Aprea Therapeutics (NASDAQ:APRE) highlighted early clinical activity and a tolerability profile it believes could differentiate its lead WEE1 inhibitor program, APR-1051, during an Oppenheimer-hosted presentation led by CEO Dr. Oren Gilad. The company, which focuses on the DNA damage response (DDR) pathway, said its strategy centers on precision oncology—matching therapies to biomarker-defined patient populations rather than using broadly cytotoxic chemotherapy.
Focus on APR-1051 and the WEE1 competitive landscape
Gilad devoted the presentation to APR-1051, a next-generation WEE1 inhibitor currently in dose escalation. He framed the program against prior efforts in the class, including Merck’s MK-1775 (later AZD-1775), which he said demonstrated biological activity but ultimately suffered from a narrow therapeutic window. AstraZeneca later terminated development of that molecule, according to Gilad, while also pursuing an analog where the therapeutic window is still being defined. He also referenced other competitors, including Zentalis’ approach using a “5-on, 2-off” schedule and Debiopharm’s WEE1 inhibitor, which he said did not show single-agent activity and has been associated with QT prolongation.
Biomarker-driven enrollment and early efficacy signals
Aprea’s study is not an all-comers trial, Gilad said. Patients are eligible based on the presence of specific biomarkers and mutations, including CCNE1, CCNE2, FBXW7, PPP2R1A, KRAS/p53, and HPV status. In the presentation, the company focused on PPP2R1A, FBXW7, and HPV-positive cancers.
Gilad said the first response observed on the first scan occurred at 150 mg, which the company is treating as the “minimum efficacious dose.” He added that at 150 mg and 220 mg, two patients showed partial responses on first scans, each with a 50% reduction in target lesions and approximately 90% reduction in a biomarker, with “very minimal” drug-related adverse effects. Both responses were described as awaiting confirmation on a second scan.
Discussing dose escalation plans, Gilad said the company has completed enrollment in the 220 mg cohort and is waiting for the last patient to complete the dose-limiting toxicity (DLT) period before moving to 300 mg. If the program clears 220 mg, Aprea expects to enroll three patients at 300 mg and then add additional patients back at 220 mg to increase the number of responders. The company’s intended enrichment areas include endometrial cancer, colorectal cancer (CRC), and HPV-positive patients.
Patient vignettes and dose-response observations
Gilad pointed to a “nice dose response” in an updated swimmer plot, including stable disease at lower doses and partial responses at higher doses. He said that at 70 mg and 100 mg, Aprea observed stable disease in multiple patients, while at 150 mg the company saw its first partial response on first scan.
He also provided details on four patients highlighted during the talk:
- PPP2R1A mutation, 220 mg cohort: Gilad described a patient with a partial response on first scan who remained on treatment. He said the target lesion shrank by 50% and CA-125 declined about 85%, with minimal adverse effects.
- PPP2R1A mutation, 150 mg cohort: A heavily pre-treated 60-year-old female patient showed a 50% reduction in target lesion size and a 90% decline in CA-125, and remained on treatment, according to Gilad.
- Stable disease case, 100 mg cohort: Gilad described disease stabilization lasting about six months, with a best response of -15% (stable disease) on daily oral monotherapy.
- HPV-positive case, 70 mg cohort: A 52-year-old male patient remained on APR-1051 for 223 days, which Gilad said was longer than the patient’s prior time on earlier therapy lines. He noted this occurred at a dose below the company’s stated minimum efficacious dose.
Gilad emphasized that the company plans to enrich for PPP2R1A based on what he characterized as “two for two” responses in that mutation so far, while also expanding cohorts in CRC and HPV-positive disease to assess response rate, durability, consistency, and safety.
Safety and dosing schedule
On tolerability, Gilad characterized APR-1051’s treatment-related adverse event profile as “pretty clean,” stating the company has not observed the gastrointestinal or hematologic toxicities that have been reported in other WEE1 programs. He cited nausea and fatigue as observed events, and referenced one patient with ALT/AST elevations at 50 mg who had liver metastases; he said subsequent patients with liver metastases did not repeat the finding.
Gilad also contrasted APR-1051’s daily oral dosing with competitors that use intermittent schedules, noting that cell-cycle targeting therapies may benefit from consistent dosing.
Combination rationale, development timeline, and capital position
While most of the clinical discussion centered on single-agent use, Gilad highlighted preclinical combination data. He described work generated at MD Anderson in HPV cancer models showing synergy between APR-1051 and cisplatin in a resistant model, and a strong response in combination with PD-1 in another model. He also discussed in-house data combining Aprea’s ATR program with WEE1, noting that halving the dose of each agent maintained efficacy in the model, which he suggested could provide flexibility if toxicity emerges.
In a Q&A, Gilad said he believes dose reductions seen in some other WEE1 programs may stem from off-target effects rather than on-target WEE1 biology. He cited co-inhibition of WEE1 and PLK family members as a potential liability, arguing that PLK co-inhibition may reduce WEE1 activity and necessitate higher dosing, increasing toxicity risk. He also said Aprea has not disclosed the molecular structure of APR-1051.
On timing, Gilad said Aprea expects to complete dose escalation by Q3, while acknowledging that ongoing escalation to higher doses could be viewed positively if it reflects a wider therapeutic window. He added that the company plans to provide updates as data become available given the open-label nature of the trial.
Gilad said Aprea recently completed a financing intended to support enrolling additional patients and generating more data, rather than extending runway. He stated the company has cash runway into Q1 2027 and noted the addition of Jean-Pierre Bizzari to the clinical team, which he said is already having a positive impact.
About Aprea Therapeutics (NASDAQ:APRE)
Aprea Therapeutics is a clinical‐stage biopharmaceutical company dedicated to developing targeted therapies that restore tumor suppressor function in cancers driven by TP53 mutations. The company’s lead investigational agent, eprenetapopt (APR-246), is designed to convert mutant p53 protein into a form that induces programmed cell death in malignant cells. Aprea’s research focuses on hematologic malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), as well as solid tumors harboring TP53 mutations.
Eprenetapopt has advanced through multiple clinical trials, including pivotal studies assessing its efficacy in combination with hypomethylating agents for patients with MDS.
