Zentalis(ZNTL) - 2021 Q4 - Annual Report

Drug Development and Clinical Trials - The company is developing ZN-c3, a Wee1 inhibitor, and ZN-c5, an oral selective estrogen receptor degrader, with a focus on large patient populations in oncology [29]. - ZN-c3 is currently in multiple Phase 1/2 clinical trials for advanced solid tumors, including a Phase 2 trial for recurrent uterine serous carcinoma, with Fast Track designation granted by the FDA [36][56]. - ZN-c5 is being evaluated in combination with Pfizer's palbociclib and Lilly's abemaciclib, with initial results expected in the first half of 2022 [42]. - The company plans to initiate combination trials for ZN-d5 and ZN-c3 in acute myeloid leukemia and ZN-c5 and ZN-c3 for CDK4/6i resistant breast cancer in 2022 [31][39]. - ZN-d5 is in a Phase 1 trial for non-Hodgkin's lymphoma and acute myelogenous leukemia, with initial results reported in Q4 2021 [43]. - ZN-e4 is undergoing a Phase 1/2 trial for advanced non-small cell lung cancer, with results expected in 2022 [44]. - In Q4 2021, the company initiated a Phase 2 trial for ZN-c3 targeting solid tumors with a predictive biomarker, and a Phase 1/2 trial in combination with niraparib for ovarian cancer [59]. - The company plans to initiate a Phase 1b trial of ZN-c5 and ZN-c3 in CDK4/6i resistant breast cancer in 2022 [59]. - The company is conducting a Phase 1/2 clinical trial for ZN-c5 as monotherapy and in combination with palbociclib, with plans to initiate a Phase 1b trial in 2022 [133]. - The company plans to open enrollment for a Phase 1 study of ZN-d5 in patients with relapsed or refractory amyloidosis in Q1 2022 [165]. - A Phase 1/2 combination trial of ZN-d5 with ZN-c3 in AML is planned for 2022, aiming to enroll up to 100 subjects [186]. Efficacy and Safety of Drug Candidates - ZN-c3 demonstrated a solubility of 2,132,000 nM, approximately 35 times greater than adavosertib, which may reduce inter-patient drug exposure variability [82]. - In preclinical studies, ZN-c3 showed superior anti-tumor activity compared to adavosertib across various solid tumor cell lines [74]. - ZN-c3 exhibited a Cmax of 5,100 ng/mL at a dose of 80 mg/kg/day, significantly higher than adavosertib's Cmax of 4,703 ng/mL at the same dose [91]. - The combination of ZN-c3 and gemcitabine in preclinical osteosarcoma models resulted in better anti-tumor effects than either treatment alone [93]. - ZN-c3 was well tolerated across varying dosage levels in preclinical studies and clinical trials [80]. - The company believes ZN-c3's characteristics may allow for sequential therapy with PARP inhibitors, maintaining strong anti-tumor activity [72]. - Adavosertib demonstrated an overall response rate of 43% in a Phase 2 trial for relapsed ovarian cancer, indicating the potential efficacy of Wee1 inhibitors [66]. - ZN-c3 demonstrated better anti-tumor activity in combination with carboplatin compared to monotherapy treatments, with a dosing regimen of 60 mg/kg QD for ZN-c3 and 50 mg/kg QW for carboplatin [96]. - In the Phase 1 clinical trial of ZN-c3, the overall objective response rate (ORR) increased from 40% to 43%, with five confirmed partial responses (PRs) reported [109]. - The maximum tolerated dose (MTD) for ZN-c3 was determined to be 350 mg QD, while the recommended Phase 2 dose (RP2D) was set at 300 mg QD [114]. - ZN-c5, an oral SERD, is being developed for ER+/HER2- breast cancer, which affects approximately 70% of breast cancer patients in the U.S. [120]. - As of September 15, 2021, the clinical benefit rate (CBR) for ZN-c5 was reported at 38% in the Phase 1 trial, with confirmed PRs at 150 mg/day and 300 mg/day [128]. - ZN-c5 is designed for once-daily oral administration, potentially improving patient convenience compared to existing treatments [132]. - ZN-c5 has demonstrated anti-tumor activity in preclinical studies, showing superior tumor growth inhibition compared to fulvestrant [127]. - The combination of ZN-c5 (20 mg/kg) and ZN-c3 (80 mg/kg) demonstrated greater anti-tumor activity than ZN-c5 alone in preclinical studies [135]. - ZN-c5 was well tolerated in the Phase 1 monotherapy trial, with 96% of patients experiencing treatment-emergent adverse events (TEAEs), primarily of Grade 1 or 2 severity [143][145]. - The pharmacokinetic analysis showed ZN-c5 had fast absorption with median Tmax values of 1 to 2 hours, and no significant accumulation was observed after 15 days of dosing [153]. - In the Phase 1 combination trial with palbociclib, ZN-c5 was also well tolerated, with no dose-limiting toxicities reported [147]. - ZN-d5 shows over 600 times greater selectivity for BCL-2 compared to BCL-xL, which may limit thrombocytopenia incidence [165]. - ZN-d5 demonstrated potent anti-tumor activity in a RS4;11 xenograft leukemia mouse model, with durable complete responses observed after treatment cessation [175]. - The combination of ZN-d5 and ZN-c3 resulted in 94% tumor regression in a preclinical study, indicating synergistic effects [178]. - ZN-d5 has been well-tolerated in clinical studies, with 74% of NHL subjects experiencing adverse events, primarily anemia (22%), diarrhea (13%), and nausea/vomiting (9%) [183]. Market Potential and Competitive Landscape - Sales of FDA-approved PARP inhibitors were approximately $1.6 billion in 2019, projected to grow to $6.9 billion by 2026 [64]. - Osimertinib, a third-generation EGFR inhibitor, reported sales of $4.3 billion in 2020, a 36% increase from 2019, with projections to grow to $9.5 billion by 2026 [192]. - The biotechnology and pharmaceutical industries are characterized by significant competition, with potential competitors having greater financial resources and expertise [226]. - Key competitive factors for the company's product candidates include efficacy, safety profile, convenience, and cost [227]. Manufacturing and Supply Chain - The company relies on third-party contract manufacturing organizations (CMOs) for the production of product candidates and does not own manufacturing facilities [222]. - The company has engaged CMOs to manufacture and package ZN-c3, ZN-c5, ZN-d5, and ZN-e4 for preclinical and clinical use [223]. - The company aims to identify and contract with at least two manufacturers for active pharmaceutical ingredients and drug products prior to seeking regulatory approval [223]. - The company does not currently have long-term supply arrangements in place with its CMOs, which may impact production stability [223].