Dual BTK/LCK inhibitors ( Aegera Therapeutics, Inc.)

SHANGHAI, Dec. 12, 2023 /PRNewswire/ -- Dizal presented compelling data from its robust portfolio of hematological oncology at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition held in San Diego, California from December 9-12. The data showcased updated results of Dizal's two leading assets: golidocitinib, the first and only JAK1 selective inhibitor for the treatment of peripheral T-cell lymphoma (PTCL), and DZD8586, a first-in-class LYN and BTK dual inhibitor for the treatment of relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). This underscores Dizal's dedication to developing and delivering innovative, life-changing medicines in the field of hematological oncology. Golidocitinib The first and only JAK1 selective inhibitor for the treatment of PTCL Golidocitinib, a novel JAK1-only inhibitor developed by Dizal, is currently in the NDA stage for the treatment of r/r PTCL. The China National Medical Products Administration (NMPA) recognized its potential and granted it Priority Review in September 2023. Notably, golidocitinib stands as the world's first and only highly selective JAK1 inhibitor specifically developed for PTCL. Furthermore, it has obtained Fast Track Designation from the U.S. Food and Drug Administration (FDA), positioning it as the first Chinese innovative PTCL drug to receive this designation. The efficacy of golidocitinib in PTCL was highlighted at 2023 ASH, with two studies being selected for presentation. Particularly noteworthy is the multinational, pivotal study of golidocitinib for the treatment of r/r PTCL (JACKPOT8 PART B), which was selected for oral presentation and simultaneously published in the peer-reviewed journal The Lancet Oncology (Impact Factor: 54.4). The potential best-in-class treatment option for r/r PTCL There is no consensus on the standard treatment for r/r PTCL and the 5-year survival rate is below 30%. The results of JACKPOT8 PART B study revealed that golidocitinib demonstrated superior and durable clinical benefits in the treatment of r/r PTCL with a favorable safety profile that outperformed existing treatment options. Per independent review committee (IRC) assessment, golidocitinib achieved an overall response rate (ORR) of 44.3% and a complete response rate (CRR) of 23.9%. Both were more than double that of existing treatment options. Tumor responses were observed across various PTCL subtypes. The responses were durable, with the median duration of response (mDoR) of 20.7 months. This is higher than the DoR observed with existing therapies, which is typically below 12 months. The median progression-free survival (mPFS) was 5.6 months, and the median overall survival (mOS) was 19.4 months and still ongoing. Promising and durable efficacy in PTCL after first-line systemic therapy Approximately 40% of patients with complete response (CR) and 80% of patients with partial response (PR) have disease relapse within 2 years after initial tumor response. These patients currently lack a standard maintenance therapy. JACKPOT 26 is a phase 2, single-arm, multicenter study to evaluate the safety and efficacy of golidocitinib for maintenance treatment after first-line therapy. At the data cut-off date of October 12, 2023, in the cohort of patients achieving CR post first-line therapy, median disease-free survival (DFS) has not been reached, with 76.7% patients still event free. In the cohort of patients achieving PR post first-line therapy, median DoR has not been reached, with 33% of patients achieving a CR and 85.7% of patients still responding to the treatment. The median PFS was 16.7 months. The treatment-related adverse events (TRAEs) observed in this study were similar to those previously reported for golidocitinib and were clinically manageable and reversible. DZD8586 A first-in-class non-covalent LYN and BTK dual inhibitor with excellent blood-brain barrier (BBB) penetration DZD8586 is a rationally designed, oral, non-covalent, LYN/BTK dual inhibitor with excellent BBB penetration as a potential treatment option for B-NHL. While Bruton's Tyrosine Kinase (BTK) inhibitors have been approved for the treatment of B-NHL, resistance can emerge due to various mechanisms. This includes acquired mutations at residue C481X of BTK which disrupts covalent BTKi binding, as well as non BTK-driven mutations that seems more common in patients who have failed non-covalent BTKi such as pirtobrutinib. Currently, there is no targeted therapy available to address both resistance mechanisms, highlighting an urgent need for a safe and effective treatment option for patients with r/r B-NHL. Potential to overcome resistance to both covalent and non-covalent BTK inhibitors Preclinical studies have shown that DZD8586 can overcome resistance mutations observed with approved covalent and non-covalent BTK inhibitors. DZD8586 has exhibited potent inhibition of cell growth by blocking both BTK-dependent and BTK-independent signaling pathways. No BTK inhibitor has been approved