BXQ-350 通过调节鞘脂代谢降低化疗诱导的周围神经病变的发生率、严重程度并延缓其发病时间

Background: Chemotherapy Induced Peripheral Neuropathy (CIPN) is a debilitating side effect associated with many chemotherapeutic agents including cytotoxic and targeted agents. Damages to nerve cells are believed to be directly resulting from the antineoplastic agents' cytotoxicity, however, inflammation and the immune system are also involved and contribute to chronic CIPN. Increasing evidence also suggests that specific species of sphingolipids, including gangliosides (GM), lactosyl ceramides (LacCer), glucosyl ceramides (GluCer) and sphingosine-1-phosphate (S1P), may be involved as altered neuronal sphingolipid metabolism has been linked to neuropathic pain and development of CIPN. BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of multiple enzymes controlling sphingolipid metabolism, that lowers systemic GM, LacCer, GlucCer and S1P. Method: BXQ-350 has been investigated preclinically in CIPN models. Clinically, BXQ-350 was investigated in an adult Phase 1 dose-escalation safety study in heavily pretreated all-comer cancer patients with advanced solid malignancies (NCT02859857), in a Phase 1 Proof of Concept (PoC) study in patients with established chronic CIPN from prior cancer treatments (NCT05291286) and is being investigated in a Phase 1b/2a study in combination with FOLFOX7+ Bevacizumab in newly diagnosed first line mCRC patients (NCT05322590). Results: Preclinical results revealed that BXQ-350 is neuroprotective against chemotherapeutic agents known to induce CIPN. Clinically, in the Phase 1 single agent study, several patients spontaneously reported a significant improvement of their neuropathic symptoms shortly after receiving BXQ-350. In the PoC phase 1 study, BXQ-350 treatment arm showed clinically meaningful and statistically significant improvement over placebo. In the combination study in 1L mCRC patients, BXQ-350 seems to delay the onset, severity and frequency of CIPN while enabling the administration of a higher cumulative dose of oxaliplatin. Longitudinal analyses of biomarkers (plasma cytokines, Neurofilament Light (NfL) chains, sphingolipids), and results from CIPN 20 questionnaires, and physician assessments, revealed there were positive correlations between physician assessments, CIPN 20 questionnaire results, NfL and sphingolipid profile changes. A strong correlation was noted between LacCer, a sphingolipid known to induce neurodegeneration and inflammation, in patients developing CIPN and with established chronic CIPN. Conclusions: Preclinical and clinical results suggest that BXQ-350 protects cancer patients from antineoplastic agents known to induce CIPN enabling the administration of higher cumulative doses of oxaliplatin in mCRC patients. A strong correlation was noted between CIPN and LacCer plasma levels and other CIPN biomarkers.