Debio 0123 / Almac Discovery, Debiopharm - LARVOL DELTA

WIN-B: Clinical Study to Evaluate Debio0123 + Sacituzumab Govitecan Combination in TNBC or HR+/HER2- Advanced Breast Cancer (clinicaltrials.gov) - P1/2 | N=76 | Active, not recruiting | Sponsor: MedSIR | Recruiting ➔ Active, not recruiting

Enrollment closed • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Debio 0123-101: Study of Oral Debio 0123 in Combination With Carboplatin in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=76 | Terminated | Sponsor: Debiopharm International SA | Trial completion date: Nov 2027 ➔ Oct 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: Nov 2027 ➔ Oct 2025; This trial was concluded for strategic reasons.

Trial completion date • Trial primary completion date • Trial termination • Solid Tumor

Debio 0123-SCLC-104: Debio 0123 in Combination With Carboplatin and Etoposide in Adult Participants With Small Cell Lung Cancer That Recurred or Progressed After Previous Standard Platinum-Based Therapy (clinicaltrials.gov) - P1 | N=34 | Active, not recruiting | Sponsor: Debiopharm International SA | Trial completion date: Jul 2026 ➔ Feb 2026

Trial completion date • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Debio 0123 in Combination With Carboplatin and Etoposide in Adult Participants With Small Cell Lung Cancer That Recurred or Progressed After Previous Standard Platinum-Based Therapy (clinicaltrials.gov) - P1 | N=34 | Active, not recruiting | Sponsor: Debiopharm International SA | Recruiting ➔ Active, not recruiting | N=78 ➔ 34

Enrollment change • Enrollment closed • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

A Study to Evaluate Safety and Preliminary Anti-tumor Activity of Debio 0123 as Monotherapy in Adult Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=155 | Active, not recruiting | Sponsor: Debiopharm International SA | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Oncology • Solid Tumor

ACR-2316 is a novel, differentiated, clinical-stage WEE1/PKMYT1 inhibitor designed by Acrivon's Generative Phosphoproteomics AP3 Platform for optimal pro-apoptotic pathway effects in tumor cells resulting in superior preclinical activity (AACR-NCI-EORTC 2025) - "In cellular TE assays, ACR-2316 displayed more potent WEE1 TE than all benchmark WEE1 inhibitors (azenosertib, adavosertib, Debio0123), while simultaneously targeting MYT1... WEE1 inhibitor-induced MYT1 activation constitutes a resistance mechanism that may limit the clinical efficacy of WEE1 inhibition. ACR-2316 is a potent, selective WEE1/MYT1 inhibitor that displays superior preclinical efficacy via its differentiated profile optimized by AP3 pathway-based structure-activity relationships in the intact cell. Acrivon's ongoing Phase 1 ACR-2316 monotherapy trial in solid tumors has already demonstrated clinical activity during dose escalation prior to reaching Recommended Phase 2 Dose."

Preclinical • Tumor cell • Oncology • Solid Tumor • BRAF • CDK1 • CDK2 • PKMYT1 • PLK1

Global pharmacodynamic effects uncovered with AP3 phosphoproteomic profiling of novel WEE1/PKMYT1 inhibitor ACR-2316 reveals the critical importance of PLK1 for ACR-2316's superior preclinical activity and differentiated mechanism of action (AACR-NCI-EORTC 2025) - "The clinical WEE1 inhibitors azenosertib and Debio0123, and the PKMYT1 inhibitor lunresertib were administered in parallel at maximum tolerated/formulable doses... ACR-2316 is a potential first- and best-in-class dual inhibitor of WEE1 and PKMYT1, rationally designed using Acrivon's proprietary AP3 platform to deliver superior single-agent efficacy. Potent activation of PLK1, together with CDK1/2, is essential for the superior activity of ACR-2316. ACR-2316 has shown clinical activity in its ongoing Phase 1b monotherapy trial in solid tumors during dose escalation."

PK/PD data • Preclinical • Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • CDK1 • PKMYT1 • PLK1 • RRM2 • WEE1

Debio 0123 in Combination With Carboplatin and Etoposide in Adult Participants With Small Cell Lung Cancer That Recurred or Progressed After Previous Standard Platinum-Based Therapy (clinicaltrials.gov) - P1 | N=78 | Recruiting | Sponsor: Debiopharm International SA | Trial completion date: Apr 2026 ➔ Jul 2026

Trial completion date • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

In silico evaluation of the interaction of P-gp and 3A4 substrates with the WEE1 inhibitor Debio 0123 and clinical application in the Debio 0123-104 combination trial with carboplatin and etoposide. (ASCO 2025) - P1 | " No clinically significant DDIs were predicted between Debio 0123 given for 3 consecutive days and the CYP3A4 probe substrate, midazolam...A weak DDI was predicted towards the P-gp probe substrate dabigatran etexilate... Overall, these results indicate that there is no relevant PK interaction between Debio 0123 and IV etoposide. For concomitant medications that are P-gp substrates, only a weak DDI is expected with Debio 0123. Furthermore, the absence of significant DDIs predicted with CYP3A4 substrates suggests that Debio 0123 can be combined with a wide range of therapies."