for treating diffuse large B-cell lymphoma (DLBCL). It is hypothesized that blockage of BTK pathway alone is not sufficient to bring meaningful clinical benefit in DLBCL. DZD8586 shows strong inhibition of LYN and BTK phosphorylation and achieves superior anti-tumor efficacy in DLBCL and chronic lymphocytic leukemia (CLL) models than selective BTK inhibitors. Due to limited BBB penetration of the current therapies, treatment of central nervous system lymphoma (CNSL) remains a clinical challenge. DZD8586 indicated CNS penetration with the potential to treat CNSL. A novel treatment option for r/r B-NHL DZD8586 is currently being evaluated in two phase 1/2 clinical trials for patients with r/r B-NHL worldwide. At 2023 ASH, the pooled analysis from the two studies were debuted. The results revealed that DZD8586 showed encouraging anti-tumor activity with manageable safety and favorable PK profile in heavily pre-treated B-NHL patients. Highlights of the study findings include: ORR of 64.7% across all dose levels, 71.4% at 50 mg Tumor response in different subtypes, including DLBCL (ORR 83.3%), CNSL, and CLL ORR of 50% in patients resistant to BTKi treatment "Our research findings presented at ASH demonstrate Dizal's distinctive competitiveness in the field of hematological oncology. We are fully committed to pushing the boundaries of innovation and developing transformative drugs to improve the lives of patients globally." said Xiaolin Zhang, PhD, Chairman and CEO of Dizal. - End - About golidocitinib (DZD4205) Golidocitinib is currently the first and only Janus kinase 1 (JAK1) selective inhibitor being evaluated for the treatment of r/r PTCL. At the data cut-off date of August 31, 2023, golidocitinib has demonstrated robust and durable anti-tumor efficacy, with an ORR of 44.3%. More than 50% of the patients with tumor remission achieved a complete response with a CRR of 23.9%. Per IRC assessment, mDoR reached 20.7 months. Golidocitinib was granted Fast Track Designation by the U.S. FDA for the treatment of r/r PTCL in February 2022. In September 2023, the CDE accepted its NDA and granted Priority Review for the treatment of r/r PTCL. The Phase I clinical data of golidocitinib (JACKPOT8 PART A) was published in Annals of Oncology (Impact Factor: 51.8), and global pivotal trial data of golidocitinib for the treatment of r/r PTCL (JACKPOT PART B) was published in The Lancet Oncology (Impact Factor: 54.4). About DZD8586 DZD8586 is an orally available, highly selective small molecule inhibitor to target both BTK-dependent and BTK-independent B-cell receptor (BCR) signaling pathways, with full blood-brain barrier penetration. Pre-clinical research revealed that DZD8586 demonstrated good safety profile and could effectively inhibit the growth of B-NHL cells. A healthy volunteer study of DZD8586 has been completed to investigate the clinical safety and PK/PD correlation. Additionally, a global phase I/II study is ongoing to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor efficacy of DZD8586 in patients with r/r B-NHL. Preliminary results from the clinical trial suggest that DZD8586 exhibits favorable PK properties, good safety profile, and preliminary anti-tumor efficacy in patients with B-NHL. About Dizal Dizal is a biopharmaceutical company, dedicated to the discovery, development and commercialization of differentiated therapeutics for the treatment of cancer and immunological diseases. The company aims to develop first-in-class and groundbreaking new medicines, and further address unmet medical needs around the world. Deep-rooted in translational science and molecular design, it has established an internationally competitive portfolio of five clinical-stage assets with two leading assets in global pivotal studies and one already launched. To learn more about Dizal, please visit , or follow us at Linkedin or Twitter. Forward-Looking Statements This news release may contain certain forward-looking statements that are, by their nature, subject to significant risks and uncertainties. The words "anticipate", "believe", "estimate", "expect", and "intend" and similar expressions, as they relate to Dizal, are intended to identify certain forward-looking statements. Dizal does not intend to update these forward-looking statements regularly. These forward-looking statements are based on the existing beliefs, assumptions, expectations, estimates, projections, and understandings of the management of Dizal with respect to future events at the time these statements are made. These statements are not a guarantee of future developments and are subject to risks, uncertainties, and other factors, some of which are beyond Dizal's control and are difficult to predict. Consequently, actual results may differ materially from information contained in the forward-looking statements as a result of future changes or developments in our business, Dizal's competitive environment, and political, economic, legal, and social conditions. 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