ZEN-3694 / Zenith Capital Corp, Newsoara Biopharma - LARVOL DELTA

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

Dysregulating transcription and epigenetic remodeling using dual BRD4 and CDK9 inhibition in pancreatic ductal adenocarcinoma (AACR 2025) - "Here, we show preclinical evidence that combination treatment of VIP152 and ZEN3694 synergistically dysregulates PDAC transcription and remodels the epigenomic landscape. Future directions will include exploring Myc amplified subtype specific selectivity and in vivo validation of toxicity and efficacy."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRD4 • MYC

Anti-tumor effects following BET inhibition in preclinical models of pediatric and AYA osteosarcoma (AACR 2025) - "Effect of BETi (AZD5153, BMS-986378, ZEN-3694) in clinical trials for pediatric and adult solid tumors were investigated...To interrogate mechanisms of action, RNA-seq analysis of BET/BRD4 inhibition via AZD5153, PROTAC (ARV-825), and BRD4 siRNA in OS cell lines revealed distinct and overlapping patterns of alterations in gene expression...At the transcript level, increased DHRS2 was evident with no changes in TMPRSS9. These data sets reveal the promise of BETi for treatment of OS PDX derived from treatment naïve patients some of which go on to relapse, and in OS PDX derived from metastatic sites."

Preclinical • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • BRD2 • BRD4 • DHRS2 • H2AX

NCI-2021-11793: Testing the Combination of the Anticancer Drugs ZEN003694 and Binimetinib in Patients With Advanced/Metastatic or Unresectable Solid Tumors With RAS Alterations and Triple Negative Breast Cancer (clinicaltrials.gov) - P1 | N=42 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2025 ➔ Mar 2027 | Trial primary completion date: Mar 2025 ➔ Mar 2027 | Suspended ➔ Recruiting

Enrollment open • Trial completion date • Trial primary completion date • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRAF • ER • HER-2 • HRAS • KRAS • NF1 • NRAS • PGR

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

New P2 trial • Castration-Resistant Prostate Cancer • CNS Disorders • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Continuation Protocol for ZEN003694 in Patients Experiencing Clinical Benefit While Enrolled in a ZEN003694 Protocol (clinicaltrials.gov) - P1/2 | N=40 | Enrolling by invitation | Sponsor: Zenith Epigenetics | Trial completion date: Dec 2024 ➔ Dec 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2026

Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Prostate Cancer

ZEN003694 and Enzalutamide Versus Enzalutamide Monotherapy in Metastatic Castration-Resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=200 | Recruiting | Sponsor: Zenith Epigenetics | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Monotherapy • Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

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) | Suspended ➔ Recruiting

Enrollment open • Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PD-L1 • PGR

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 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Dec 2025

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

TRβ Agonism Enhances Tumor Suppression by BETi in an Anaplastic Thyroid Cancer Model (ATA 2024) - "Cell-based assays were used to determine the effects of GC-1 and BETi (JQ-1 and ZEN-3694) on 8505C ATC cell phenotype alone and in combination. PPIN analysis revealed TRβ and bromodomain and extra-terminal domain (BET) family proteins interaction nodes including BRD4. GC-1 and BETi have an additive effect in inhibiting the aggressive ATC phenotype in vitro, significantly reducing cell viability and other tumorigenic parameters. ZEN-3694 was shown, for the first time, to inhibit the aggressive ATC phenotype and reduce cellular viability both alone and in combination with GC-1."

Late-breaking abstract • Preclinical • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • BRD4