Aprea Therapeutics (APRE) Study Update summary

Program Overview and Context

• APR-1051 is a highly selective oral WEE1 inhibitor designed to avoid off-target PLK inhibition, aiming for a best-in-class safety profile and addressing synthetic lethality in cancer via the DNA damage response pathway.

• The IND for APR-1051 was recently cleared, with the first patient dosed in June 2024 and no FDA concerns regarding sepsis or intestinal barrier function.

• Preclinical data show potent anti-tumor activity and tumor suppression in xenograft models without significant body weight loss, suggesting preserved intestinal barrier function.

• Investigators have shown increased enthusiasm for the trial following recent safety issues with competitor molecules.

• The program targets significant unmet needs in oncology, with ongoing clinical evaluation and upcoming data readouts.

Clinical and Safety Findings from Other WEE1 and PLK1 Inhibitors

• Competing WEE1 inhibitors (azenosertib, adavosertib) with off-target PLK1 inhibition have been linked to severe neutropenia and fatal sepsis in multiple trials.

• PLK1 inhibitors like volasertib and MK-1496 have demonstrated high rates of grade 3+ neutropenia, sepsis, and increased mortality.

• PLK1 inhibition is mechanistically linked to hematologic toxicity and impaired intestinal barrier recovery, exacerbating sepsis risk.

Medicinal Chemistry and Differentiation of APR-1051

• APR-1051 was designed using a novel scaffold lacking the alcohol group that mediates PLK1 binding, resulting in minimal PLK1, 2, or 3 inhibition.

• In vitro, APR-1051 shows potent WEE1 inhibition (IC50 1.8 nM) and negligible PLK family inhibition (IC50s >1,800 nM for PLK1, 15,900 nM for PLK1), suggesting a higher therapeutic index.

• The compound’s selectivity is expected to reduce the risk of neutropenia and sepsis seen with less selective WEE1 inhibitors.

• In vitro efficacy is similar to other WEE1 inhibitors but with over 150-fold less PLK1 inhibition.