MDM2-p53 antagonist (BI 907828)

MDM2-p53 antagonist (BI 907828)

BI 907828: an MDM2-p53 antagonist

BI 907828* is an oral, small-molecule murine double minute 2 (MDM2)-p53 antagonist that may promote p53-mediated cell-cycle arrest and apoptosis.1

 

Clinical trials (monotherapy and combination therapy): BI 907828 is undergoing investigation in Phase I trials as a monotherapy in patients with TP53 wild-type solid tumors,2 and in combination with ezabenlimab (BI 754091)*, a programmed cell death protein-1 (PD-1) inhibitor, in patients with advanced solid tumors.3

Roles of MDM2 and p53

MDM2 is a negative regulator of the tumor suppressor p53.4-7 In non-malignant cells unexposed to stress signals, the auto-regulatory feedback loop between MDM2 and p53 is central to keeping p53 concentrations low and to limiting aberrant p53 activity.8-10

p53 can be activated in response to a wide variety of stress signals and can mediate downstream cellular responses, including cell-cycle arrest, DNA repair, senescence and apoptosis.1,6 In human cancers, the TP53 gene encoding p53 is frequently mutated or deleted or the function of wild-type p53 protein is inhibited by high MDM2 levels, leading to downregulation of the p53 pathway.6

Previous studies in patients with wild-type p53 tumors suggest that small-molecule inhibitors of the MDM2-p53 interaction can activate the p53 pathway and induce cell-cycle arrest and apoptosis in tumor cells.11

About BI 907828

Mechanism of action

BI 907828 is a MDM2-p53 antagonist that blocks the interaction between MDM2 and p53 by binding to free MDM2. This prevents MDM2 from inactivating p53, thereby restoring p53 function in tumors with wild-type p53 and inducing target gene expression in processes such as cell-cycle arrest and DNA repair, senescence and apoptosis.1,6,7

Mechanism of action: inhibition of the interaction between MDM2 and p534-7,9

MDM2-mechanism of action
MDM2, murine double minute 2; wt, wild type.

Watch the MDM2-p53 antagonist mechanism of action animation

Watch the MDM2-p53 antagonist mechanism of action animation

In preclinical models, immune modulation by PD-1 inhibition has been shown to contribute to the activity of BI 907828, with increased activity observed when used in immune-competent (vs immune-deficient) mice in Trp53 wild-type Colon-26 syngeneic mouse tumor models.4

Mechanism of action: MDM2-p53 antagonism in combination with PD-1 inhibition4-7,9

MDM2-p53 antagonist plus PD-1 mechanism of action
CD, cluster of differentiation; MDM2, murine double minute 2; PD-1, programmed cell death protein-1; Treg, regulatory T cell; wt, wild type.

Clinical development

BI 907828 is currently undergoing clinical investigation as a monotherapy in a Phase I trial in patients with solid tumors:2 dose escalation is being investigated in patients with TP53 wild-type or unknown tumor status (regardless of MDM2 amplification status), and dose expansion in patients with TP53 wild-type tumors, with or without MDM2 amplification.2

BI 907828 is also currently undergoing clinical investigation in a Phase I trial as a combination therapy with ezabenlimab in patients with advanced solid tumors.3 In this trial, dose escalation is being investigated in patients irrespective of TP53 mutation status, and dose expansion in patients with MDM2 amplification and without any known TP53 mutations.3

More information about Boehringer Ingelheim oncology clinical trials can be found on the MyStudyWindow website. Relevant trials for our MDM2-p53 antagonist include: BI 1403-0001.

MDM2-p53 antagonist (BI 907828) clinical trials

Trial number Phase Treatment Patient population Status

NCT034493812

(1403.1)

I

BI 907828

Advanced solid tumors

Recruiting

NCT039642333(1403.2)

I

BI 907828 + ezabenlimab (BI 754091)

Advanced solid tumors

Recruiting

Explore our latest MDM2-p53 antagonist data

Our latest data on the clinical trial program for the MDM2-p53 antagonist (BI 907828) were presented at the American Society for Clinical Oncology (ASCO). 

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References

1

Boehringer Ingelheim. Data on file.

2

ClinicalTrials.gov. NCT03449381. https://clinicaltrials.gov/ct2/show/NCT03449381 (Accessed: March 2021).

3

ClinicalTrials.gov. NCT03964233. https://clinicaltrials.gov/ct2/show/NCT03964233 (Accessed: March 2021).

4

Rudolph D, et al. Presented at the Annual Meeting of the American Association for Cancer Research 2018. Abstract 4868 and poster.

5

Rinnenthal J, et al. Presented at the Annual Meeting of the American Association for Cancer Research 2018. Abstract 4865 and poster.

6

Zhao Y, et al. Acta Biochim Biophys Sin (Shanghai) 2014;46(3):180–9.

7

Montes de Octa Luna R, et al. Nature 1995;378(6553):203–6.

8

Ringhausen I, et al. Cancer Cell 2006;10(6):501–14.

9

Nag S, et al. J Biomed Res 2013;27(4):254–71.

10

Landré V, et al. Oncotarget 2014;5(18):7988–8013.

11

Shangary S, et al. Proc Natl Acad Sci USA 2008;105(10):3933–8.

*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.

© 2021 Boehringer Ingelheim International GmbH. All rights reserved.

Last updated: March 2021