Clinical Efficacy and Safety - Zilovertamab demonstrated an objective response rate (ORR) of 81% and a complete response (CR) rate of 35% in patients with relapsed/refractory mantle cell lymphoma (MCL) when combined with ibrutinib, compared to historical ORR of 66% and CR rate of 20% for ibrutinib alone [22]. - The median progression-free survival (PFS) for patients treated with zilovertamab plus ibrutinib was reported at 35.9 months, significantly higher than the 12.8 months for those treated with ibrutinib alone [22]. - Zilovertamab demonstrated a favorable safety profile, with no dose-limiting toxicities or serious adverse events reported in the Phase 1 trial [56]. - The combination therapy of zilovertamab and ibrutinib showed lower rates of Grade 3 or higher neutrophil and platelet decreases compared to historical data for ibrutinib alone [64]. - In a Phase 1 clinical trial of zilovertamab in CLL, 22 patients were evaluable, with 17 achieving stable disease and an average delay of 262 days before further treatment was needed [57]. - The overall response rate (ORR) for patients with MCL in Study CIRM-0001 was 81%, with 35% achieving complete response (CR) and 46% achieving partial response (PR), resulting in a total clinical benefit rate of 92% [66]. - For high Ki-67 patients, the ORR was 85% with a median duration of response of 14 months, while patients with more than one prior systemic therapy had an ORR of 82% [66]. - In the CLL cohort, the ORR was 91%, with a CR rate of 6% and a total clinical benefit rate of 100% [72]. - The median PFS for CLL patients with more than two prior therapies was 36.1 months, while landmark PFS was 100% at 36 months for those with two or fewer prior lines of therapy [72]. Drug Development and Regulatory Status - The FDA granted orphan drug designations for zilovertamab for MCL and chronic lymphocytic leukemia (CLL) in 2020, indicating its potential for treating rare diseases [21]. - The company plans to conduct a Phase 3 clinical trial (ZILO-301) for zilovertamab in relapsed/refractory MCL, with a primary endpoint of PFS and an interim analysis for ORR [77]. - ZILO-301 will be conducted internationally in at least 50 centers, with an expected enrollment of up to 250 randomized patients [78]. - The company is also planning Study ZILO-302 to evaluate zilovertamab plus ibrutinib for patients with progressive disease during initial ibrutinib monotherapy [79]. - The company expects to continue relying on third parties for the production and testing of clinical and commercial quantities of all product candidates, maintaining flexibility in its manufacturing strategy [174]. - The company has established a quality control and assurance program to ensure compliance with current Good Manufacturing Practices (cGMPs) [175]. - The FDA requires substantial time and financial resources for obtaining regulatory approvals for drug candidates [197]. - The IND submission must include preclinical study results, clinical protocols, and CMC information before human trials can begin [198]. - The FDA reviews NDAs and BLAs within 60 days to determine if they are complete for substantive review [209]. - Standard applications are reviewed within ten months, while priority applications are reviewed within six months after filing [210]. - The FDA may issue a Complete Response Letter (CRL) if the NDA or BLA does not meet regulatory criteria, outlining specific deficiencies [213]. - Approval may be limited to specific disease subsets or dosages, potentially restricting commercial value [214]. - The Pediatric Research Equity Act requires pediatric clinical trials for most new drugs and biologics unless a deferral or waiver is granted [215]. - Clinical trials must adhere to Good Clinical Practices (GCP) and require independent review board approval [202]. - The manufacturing process must comply with current Good Manufacturing Practices (cGMP) to ensure product quality [211]. - The FDA may require post-marketing studies to further assess product safety and effectiveness after approval [214]. - The FDA grants orphan designation to drugs for rare diseases affecting fewer than 200,000 individuals in the U.S. or where development costs cannot be recovered from sales [216]. - Products with orphan designation that receive the first FDA approval are entitled to seven years of orphan product exclusivity [218]. Research and Collaborations - The company announced a research collaboration with Karolinska Institutet to advance ROR1-targeting cell therapies, focusing on CAR-T and CAR-NK cells [90]. - A collaboration with Celularity Inc. was established to evaluate placental-derived cellular therapies targeting ROR1, including preclinical studies on zilovertamab and CAR gene modification [90]. - The company is collaborating with SPH USA to develop ROR1-targeted CAR-T cell therapy candidates in Greater China, with initial clinical trials planned at experienced hospitals [92]. - The company has entered into a research agreement with the Regents of UC San Diego for further research on the ROR1 therapeutic development program, with a budget of $1.6 million over four years [161]. - The company has established a research collaboration with Celularity to evaluate placental-derived cellular therapies targeting ROR1, including the use of zilovertamab in combination with CYNK-101 [165]. Market Potential and Competitive Landscape - The global market for CLL therapies was estimated at $9.1 billion in 2021, driven by targeted therapies such as ibrutinib and venetoclax, indicating a significant commercial opportunity for zilovertamab [50]. - The company is developing multiple therapies targeting oncology indications, including zilovertamab and ONCT-534, amidst high competition in the market [157]. Patent and Intellectual Property - The company is actively seeking to protect its proprietary technology through patent applications and relies on trade secrets and know-how to maintain its competitive position in cancer therapeutics [176]. - As of February 4, 2022, the company owned approximately 42 issued U.S. patents and 42 pending U.S. patent applications related to proprietary technology, with an additional 57 issued patents and 66 pending applications in jurisdictions outside of the U.S. [179]. - The company has an exclusive, worldwide license for a portfolio of patents related to ROR1 antibodies and CAR-T therapies, which includes know-how and trade secrets for treating cancers [180]. - The zilovertamab clinical candidate is currently in Phase 1 and Phase 2 clinical trials, with two issued U.S. patents related to its composition not expiring before 2032 and 2033 [181]. - The company has approximately 29 licensed patent applications pending in the U.S. and abroad related to methods of treating cancer using zilovertamab and small-molecule chemotherapeutics, with one issued patent directed to the combination with a BTK inhibitor [182]. - The DAARI program includes ten issued U.S. patents and approximately three pending U.S. patent applications, with a patent term not due to expire before April 2036 [188]. - The ONCT-216 portfolio contains approximately eight U.S. issued patents and two pending applications, with a patent term not due to expire before October 2035 [193]. - The Georgetown Licensed Portfolio includes three U.S. patents directed to compounds for treating Ewing sarcoma or pancreatic cancer, with patent terms not expiring before November 2028, August 2028, and December 2027 [194]. - The company has a total of approximately 17 patents outside the U.S. related to the Georgetown Licensed Portfolio, with patent terms not expiring before April 2033 [195]. - The validity of one of the issued European patents is being challenged, but the company believes it has strong defenses against the opposition [181]. - The company holds a portfolio of patents and applications related to methods of screening for antibodies that specifically bind to ROR1, with two issued U.S. patents not expiring before January 2032 [186].
Oncternal Therapeutics(ONCT) - 2021 Q4 - Annual Report