ZN-c5 / Zentalis Pharma - LARVOL DELTA

The Selective Estrogen Receptor Degrader ZN-c5 Has Broad Anti-Tumor Activity in Wild-Type and Mutant ER-Positive Breast Cancer Models. (PubMed, Mol Cancer Ther) - "Fulvestrant, a selective estrogen receptor degrader (SERD) that antagonizes and degrades ER simultaneously, has demonstrated activity in ER+/HER2- breast cancers the ability to overcome endocrine resistance. These data support the clinical utility of ZN-c5 as monotherapy and as a combination therapy for patients with ER+/HER2- breast cancers. While encouraging plasma exposure and tolerability have been observed for ZN-c5 in patients, further studies are needed to optimize its therapeutic efficacy."

Journal • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Rheumatology • Solid Tumor • ER • HER-2

Discovery of ZN-c5, an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) with Improved Pharmacokinetics. (PubMed, J Med Chem) - "After fully profiling the compound, we nominated compound 4 (ZN-c5) for clinical development. Compound 4 advanced into Phase 1/2 clinical trials, which demonstrated high human exposure upon dosing patients with 50 mg once a day."

Journal • PK/PD data • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER

Discovery of an Orally Bioavailable and Brain Penetrant Selective Estrogen Receptor Degrader. (PubMed, J Med Chem) - "Our strategy to convert the acrylic acid-containing motif of ZN-c5 to a basic amine-containing tail resulted in compounds with much improved brain penetration and excellent ER degradation activity. Further optimization led to the discovery of compound 5 with excellent in vitro and in vivo efficacy. Compound 5 showed good in vitro ADME properties, good oral bioavailability in mouse, rat, and dog, as well as superior brain penetration, which translated into excellent efficacy in multiple brain metastasis breast cancer mouse models."

Journal • Breast Cancer • Oncology • Solid Tumor • ER

ZN-c5-001: A Study of ZN-c5 in Subjects With Breast Cancer (clinicaltrials.gov) - P1/2 | N=181 | Completed | Sponsor: Zeno Alpha Inc. | Active, not recruiting ➔ Completed | Trial completion date: Jun 2024 ➔ Dec 2022

Combination therapy • Metastases • Trial completion • Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

ZN-c5, an oral selective estrogen receptor degrader (SERD), in women with advanced estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer (SABCS 2021) - "Although fulvestrant binds and degrades the ER and shows anti-tumor activity in patients with advanced breast cancer, intramuscular injection is inconvenient and precludes achievement of higher and potentially more efficacious exposure. Conclusions : In this first-in-human study, ZN-c5 monotherapy was well tolerated and showed clinical benefit, including confirmed PRs, in subjects with advanced ER+/HER2- breast cancer. These data warrant further evaluation of ZN-c5 as monotherapy and in combination with palbociclib."

Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

[VIRTUAL] A phase I/II dose-escalation and expansion study of ZN-c5, an oral selective estrogen receptor degrader (SERD), as monotherapy and in combination with palbociclib in patients with advanced estrogen receptor (ER)+/HER2- breast cancer (ESMO 2021) - P1/2 | "Combination therapy of fulvestrant or letrozole with palbociclib, a CDK4/6 inhibitor, significantly improved progression-free survival compared to ET alone in phase 3 trials.Trial designThis phase 1/2, open-label, multicenter study is evaluating the safety, pharmacokinetics, and anti-tumor activity of ZN-c5 alone and in combination with palbociclib. Biomarkers and pharmacodynamic effects of therapy will be explored. Subject recruitment is ongoing."

Clinical • Combination therapy • Monotherapy • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

A Study of ZN-c5 and Abemaciclib in Participants With Breast Cancer (clinicaltrials.gov) - P1b | N=14 | Completed | Sponsor: Zeno Alpha Inc. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2023 ➔ Oct 2022 | Trial primary completion date: Apr 2023 ➔ Oct 2022

Combination therapy • Trial completion • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

[VIRTUAL] A phase Ib dose-escalation study of ZN-c5, an oral selective estrogen receptor degrader (SERD), in combination with abemaciclib in patients with advanced estrogen receptor (ER)+/HER2- breast cancer (ESMO 2021) - P1b | "Although fulvestrant binds and degrades the ER and shows anti-tumor activity in this population, intramuscular injection is inconvenient, associated with injection-site reactions, and precludes achievement of higher and potentially more efficacious exposures. Correlations between biomarkers and clinical outcomes will be explored. Subject recruitment is ongoing."

