Form 8-K - Current report

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 8-K

CURRENT REPORT

Pursuant to Section 13 or 15(d)

of the Securities Exchange Act of 1934

January 4, 2024

Date of Report (Date of earliest event reported)

Aprea Therapeutics, Inc.

(Exact name of registrant as specified in its charter)


Delaware	001-39069	84-2246769
(State or other jurisdiction of incorporation)	(Commission File Number)	(IRS Employer Identification No.)


3805 Old Easton Road Doylestown, PA (Address of principal executive offices)	18902 (Zip Code)

Registrant’s telephone number, including area code: (617) 463-9385

(Former name or former address, if changed since last report): Not applicable

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:


☐	Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
☐	Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
☐	Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
☐	Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Securities registered pursuant to Section 12(b) of the Act:


Title of each class	Trading Symbol(s)	Name of each exchange on which registered
Common stock, par value $0.001 per share	APRE	The Nasdaq Stock Market LLC

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).

Emerging growth company ☒

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☒

Item 8.01Other Events.

On January 4, 2024, Aprea Therapeutics, Inc. issued a press release announcing a corporate update and development plans for 2024 and updated its corporate presentation slide deck. A copy of the press release is filed as Exhibit 99.1 hereto and incorporated herein by reference. A copy of the corporate presentation slide deck is filed as Exhibit 99.2 hereto and incorporated herein by reference.

Item 9.01Financial Statements and Exhibits.

(d) Exhibits.


Exhibit Number		Description
99.1		Press release dated January 4, 2024.
99.2		Corporate Presentation (January 2024)
104		Cover Page Interactive Data File (embedded within the inline XBRL document).

SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.


	Aprea Therapeutics, Inc.

Dated: January 4, 2024	By:	/s/ Oren Gilad
	Name:	Oren Gilad, Ph.D.
	Title:	President and Chief Executive Officer

Exhibit 99.1

Aprea Therapeutics Provides Corporate Update and Announces Development Plans for 2024

DOYLESTOWN, Pa., January 4, 2024 – Aprea Therapeutics, Inc. (Nasdaq: APRE) (“Aprea”, or the “Company”), a clinical-stage biopharmaceutical company focused on precision oncology through synthetic lethality, today provided a corporate update highlighting recent developments and plans for advancement of its pipeline of DNA Damage Response (DDR) anti-cancer agents in 2024.

“Having made substantial progress over the past twelve months, we are well positioned for ongoing success in 2024 as we execute on our mission to be a global leader in synthetic lethality,” said Dr. Oren Gilad, President and CEO of Aprea. “We continue to advance towards achieving our milestones in the ongoing dose-escalation Phase 1 study of our novel macrocyclic ATR inhibitor, ATRN-119, and are finalizing submission of the IND for our next-generation, best-in-class WEE1 inhibitor, APR-1051. This IND is supported by a compelling pre-clinical package showing highly potent and selective anti-tumor activity, limited off-target effects, and favorable pharmacokinetics.”

Update on Phase 1/2a Ongoing Trial of ATR Program, ATRN-119

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.

Investigational New Drug (IND) for WEE1 Program, APR-1051

Aprea completed IND-enabling studies and is finalizing the submission of the IND application with the FDA to begin clinical trials of APR-1051 in the first half of the year. APR-1051 is being developed as a next-generation, potential best-in-class inhibitor of WEE1 kinase with the following properties:

●

APR-1051 has a different molecular structure from all other WEE1 inhibitors currently in development with improved selectivity for the target. The improved properties of APR-1051 relative to the other WEE1 inhibitors include its limited effects on red blood cell counts, hERG inhibition, and body weight loss in pre-clinical studies.

●

The selectivity of APR-1051 may solve a long-standing problem with WEE1 inhibitors. Preclinical studies have shown that APR-1051 is site-specific to WEE1 and does not significantly inhibit the PLK1, PLK2, and PLK3 family of kinases, potentially increasing the cancer-killing effects of WEE1i inhibition and reducing hematological toxicity caused by PLK off-targeting. PLK off-target activity has been a challenge for other WEE1 inhibitors. Recent studies indicate that PLK1 off-targeting partially counters the intracellular effects of WEE1 inhibition and could potentially contribute to the myelosuppression observed with other WEE1 inhibitors.

●

Specific genetic mutations driving patient selection have been identified.

