Summary: 

        IPG1094 is a first-in-class, BBB-penetrant oral small-molecule inhibitor of macrophage migration inhibitory factor (MIF) tautomerase activity. It is the first selective MIF inhibitor to advance into clinical development, with therapeutic potential spanning immuno-oncology and neurology.

        By precisely targeting the enzymatic activity of MIF, IPG1094 is designed to address two distinct areas of high unmet medical need: reversing tumor-induced immunosuppression for the treatment of brain metastases, and reducing neuroinflammation to provide a disease-modifying therapy for acute ischemic stroke. With a novel chemical structure and a favorable safety profile established in the completed Phase 1 trial, IPG1094 holds potential across multiple indications with high unmet medical need.

IPG1094 in Oncology 

Mechanism of Action

￭ In the tumor microenvironment, many cancers secrete MIF via exosomes. This process drives the recruitment, expansion, and immunosuppressive function of myeloid-derived suppressor cells (MDSCs)—a dominant immunosuppressive population that abrogates the antitumor activity of CD8+ cytotoxic T cells, allowing tumors to evade immune surveillance.

￭ IPG1094 potently inhibits the MIF tautomerase activity essential for this cascade, thereby reducing MDSC generation and function, restoring CD8+ T cell-mediated antitumor immunity, and directly suppressing tumor growth and metastasis.

Key Differentiation

￭ Exceptional Brain Penetration: Its ability to cross the BBB addresses a key unmet need, where most systemic therapies achieve limited exposure within brain metastases.

￭ Precision Immuno-Oncology: By selectively targeting the MIF signaling axis on myeloid cells, IPG1094 is designed to reprogram the tumor microenvironment while minimizing broad systemic immune suppression.

￭ Synergistic Combination Potential: Its distinct mechanism of action supports synergistic use with standard-of-care therapies, including radiotherapy and immune checkpoint inhibitors, with the aim of improving patient outcomes.

Current Development & Status

￭ Phase 1/2a (Ongoing): A multi-center, open-label Phase 1/2a trial of IPG1094 in patients with advanced solid tumors is ongoing in China, with planned expansion cohorts in NSCLC brain metastases and glioma.

￭ Upcoming Milestones: A Phase 2 trial is planned to evaluate IPG1094 in combination with whole-brain radiotherapy in patients with driver-gene-negative NSCLC brain metastases.

In vitro properties 

￭ Reverses Tumor-Induced Immune Suppression: In vitro studies showed that IPG1094 abrogated the generation of immunosuppressive MDSCs induced by pancreatic cancer-derived exosomes and restored the proliferative capacity of CD8+ cytotoxic T cells.

In vivo Properties

￭Dose-Dependent Tumor Growth Inhibition: In a subcutaneous pancreatic cancer mouse model, IPG1094 treatment demonstrated significant, dose-dependent inhibition of tumor growth compared to vehicle control.

IPG1094 in ischemic stroke

Mechanism of Action

￭ During acute ischemic stroke, MIF acts as a key upstream pro-inflammatory cytokine that is rapidly and markedly upregulated. It initiates and amplifies the pathological cascade by promoting blood-brain barrier (BBB) disruption, cerebral edema, glial cell activation, and neuronal cell death—processes that cause permanent neurological disability.

￭ By inhibiting MIF tautomerase activity at the apex of this inflammatory hierarchy, IPG1094 interrupts these damaging pathways, thereby preserving BBB integrity, reducing neuronal apoptosis, limiting infarct volume, and mitigating long-term neurological deficits.

Key Differentiation

■ Disease-Modifying Neuroprotection: Unlike current reperfusion therapies, which restore blood flow but do not directly target the secondary neuroinflammatory cascade, IPG1094 is designed to address post-stroke neuroinflammation that contributes to long-term disability.

■ Extended Therapeutic Window: Its unique mechanism positions it as a potential therapy capable of providing neuroprotection beyond the narrow acute reperfusion window, potentially benefiting a much larger patient population.

■ Direct CNS Activity: IPG1094's robust BBB penetration allows it to act directly within the central nervous system, where ischemic damage occurs.

Current Development & Status

￭ Phase 1 (Completed): The Phase 1 trial in healthy volunteers in Australia provides a strong safety and tolerability foundation for development in acute ischemic stroke.

￭ Phase 2 Initiation: IND approvals for ischemic stroke have been received from both the FDA and NMPA. A Phase 2 trial is expected to begin enrolling patients with acute ischemic stroke.

Clinical Studies

￭ In the Phase 1 trial, no serious adverse events were reported; adverse events (primarily headache and nausea) were mild to moderate and dose-dependent. Exposure increased with dose across the studied single-dose range of 100 to 1200 mg.

In vivo Properties

￭ In a stroke model with high translational relevance using spontaneously hypertensive rats (SHR), IPG1094 treatment significantly reduced cerebral infarct area.

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￭ This neuroprotective effect was accompanied by a robust and dose-dependent improvement in neurological and sensorimotor functions, including motor coordination, muscle strength, and endurance.

Publication

•Jia X, Xi J, Tian B, Zhang Y, Wang Z, Wang F, Li Z, Long J, Wang J, Fan GH, Li Q. The Tautomerase Activity of Tumor Exosomal MIF Promotes Pancreatic Cancer Progression by Modulating MDSC Differentiation. Cancer Immunol Res. 2024 Jan 3;12(1):72-90. doi: 10.1158/2326-6066.CIR-23-0205. PMID: 37956411.