Pipeline

Pipeline

Overcoming the Affinity Barrier

AVB-S6-500 is a GAS6 binding protein and AXL decoy receptor. This novel, high-affinity, soluble, Fc-fusion protein is designed to block the activation of GAS6-AXL signaling. AVB-S6-500 is under clinical development as a targeted therapy against ovarian cancer. Additional clinical trials may involve combining AVB-S6-500 with standard of care in a number of tumor types, which may include renal cell carcinoma, acute myeloid leukemia, triple negative breast cancer and pancreatic cancer. This GAS6-binding protein therapeutic, which is a fusion of the extracellular domain of AXL (the receptor for GAS6) with a human IgG1 Fc domain, is designed to bind GAS6 with low femtomolar range affinity and reduce or eliminate its ability to stimulate the AXL pathway. The novel Fc-fusion protein drug candidate neutralizes GAS6 and effectively turns off AXL signaling in tumor cells in preclinical studies.

In its recently completed Phase 1 clinical trial with AVB-S6-500, the lead development candidate selected from the AVB-S6 family of proteins, Aravive demonstrated clinical proof-of-mechanism for AVB-S6-500 in neutralizing GAS6. In an analysis of the single ascending dose portion of the study, AVB-S6-500 administration resulted in a dose-dependent decrease in measurable, circulating free GAS6 in serum. Importantly, AVB-S6-500 had a favorable safety profile in this first in human study and in preclinical studies. Aravive is poised to initiate the Phase 1b portion of its first Phase 1b/2 clinical trial in patients with platinum resistant ovarian cancer.

Preclinically, the Company has conducted several proof-of-principle studies and established compelling data demonstrating AVB-S6’s efficacy and tolerability in multiple in vitro studies and in vivo models of cancer. In preclinical models, treatment with AVB-S6 proteins alone and in combination with standard chemotherapy have been associated with anti-tumor effects coupled with excellent tolerability. In fact, there has been no appreciable normal tissue toxicity with treatment of AVB-S6.


Aravive-S6 MOA: Prevents Binding of GAS6 to AXL on Cell membrane and Blocks AXL Signaling We have developed a series of high-affinity soluble decoy receptors targeting GAS6. These molecules have different affinities and different pharmacokinetics profiles that can be used in different clinical indications. Our current pipeline indications include leukemia and certain advanced solid tumors.

AVB-S6-500 has better than 100-fold tighter affinity for GAS6 compared to the natural affinity between the ligand and the receptor, providing high specificity and selectivity for the GAS6-AXL pathway.

AVB-S6-500’s neutralization of GAS6 and inhibition of the GAS6-AXL pathway offers the potential for a novel, targeted therapeutic approach that may be used alone with low toxicity or in combination with other standard-of-care anti-cancer agents.

In both laboratory and animal experiments, inhibition of the GAS6-AXL interaction stops the progression of cancer. In solid tumors, GAS6-AXL inhibition has been shown to have dual anti-cancer effects, including direct anti-tumor effects on survival, invasion, and chemoresistance, and indirect anti-tumor effects via stimulating innate anti-cancer immunity, given the GAS6 role as an innate immunity checkpoint. In AML, other treatments in development have toxicity and low response rates with increased likelihood of developing resistance.