Boehringer moves liposarcoma drug into pivotal trial

Boehringer Ingelheim has started a registration trial of its experimental therapy brigimadlin as a treatment for dedifferentiated liposarcoma (DDLPS), a rare cancer with limited treatment options.

The orally-available MDM2-p53 agonist is designed to restore the function of p53, the most frequently mutated gene in cancer, which has so far resisted drug development efforts. The p53 gene itself is mutated in one-half of all cancers, while its signalling pathway is disrupted in the other half.

Brigimadlin (also known as BI 907828) is a small molecule that blocks the interaction between the p53 protein – which suppresses cancer by stimulating the expression of genes that are involved in DNA repair and programmed cell death – and MDM2, which inhibits its activity.

Advancing the compound into a phase 2/3 trial is a landmark moment for p53 as a drug target, with prior efforts to develop drugs that target mutant p53 held back by difficulties in finding a suitable binding site as well as delivering them to the nucleus of cells, where the protein is mainly located.

The BRIGHTLINE-1 study compares brigimadlin to chemotherapy with doxorubicin in patients with advanced, inoperable DDLPS, an aggressive tumour type that starts in fat cells and is characterised by amplification of the MDM2 gene.

At the moment, the only treatment option is chemotherapy, but this typically stops working in a few months and has a lot of side effects. Five-year survival for advanced DDLPS patients is low, coming in somewhere between 20% and 44%.

In early-stage clinical testing, brigimadlin was shown to slow the growth of DDLPS as well as other p53-mutated solid tumours, both alone and in combination with Boehringer's experimental PD-1 inhibitor ezabenlimab (BI 754091).

Boehringer announced the start of the pivotal trial in its interim update today, in which it also said it had accelerated the clinical development of two other cancer therapies – HER2-directed tyrosine kinase inhibitor zongertinib (BI 1810631) and DLL3/CD3 bispecific T-cell engager BI 764532 – after "positive early…data."

Outside oncology, the German pharma also said it had moved PDE 4B inhibitor BI 1015550 into two phase 3 trials in idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis. Boehringer is already a big player in IPF with its Ofev (nintedanib) therapy.

In its update, Boehringer said currency-adjusted net sales rose by 9.7% to €12.2 billion ($13.4 billion), led by growth for Eli Lilly-partnered diabetes and heart failure and chronic kidney disease therapy Jardiance (empagliflozin).