The company expects to receive FDA clearance on the IND during Q1 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.

Company to Participate in 2024 Corporate Access Event

Aprea will be hosting institutional investor and business development meetings at the Annual Corporate Access Event in San Francisco, hosted by our investor relations firm LifeSci Partners. Management will be available for meetings on Wednesday, January 10, 2024. To schedule a meeting, interested parties can register here or send an email to access@lifesciadvisors.com.

About Aprea

Aprea Therapeutics, Inc. is a clinical-stage biopharmaceutical company headquartered in Doylestown, Pennsylvania, focused on precision oncology through synthetic lethality. The Company’s lead program is ATRN-119, a clinical-stage small molecule ATR inhibitor in development for solid tumor indications. Aprea completed all IND enabling studies and is moving towards the submission of an oral, small molecule WEE1 inhibitor, APR-1051. For more information, please visit the company website at www.aprea.com.

The Company may use, and intends to use, its investor relations website at https://ir.aprea.com/ as a means of disclosing material nonpublic information and for complying with its disclosure obligations under Regulation FD.

Forward-Looking Statement

Certain information contained in this press release includes “forward-looking statements”, within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended related to our study analyses, clinical trials, regulatory submissions, and projected cash position. We may, in some cases use terms such as “future,” “predicts,” “believes,” “potential,” “continue,” “anticipates,” “estimates,” “expects,” “plans,” “intends,” “targeting,” “confidence,” “may,” “could,” “might,” “likely,” “will,” “should” or other words that convey uncertainty of the future events or outcomes to identify these forward-looking statements. Our forward-looking statements are based on current beliefs and expectations of our management team and on information currently available to management that involve risks, potential changes in circumstances, assumptions, and uncertainties. All statements contained in this press release other than statements of historical fact are forward-looking statements, including statements regarding our ability to develop, commercialize, and achieve market acceptance of our current and planned products and services, our research and development efforts, including timing considerations and other matters regarding our business strategies, use of capital, results of operations and financial position, and plans and objectives for future operations. Any or all of the forward-looking statements may turn out to be wrong or be affected by inaccurate assumptions we might make or by known or unknown risks and uncertainties. These forward-looking statements are subject to risks and uncertainties including, without limitation, risks related to the success, timing, and cost of our ongoing clinical trials and anticipated clinical trials for our current product candidates, including statements regarding the timing of initiation, pace of enrollment and completion of the trials, futility analyses, presentations at conferences and data reported in an abstract, and receipt of interim or preliminary results (including, without limitation, any preclinical results or data), which are not necessarily indicative of the final results of our ongoing clinical trials, and the other risks, uncertainties, and other factors described under “Risk Factors,” “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and elsewhere in the documents we file with the U.S. Securities and Exchange Commission. For all these reasons, actual results and developments could be materially different from those expressed in or implied by our forward-looking statements. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of the date of this press release. We undertake no obligation to update such forward-looking statements for any reason, except as required by law.

Investor Contact:

Mike Moyer

LifeSci Advisors

mmoyer@lifesciadvisors.com

Exhibit 99.2

Precision Oncology Through Synthetic Lethality January 2024

2 © 2024 Aprea Therapeutics, Inc. All Rights Reserved Forward-Looking Statements Certain information contained in this presentation includes “forward-looking statements”, within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, related to our clinical trials, regulatory submissions and strategic plans. We may, in some cases use terms such as “predicts,” “believes,” “potential,” “continue,” “anticipates,” “estimates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “likely,” “will,” “should” or other words that convey uncertainty of the future events or outcomes to identify these forward-looking statements. The forward-looking statements are based on current beliefs and expectations of our management team that involve risks, potential changes in circumstances, assumptions, and uncertainties. Any or all of the forward-looking statements may turn out to be wrong or be affected by inaccurate assumptions our management team might make or by known or unknown risks and uncertainties. These forward-looking statements are subject to risks and uncertainties including, without limitation, risks related to the success and timing of our clinical trials or other studies and the other risks set forth in our filings with the U.S. Securities and Exchange Commission, including our Annual Reports on Form 10-K and Quarterly Reports on Form 10-Q. Forward-looking statements regarding our product candidates are also subject to additional risks and uncertainties, including without limitation, with respect to: our dependence on additional financing to fund our operations and complete the development and commercialization of our product candidates, and the risks that raising such additional capital may restrict our operations or require us to relinquish rights to our technologies or product candidates; our limited history and preclinical status of the assets we acquired from Atrin Pharmaceuticals Inc.; our business plan or the likelihood of the successful implementation of such business plan; the timing of initiation of planned clinical trials for our product candidates; the future success of such trials; the successful implementation of our research and development programs and collaborations and the interpretation of the results and findings of such programs and collaborations and whether such results are sufficient to support the future success of our product candidates; the success, timing and cost of our anticipated clinical trials for our current product candidates; the timing of initiation, futility analyses, data presentation, reporting and publication and receipt of interim results (including, without limitation, any preclinical results or data); any statements about our understanding of product candidates mechanisms of action and interpretation of preclinical and early clinical results from its clinical development programs and any collaboration studies; and other factors, including legislative, regulatory, political and economic developments not within our control. For all these reasons, actual results and developments could be materially different from those expressed in or implied by our forward-looking statements. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of the date of this presentation. We undertake no obligation to update such forward-looking statements to reflect subsequent events or circumstances, except to the extent required by law or regulation.