Clinical • Combination therapy • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Zentalis Pharmaceuticals Announces Positive Initial Clinical Data on ZN-c3, its Wee1 Inhibitor, in Patients with Advanced Ovarian Cancer at AACR (GlobeNewswire) - "Update on Additional AACR Presentations: Interim data from the Phase 1 monotherapy USC expansion cohort receiving ZN-c3 ≥300mg QD were also released today...Updated data from the USC expansion cohort of the Phase 1 monotherapy trial will be presented at the mini symposium on April 11, 2022 at 2:50 p.m. CT. In addition, Zentalis has three preclinical posters demonstrating the broad potential of ZN-c3 in multiple settings including AML (Abstract #2591), overcoming PARP resistance (Abstract #2606), and in novel biology when combined with our BCL-2 inhibitor, ZN-d5 (Abstract #2605). These findings further support ZN-c3 as a potential cornerstone treatment, creating a significant market opportunity across a broad range of solid and liquid tumors...Zentalis plans to initiate a combination study of ZN-c5 + ZN-c3 in ER+/HER2- CDK 4/6i-resistant breast cancer patients in 2022."

P1 data • Preclinical • Trial status • Acute Myelogenous Leukemia • Genito-urinary Cancer • Gynecologic Cancers • Hematological Malignancies • Oncology • Uterine Cancer

A PHASE 1B STUDY OF ZN-C5 IN CHINESE SUBJECTS (clinicaltrials.gov) - P1b | N=12 | Completed | Sponsor: Zentera Therapeutics HK Limited | Active, not recruiting ➔ Completed | N=24 ➔ 12 | Trial completion date: Jun 2023 ➔ Jun 2022

Enrollment change • Trial completion • Trial completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

A Study of ZN-c5 in Participants With Breast Cancer (clinicaltrials.gov) - P1 | N=35 | Completed | Sponsor: Zeno Alpha Inc. | Recruiting ➔ Completed

Biomarker • Trial completion • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • PGR

ZN-c5-001: A Study of ZN-c5 in Subjects With Breast Cancer (clinicaltrials.gov) - P1/2 | N=181 | Active, not recruiting | Sponsor: Zeno Alpha Inc. | Recruiting ➔ Active, not recruiting | N=458 ➔ 181 | Trial primary completion date: Dec 2023 ➔ Apr 2022

Combination therapy • Enrollment change • Enrollment closed • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

A Study of ZN-c5 and Abemaciclib in Participants With Breast Cancer (clinicaltrials.gov) - P1b | N=14 | Active, not recruiting | Sponsor: Zeno Alpha Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

ZN-c3, a potent and selective Wee-1 inhibitor demonstrates anti-tumor activities in combination with other targeted therapies and overcomes PARP inhibitor resistance (AACR 2022) - "In the ER-positive MCF-7 efficacy model, ZN-c3 demonstrated anti-tumor activity as a single agent as well as in combinations with a CDK4/6 inhibitor (Palbociclib) or ZN-c5, a selective estrogen receptor degrader (SERD). In the MDA-MB-436, a triple negative breast cancer tumor xenograftmodel, ZN-c3 demonstrated efficacy as a single agent and in combination with the PARP inhibitors Olaparib or Niraparib...Moreover, ZN-c3 can overcome the acquired resistance to PARP inhibitors and trastuzumab. ZN-c3 is currently in clinical trials for several indications and has demonstrated promising clinical activity and good tolerability."

Combination therapy • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2

A PHASE 1B STUDY OF ZN-C5 IN CHINESE SUBJECTS (clinicaltrials.gov) - P1b; N=24; Active, not recruiting; Sponsor: Zentera Therapeutics HK Limited; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Zentalis Pharmaceuticals to Present at the European Society for Medical Oncology (ESMO) Congress 2021 (GlobeNewswire) - “Zentalis Pharmaceuticals, Inc…announced that six abstracts have been accepted for poster presentation at the upcoming European Society for Medical Oncology (ESMO) Congress, being held virtually September 16-21, 2021.”

Clinical data • Acute Myelogenous Leukemia • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Fallopian Tube Cancer • Gynecologic Cancers • Hematological Malignancies • HER2 Negative Breast Cancer • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Peritoneal Cancer

Zentalis Pharmaceuticals Reports Second Quarter 2021 Financial Results and Operational Update (GlobeNewswire) - “Program Highlights…ZN-c3 in combination with chemotherapy for the treatment of osteosarcoma. Zentalis expects to initiate a Phase 1/2 trial in 3Q 2021….ZN-c3 and niraparib, GSK’s poly (ADP-ribose) polymerase (PARP) inhibitor, in patients with advanced epithelial ovarian cancer. The Company expects to initiate a Phase 1b trial with this combination in the second half of 2021….ZN-c3 in combination, ZN-c5 and ZN-d5. Two clinical trials are ongoing with plans to initiate one more trial by year-end 2021.”

