Preclinical Studies of MDMX and MDM2 Lead to Phase I Trials in Patients With AML

Ulrich Steidl, MD, PhD

In an ideal world, researchers conduct preclinical studies that generate a targeted therapy, which eventually makes its way through early, middle, and late-stage trial development and FDA approval. That smooth transition does not happen often, but early results involving an agent that affects 2 endogenous inhibitors of p53 look promising.

Results of preclinical research conducted on the endogenous inhibitors MDMX and MDM2 has led to the launch of a phase I study involving the targeted agent ALRN-6924. The tumor suppressor p53 is usually inactivated via its interaction with inhibitors MDMX and MDM2, which are overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Ulrich Steidl, MD, PhD, and colleagues demonstrated that MDMX is “considerably overexpressed in AML, including in leukemia stem cells, compared with age-matched controls.”

“We know that p53 is a powerful member of this class of transcription factors—the gene activators,” said Steidl, professor of cell biology and medicine at the Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.

Amit Verma, MD

The researchers investigated the effects of dual MDMX/ MDM2 inhibition using a stapled alpha-helical peptide in cells from patients with leukemia. Their findings provided a rationale for further development and clinical testing of ALRN-6924 as a therapeutic approach in cancers with wild-type TP53.¹The researchers found that ALRN-6924 activates p53-dependent transcription at the single-cell and single-molecule levels and displays robust biochemical and molecular biological on-target activity in leukemia cells.

“If you identify a targeted therapy that can reactivate the p53 molecule, then you don’t have these tumor-promoting effects on cell cycle and cell death,” said Steidl. “MDMX and MDM2 bind to p53 so that it cannot carry out its normal function. This is one of the endogenous ways to inhibit a tumor suppressor.” The new drug is effective at killing leukemia cells from cell lines and primary cells obtained from patients.

The agent is now undergoing investigation in early phase I clinical trials (NCT02264613 and NCT02909972) to determine its safety, as well as its therapeutic potential in AML and high-risk myelodysplastic syndromes. ALRN-6924 has thus far demonstrated efficacy and safety, with no reported grade 3/4 thrombocytopenias, and grade 3/4 neutropenia reported in less than 5% of patients.²

“The trials are actively recruiting,” said Amit Verma, MD, Steidl’s collaborator and a study investigator and director, Division of Hemato-Oncology at the Albert Einstein College of Medicine and Montefiore Medical Center.

NCT02264613 is an open-label, multicenter dose escalation (DEP) and dose expansion (EXP) study evaluating the safety, tolerability, PK (pharmacokinetics), PD (pharmacodynamics) and antitumor effects of ALRN-6924 in patients with advanced solid tumors or lymphomas with wild-type TP53.

The DEP portion of the study will enroll adults with histologically or cytologically confirmed malignancies that are metastatic or unresectable and for which standard treatment is not available or is no longer effective. The EXP portion of the study investigates the clinical safety profile and potential efficacy of ALRN-6924 at the maximum-tolerated dose or optimal biological dose. Peripheral T-cell lymphoma has been selected as one of the EXP groups to be further studied.

Treatment of patients in the DEP and EXP phases will continue in the study until disease progression, unacceptable toxicity, or when the patient or physician decides to discontinue therapy. In NCT02909972, ALRN-6924 is undergoing investigation in patients with relapsed or refractory AML or advanced MDS with wild-type TP53.

“With these stapled peptides, which represent a new class of drugs based on novel chemistry that wasn’t available 10 years ago, it is now possible, in principle, to target these transcription factors,” said Steidl. “The hope is that our study has provided proof of concept, and opens the door for researchers to explore pharmacological targeting of many other of these hard-to-target molecules that play key roles in many cancers including leukemia.”

References:

1. Carvajal L, Neriah DB, Senecal A, et al. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Sci Transl Med. 2018;10(436). pii: eaao3003. doi: 10.1126/scitranslmed.aao3003.
2. Meric-Bernstam F, Saleh MN, Infante JR, et al. Phase I trial of a novel stapled peptide ALRN-6924 disrupting MDMX- and MDM2-mediated inhibition of WT p53 in patients with solid tumors and lymphomas. J Clin Oncol. 2017;35(suppl 15):2505. doi: 10.1200/JCO.2017.35.15_suppl.2505.