3 © 2024 Aprea Therapeutics, Inc. All Rights Reserved Aprea Therapeutics (NASDAQ: APRE) All programs address significant unmet medical need, are synergistic with other anticancer therapies, and potentially differentiated in safety and tolerability ATR - Ataxia telangiectasia and Rad3‐related DDR – DNA Damage Response Precision Oncology via Novel Synthetic Lethality Therapeutics • First macrocyclic ATR inhibitor • Highly selective with continuous daily dosing targeted • Phase 1/2a – Ongoing Dose Escalation • Readout 4Q2024 • Solid tumor with DDR mutation • Pre-clinical proof-of-principle • Anti-tumor activity at nanomolar concentration • Preserved hematologic safety profile • Best in class, next generation • IND Clearance 1Q2024 • Pre-clinical proof-of-principle • Highly potent and selective anti-tumor activity • Limited off target effect • Ovarian cancer with Cyclin E over expression (OVCAR-3) • Stable hematologic function • Favorable pharmacokinetics • Lead optimization • Target identified from our RepliBiom discovery platform ATR Inhibitor: ATRN-119 WEE1 Inhibitor: APR-1051 DDR Inhibitor: Undisclosed

4 © 2024 Aprea Therapeutics, Inc. All Rights Reserved Synthetic Lethality • Cancer cell death only upon the loss of function of two codependent pathways • Single pathway loss of function is inconsequential • DNA Damage Response (DDR) allows cells to pause and self repair during replication (mitosis) • Inhibition of DDR leads to mitotic catastrophe and cell death • ATR and WEE1 inhibitors are integral to stopping DDR and are emerging targets for cancer cell death • Builds on scientific innovation led by Aprea founder and key personnel1 1 Gilad et al, (2010) Cancer Res. Healthy cell Pathway A Pathway B Active cancer cell Pathway A Pathway B Dead cancer cell Pathway A Pathway B Active cancer cell Pathway A Pathway B

5 © 2024 Aprea Therapeutics, Inc. All Rights Reserved Leadership with Strong Drug Development and Commercial Expertise Pioneers in Synthetic Lethality Management Board of Directors Richard Peters, M.D., Ph.D. Chairman of the Board Oren Gilad, Ph.D. President and CEO Jean-Pierre Bizzari, M.D. Director Marc Duey Director Michael Grissinger Director Gabriela Gruia, M.D. Director John Henneman Director Rifat Pamukcu, M.D. Director Bernd R. Seizinger, M.D., Ph.D. Director Oren Gilad, Ph.D. President and CEO John Hamill CFO Nadeem Mirza, M.D., MPH Senior Medical Advisor Ze’ev Weiss, CPA, B.Sc. Chief Business Advisor Mike Carleton, Ph.D. Translational Medicine Advisor Brian Wiley SVP, Corporate Strategy

