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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 combinations): BI 907828 is undergoing investigation in Phase I trials as monotherapy in patients with wild‑type TP53‑enriched solid tumours,2 and in combination with BI 754091* (an investigational programmed cell death protein-1 [PD-1] inhibitor) and BI 754111* (a lymphocyte activation gene 3 [LAG-3] inhibitor).3

The roles of MDM2 and p53

MDM2 is a negative regulator of the tumour 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 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 tumours suggest that small molecule inhibitors of the MDM2-p53 interaction can activate the p53 pathway and induce cell cycle arrest and apoptosis in tumour 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 tumours 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-p53 antagonist mechanism of action

MDM2, molecule murine double minute 2; wt, wild type

Combination therapy

In preclinical models, immune modulation 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 tumour models.

BI 907828 has also been shown to act synergistically when used in combination with checkpoint inhibitors. In Trp53 wild-type syngeneic mouse models of cancer, the triple combination of BI 907828 and antibodies against mouse PD-1 and LAG-3 has shown superior activity to single and dual agent approaches, achieving response rates of 50–90% as well as tumour regression.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, molecule 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 and in combination with the PD-1 inhibitor BI 754091 and the LAG-3 inhibitor BI 754111 in Phase I trials in patients with solid tumours.2,3

In the monotherapy trial, dose escalation is being investigated in a population with TP53 wild-type or unknown status (regardless of MDM2 amplification status), and dose expansion in TP53 wild-type patients with or without MDM2-amplified disease.2

In the combination trial, dose escalation is being performed in an unselected patient population, and dose expansion in TP53 wild-type patients with non-small cell lung cancer (NSCLC) (Cohort 1), melanoma (Cohort 2), liposarcoma or undifferentiated pleomorphic sarcoma (Cohort 3), and hepatocellular carcinoma (Cohort 4).3

Clinical trials of an MDM2-p53 antagonist in patients with solid tumours

AE, adverse event; DCR, disease control rate; DLT, dose-limiting toxicity;  LAG-3, lymphocyte activation gene 3 protein; MDM2, murine double minute 2; MTD, maximum tolerated dose; ORR, objective response rate; PD-1, programmed cell death protein-1; PFS, progression-free survival; PK/PD, pharmacokinetics/pharmacodynamics.

References

1

Boehringer Ingelheim. Data on file.

2

ClinicalTrials.gov. NCT03449381. https://clinicaltrials.gov/ct2/show/NCT03449381 (Accessed: November 2019).

3

ClinicalTrials.gov. NCT03964233. https://clinicaltrials.gov/ct2/show/NCT03964233 (Accessed: November 2019).

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.

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

© 2019 Boehringer Ingelheim International GmbH. All rights reserved.

Last updated: November 2019