The effects of transient receptor potential cation channel inhibition by BI 1358894 on cortico-limbic brain reactivity to negative emotional stimuli in major depressive disorder

Grimm, Simone; Keicher, Christian; Paret, Christian; Niedtfeld, Inga; Beckmann, Christian F.; Mennes, Maarten; Just, Stefan; Sharma, Vikas; Fuertig, René; Herich, Lena; Mack, Salome Rebecca; Thamer, Claus; Schultheis, Christian; Weigand, Anne; Schmahl, Christian; Wunder, Andreas

doi:10.1016/j.euroneuro.2022.10.009

Cited by 11 publications

(6 citation statements)

References 44 publications

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“…In a Phase I study, BI 1358894 reduced cholecystokinin-tetrapeptide-induced panic symptoms, indicating target engagement and functional mechanistic effects [ 17 ]. In another Phase I study of patients with MDD, BI 1358894 attenuated activity in the bilateral amygdala region, an area of the brain associated with the processing of emotion and mood implicated in MDD [ 15 – 17 ]. These studies indicate that TRPC4/5 ion channel modulation of the amygdala by BI 1358894 may represent a novel mechanism of action for the treatment of patients with MDD and as such should be investigated further.…”

Section: Discussionmentioning

confidence: 99%

“…A recent Phase I study of 73 patients with MDD using functional magnetic resonance imaging indicated that BI 1358894 attenuated activity in several cortico-limbic brain regions, including the bilateral amygdala region [ 15 ]. Cholecystokinin-tetrapeptide (CCK-4), a neuropeptide, stimulates amygdala neuronal activity and can induce anxiety/panic attacks; BI 1358894 was shown to reduce the psychological and physiological responses of CCK-4-induced anxiety and panic symptoms in healthy volunteers [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Safety, Tolerability, and Pharmacokinetics of Oral BI 1358894 in Healthy Japanese Male Volunteers

Yoon,

Sharma,

Harada

2024

Clin Drug Investig

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Background and Objectives BI 1358894, a novel small-molecule inhibitor of transient receptor potential canonical ion channels, is under development for treatment of major depressive disorder. Phase I trials assessing the safety and pharmacokinetics of BI 1358894 in Caucasian male healthy volunteers (HVs) have been performed. This Phase I, double-blind, placebo-controlled, parallel-group trial assessed the safety, tolerability and pharmacokinetics of BI 1358894 in Japanese male HVs. Methods Male HVs were randomized to receive oral BI 1358894 ( n = 18) or placebo ( n = 6) after a high-fat, high-calorie meal within three dose groups (50 mg, 100 mg, 200 mg), administered sequentially in dose-ascending order. The primary endpoint was number of HVs with drug-related adverse events (DRAEs). Secondary endpoints were the pharmacokinetic parameters of BI 1358894. Results Overall, 24 male HVs entered the trial [mean (standard deviation) age: 30.0 (7.6) years]. DRAEs occurred in 3/18 HVs (BI 1358894 100 mg group: one HV experienced dizziness and headache; BI 1358894 200 mg group: one HV experienced headache, another reported sleep disorder). BI 1358894 exposure increased dose dependently and proportionally, peaking 4–6 h after administration before declining in a multiphasic manner with a terminal elimination half-life of ~70 h in the 50 mg and 100 mg dose groups, and 203 h in the 200 mg dose group. Conclusion BI 1358894 was well tolerated with a favorable pharmacokinetic profile in Japanese male HVs, similar to findings from a previous study in Caucasian male HVs. Trial Registration ClinicalTrials.gov (NCT03875001; 08-Mar-2019). Supplementary Information The online version contains supplementary material available at 10.1007/s40261-024-01357-z.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Safety, Tolerability, and Pharmacokinetics of Oral BI 1358894 in Healthy Japanese Male Volunteers