7 © 2024 Aprea Therapeutics, Inc. All Rights Reserved ATRN-119: First and Only Macrocyclic ATR Inhibitor1 Macrocycles: A Well-Evolved Approach for PIK-Related Kinase Inhibition (e.g., rapamycin and mTOR)2-4 1 Based on company knowledge 2 Brown, EJ et al, (1994) Nature 3 Brown, EJ et al, (1995) Nature 4 Brown, EJ and SL Schreiber, (1996) Cell Benefits of Unique Cyclic Skeleton Structure vs Competitors’ First-Generation Acyclic Structure Macrocycles restrict the number of conformations that can be formed, which can: • Increase potency • Increase selectivity These effects can then promote: • Increased tolerability by decreasing off-targeting • Permit more efficacious dosing

8 © 2024 Aprea Therapeutics, Inc. All Rights Reserved AR-276-01: Aprea Phase 1/2a - Study Overview A Phase 1/2a, Open-Label, Safety, Pharmacokinetic, and Preliminary Efficacy Study of Oral ATRN-119 in Patients with Advanced Solid Tumors Part 1 Up to 18 patients Dose escalation (6 dose levels) 3+3 design Primary objectives: • Safety, MTD, RP2D • Pharmacokinetics Secondary objectives: • Antitumor activity (RECIST/PCWG3) Exploratory objectives: • Association between identified mutations and clinical outcomes Patient Population: Male or female subjects 12 years of age or older with solid tumors harboring specific DDR mutations per NGS Part 2 Up to 30 patients Dose expansion, after MTD / RP2D established Sites: 4 US sites for dose escalation • University of Pennsylvania • Mary Crowley Cancer Research • University Hospitals Cleveland Medical Center • Yale Cancer Center Patient enrollment: 48 patients in total • Escalation phase: up to 18 patients • Expansion phase: up to 30 patients IMP: ATRN-119 is an oral ATR kinase inhibitor given daily

9 © 2024 Aprea Therapeutics, Inc. All Rights Reserved 3+3 dose escalation with once-daily dosing (up to 24* patients) Dose expansion (up to 30 patients) Potential indications Breast Colorectal Ovarian Mutations Undisclosed RepliBiom biomarkers Aprea AR-276-01 Study Status MTD/RP2D *Planned protocol amendment adding cohorts 7 and 8 = cleared Dose level 1 50 mg Dose level 2 100 mg Dose level 3 200 mg Dose level 4 350 mg Dose level 5 550 mg Dose level 6 800 mg Enrollment Completed Dose level 7 1000 mg Dose level 8 1200 mg

10 © 2024 Aprea Therapeutics, Inc. All Rights Reserved Site Key 001 - University of Pennsylvania 002 - Mary Crowley 003 - University Hospitals Cleveland Medical Center 004 - Yale Cancer Center 30 55 112 55 25 45 57 55 118 50 44 28 0 20 40 60 80 100 120 140 001-001 002-002 003-003 003-004 002-005 002-006 003-007 002-008 003-009 003-010 003-011 004-012 350 mg 200 mg 100 mg 50 mg * AR-276-01 Summary of Duration of Treatment Not all data source verified Update – Jan 2, 2023 Study patient Days on treatment * * * * * * * * Stable disease Treatment continues * Progressive Disease ATRN-119 once-daily dose

11 © 2024 Aprea Therapeutics, Inc. All Rights Reserved No ATRN-119 Related Grade 3 or 4 Adverse Events Reported As of January 2, 2023: Six Of Twelve Patients Experienced AEs# Possibly/probably Related to ATRN-119 # No grade 3 or 4 AEs were observed * Resulted in treatment interruption Not all data source verified Related AEs Diarrhea, Grade 1 (001-001*, 003-003) Vomiting, Grade 1 (001-001*) Non-cardiac chest pain, Grade 1 (001-001) Dehydration, Grade 2 (001-001*) Decreased Appetite, Grade 1 (001-001) Hypotension, Grade 2 (001-001*) Nausea, Grade 1 (002-006, 004-012) Fatigue, Grade 1 and Grade 2 (002-005, 002-008) Gastrointestinal General Metabolism Vascular

12 © 2024 Aprea Therapeutics, Inc. All Rights Reserved ATRN-119 2024-2025 Anticipated Clinical Milestones Planned protocol amendment adding cohorts 7 and 8 to monotherapy dose escalation 1Q2024 Milestone Timeline Phase 1/2a – Monotherapy Dose Escalation Complete Dose Escalation 2H 2024 Phase 1/2a – Monotherapy Dose Expansion First Patient Enrolled 4Q 2024

