306-mediated effects on placebo-corrected change from baseline in resting HR (ΔΔHR) were evaluated based on exposure–response analysis and a random coefficient model. Adverse events (AEs) were recorded. Results Overall, 19/20 volunteers completed. Resting ΔΔHR versus BI 409306 concentration yielded a slope of 0.0029 beats/min/nmol/L. At the geometric mean (gMean) maximum plasma concentration (Cmax) for BI 409306 50 and 200 mg, predicted mean (90% CI) ΔΔHRs were 0.80 (− 0.76, 2.36) and 5.46 (2.44, 8.49) beats/min, respectively. Maximum adjusted mean differences from placebo (90% CI) in resting HR for BI 409306 50 and 200 mg were 3.85 (0.73, 6.97) and 4.93 (1.69, 8.16) beats/min. Maximum differences from placebo in resting HR occurred at/near gMean Cmax and returned to baseline after approximately 4 h. The proportion of volunteers with AEs increased with BI 409306 dose. Conclusion Observed hemodynamic effects following BI 409306 administration were of low amplitude, transient, and followed the pharmacokinetic profile of BI 409306.

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S190. Prevention of Relapse in Schizophrenia: A Phase II Study Evaluating Efficacy, Safety, and Tolerability of Oral BI 409306

Cited by 2 publications

References 0 publications

Symptomatic and preventive effects of the novel phosphodiesterase-9 inhibitor BI 409306 in an immune-mediated model of neurodevelopmental disorders

Symptomatic and preventive effects of the novel phosphodiesterase-9 inhibitor BI 409306 in an immune-mediated model of neurodevelopmental disorders

The effect of BI 409306 on heart rate in healthy volunteers: a randomised, double-blind, placebo-controlled, crossover study

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