New P1 trial • New P1/2 trial • New trial • Gynecologic Cancers • Oncology • Osteosarcoma • Ovarian Cancer • Sarcoma

Zentera’s oncology efforts turbocharged by USD 75m Series B funding (GBI Health) - "Shanghai-based clinical-stage biopharma Zentera Therapeutics announced the completion of a Series B financing round at USD 75 million...Zentera, formed by US firm Zentalis Pharmaceuticals Inc., (Nasdaq: ZNTL) to develop cancer therapies in China, plans to utilize the proceeds to advance clinical development of three of Zentalis' drug candidates, a WEE1 inhibitor ZN-c3, oral SERD ZN-c5, and BCL-2 inhibitor ZN-d5, as well as expand its pipeline through additional business development opportunities for China and global development."

Financing • Oncology

Zentalis Pharmaceuticals Announces Updates Across its Pipeline Including Promising New Interim Clinical Data on ZN-c3 (WEE1i) and ZN-c5 (SERD) and Two Potentially Registrational Trials for ZN-c3, with the First Trial Already Initiated (GlobeNewswire) - "Abemaciclib...The two separate trials will continue to enroll patients and the Company expects to report interim results in 1H 2022 from one or more of these trials....The Phase 1 monotherapy dose-escalation trial, initiated in 4Q 2020, has enrolled 14 patients with relapsed/refractory non-Hodgkin's lymphoma (NHL) thus far in the fifth dose cohort...Patients with acute myeloid leukemia will begin enrollment in 3Q 2021. Interim results from this Phase 1 trial are expected in 1H 2022....ZN-e4 has been well-tolerated at all doses as of the March 25, 2021 data cut-off, and clinical activity was identified at doses greater than 80 mg QD. Interim results from the Phase 1/2 trial are expected in 4Q 2021."

Enrollment status • P1 data • Breast Cancer • Hematological Malignancies • Lung Cancer • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology

A PHASE 1B STUDY OF ZN-C5 IN CHINESE SUBJECTS (clinicaltrials.gov) - P1b; N=24; Recruiting; Sponsor: Zentera Therapeutics HK Limited; Not yet recruiting ➔ Recruiting

Enrollment open • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Zentalis Pharmaceuticals Reports First Quarter 2021 Financial Results and Operational Update (GlobeNewswire) - “…ZN-c3, our oral WEE1 inhibitor, and niraparib, GSK’s poly (ADP-ribose) polymerase (PARP) inhibitor, in patients with advanced epithelial ovarian cancer. The Company expects to initiate a Phase 1b trial with this combination in the second half of 2021…The Company plans to report interim results from numerous ongoing trials with ZN-c5 and to share guidance on future development plans for this product candidate in the second quarter of 2021. Zentalis expects to initiate several studies in the coming months, including: A Phase 2 trial of ZN-c3 in uterine serous carcinoma in the third quarter of 2021; A Phase 1/2 trial of ZN-c3 in combination with chemotherapy in osteosarcoma in the third quarter of 2021; and A Phase 1/2 trial of ZN-c3 in combination with GSK’s niraparib in ovarian cancer in the second half of 2021.”

Clinical data • Trial status • Breast Cancer • Genito-urinary Cancer • Gynecologic Cancers • Oncology • Osteosarcoma • Ovarian Cancer • Uterine Cancer

A PHASE 1B STUDY OF ZN-C5 IN CHINESE SUBJECTS (clinicaltrials.gov) - P1b; N=24; Not yet recruiting; Sponsor: Zentera Therapeutics HK Limited

New P1 trial • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Zentalis Pharmaceuticals Reports Fourth Quarter and Full Year 2020 Financial Results and Operational Update (GlobeNewswire) - "Zentalis expects to report clinical data from the Phase 1 portion of its Phase 1/2 monotherapy trial of ZN-c3 in advanced solid tumors. Zentera Therapeutics, Zentalis’ majority-owned joint venture, submitted two IND applications in China for ZN-c5 and ZN-c3 in December 2020 and February 2021, respectively. A third IND application for ZN-d5 is expected to be submitted in 2021."

IND • P1/2 data • Oncology • Solid Tumor

A Study of ZN-c5 and Abemaciclib in Participants With Breast Cancer (clinicaltrials.gov) - P1b; N=18; Not yet recruiting; Sponsor: Zeno Alpha Inc.

Clinical • Combination therapy • New P1 trial • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

A Study of ZN-c5 and Abemaciclib in Participants With Breast Cancer (clinicaltrials.gov) - P1b; N=18; Recruiting; Sponsor: Zeno Alpha Inc.; Trial completion date: Dec 2022 ➔ Dec 2023; Trial primary completion date: Jun 2022 ➔ Apr 2023

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2