ZEN-3694 / Zenith Epigenetics, Newsoara Biopharma - LARVOL DELTA

CRISPR druggable-genome screen identifies BRD4 as a synergistic vulnerability with the natural product cerberin in pancreatic cancer organoids (AACR 2026) - "Adopting a CRISPR/Cas9 druggable screen in 3D PDAC PDO models, we provide proof-of-concept for synergy between cardiac glycosides and BRD4/BET inhibitors. This work links a PDO-based CRISPR platform with natural-product pharmacology to provide a framework for mechanistic partners to advance the use of cardiac glycosides for clinical translation."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ANXA2 • BRD4 • ENPP2 • FDX1 • KRAS • NR1I2 • PIK3R1

Activity of dual BET and CDK9 inhibition in murine models of pancreatic ductal adenocarcinoma (AACR 2026) - "Across two independent PDAC PDX models, ZEN3694 and VIP152 yield tumor growth inhibition. All treatments were well tolerated in two independent PDAC models, PDX1and PDX2. Ongoing studies are analyzing early timepoints for a putative mechanism involving transient disruption in the activation of RNA polymerase II."

Preclinical • Oncology • Pancreatic Ductal Adenocarcinoma • CDKN2A • CDKN2B • KRAS • MTAP • PDX1 • SMAD4

A Study of ZEN003694 in People With Squamous Cell Lung Cancer (clinicaltrials.gov) - P2 | N=13 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2026 ➔ Nov 2027 | Trial primary completion date: Nov 2026 ➔ Nov 2027

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NSD3

Testing the Combination of ZEN003694 and Nivolumab With or Without Ipilimumab in Solid Tumors (clinicaltrials.gov) - P1 | N=66 | Suspended | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jan 2026 ➔ Sep 2028 | Recruiting ➔ Suspended | Trial primary completion date: Jan 2026 ➔ Sep 2028

IO biomarker • Platinum resistant • Trial completion date • Trial primary completion date • Trial suspension • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • PD-L1

A phase 1 study of the BET inhibitor ZEN003694 in combination with the MEK1/2 inhibitor binimetinib in solid tumors with RAS pathway alterations and triple-negative breast cancer (NCI number 10449). (ASCO 2024) - "Prior therapy with BET, RAF, MEK, or ERK inhibitor is not permitted. This study is currently ongoing in dose escalation."

Combination therapy • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRAF • ER • HER-2 • HRAS • KRAS • NF1 • NRAS • PGR

A phase 1b/2 study of the BET inhibitor ZEN-3694 in combination with talazoparib for treatment of patients with TNBC without gBRCA1/2 mutations. (ASCO 2022) - P2 | "Combination of ZEN-3694 and talazoparib demonstrated anti-cancer activity in pretreated mTNBC WT gBRCA1/2 patients. All confirmed responses were observed in TNBC at diagnosis patients, whose tumors are expected to be more sensitive to the combination due to their basal-like properties. The trial is being expanded to Ph."

Clinical • Combination therapy • P1/2 data • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • Thrombocytopenia • Triple Negative Breast Cancer • BRCA1 • BRCA2 • HER-2 • HRD

Testing the Safety and Efficacy of the Addition of a New Anti-cancer Drug, ZEN003694, to Chemotherapy Treatment (Cisplatin and Etoposide or Carboplatin and Paclitaxel) for Adult and Pediatric Patients (12-17 Years) With NUT Carcinoma (clinicaltrials.gov) - P1/2 | N=36 | Recruiting | Sponsor: National Cancer Institute (NCI) | Phase classification: P1 ➔ P1/2

Phase classification • NUT Midline Carcinoma • Oncology • Pediatrics • BRD4 • NUTM1

Testing A New Anti-cancer Drug Combination, Entinostat and ZEN003694, for Advanced and Refractory Solid Tumors (clinicaltrials.gov) - P1/2 | N=49 | Recruiting | Sponsor: National Cancer Institute (NCI) | N=30 ➔ 49

