Roche's First-in-Class MDM2-p53 Inhibitor Idasanutlin Receives CDE Clinical Trial Acceptance, Ranking Second in China

On July 31, according to the New Drug R&D Monitoring Database (CPM), the clinical trial application for Roche’s MDM2-p53 inhibitor “Idasanutlin Tablets” was accepted by the Center for Drug Evaluation (CDE).

The p53 gene is one of the most extensively studied tumor suppressor genes. Its expression product, the p53 protein, promotes apoptosis in cancer cells, thereby preventing carcinogenesis and tumor growth. Additionally, it facilitates the repair of cellular genetic defects, providing a protective effect on the human body.

However, the p53 gene frequently undergoes mutations; in approximately 50% of human cancer cells, p53 protein is inactivated due to these mutations. Furthermore, interactions between p53 and other proteins constitute a major cause of the loss of its normal biological functions.

MDM2 (murine double minute 2) is one of the most important inhibitors of p53. The binding of MDM2 to p53 leads to the degradation of the p53 protein, reduced activity, and attenuated tumor-suppressive effects. The design and development of novel anti-tumor drugs targeting the MDM2-p53 interaction represent a major focus and hotspot in global oncology drug research and development. However, the unique characteristics of the MDM2-p53 protein-protein interaction pose significant challenges to the development of small-molecule inhibitors, resulting in only a handful of investigational drugs worldwide in this field. In addition to idasanutlin, notable examples include Amgen’s AMG-232 and Novartis’s HDM201.

Idasanutlin (RG7388) is the world’s first potent oral MDM2 protein inhibitor developed by Roche. Idasanutlin selectively binds to the p53-binding site on the surface of MDM2, thereby disrupting the p53-MDM2 interaction. This leads to p53 stabilization and activation of the apoptotic pathway, resulting in cancer cell death.

Idasanutlin Structural Formula

Idasanutlin exhibits potent inhibitory activity against cancer cells harboring wild-type p53 protein, including human osteosarcoma cells (SJSA-1), human colon cancer cells (HCT-116), and human colon adenocarcinoma cells (RKO). The potential indications for idasanutlin primarily include chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, melanoma, neuroblastoma, and mantle cell lymphoma. These cancers are characterized by the frequent presence of wild-type p53 alongside MDM2 overexpression.

Xenograft model experiments demonstrated that the combination of Idasanutlin and Obinutuzumab enhances resistance to cancer cells without affecting the antibody-dependent cellular cytotoxicity (ADCC) of Obinutuzumab. When combined with Venetoclax in chronic lymphocytic leukemia (CLL), Idasanutlin significantly increases anticancer activity, effectively inhibiting the growth and proliferation of acute myeloid leukemia (AML) cells. Furthermore, Idasanutlin exhibits synergistic effects with Rucaparib in ovarian cancer, allowing for a reduced dosage of Rucaparib. Additionally, in vitro studies revealed that Idasanutlin possesses potent inhibitory activity against non-small cell lung cancer (NSCLC) cell lines harboring the p53 gene and pediatric neuroblastoma.

According to the New Drug R&D Monitoring Database (CPM), Idasanutlin is currently involved in 15 clinical trials. The most advanced global development status is an international, multicenter Phase III clinical trial (NCT02545283) evaluating its combination with cytarabine for the treatment of relapsed or refractory acute myeloid leukemia (AML), which is expected to be completed this December.

Free Data Source: Yao Fenxiang Plus

Notably, the primary endpoint of this study was overall survival (OS) in patients with wild-type p53, while the secondary endpoint was OS in all patients. Given that the mechanism of action of idasanutlin is dependent on the p53 protein, it was critical to designate OS in patients with wild-type p53 as the primary endpoint for this trial.

Relapsed or refractory AML is a disease that is difficult to cure, with the remission rate of first-line salvage therapy decreasing from 75% for initial treatment to 40%, and the remission rate of second-line salvage therapy being only 15-20%.

In a previous Phase Ib study, researchers demonstrated the efficacy of idasanutlin in combination with cytarabine and established the appropriate dosing for the combination regimen. Following treatment, among 75 patients with acute myeloid leukemia (AML) who received the combination therapy, the objective response rate (ORR) was 33%, the complete remission (CR) rate was 29%, and the median duration of response was 6.4 months.

However, in the Phase Ib study, no statistically significant correlation was observed between p53 mutation status and response rate. Nevertheless, a trend emerged in this study suggesting that p53 mutation status serves as a negative predictive biomarker. When the analysis of trial results was restricted to patients with wild-type p53, a significant correlation was found between MDM2 protein expression and complete response with confirmed durability (CRc), laying the foundation for future studies.

Furthermore, since MDM2-p53 inhibitors are cell cycle-dependent, their pro-apoptotic effects become significant only after cells have undergone at least two cycles. Bcl-2 inhibitors can eliminate this dependency, thereby accelerating the initiation of cell death. Currently, Roche has initiated a Phase II clinical trial evaluating the combination of Idasanutlin and the Bcl-2 inhibitor Venetoclax for the treatment of relapsed or refractory acute myeloid leukemia (AML).

In China, Ascentage Pharma’s drug APG-115, which targets the same mechanism, received approval from the Center for Drug Evaluation (CDE) to commence clinical trials as early as July 2017. It is currently undergoing Phase I clinical trials in both China and the United States for patients with adenoid cystic carcinoma (ACC) and other sarcomas. Additionally, APG-115 is being evaluated in a Phase Ib/II clinical trial in combination with pembrolizumab in the United States.

In June 2019, Ascentage Pharma announced the latest data from two clinical trials of APG-115 at the ASCO Annual Meeting.

Phase I Study of APG-115 for the Treatment of Advanced Soft Tissue Sarcoma

Preliminary data indicate that APG-115 demonstrates robust antitumor activity in MDM2-amplified and TP53-wild-type liposarcoma. Its safety profile and pharmacodynamic (PD) effects are consistent with those of other MDM2 inhibitors. Optimization of the current dosing regimen is ongoing.

Phase I Study of APG-115 for the Treatment of Advanced Solid Tumors

APG-115 demonstrated good tolerability, with no uncontrollable adverse events observed. The study of APG-115 as an oral monotherapy in patients with advanced solid tumors determined the maximum tolerated dose and the recommended Phase II dose of 100 mg.

Original Title: Roche’s Global First MDM2-p53 Inhibitor Is Here! But It Ranks Second in China...