Aprea Therapeutics, Inc. provided a corporate update highlighting recent developments and plans for advancement of its pipeline of DNA Damage Response (DDR) anti-cancer agents in 2024. Enrollment of patients continues in the dose escalation portion of the Phase 1/2a clinical trial (study AR-276-01) evaluating ATRN-119 in patients with advanced solid tumors having mutations in defined DDR-related genes. The primary objective of the Phase 1 part of this trial is evaluating the tolerability and pharmacokinetics of ATRN-119 when administered orally on a continuous, once-daily schedule.

The daily dosing of ATRN-119 provides continuous ATR inhibition that may be preferable to intermittent dosing for both efficacy and safety, potentially supporting an important competitive advantage over the current class of ATR inhibitors. The secondary objective is the evaluation of antitumor efficacy. The most recent analysis of the data cut (January 2, 2024) shows that two patients have achieved stable disease ?

one each in the 50 mg and 200 mg cohorts. Importantly, both these patients? tumors have mutations that have been predicted to confer sensitivity to ATR inhibition.

The dose-limiting toxicity period for cohort 4 (350 mg) has been completed. The most recent patient with stable disease from cohort 3 (200mg), with a history of five prior lines of therapy is at approximately four months of treatment duration with ATRN-119, and, following clearance of the 350 mg cohort, is expected to be increased from 200 mg to 350 mg daily, as per the dose escalation trial protocol. ATRN-119 is being developed as the first and only macrocyclic ATR inhibitor.

Macrocycles restrict the number of conformations that a molecule can form, potentially resulting in increased potency and increased selectivity. These properties are expected to permit higher dosing that is potentially more effective with increased tolerability and decreased off-target activity. The company plans to amend the design of the ongoing study beyond the current 800 mg high-dose cohort to incorporate additional higher dose groups.

Upon the addition of the higher dose cohorts, Aprea expects to determine the recommended Phase 2 dose (RP2D) in the second half of 2024. Following dose escalation, the Phase 2a dose expansion part of the study may include patients with NSCLC, breast, colorectal, prostate, and ovarian cancers with selected genetic mutations. Importantly, the potential for reduced hematologic toxicity from ATRN-119 suggests it may be an ideal DDR inhibitor for novel combination therapies.

These potential combinations include ATRN-119 with PARP inhibitors, WEE1 inhibitors, and Antibody-Drug Conjugates (ADCs). The latter of these possibilities could provide a significant breakthrough for the use of ADCs linked to standard chemotherapies, as these promising biopharmaceuticals are often constrained by aberrant drug release and dose-limiting toxicities. Combination with ATRN-119 would potentially amplify the DNA-damaging effects of these ADCs in the targeted tumor cells, thus affording greater efficacy at lower ADC doses.

A more comprehensive dataset from the Phase 1 part of AR-276-01 will be submitted for presentation at a medical meeting in the first half of 2024. For more information, please refer to clinicaltrials.gov NCT04905914. The company expects to receive FDA clearance on the IND during first quarter 2024.

Clinical development is in line with FDA requirements for a dose escalation trial to evaluate safety and pharmacokinetics. Leading institutions and a Principal Investigator have been identified for the trial.