Yoon,

Sharma,

Harada

2024

Clin Drug Investig

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“…The diminished anxiety resulting from a lack of TRPC4/5 antagonism is paralleled by reduced CCK-4 responses in the amygdala in mice [22,24,25], suggesting a role for amygdala TRPC4/5 and CCK-4 activity in anxiety-like behaviors. Further support for the targeting of amygdala TRPC4/5 signaling is provided by a recent clinical study of BI 1358894-treated patients with MDD who exhibited attenuated amygdala hyperreactivity in response to negative faces and scenes [37].…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with the findings of two parallel studies evaluating the safety, pharmacokinetic and food effect of single and multiple rising doses of BI 1358894 (NCT03210272 and NCT03754959), single oral doses of BI 1358894 were generally well tolerated by the healthy volunteers included in this study [49]. An additional functional magnetic resonance imaging proof of clinical principal (PoCP) study for BI 1358894 to treat MDD (NCT03854578) has found that BI 1358894 significantly reduced activation in several brain regions involved in emotional processing [37], and thus has the potential to impact multiple transmitter systems.…”

Section: Conclusion and Future Researchmentioning

confidence: 99%

Effect of BI 1358894 on Cholecystokinin-Tetrapeptide (CCK-4)-Induced Anxiety, Panic Symptoms, and Stress Biomarkers: A Phase I Randomized Trial in Healthy Males

Goettel,

Fuertig,

Mack

et al. 2023

CNS Drugs

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Introduction Depression, anxiety, and/or panic disorder are often comorbid and have a complex etiology mediated through the same neuronal network. Cholecystokinin-tetrapeptide (CCK-4), a synthetic analog of the endogenous neuropeptide cholecystokinin (CCK), is thought to be implicated in this network. The CCK-4 challenge model is an accepted method of investigating the pathophysiology of panic and has been shown to mediate neuronal activation via the transient receptor potential canonical (TRPC) ion channels. Objectives This study aimed to assess the pharmacodynamic effects of BI 1358894, a small-molecule inhibitor of TRPC ion channel members 4 and 5 (TRPC4/5), on CCK-4-induced anxiety/panic-like symptoms and evaluate circuit engagement. Methods Twenty healthy male CCK-4-sensitive volunteers entered a Phase I, double blind, randomized, two-way cross-over, single dose, placebo-controlled trial. Randomization was to oral BI 1358894 100 mg in the fed state followed by oral placebo in the fed state, or vice versa. Treatments were administered 5 h prior to intravenous CCK-4 50 µg. The primary endpoint was maximum change from baseline of the Panic Symptom Scale (PSS) sum intensity score after CCK-4 injection. Further endpoints included the emotional faces visual analog score (EVAS), the Spielberger State-Trait Anxiety Inventory (STAI), plasma adrenocorticotropic hormone (ACTH), and serum cortisol values. The safety and tolerability of BI 1358894 was assessed based on a number of parameters including occurrence of adverse events (AEs). All pharmacodynamic, pharmacokinetic, and safety endpoints were analyzed using descriptive statistics. Results Single oral doses of BI 1358894 were generally well tolerated by the healthy male volunteers included in this study. Adjusted mean maximum change from baseline in PSS sum intensity score was 24.4 % lower in volunteers treated with BI 1358894 versus placebo, while adjusted mean maximum change from baseline of EVAS was reduced by 19.2 % (BI 1358894 vs placebo). The STAI total score before CCK-4 injection was similar in both groups (placebo: 25.1; BI 1358894: 24.3). Relative to placebo, BI 1358894 reduced CCK-4-induced mean maximum plasma ACTH and serum cortisol values by 58.6 % and 27.3 %, respectively. Investigator-assessed drug-related AEs were reported for 13/20 participants (65.0 %). There were no serious or severe AEs, AEs of special interest, AEs leading to discontinuation of trial medication, or deaths. Conclusions Overall, BI 1358894 reduced psychological and physiological responses to CCK-4 compared with placebo, as measured by PSS, subjective EVAS and objectively measured stress biomarkers. BI 1358894 had a positive safety profile, and single oral doses were well tolerated by the healthy volunteers. This trial (NCT03904576/1402-0005) was registered on Clinicaltrials.gov on 05.04.19.