Clinical • Lung Cancer • Oncology • Solid Tumor • CYP3A4

Phase IB/II study to evaluate safety and preliminary efficacy of the WEE1 inhibitor Debio 0123 in combination with sacituzumab govitecan (SG) in triple-negative or hormone receptor–positive (HR+)/HER2-negative (HER2–) advanced breast cancer (ABC): The WIN-B study. (ASCO 2025) - P1/2 | "The primary analyses will estimate ORR (H0: ORR≤29% for TNBC and ORR≤19% for HR+/HER2- tumors vs H1: ORR≥55% for TNBC and ORR≥41% for HR+/HER2- tumors). The phase 2 part of the study will be deemed positive if at least 12 (46.2%) and nine (34.6%) pts with TNBC and HR+/HER2- tumors, respectively, achieve an objective response."

Clinical • Combination therapy • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDK1 • HER-2

Debio 0123, a highly selective WEE1 inhibitor in adult patients with advanced solid tumors: A phase 1 dose escalation and expansion monotherapy study. (ASCO 2025) - P1 | "Secondary endpoints include duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Enrolment is ongoing in Spain, Switzerland and US."

Clinical • Metastases • Monotherapy • P1 data • Endometrial Serous Adenocarcinoma • Epithelial Ovarian Cancer • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • Uterine Cancer • CCNE1

Debio 0123, a highly selective WEE1 inhibitor, in combination with carboplatin (C) and etoposide (E), in patients (pts) with recurrent small cell lung cancer (SCLC): Determination of recommended dose (RD) from a phase 1 escalation. (ASCO 2025) - P1 | "Debio 0123 combined with C + E is well tolerated, with a manageable safety profile, up to 200 mg; this combination led to promising antitumor activity in pts with recurrent SCLC after prior platinum-based therapy with CFI > 45 days. Further investigation of Debio 0123 at 200 mg in pts with a CFI > 90 days is ongoing. Summary of treatment-emergent adverse events (TEAEs) related to Debio 0123 in ≥ 2 pts at the RD (200 mg)."

Clinical • Combination therapy • P1 data • Tumor mutational burden • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • TMB

Debio 0123-101: Study of Oral Debio 0123 in Combination With Carboplatin in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=76 | Active, not recruiting | Sponsor: Debiopharm International SA | N=115 ➔ 76

Enrollment change • Solid Tumor

Debiopharm Ignites Oncology Innovation With Clinical and Translational Data on Debio 0123 at the 2025 ASCO Annual Meeting in Chicago (Businesswire) - "The contributions feature three clinical poster presentations and one translational research abstract publication, highlighting Debio 0123’s potential across solid tumors. Among them is new data from the Debio 0123-SCLC-104 trial in small-cell lung cancer, offering insights into the candidate’s therapeutic potential in this difficult-to-treat disease. A Trial in Progress (TiP) poster from the investigator-initiated MedSir study-co-authored by Debiopharm-will present the design and methodology of the study investigating the combination of Debio 0123 with Trodelvy in breast cancer patients. In parallel, a separate TiP poster for the Debio 0123-102 monotherapy study will outline the framework and objectives of the ongoing dose expansion phase."

Clinical protocol • P1 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Small Cell Lung Cancer • Triple Negative Breast Cancer

The WEE1 inhibitor Debio 0123 is synergistic with the PKMYT1 inhibitor lunresertib in preclinical models of ovarian and breast cancer (AACR 2025) - "Lunresertib (RP6306) is a selective and potent PKMYT1 inhibitor currently in phase 1 clinical studies as a monotherapy or in combination. These results demonstrate, in preclinical models of ovarian and breast cancer, the WEE1 inhibitor, Debio 0123, is synergistic with the PKMYT1 inhibitor, lunresertib, and consistently leads to deep and sustained regressions in vivo."

Preclinical • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • PKMYT1

Biology-driven, machine learning-based development of a biomarker to predict response to WEE1 inhibitor Debio 0123 (AACR 2025) - "This biology-driven, machine learning-based classifier predicts response to Debio 0123 in patient derived organoid and xenograft models at an accuracy significantly greater than that of a dummy model and serves as a basis for further optimization and retrospective analyses of Debio 0123 clinical studies."

Biomarker • Machine learning • Oncology • TP53

Genialis Highlights Power of Its Supermodel to Predict and Explain Therapeutic Response at AACR 2025 (Businesswire) - "In poster presentations at the American Association for Cancer Research (AACR) Annual Meeting 2025, Genialis showed its AI foundation model of cancer—the Genialis™ Supermodel—can predict how a patient will respond to a specific therapy (Abstract 3313 / 16). The Supermodel can also help explain how drugs work in the body and how the tumor learns to resist treatment, as well as propose potential new drug combinations to improve outcomes. The AACR presentations share these insights from Genialis’ own work with KRAS G12C NSCLC patient data and its collaboration with Debiopharm on the Debio 0123 WEE1 inhibitor in various cancer types. (Abstract 3659 / 21)."

