Aprea Therapeutics Announces Presentations On Its Next Generation WEE1 Inhibitor, APR-1051, And A Novel Macrocyclic ATR Inhibitor, ATRN-119, At AACR Annual Meeting 2024

Pre-clinical findings underscore the potential of APR-1051, a next-generation WEE1 kinase inhibitor, to be a well-tolerated and effective treatment for Cyclin E-overexpressing cancers

 

IND for APR-1051 has been cleared; details on planned Phase 1 first in human trial (ACESOT-1051) presented

ATRN-119, a novel macrocyclic ATR inhibitor, continues to appear safe and well tolerated with no Dose Limiting Toxicities observed in ongoing Phase 1/2a study; preliminary signs of clinical benefit reported; enrollment in the study continues

DOYLESTOWN, Pa., April 10, 2024 (GLOBE NEWSWIRE) -- Aprea Therapeutics, Inc. (NASDAQ:APRE) ("Aprea", or the "Company"), a clinical-stage biopharmaceutical company focused on precision oncology through synthetic lethality, today released details about four poster presentations at the ongoing American Association of Cancer Research (AACR) Annual Meeting, taking place April 5 to 10, 2024 in San Diego, CA. The posters feature APR-1051, Aprea's next-generation inhibitor of WEE1 kinase, as well as a clinical update on ATRN-119, its novel macrocyclic ATR inhibitor. The Company also presented a poster highlighting a new set of preclinical data in glioblastoma with a next-generation macrocyclic ATR inhibitor, ATRN-333.

"The four poster presentations at this prestigious conference highlight our growing pipeline and commitment to help cancer patients in need," said Dr. Oren Gilad, President and CEO of Aprea. "We are pleased to share the strong pre-clinical data and future clinical strategy for our promising next-generation WEE1 kinase inhibitor, APR-1051. We are also very excited to provide an encouraging update on the ongoing clinical study of our novel macrocyclic ATR inhibitor, ATRN-119."

Copies of the posters will be available on the Aprea corporate website here, at the conclusion of the AACR meeting.

APR-1051

The novel WEE1i, APR-1051, is a potentially well tolerated and effective treatment for cyclin E-overexpressing cancers

• This poster summarizes the pre-clinical data of APR-1051
• APR-1051 exhibits high potency for WEE1 inhibition in vitro
  
  
  • Selectivity is key for success. APR-1051 shows low off-target inhibition of the PLK family of kinases.
    
    
    • To measure the potential for off-target inhibition of the PLK family of enzymes, in vitro experiments were conducted to determine the IC50s of APR-1051 vs ZN-c3 (Zentalis Pharmaceuticals)
    • The results showed significantly lower off-targeting of PLK1, PLK2 and PLK3 as indicated by higher IC50 values for APR-1051 compared to ZN-c3.
      
      IC50 of APR-1051 over IC50 of ZN-c3
      
      • PLK1: > 150-fold
      
      • PLK2: > 50-fold
      
      • PLK3: > 600-fold

• Off-targeting of PLK1 by other WEE1 inhibitors may compromise the efficacy of these drugs.

• Off-targeting of the PLK family may increase the risk of producing PLKi-associated adverse effects.

• Cyclin E as a potential biomarker for APR-1051 treatment
  • APR-1051 demonstrated effectiveness in suppressing the growth of Cyclin E-overexpressing breast and ovarian cancer cell lines.
  • The dose and scheduling of APR-1051 that causes significant suppression of CCNE1-amplified high-grade serous ovarian cancer tumors in mice is well tolerated.
  • Red blood cell and platelet counts remained within non-pathogenic ranges after a 28-day treatment period, consistent with proposed minimal off target PLK1 inhibition
• APR-1051 will potentially exhibit low cardiotoxicity.
  • Inhibition WEE1 by APR-1051 occurs at an IC50 that is 200-fold lower on average than the IC50 of hERG potassium channel inhibition.
• Strong evidence for combination therapy
  • APR-1051 was evaluated in combination with Aprea's second-generation ATR inhibitors (ATRN-330 and ATRN-354) in xenografted tumors. The results showed higher anti-tumor activity for the combinations, compared with vehicle or monotherapy.
• APR-1051 received U.S. FDA clearance for a clinical trial, now with plans to dose the first patient in June 2024

ASECOT-1051: First-in-human phase 1 study of WEE1 inhibitor APR-1051 in patients with advanced solid tumors harboring cancer-associated gene alterations.

• This poster summarizes the strategy for the upcoming clinical trial of APR-1051
• The aim of this first-in-human Phase 1 study (ACESOT-1051: A Multi-Center Evaluation of WEE1 Inhibitor in Patients with Advanced Solid Tumors, APR-1051) is to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent APR-1051 in advanced solid tumors harboring cancer-associated gene alterations (NCT06260514)
• This biomarker-driven study will include patients with advanced/metastatic solid tumors harboring cancer-associated gene alterations, such as CCNE1 or CCNE2, FBXW7, PPP2R1A, or KRAS G12
  • Oral APR-1051 will be administered once daily for 28-day cycles.
• The study will consist of two parts.
  • Part 1 will be dose escalation and is expected to enroll up to 39 patients with advanced solid tumors harboring cancer-associated gene alterations. In the dose escalation phase the first three dose levels will use accelerated titration followed by Bayesian Optimal Interval (BOIN) design for the remaining dose levels
  • Part 2 (up to 40 patients) is designed for dose optimization, with the goal of selecting the Recommended Phase 2 Dose (RP2D)
• The primary objectives are to measure safety, dose-limiting toxicities (DLTs), maximum tolerated dose or maximum administered dose (MTD/MAD), RP2D; Secondary objectives are to evaluate pharmacokinetics, preliminary efficacy according to RECIST or PCWG3 criteria; Pharmacodynamics is an exploratory objective.
• Enrollment is anticipated to begin in Q2 2024
• MD Anderson Cancer Center is the lead site, and the study will be performed at between 3 and 10 sites in the U.S