14 © 2024 Aprea Therapeutics, Inc. All Rights Reserved ATR Inhibitor – ATRN-119 Mechanism of Action – Prevent CHK1 Phosphorylation by ATR Kinase pCHK1 – Phosphorylated Checkpoint kinase 1 Data on file No Treatment ATRN-119 Tumor Samples Pharmacodynamics - ɣH2AX (green) -9 -8 -7 -6 -5 0 20 40 60 80 100 120 ATRN-119 / E v ATR/ATRIP(h) Log10 [ATRN-119] (M) Activity (% Control) ATRN-119 binds to ATR …inhibits its biological activity… …and triggers replication fork collapse and double-strand breaks (ɣH2AX) -9 -8 -7 -6 -5 0 20 40 60 80 100 120 ATRN-119 / E v ATR/ATRIP(h) Log10 [ATRN-119] (M) A c t i v i t y ( % C o n t r o l ) NT NT 125 62 32 16 8 4 2 1 Phos-CHK1 Control (GAPDH) nM 0.5 0.25 + Replication stress Replication fork collapse Double strand breaks Cancer cell death ATR Inactive ATRN-119 Active pCHK1 Inactive CHK1 ATR active Cell cycle pause DNA repair Cancer cell survival

15 © 2024 Aprea Therapeutics, Inc. All Rights Reserved ATRN-119 Preclinical Profile Nanomolar potency in vitro across a broad spectrum of cancer cell lines Strong tumor control observed in vivo, including in challenging genetic backgrounds N=4 female mice per group, ATRN-119 - 100 mg/kg/day P.O, ATRN-157 - 20 mg/kg/day SQ. ATRN-157 is an active metabolite identified in dogs receiving ATRN-119 P.O.. In vitro metabolism studies in dog and human hepatocytes and liver microsomes indicated formation of ATRN-157 in both species. Potency and selectivity of ATRN-157 was comparable to ATRN-119. Pre-clinical studies with ATRN-119 and ATRN-157. Tumor Growth Inhibition HCT-116 (KRASG13D, p53 null) Body Weight HCT-116 (KRASG13D, p53 null)

16 © 2024 Aprea Therapeutics, Inc. All Rights Reserved ATRN-119 + Olaparib: Regression of BRCA2-Deficient Ovarian (HGSOC) Tumors N=6-8 mice per group, ATRN-119 - 90 mg/kg P.O BID, Olaparib - 50 mg/kg/day P.O, ATRN-119+Olaparib at the same doses and schedules. Pre-clinical studies with ATRN-119. Data on file ATRN-119 + Olaparib Inhibits Ovarian Tumor Growth Over Time ATRN-119 + Olaparib Shows Negligible Weight Loss Over Time Body Weight Human ovarian PDX Tumor Growth Inhibition Human ovarian PDX

18 © 2024 Aprea Therapeutics, Inc. All Rights Reserved Reported Challenges with Other ATR Inhibitors First Generation Compounds Share Similar Core, Backbone, Toxicity, and Intermittent Dosing Schedule Note: Head-to-head studies with ATRN-119 have not been conducted 1 Phase I study of ATR inhibitor, AZD6738, as monotherapy in advanced solid tumors (PATRIOT part A, B), Dillon et al, Volume 30, October 2019, Pages v165-v166 2 Poster CT084: A Phase I dose-escalation study of ATR inhibitor monotherapy with AZD6738 in advanced solid tumors (PATRIOT Part A), AACR 2017 3 First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors, Yap et al, Cancer Discov 2021;11:80-91 and 2019 ASCO Poster, De-Bono et al. 4 Repare announced a worldwide license and collaboration agreement with Roche on June 1, 2022 5 Preliminary Phase 1 Data From Ongoing First-in-Human Phase 1/2 TRESR Study of RP-3500, AACR 2022 Parameter Route of Administration Oral Oral Oral MTD/RP2 Dose Schedule 160mg BID, 2-weeks-on, 2-weeks-off, or: Continuous dosing1 40mg BID, 3-days-on/4-days-off 160mg QD, 3-days-on/4-days-off Main Grade ≥3 Hematological toxicities Patriot 1, Escalation Phase, 160mg, BID2 : Anemia (1/6, 17%) Patriot 2, Expansion Phase1 : Fatigue, anemia, nausea, and thrombocytopenia (not differentiated) (4/6, 67%) with continuous dosing (3/15, 20%) with 2-week-on, 2-week-off Anemia (2/2, 100%) Neutropenia (1/2, 50%) Anemia (23/95, 24%) Neutrophil count decreased (10/95, 11%) Platelet count decreased (5/95, 5%) AstraZeneca AZD67381,2 Bayer BAY18953443 Repare / Roche4 RP-35005 N N NH N N N N O N N N O S O HN CH3 N NH N N O N N HO O N NH

