A Randomized, Placebo Controlled, Double-blind, Double-dummy, Three-way Crossover Trial to Investigate the Effect of Two Doses of BI 474121 on Ketamine Induced Cognitive Deficits in Healthy Male Subjects

To investigate the effect of BI 474121 compared to placebo on ketamine-induced cognitive deficits to predict efficacy in patients with cognitive disorders.

Start Date07 Nov 2022

Sponsor / Collaborator

Boehringer Ingelheim GmbH

NCT04964453 / CompletedPhase 1

Safety, Tolerability, and Pharmacokinetics of Single Rising Oral Doses of BI 474121 in Healthy Japanese Male Subjects (Doubleblind, Randomised, Placebo-controlled, Parallel Group Design)

Safety, tolerability, and pharmacokinetics of BI 474121 will be assessed in healthy Japanese male using single rising oral doses in order to provide the basis for an ongoing clinical development of BI 474121 for the treatment of cognitive impairment in patients with Alzheimer's Disease and schizophrenia.

Start Date21 Jul 2021

Sponsor / Collaborator

Boehringer Ingelheim GmbH

NCT04716894 / CompletedPhase 1

Effect of Itraconazole on the Pharmacokinetics of a Single Oral Dose of BI 474121 in Healthy Male Subjects (an Open-label, Two-period Fixed Sequence Design Study)

The main objective of this trial is to investigate the effect on the exposure of BI 474121 in plasma when given as oral single dose together with multiple oral doses of itraconazole (Test, T) as compared to when given alone as oral single dose (Reference, R).

Start Date01 Feb 2021

Sponsor / Collaborator

Boehringer Ingelheim GmbH

100 Clinical Results associated with BI-474121

100 Translational Medicine associated with BI-474121

100 Patents (Medical) associated with BI-474121

Literatures (Medical) associated with BI-474121

British Journal of Clinical Pharmacology

Effects of the phosphodiesterase 2 inhibitor BI 474121 on central nervous system cyclic guanosine monophosphate concentrations: Translational studies

Article

Author: Rosenbrock, Holger ; Zambori, Janos ; Schaible, Jennifer ; Goeldner, Rainer-Georg ; van Kraaij, Sebastiaan ; Groeneveld, Geert Jan ; Kremer, Philip ; Schultheis, Christian

AbstractAimsPhosphodiesterase 2 (PDE2) regulates intracellular cyclic adenosine monophosphate and guanosine monophosphate (cAMP/cGMP) levels, which contribute to processes crucial for learning and memory. BI 474121, a potent and selective PDE2 inhibitor, is in development for treating cognitive impairment associated with schizophrenia.MethodsThe effects of BI 474121 on cGMP concentrations were first assessed in rat cerebrospinal fluid (CSF) to demonstrate central nervous system (CNS) and functional target engagement. Next, a Phase I study in healthy participants assessed the pharmacokinetics of BI 474121 in CSF vs. plasma, the pharmacodynamics of BI 474121 by measuring cGMP concentrations in the CSF, and the safety of BI 474121.ResultsIn rats, BI 474121 was associated with a dose‐dependent increase (71% at the highest dose tested [3.0 mg kg−1]) in cGMP levels in the CSF relative to vehicle (P < 0.001). In healthy participants, the maximum‐measured concentration CSF‐to‐plasma ratio for BI 474121 exposure was similar following single oral doses of BI 474121 2.5, 10, 20 and 40 mg (dose‐adjusted geometric mean: 8.96% overall). BI 474121 2.5–40 mg administration in healthy participants also increased cGMP levels in CSF (maximum exposure‐related change from baseline ratio, BI 474121: 1.44–2.20 vs. placebo: 1.26). The most common treatment‐emergent adverse event (AE) was mild‐to‐moderate post‐lumbar puncture syndrome, which resolved with standard treatment. No AEs of special interest were observed.ConclusionsBI 474121 crosses the blood–brain barrier to inhibit PDE2, supporting cGMP as a translational marker to monitor CNS target engagement. These findings promote further clinical development of BI 474121.ClinicalTrials.gov number (NCT04672954).

100 Deals associated with BI-474121

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder, Major	Phase 1	FR	Boehringer Ingelheim GmbH	20 Nov 2020
Depressive Disorder, Major	Phase 1	AU	Boehringer Ingelheim GmbH	20 Nov 2020
Depressive Disorder, Major	Phase 1	PL	Boehringer Ingelheim GmbH	20 Nov 2020
Depressive Disorder, Major	Phase 1	RU	Boehringer Ingelheim GmbH	20 Nov 2020
Depressive Disorder, Major	Phase 1	US	Boehringer Ingelheim GmbH	20 Nov 2020
Depressive Disorder, Major	Phase 1	CZ	Boehringer Ingelheim GmbH	20 Nov 2020
Depressive Disorder, Major	Phase 1	HU	Boehringer Ingelheim GmbH	20 Nov 2020
Depressive Disorder, Major	Phase 1	SK	Boehringer Ingelheim GmbH	20 Nov 2020
Depressive Disorder, Major	Phase 1	ES	Boehringer Ingelheim GmbH	20 Nov 2020
Depressive Disorder, Major	Phase 1	DE	Boehringer Ingelheim GmbH	20 Nov 2020

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04672954 (Pubmed)	Phase 1	cGMP	-	BI 474121 2.5 mg	mwhzpsmbfe(rjormutjtv) = No AEs of special interest were observed xytmqrospc (karrvxgrgm ) View more	Positive	16 Jun 2024
				BI 474121 10 mg
NCT04672954 (CTgov)	Phase 1	-	24	Placebo (Placebo)	oiocnfvdsj(gijnpsnrlp) = cpzqcgtczu rkrpvzahlw (ylyiqliyer, qauashrmkm - xwkrnuzoyj) View more	-	08 Mar 2024
				2.5 milligram (mg) BI 474121 (2.5 Milligram (mg) BI 474121)	oiocnfvdsj(gijnpsnrlp) = kjxazqktvh rkrpvzahlw (ylyiqliyer, udxmwxfvsj - oktjmdgleb) View more
NCT04964453 (CTgov)	Phase 1	-	32	Placebo (Placebo)	gllbhmgeho(nszqxcbuoz) = mixtwduwoe yfadhfelzu (lgkkntmokt, pqomcbhgvx - ouwsbosvzw) View more	-	07 Mar 2024
				BI 474121 (2.5 mg BI 474121)	gllbhmgeho(nszqxcbuoz) = fswcdjvsfe yfadhfelzu (lgkkntmokt, wysbexzvzh - ibcvoelqgx) View more

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