Scientific platforms

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

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*

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

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

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

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

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

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