19 © 2024 Aprea Therapeutics, Inc. All Rights Reserved Tumor reduction and regrowth Continuous tumor reduction Drug “On” Drug “Off” Drug “On” ATRN-119 Daily Dosing Means Continuous Tumor Reduction Intermittent Dosing May Lead to Tumor Resistance

20 © 2024 Aprea Therapeutics, Inc. All Rights Reserved Daily Dosing Is Clinically Superior Based on Other ATRi in Development Artios ATR Inhibitor: ART0380 Initial Results From Phase 1 Dose Escalation1 1ART0380-ESMO-Poster-2023 Efficacy Among Measurable Patients • Continuous – ORR 29% (2/7). One of two responders treated at twice the RP2D. • Intermittent – ORR 8% (2/26). One of two responders treated at twice the RP2D. Dose Escalation Phase • 49 patients • Continuous dosing: QD; Range 200-400mg, (n=10) • Intermittent dosing: 3D on/4D off; Range 100 - 1,200mg, (n=39) RP2D • Continuous = 200mg • Intermittent dosing = 600mg Safety • 36% Anemia Grade 3 at doses considered tolerable

21 © 2024 Aprea Therapeutics, Inc. All Rights Reserved ATRN-119: Potential Best-in-Class Oral ATR Inhibitor with Structurally Differentiated Core, Backbone, and Toxicity Profile Note: ATRN-119 has not yet been tested clinically 1 ATRN-119, Phase 1/2a Clinical Study Protocol 2 Internal pre-clinical head-to-head tolerability study in male beagle dogs. Parameter Route Of Administration Oral Clinical Studies Chosen (MTD/RP2D), Dose Schedule Continuous daily dosing (RP2D TBD in Phase 1)1 Hematological toxicities in preclinical studies Pre-Clinical, Toxicology Studies: • In 28-day GLP tox study in dogs, hematological changes were of small magnitude and within normal ranges • In a head-to-head comparative tolerability study, ATRN-119 demonstrated significantly less toxicity than another oral ATRi that is currently in clinical development2 ATRN-119 potential for reduced toxicity could make it a preferred ATR inhibitor as a single agent, as well as a candidate for combination with standard-of-care therapies. ATRN-119 (1)

23 © 2024 Aprea Therapeutics, Inc. All Rights Reserved WEE1 Inhibitor – APR-1051 Mechanism of Action – Prevent CDK1 Phosphorylation by WEE1 Kinase pCDK1- Phosphorylated Cyclin Dependent Kinase 1 Data on file -10 -9 -8 -7 -6 0 20 40 60 80 100 120 ATRN-1051 Log10 [ATRN1051] (M) Activity (% Displacement) -5 -4 -3 -2 -1 0 1 2 3 4 5 0 1 2 3 4 5 6 Cumulative Cell Doublings Days Post Initial Treatment NT 125nm 250nm 500nm APR-1051 binds to WEE1 …inhibits its biological activity… …and triggers mitotic catastrophe and cancer cell death Mitotic catastrophe Cancer cell death WEE1 inactive APR-1051 Active pCDK1 Inactive CDK1 Mitotic cycle pause DNA repair WEE1 Cancer cell survival active Phos-CDK1 Control (Tubulin) µM APR-1051

24 © 2024 Aprea Therapeutics, Inc. All Rights Reserved Pre-clinical studies with APR-1051 Data on file Tumor Growth Inhibition OVCAR-3 N=7 mice per group, APR-1051, exploratory formulation - 30 mg/kg/day APR-1051 Demonstrated Potentially Compelling Anti-tumor Activity IND Clearance 1Q2024 Vehicle APR-1051

