IND-enabling development of a novel STING agonist, IMGS-203, for the treatment of glioblastoma

Background: Glioblastoma multiforme (GBM) is a lethal malignancy with a highly immunosuppressive tumor microenvironment (TME) enriched in myeloid-derived suppressor cells, tumor-associated macrophages, and tumor-associated neutrophils. IMGS-203 is a potent STING (Stimulator of Interferon Genes) agonist developed for intratumoral (IT) delivery, a route of administration (ROA) particularly suited for GBM, a tumor that rarely metastasizes and is readily accessible for local delivery during standard procedures such as biopsy. In vitro assays and preclinical murine studies, including a humanized model with epigenetically silenced STING, demonstrated the antitumor efficacy, specificity, and mechanism of action of IMGS-203, provided pharmacokinetic information, and supported the translational potential for local delivery [1-3]. The IT ROA is critical to IMGS-203 efficacy, enabling high local drug concentrations, precise tumor targeting, and minimal systemic exposure and toxicity. Objective: To design an Investigational New Drug (IND)-enabling toxicology study using healthy dogs as a translational model to define a safe, pharmacologically relevant dose range for intracranial administration of IMGS-203. Methods: Murine glioma CT-2A was orthotopically implanted and treated with 1-2 doses of IT administered 0.01-10µg IMGS-203. In vitro, canine peripheral blood mononuclear cells (PBMCs) were incubated with IMGS-203 and IFNbeta response was measured. In a pilot safety study, healthy dogs received intracranial IMGS-203 (5-100µg) via frontal lobe injection. Clinical observations, body weight, hematology, clinical chemistry, cerebrospinal fluid (CSF) parameters, immunophenotyping, bioanalysis, and histopathology were evaluated. Results: Significant extension of survival was observed for mice receiving as little as 0.01µg IMGS-203. 25% (3/12) of mice were completely cured after 2 doses at ≤0.1µg. Canine PBMCs secreted IFNbeta in response to IMGS-203, confirming dogs as an appropriate preclinical species. Intracranial administration of IMGS-203 at high dose (≥50µg) to the front lobe of healthy dogs was poorly tolerated. Local edema and inflammation at the injection site were observed. Further, systemic effects included increased white blood cell counts, and behavioral changes were reported. In contrast, a 5µg dose was well tolerated, with only mild local edema and no systemic effects. IMGS-203 was undetectable in serum or CSF at all points and all doses. Conclusions: Dose range findings and pilot data informed an IMGS-203 toxicology study incorporating single intracranial doses of 1-10µg in dogs. Inter-species brain-mass scaling predicts human-equivalent doses of 14-140µg, consistent with clinician expectations. The FDA reviewed this design at a pre-IND meeting and deemed it adequate to support initiation of a Phase I clinical trial upon study completion.