Enrollment change • Oncology • Pancreatic Cancer • Solid Tumor

Testing the Safety and Efficacy of the Addition of a New Anti-cancer Drug, ZEN003694, to Chemotherapy Treatment (Cisplatin and Etoposide or Carboplatin and Paclitaxel) for Adult and Pediatric Patients (12-17 Years) With NUT Carcinoma (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: National Cancer Institute (NCI) | Phase classification: P1/2 ➔ P1 | N=55 ➔ 36

Enrollment change • Phase classification • NUT Midline Carcinoma • Oncology • Pediatrics • BRD4 • NUTM1

Testing the Addition of Anti-Cancer Drug, ZEN003694 (ZEN-3694) and PD-1 Inhibitor (Pembrolizumab), to Standard Chemotherapy (Nab-Paclitaxel) Treatment in Patients With Advanced Triple-Negative Breast Cancer (clinicaltrials.gov) - P1 | N=57 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2025 ➔ Mar 2027 | Trial primary completion date: Dec 2025 ➔ Mar 2027

Trial completion date • Trial primary completion date • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PD-L1 • PGR

A Study of ZEN003694 in People With Squamous Cell Lung Cancer (clinicaltrials.gov) - P2 | N=13 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial primary completion date: Nov 2025 ➔ Nov 2026 | N=25 ➔ 13 | Trial completion date: Nov 2025 ➔ Nov 2026

Enrollment change • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NSD3

Zenith Epigenetics Ltd. (“Zenith” or the “Company”) is pleased to announce that the U.S. Food and Drug Administration (“FDA”) has granted Orphan Drug designation to ZEN-3694 for treatment of NUT carcinoma (Zenith Epigenetics Press Release) - "ZEN-3694, is currently being evaluated in two (2) active NUT carcinoma clinical trials in combination with abemaciclib (ClinicalTrials.gov ID: NCT05372640) and cisplatin & etoposide (ClinicalTrials.gov ID: NCT05019716)."

Orphan drug • NUT Midline Carcinoma

BET bromodomain inhibition reverses CDK4/6 inhibitor resistance in estrogen receptor-positive breast cancer via induction of miR-34a-5p. (PubMed, Clin Cancer Res) - "Our findings highlight BET inhibition or application of miR-34a-5p mimics as promising strategies to reverse CDK4/6 inhibitor resistance in a subset of ER+ breast cancers."

IO biomarker • Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • BCL2 • BRD4 • CCND1 • ER • MIR34A

The COSMYC Trial (COmbined Suppression of MYC) (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting ➔ Recruiting

Enrollment open • Castration-Resistant Prostate Cancer • CNS Disorders • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

NCI-2022-04099: Testing the Safety and Efficacy of the Combination of Two Anti-cancer Drugs, ZEN003694 and Abemaciclib, for Adult and Pediatric Patients (12-17 Years) With Metastatic or Unresectable NUT Carcinoma, Breast Cancer and Other Solid Tumors (clinicaltrials.gov) - P1 | N=45 | Recruiting | Sponsor: National Cancer Institute (NCI) | N=30 ➔ 45

Enrollment change • Breast Cancer • NUT Midline Carcinoma • Oncology • Pediatrics • Solid Tumor • NUTM1

ZEN-3694, Enzalutamide, and Pembrolizumab for the Treatment of Metastatic Castration-Resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=61 | Active, not recruiting | Sponsor: Rahul Aggarwal | Recruiting ➔ Active, not recruiting

Enrollment closed • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • PD-L1 • RB1

Testing the Safety and Efficacy of the Addition of A New Anti-cancer Drug, ZEN003694, to Chemotherapy Treatment (Etoposide and Cisplatin) for Adult and Pediatric Patients (12-17 Years) With NUT Carcinoma (clinicaltrials.gov) - P1/2 | N=55 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2025 ➔ Jun 2026 | Trial primary completion date: Dec 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • NUT Midline Carcinoma • Oncology • Pediatrics • BRD4 • NUTM1