26 © 2024 Aprea Therapeutics, Inc. All Rights Reserved AstraZeneca Adavosertib (AZD-1775)1,2 Zentalis Azenosetrib (ZN-c3)1 Aprea APR-1051 On-Target IC50 (nM) WEE1 3.8 3.8 2.2 Off-Target Inhibition at 1 µM (%) PLK1 70 79 17 PLK2 101 96 33 PLK3 91 92 12 APR-1051 Potentially Differentiated from Other WEE1 Inhibitors APR-1051 Potent and Structurally Differentiated, with High Selectivity to Limit Off-target Toxicity Note: Head-to-head studies have not been conducted 1 Huang et al, (2021) J Med Chem 2AstraZeneca announced in July 2022 the discontinuation of development of AZD-1775 26 AACR-NCI-EORTC Meeting, Poster C147, 2023 Undisclosed

27 © 2024 Aprea Therapeutics, Inc. All Rights Reserved PLK1 Inhibition Reduces Cytotoxic Effects of WEE1 Inhibitors Minimal PLK1 Co-inhibition Enables Full Therapeutic Potential APR-1051 AACR-NCI-EORTC Meeting, Poster C147, 2023 0 nM 37 nM 111 nM 333 nM APR-1051 1 µM 37 nM 111 nM 333 nM 1 µM Phos-H2AX Control (MCM3) NT 75 nM GSK-461364 Phos-CDK1 Control (MCM3) 37 nM 111 nM 333 nM 1 µM 37 nM 111 nM 333 nM NT 1 µM 400 nM BI-2536 APR-1051 Phos-H2AX Phos-CDK1 Dose range of PLK inhibitor GSK-461364 in combination with a single dose of APR-1051 in OVCAR-3 cells PLK inhibitor, GSK-461364 interferes with the effects of APR-1051 in OVCAR-3 cells PLK inhibitor, BI-2536, interferes with the effects of APR-1051 in OVCAR-3 cells

28 © 2024 Aprea Therapeutics, Inc. All Rights Reserved APR-1051 Preclinical Data Highlight Potentially Favorable PK Properties Note: Head-to-head studies have not been conducted 1 Data from an exploratory formulation of APR-1051 administered to fasted Balb/c mice 2 Data from study in A-427 NSCLC xenograft model as reported in Zentalis Corporate Overview, March 2022 Based on Pre-clinical Studies, APR-1051 Shows Potentially Favorable Drug Exposure AACR-NCI-EORTC Meeting, Poster C147, 2023 APR-10511 Zentalis Azenosertib (ZN-c3)2 AstraZeneca Adavosertib (AZD-1775)2 Dose (mg/kg/d) 10 20 40 80 20 40 80 Cmax ng/ml 1,460 1,167 1,997 5,100 635 2,460 4,703 Tmax hr 3 1 1 1 1 1 1 AUC0-24, ng*hr/ml 16,739 4,863 17,088 39,722 1,494 6,313 13,408

29 © 2024 Aprea Therapeutics, Inc. All Rights Reserved APR-1051 Shows Negligible Inhibition of hERG Channels AACR-NCI-EORTC Meeting, Poster C147, 2023 In vitro kinase assays IC50 Average WEE1 kinase IC50 hERG inhibition IC50 Average hERG IC50 Fold difference between kinase IC50 and hERG IC50 LanthaScreen (Thermo) Hotspot (Reaction Biology) HEK293 cells (Medicilon) CHO cells (WuXi) hERG inhibition over WEE1 kinase inhibition 2.2 nM 41.4 nM 21.8 nM 8,840 nM 660 nM 4,750 nM 218-fold (range 16- to 3,946-fold) QT prolongation AEs were reported with some competitor WEE1 inhibitors

30 © 2024 Aprea Therapeutics, Inc. All Rights Reserved APR-1051 Suppresses Tumor Growth While Causing Little Effect on RBCs and Body Weight Vehicle ATRN-1051, 15mg/kg PO, BID, 5 on/ 2 of 0 5 10 15 RBC (10 12 /L) Vehicle ATRN-1051, 15mg/kg PO, BID, 5 on/ 2 of 0 200 400 600 800 Retiuclocyte Count (10 9 /L) AACR-NCI-EORTC Meeting, Poster C147, 2023 Tumor Volume (mm3 ) (Mean±SEM) Body Weight (g) (Mean±SEM) APR-1051 15mg/kg, PO, BID, 5 on/2 off x 28 days Vehicle 10mL/kg, PO, QD x 28 days OVCAR Xenograft Tumor Model in Female Nude Mice Heme Toxicity (Mean±SEM) Days Post Treatment 28 Days Post Treatment Days Post Treatment

