Scientific Platforms

Intravenous (IV) chemotherapy has significant limitations

• IV therapy is invasive, time-consuming, and burdensome for patients with cancer
• Adverse effects such as chemotherapy-induced peripheral neuropathy can lead to dose reductions or discontinuation of therapy, potentially affecting outcomes and quality of life
• Some chemotherapy agents require administration of steroids prior to therapy to address infusion-related reactions
• The potential to deliver IV chemotherapy agents orally is limited due to P-glycoprotein (P-gp) activity in the gastrointestinal (GI) tract, which inhibits absorbed drugs that are substrates of P-gp

Inhibition of P-gp in the GI tract improves the absorption of chemotherapy agents that are substrates of P-gp

• The Orascovery platform may help overcome the limitations of oral chemotherapy by including the administration of encequidar (formerly HM30181A), a P-gp inhibitor, prior to therapy
• Inhibition of P-gp in the GI tract improves absorption of P-gp substrate chemotherapy agents, achieving systemic exposure profiles that may enhance efficacy and reduce toxicity
• Oral administration would avoid adverse reactions associated with Cremophor EL, which is a solubilizing agent used in the formulation of IV paclitaxel*

Orascovery with P-gp inhibition may help overcome limitations associated with IV administration of certain chemotherapies, such as dosing, tolerability, and efficacy

Adverse effects and frequent dosing can be significant barriers with field therapy-based AK treatment

• • Although there is poor disease awareness among patients and physicians, AK (precancerous dermal lesions) is a common condition affecting >50 million Americans
  • Today’s field therapy treatments are limited by local skin reactions that can compromise patient compliance
  • Prolonged treatment administration may jeopardize patient adherence

Src kinase inhibition broadens antitumor activity with potentially better tolerability

• • Src kinase inhibitors contain a dual mechanism of action; inhibition of activity of Src kinase and inhibition of tubulin polymerization
  • By binding to a novel site on tubulin heterodimers, these therapies may provide broader antitumor activity beyond Src inhibition alone
  • Reducing treatment duration from months to days with an improved tolerability profile has the potential to improve compliance

Src kinase inhibition may improve the AK treatment experience by providing improved efficacy, tolerability, and reduced dosing

Tumors can avoid today’s asparagine-depleting agents

• • Many malignancies lack the relevant metabolic enzymes to produce arginine, such as argininosuccinate synthetase and/or ornithine transcarbamylase
  • For tumors that are completely dependent upon external sources of arginine, arginine-deprivation therapy is a potential strategy for treatment
  • Arginine is an essential amino acid to many tumor types

Pegylated genetically-modified human arginase is a bioengineered enzyme that may deplete the tumor cell of arginine, leading to tumor cell death

In preclinical studies, pegylated genetically-modified human arginase is showing an arginine-depleting effect, offering potential as monotherapy, as well as in combination with other Athenex therapies

Scope and selectivity issues limit the use of chimeric antigen receptor (CAR) T-cell therapy

• • Surface proteins available for targeting with CAR T-cell technology are limited, severely restricting the development of CAR T-cells for multiple tumor types
  • Targeted surface proteins are also expressed in normal cells, resulting in CAR T-cell mediated lysis of non-cancerous cells
  • This can lead to potentially life-threatening side effects related to the ensuing immune response

TCR-T therapy may address a large number of additional targets due to its ability to recognize intracellular targets

• • Central to this platform is the potential to identify endogenous TCRs and enhance the affinity of the TCR to optimize results
  • High-affinity TCR-Ts may be incorporated into a patient’s own T-cells, potentially converting the cells into a potent anticancer therapy

TCR-T may demonstrate improved overall survival, safety, and durability across multiple tumor types