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Preventing Opioid Induced Immunodeficiency(OII) in Cancer
Opioids, essential for managing severe cancer pain, inadvertently compromise cancer treatment efficacy. The blocking of Immune Checkpoint Inhibitors (ICI) by opioids leads to a reduction in treatment efficacy across 4000 patients of 50% (Mao et al, 2022), impacting patient survival rates and quality of life. This issue, termed Opioid-Induced Immunodeficiency (OII), stems from opioids' binding to T-cells blocking T-cell infiltration into tumors and their pro-angiogenic and pro-metastatic properties, weakening the immune response to cancer and reducing ICI effectiveness.
For data on opioids vs. no opioids in 1012 mixed checkpoint inhibitor patients, see Figure 2-C in Cortellini et al, 2020.
PFS in 1012 mixed checkpoint inhibitor (ICI) patients
Axelopran: Best in class peripherally-active μ-opioid receptor antagonist
Innovative OII Treatment
Axelopran is a selective antagonist of peripheral μ-opioid receptors. It blocks opioid signaling outside the brain, particularly on immune cells, without affecting pain relief. By restoring T-cell infiltration and reducing angiogenesis and immune exhaustion, axelopran reactivates the immune system’s ability to fight cancer. Its host-level mechanism targets both the immune macroenvironment and the tumor microenvironment, making it applicable across multiple solid tumor types.
Proven Development
Initially developed for opioid-induced constipation and advanced to clinical significance in Phase 2b trials, axelopran has had comprehensive development work completed and safety data.
Validated in Multiple Solid Tumor Models
Axelopran’s mechanism has been confirmed in preclinical studies across melanoma, head and neck cancer, lung cancer and others. It reversed immune suppression caused by both tumor-derived and medication-based opioid signaling. These studies showed reduction in tumor volume and increased immune activation when axelopran was combined with checkpoint inhibitors.
Safety and Tolerability
Demonstrated in clinical trials with 544 patients, showing excellent tolerability with no severe adverse events, supporting its use in broader oncology applications as Glycyx enters Phase 2 trials.
Phase 2b Ready
Bioavailable, efficacious dose demonstrated in OIC Phase 2 with excellent safety and tolerability: 10-15mg. CMC validated with long-term manufacturing partnership. IND active in April 2024. Drug substance completed production in February 2024 and formulated in once daily capsules ready for clinical trial use.
Opioids block T-cell infiltration in HNSCC, axelopran enables infiltration
Understanding the Opioid System
The opioid system evolved to help the body respond to acute injury. When tissue is damaged, the body produces natural opioids that relieve pain, suppress inflammation, promote tissue regeneration, support new blood vessel growth, and redirect immune function toward healing. These actions are critical for survival in the short term. However, in cancer, these same processes are chronically activated. Tumors hijack this system by increasing opioid signaling in the local environment, which reduces immune cell infiltration, promotes angiogenesis, and activates pathways like epithelial-mesenchymal transition. These effects help tumors grow, escape immune detection, and spread to other parts of the body.
Axelopran Enhances Checkpoint Inhibitor Activity in Multiple Solid Tumor Models, Including Melanoma and HNSCC
Next step:
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Basket Phase 2b study with common design across 3-4 cohorts of different tumor types:
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Recurrent/metastatic head & neck squamous cell carcinoma (HNSCC), CPS ≥1
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Recurrent/metastatic non small cell lung cancer (NSCLC)
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Recurrent/metastatic melanoma
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RCT: Standard of care ICI +/- axelopran in frontline Stage IV ICI-eligible patients receiving opioids at baseline
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Bayesian Simon 2-stage design with powered interim safety and futility analysis; final efficacy powering based on interim view results