31 © 2024 Aprea Therapeutics, Inc. All Rights Reserved APR-1051 2024-2025 Anticipated Preclinical and Clinical Milestones Milestone Timeline IND Clearance 1Q 2024 Phase 1/2a – Monotherapy Dose Escalation First Patient Enrolled (subject to funding) 1H 2024

32 © 2024 Aprea Therapeutics, Inc. All Rights Reserved Strong Intellectual Property Portfolio Family 1: Ataxia Telengiectasia and Rad3-Related (ATR) Protein Kinase Inhibitors • Macrocyclic inhibitors of ATR & methods of using them to treat various cancers, filed on Oct. 13th, 2015 • Patents granted in AU, CA, CN, EP, IL, JP, MX, HK. National phase examinations ongoing in BR, IN, KR • 1.1: Issued on May 30, 2017 as U.S. Patent 9,663,535 • 1.2: Issued on May 29, 2018 as U.S. Patent 9,981,989 • 1.3: Issued on Feb. 5, 2019 as U.S. Patent 10,196,405 Family 2: ATR Inhibitors and Methods of Use • Carboxylic acid-containing macrocyclic ATR inhibitors, and prodrugs; methods of using these inhibitors to treat various cancers; filed on Apr. 12th, 2017 • Issued on May 28th, 2019 as U.S. Patent 10,301,324 Family 3: ATR Inhibitor Pharmaceutical Composition and Methods • International application filed on Apr. 14th, 2023 • Pharmaceutical formulation and composition of our lead molecule in the clinic Family 4: WEE1 Inhibitor Pharmaceutical Compositions and Methods • International Application filed on Jun. 3rd, 2022 • Composition of our lead WEE1 inhibitor compounds Family 5: Methods of Treating Cancer • U.S. Provisional Application filed on Oct. 20th, 2023 • Clinical methods of treating advanced solid cancer tumors using lead molecule Four issued US patents protecting lead molecule and analogs

33 © 2024 Aprea Therapeutics, Inc. All Rights Reserved Aprea Therapeutics (NASDAQ: APRE) Financial Summary & Capitalization Cash & Equivalents of $25.4M as of September 30, 2023 Closed $4.9M (net) public offering in February 2023 Obtained $2.0M non-dilutive funding via research grant from National Cancer Institute (NCI) Securities Common Equivalents as of Nov. 9, 2023 Preferred Stock (as converted) 28,112 Common Stock 3,736,673 Options 586,466 Restricted Stock Units 23,870 Fully Diluted Equivalents 4,375,121

34 © 2024 Aprea Therapeutics, Inc. All Rights Reserved Financed through end of 2024 • Reach short term inflection points and catalysts • Evaluate optimal strategic partnerships Near term catalysts • Phase 1/2a dose escalation ATRN-119 readout 4Q 2024 • IND clearance APR-1051 1Q2024 Diversified portfolio with best in class, de-risked clinical and preclinical programs • Highly potent and selective ATR and WEE1 inhibitors • Opportunities in ovarian, colorectal, prostate, and breast cancers • Single agent and combination therapies Technology developed by pioneers in synthetic lethality • Management with strong drug development and commercial expertise Investment Highlights

Document and Entity Information	Jan. 04, 2024
Document and Entity Information [Abstract]
Document Type	8-K
Document Period End Date	Jan. 04, 2024
Entity Registrant Name	Aprea Therapeutics, Inc.
Entity Incorporation, State or Country Code	DE
Entity File Number	001-39069
Entity Tax Identification Number	84-2246769
Entity Address, Address Line One	3805 Old Easton Road
Entity Address, City or Town	Doylestown
Entity Address State Or Province	PA
Entity Address, Postal Zip Code	18902
City Area Code	617
Local Phone Number	463-9385
Written Communications	false
Soliciting Material	false
Pre-commencement Tender Offer	false
Pre-commencement Issuer Tender Offer	false
Title of 12(b) Security	Common stock, par value $0.001 per share
Trading Symbol	APRE
Security Exchange Name	NASDAQ
Entity Emerging Growth Company	true
Entity Ex Transition Period	true
Entity Central Index Key	0001781983
Amendment Flag	false