On October 7, 2021 Aileron Therapeutics (Nasdaq: ALRN), a chemoprotection oncology company focused on fundamentally transforming the experience of chemotherapy for cancer patients, reported that new preclinical data at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) 2021 on ALRN-6924, currently in development as a novel, selective chemoprotective agent (Press release, Aileron Therapeutics, OCT 7, 2021, View Source [SID1234590934]). The new data demonstrated ALRN-6924’s activity as a radioprotective agent in preclinical mouse models of acute radiation-induced toxicity, leveraging the same mechanism of action – p53 activation and subsequent p21 upregulation as well as p21-induced cell cycle arrest – that has clinically shown protection against chemotherapy-induced toxicities.
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"Like chemotherapy, ionizing radiation is associated with serious, often dangerous side effects, as both chemotherapy and radiation destroy normal, healthy cells," said Manuel Aivado, M.D., Ph.D. "While preliminary, these new preclinical data suggest that ALRN-6924’s mechanism of action, which has demonstrated protection against chemotherapy-induced toxicities of the bone marrow, may also protect against radiation-induced toxicities. Furthermore, these preclinical studies provide our first evidence of ALRN-6924-mediated activation of p21 in epithelial mucosa cells in the GI tract, protecting irradiated mice from body weight loss, and the potential of ALRN-6924 to protect multiple tissues beyond the bone marrow from both chemotherapy and radiation-induced toxicities."
Dr. Aivado continued, "Developing ALRN-6924 as a selective chemoprotective agent in p53-mutated cancers continues to be our chief priority. Nonetheless, these encouraging preclinical data signal a potential future secondary application of ALRN-6924 complementing our ongoing chemoprotection program, and we look forward to conducting more research to further explore that possibility."
Aileron is currently developing ALRN-6924, a first-in-class MDM2/MDMX dual inhibitor, to selectively protect healthy cells in patients with cancers that harbor p53 mutations to reduce or eliminate chemotherapy-induced side effects while preserving chemotherapy’s attack on cancer cells. ALRN-6924 is designed to activate p53 in normal cells, which in turn upregulates p21, which pauses cell cycle in normal, healthy, proliferating cells but not in p53-mutated cancer cells.
In the AACR (Free AACR Whitepaper)-NCI-EORTC poster titled, "The Investigational Chemoprotection Drug ALRN-6924, a Dual Inhibitor of MDMX and MDM2, Shows Potential for Radioprotection" (Poster #P211), Aileron presented the results of preclinical studies designed to evaluate whether p53 activation with ALRN-6924 may protect healthy, proliferating cells in normal tissues from radiation-induced cellular toxicity.
In a non-lethal radiation exposure model, mice were exposed to a single dose of abdominally targeted radiation at 15 Gy following one or more doses/schedules of ALRN-6924 or placebo and then monitored for body weight. Aileron evaluated serum levels of macrophage inhibitory cytokine-1 (MIC-1), a biomarker of p53 activation, as well as biomarkers of p53-mediated cell cycle arrest (p21), and of apoptosis (cleaved poly-ADP-ribose polymerases, or cPARP) in mouse bone marrow and GI tract tissue. Repeated doses of ALRN-6924 administered every eight hours yielded sustained MIC-1 elevation, which correlated with increased p21 positivity in the bone marrow and intestine, while treatment-dependent changes in cPARP expression were minimal. Additionally, mice treated with ALRN-6924 had less radiation-induced body-weight loss than untreated mice. Mice receiving one or more doses of ALRN-6924 eight hours prior to irradiation had an average of 4% body weight loss, while placebo-treated mice had 10% to 15% body weight loss five days after irradiation. The poster will be archived on the Scientific Publications page of Aileron’s website at: View Source
Aileron is currently conducting a Phase 1b randomized, double-blind, placebo-controlled study of ARLN-6924 as a chemoprotective agent in the United States and Europe. The study is enrolling patients with advanced p53-mutated non-small cell lung cancer undergoing treatment with first-line carboplatin plus pemetrexed with or without immunotherapy. The company is pursuing a clinical development strategy designed to advance its vision to bring selective chemoprotection to all patients with p53-mutated cancer regardless of type of cancer or chemotherapy.