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“…Based largely on this preclinical validation evidence, human studies have subsequently been conducted with a small‐molecule TRPC4/5 channel inhibitor. In a single dose, randomized, placebo‐controlled phase I BOLD‐fMRI study with male and female major depressive disorder patients, TRPC4/5 channel inhibitor reduced the BOLD‐signal response to emotional faces in amygdala and insula, and to a greater extent than was the case for either placebo or the antidepressant citalopram (Grimm et al., 2022). Therefore, the male mouse CSS‐PALM model has accurately predicted that a novel mechanism of action will be efficacious in reducing aversion sensitivity in human subjects, women and men, with a current diagnosis of MDD.…”

Section: Commentarymentioning

confidence: 99%

Mouse Model of Chronic Social Stress‐Induced Excessive Pavlovian Aversion Learning‐Memory

Sigrist,

Hogg,

Senn

et al. 2024

Current Protocols

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Increased experience of aversive stimuli/events is a psychological‐neurobiological state of major importance in psychiatry. It occurs commonly in generalized anxiety disorder, post‐traumatic stress disorder, and major depression. A sustained period of exposure to threat (chronic stressor) is a common risk factor, and a major symptom is generalized excessive perception of, and reactivity to, aversive stimuli. In rodents, Pavlovian aversion learning and memory (PAL, PAM), quantified in terms of the conditioned defensive behavior freezing, is an extensively studied behavioral paradigm, and well understood in terms of underlying neural circuitry. In mice, chronic social stress (CSS) is a 15‐day resident‐intruder paradigm in which C57BL/6 adult males are exposed continuously and distally to dominant‐aggressive CD‐1 male mice (sustained threat) interspersed with a brief daily period of proximal attack (acute threat). To ensure that physical wounding is minimized, proximal attacks are limited to 30 to 60 s/day and lower incisor teeth of CD‐1 mice are blunted. Control (comparison) mice are maintained in littermate pairs. The CSS and CD‐1 mice are maintained in distal contact during subsequent behavioral testing. For PAL, CSS and control (CON) mice are placed in a conditioning chamber (context) and exposed to a tone [conditioned stimulus (CS)] and mild, brief foot shock [unconditioned stimulus (US)]. For PAM, mice are placed in the same context and presented with CS repetitions. The CSS mice acquire (learn) and express (memory) a higher level of freezing than CON mice, indicating that CSS leads to generalized hypersensitivity to aversion, i.e., chronic social aversion leads to increased aversion salience of foot shock. Distinctive features of the model include the following: high reproducibility; rare, mild wounding only; male specificity; absence of “susceptible” vs “resilient” subgroups; behavioral effects dependent on continued presence of CD‐1 mice; and preclinical validation of novel compounds for normalizing aversion hypersensitivity with accurate feedforward prediction of efficacy in human patients. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC.Basic Protocol 1: Chronic social stress (CSS)Basic Protocol 2: Pavlovian aversion learning and memory (PALM)

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The effects of transient receptor potential cation channel inhibition by BI 1358894 on cortico-limbic brain reactivity to negative emotional stimuli in major depressive disorder

Cited by 11 publications

References 44 publications

Safety, Tolerability, and Pharmacokinetics of Oral BI 1358894 in Healthy Japanese Male Volunteers

Safety, Tolerability, and Pharmacokinetics of Oral BI 1358894 in Healthy Japanese Male Volunteers

Effect of BI 1358894 on Cholecystokinin-Tetrapeptide (CCK-4)-Induced Anxiety, Panic Symptoms, and Stress Biomarkers: A Phase I Randomized Trial in Healthy Males

Mouse Model of Chronic Social Stress‐Induced Excessive Pavlovian Aversion Learning‐Memory

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