Frost Biologics' lead program, FROST-450, is a small molecule inhibitor of microtubule polymerization with a robust preclinical proof of concept and unique pharmacology for a compound with this mechanism of action.
To outline its preclinical POC, FROST450 is highly potent in biochemical and cell-based assays; its potency is greater than that of paclitaxel and vincristine in microtubule polymerization assays and similar to that of these drugs in assays of cell proliferation. It shows efficacy in multiple in vivo tumor models, including multiple sub-cutaneous xenograft models, an orthotopic model of gastric cancer, and against several treatment refractory PDX models.
FROST450 was selected as a clinical candidate based on in vivo efficacy, as well as for its ADME and pharmacokinetic properties. FROST450 is metabolically stable in serum and liver microsomes from several species, does no inhibit CYPs or HERG, and evades PGP. Its cellular permeability is exceptionally high (besting the propranolol control), in keeping with high oral bioavailability with gastric absorption. FROST450 will be developed as an oral drug.
A key feature of FROST450 is evasion of resistance to other microtubule targeting agents. This includes a lack of cross resistance with taxanes, as demonstrated in PDX models and in taxane-resistant cell lines. Conversely, cells with acquired resistance to FROST450 show no resistance to any other microtubule targeting drugs. Bioinformatics and cellular analysis of FROST450-resistant cells reveal complex mechanisms of resistance that include mutations and expression changes in microtubule-associated protein, altered expression of tubulin isoforms, and metabolic changes. Importantly, key differences in long- and short-term resistance suggest that flexibility in drug dosing is key to enhancing patient responses to microtubule targeting agents, further highlighting the advantages of oral bioavailability of FROST450.
While FROST450 has the potential for clinical utility in a number of cancer types, our focus is on gastric cancer. Currently, gastric cancer patients receive a combination of traditional chemotherapeutics that all include a version of 5-fluorouracil (5FU). Second line therapy involves microtubule targeting agent paclitaxel, but the response is poor (~20%). But 5FU treatment may predispose gastric cancer to taxane resistance, as a primary mechanism of resistance to 5FU is through MDR/PGP, a mechanism that generates taxane resistance. A lack of taxane cross-resistance by FROST450, including evasion of PGP, suggests it will generate more patient responses than taxanes in gastric cancer.
Microtubule targeting drugs are one of the most critical classes of cancer drugs and FROST450 has potential to have a large and lasting impact.