Biomarker • Clinical data • Non Small Cell Lung Cancer

Debiopharm to Reveal Insights From Their ADC, DDR Inhibitor, and Antibody Conjugation Technology Research at the 2025 AACR Conference in Chicago (Businesswire) - "Comprehensive preclinical results will be presented for Debio 1562M, a next-generation Antibody-Drug Conjugate (ADC) targeting the cell surface glycoprotein CD37 soon to undergo first-in-human evaluation. Two preclinical data releases will be included in the poster display sessions for Debio 0123, a selective WEE1 kinase inhibitor disrupting the DNA-damage response (DDR) of cancer cells. The first data release shows how Debio 0123 can be used in combination with the PKMYT1 inhibitor lunresertib as a promising therapeutic strategy in ovarian and breast cancer....The company also announces joint poster presentation with new partner on the use of its AbYlink technology in preclinical setting."

Preclinical • Acute Myelogenous Leukemia • Breast Cancer • Myelodysplastic Syndrome • Ovarian Cancer

MEDSIR & Debiopharm Announce the First Patient Dosed in the WIN-B Trial Exploring the Combination of Debio 0123 & Gilead’s Trodelvy in Advanced Breast Cancer (Businesswire) - "Debiopharm...and MEDSIR...announced that the first patient has been dosed in the WIN-B clinical trial evaluating the safety and efficacy of Debio 0123 plus Trodelvy in people with hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) and triple-negative advanced or metastatic breast cancers. The WIN-B trial is sponsored by MEDSIR and fully funded by Debiopharm."

Trial status • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Triple Negative Breast Cancer

Debio 0123-101: Study of Oral Debio 0123 in Combination With Carboplatin in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=115 | Active, not recruiting | Sponsor: Debiopharm International SA | Recruiting ➔ Active, not recruiting

Enrollment closed • Oncology • Solid Tumor

WIN-B: Clinical Study to Evaluate Debio0123 + Sacituzumab Govitecan Combination in TNBC or HR+/HER2- Advanced Breast Cancer (clinicaltrials.gov) - P1/2 | N=76 | Recruiting | Sponsor: MedSIR | Not yet recruiting ➔ Recruiting

Enrollment open • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

Genialis Advances Biomarker Discovery to Reduce Risk in Cancer Drug Development Targeting DNA Damage Response Pathways (Businesswire) - "Genialis...today announced an extension of its collaboration with Debiopharm, a Swiss-based global biopharmaceutical company, to develop a predictive biomarker for WEE1-targeted therapy. This extension builds on a 2024 agreement to define and discover biomarkers within the DNA damage response (DDR) biological space to predict the clinical benefit of one or more drugs in Debiopharm’s pipeline. Debiopharm’s WEE1 asset is currently in Phase 1 clinical research and is being studied in monotherapy and in combination in collaboration with international partners....Genialis will be attending the 8th Annual DDR Inhibitors Summit in Boston, January 28-30, 2025, and presenting an abstract with Debiopharm at the American Association for Cancer Research (AACR) Annual Meeting 2025 meeting in April."

Licensing / partnership • Solid Tumor

Recent Pipeline Progress & Upcoming Milestones of Prioritized Clinical Programs (Businesswire) - "(i) RP-3467: Potential best-in-class Polθ ATPase inhibitor...Upcoming Expected Milestones: Q3 2025: Topline safety, tolerability and early efficacy data from the POLAR trial in monotherapy and in combination with olaparib.... (ii) Lunresertib and Camonsertib...Upcoming Expected Milestone: Q2 2025: Enrollment completion of MYTHIC trial evaluating lunresertib in combination with Debio 0123 (WEE1 inhibitor)."

Enrollment status • P1 data • Solid Tumor

Debio 0123-101: Study of Oral Debio 0123 in Combination With Carboplatin in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=115 | Recruiting | Sponsor: Debiopharm International SA | Trial completion date: Apr 2027 ➔ Nov 2027 | Trial primary completion date: Jun 2025 ➔ Nov 2027

Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Rational design of a superior single agent active, potential best-in-class WEE1/PKMYT1 inhibitor using Acrivon Predictive Precision Proteomics (AP3) (EORTC-NCI-AACR 2024) - "WEE1 inhibitors azenosertib and Debio0123, or the PKMYT1 inhibitor lunresertib, had a best response of stable disease at maximum achievable dose... ACR-2316 is a potent, selective dual inhibitor of WEE1 and PKMYT1, uniquely designed using Acrivon's AP3 platform for superior single agent activity through potent activation of CDK1, CDK2, and PLK1, and is on track for IND submission in Q3 2024 and first-in-human dosing in Q4 2024."

Oncology • Ovarian Cancer • Solid Tumor • CASP3 • CDK1 • CDK2 • PKMYT1 • PLK1