NCI-2022-04099: Testing the Safety and Efficacy of the Combination of Two Anti-cancer Drugs, ZEN003694 and Abemaciclib, for Adult and Pediatric Patients (12-17 Years) With Metastatic or Unresectable NUT Carcinoma, Breast Cancer and Other Solid Tumors (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Breast Cancer • Hormone Receptor Positive Breast Cancer • NUT Midline Carcinoma • Oncology • Pediatrics • Solid Tumor • NUTM1

FDA grants Zenith's ZEN-3694 Fast Track Status (Newsfile) - "Zenith Epigenetics Ltd...is pleased to announce the designation of ZEN-3694 as a Fast Track product by the U.S. Food and Drug Administration ('FDA'). FDA officials concluded that ZEN-3694, in combination with abemaciclib, meets the criteria for Fast Track designation for the treatment of metastatic or unresectable NUT carcinoma in patients who have received at least one line of prior chemotherapy. The Company is also pursuing Orphan Drug and Breakthrough Therapy designations for ZEN-3694 in NUT carcinoma...To date, the combination of abemaciclib plus ZEN-3694 has shown superior response rate and duration of response compared to single agent BET inhibitors by inhibiting resistance to therapy."

Fast track • NUT Midline Carcinoma

Testing the Addition of Anti-cancer Drug, ZEN003694, to the Usual Chemotherapy Treatment, Cetuximab Plus Encorafenib, for Colorectal Cancer (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2025 ➔ Jan 2027 | Trial primary completion date: Jun 2025 ➔ Jan 2027

Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • BRAF

Testing A New Anti-cancer Drug Combination, Entinostat and ZEN003694, for Advanced and Refractory Solid Tumors and Lymphomas (clinicaltrials.gov) - P1/2 | N=30 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jul 2025 ➔ Jul 2026 | Trial primary completion date: Jul 2025 ➔ Jul 2026

Trial completion date • Trial primary completion date • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Pancreatic Cancer • Solid Tumor • T Cell Non-Hodgkin Lymphoma

ZEN003694 Combined With Talazoparib in Patients With Recurrent Ovarian Cancer (clinicaltrials.gov) - P2 | N=33 | Recruiting | Sponsor: Alexander B Olawaiye, MD | Trial completion date: Mar 2031 ➔ Mar 2033 | Trial primary completion date: Dec 2029 ➔ Dec 2031

Trial completion date • Trial primary completion date • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • BRCA1 • BRCA2

A randomized, open-label, phase 2b study of the BET bromodomain inhibitor (BETi) ZEN-3694 plus enzalutamide vs. enzalutamide in patients with metastatic castration resistant prostate cancer (mCRPC). (ASCO 2025) - P2 | "Funded by Newsoara Biopharma Co., Ltd, Zenith Epigenetics, Astellas Pharma Inc Clinical Trial Registration Number: NCT04986423 Background: Androgen receptor signaling inhibitors (ARSI), such as enzalutamide (Enza), and abiraterone (Abi), are standard therapies for metastatic hormone-sensitive and metastatic castration-resistant prostate cancer (mHSPC, mCRPC). The trial, conducted in collaboration with Newsoara has dosed approximately 150 of 200 patients to date. Astellas is providing enzalutamide for this study."

Clinical • Metastases • P2b data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • E2F1

ZEN-3694, Enzalutamide, and Pembrolizumab for the Treatment of Metastatic Castration-Resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=54 | Recruiting | Sponsor: Rahul Aggarwal | Trial completion date: Apr 2027 ➔ May 2028 | Trial primary completion date: Apr 2027 ➔ May 2028

Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • PD-L1 • RB1

Testing the Combination of the Anti-cancer Drugs ZEN003694 (ZEN-3694) and Talazoparib in Patients With Advanced Solid Tumors, The ComBET Trial (clinicaltrials.gov) - P2 | N=88 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Aug 2025 ➔ Dec 2026 | Trial primary completion date: Aug 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • Oncology • Ovarian Cancer • Solid Tumor • BARD1 • BRCA1 • BRCA2 • BRIP1 • FANCA • KRAS • RAD51 • RAD51C • RAD51D