News & Events
December 13, 2021: 2:45 PM (EST), Newave Pharmaceutical presented the latest data of its own proprietary LP-118, the next generation of Bcl-2 inhibitor, at the 63rd American Society of Hematology (ASH) Annual Meeting. The title is "Characterization of LP-118, a Novel Small Molecule Inhibitor of Bcl-2 and Bcl-Xl in Chronic Lymphocytic Leukemia Resistant to Venetoclax (Abstract Number: 679)". Dr. Jennifer A. Woyach of Ohio State University, Dr. Deepa Sampath of the University of Texas MD Anderson Cancer Center, and Dr John C. Byrd of University of Cincinnati were the principal investigator of this oral presentation.
Key Results
From BH3 profiling on treatment naive and Venetoclax relapsed/refractory (R/R) primary CLL cells, we found in some samples, including Venetoclax R/R primary CLL cells, cell survival showed dependency on other anti-apoptotic proteins including Bcl-xL. So here brought up a question, does the Bcl-2 inhibitor with tuned Bcl-xL activity contribute the Venetoclax R/R CLL efficacy?
From vitro anti-proliferation results, we found treatment naïve CLL cells were more sensitive to LP-118 than Venetoclax and Navitoclax with IC50 values at 0.5nM, 10 nM, and >10 nM, respectively. Venetoclax R/R CLL cells were 50% killed by 1 nM LP-118 and were not sensitive to either Venetoclax or navitoclax. A further investigation on mechanism revealed that LP-118 could activate pore-forming pro-apoptotic protein Bak transforming to an active conformation. The release of cytochrome c observed also indicated cells were going through apoptosis.
Moreover, we found the transfected RS4;11 cell harboring Bcl-2 Gly101Val mutation also responded to LP-118 with IC50 of 20nM but not sensitive to Venetoclax. Furthermore, LP-118 induced quicker and earlier Bak transformation and cytochrome c release in these mutant cells than Venetoclax. And in a RS4; 11 xenograft mouse model, mice treated daily via oral gavage and observe that 100 mpk of LP-118 significantly decreases overall tumor growth and increases survival compared to 100 mpk of Venetoclax (p=0.0004).
Conclusion
Our in vitro studies demonstrated preclinical efficacies of LP-118 in primary CLL samples and Gly101Val mutant cells. LP-118 is highly potent in Venetoclax resistant patient samples and cell lines. Additional in vivo work has further confirmed the efficacy of LP-118 in mutant cell lines. This work justifies continued preclinical and clinical work with this agent, and a phase 1 first in human study will begin soon in patients with relapsed hematologic malignancies (NCT04771572).
Abstract link：https://ash.confex.com/ash/2021/webprogram/Paper151852.html
About Chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a class of matured B lymphocyte clonal proliferative tumors with specific immunotypes that most common found in elder population, characterized by the aggregation of lymphocyte in peripheral blood, bone marrow, spleen and lymph nodes, most behave as abnormal infiltration of lymphocyte in peripheral blood and bone marrow. Despite advances in research and the development of effective treatment regimens, CLL is still largely an incurable disease. Standard chemoimmunotherapy shows poor efficacy for aged patients who have complications and poor prognosis indications (such as no IGHV mutation, TP53 mutation or deletion, del(17p) etc.), which also has serious side effects. In recent years, novel targeted small-molecule drugs, such as Bcl-2 inhibitors and BTK inhibitors, have brought more therapeutic options to patients. However, the drug resistance has also become increasingly prominent.
About LP-118
LP-118, is the newest-generation, highly potent, oral and selective Bcl-2 inhibitor, overcoming the resistance to Venetoclax, which has a wide application potential in hematological tumors and solid tumors. LP-118 shown a superior efficacy in various tumor mouse models over than Venetoclax. It also exhibited a good safety profile and pharmacokinetics (PK).
LP-118 now is under a multi-center phase I clinical trials in the U.S. and China. Dr. John C. Byrd of University of Cincinnati leads the phase I clinical trial in US (NCT04771572), aiming to evaluate the safety, PK and preliminary efficacy of LP-118 in patients with relapsed/refractory hematological malignancies. The phase I clinical trial in China, led by Dr.Yilong Wu of Guangdong Provincial People's Hospital, was designed to evaluate the safety/tolerability of LP-118 in patients with advanced B-cell malignancies, explore maximum tolerated dose (MTD) and dose-limiting toxicity (DLTs), PK, and determine the recommended dose for later clinical studies, as well as preliminary efficacy. The First-in human dose was completed on September 14, 2021.
About Newave:
We are a clinical-stage company mainly focused on the drug discovery & development of novel therapies for cancer treatment.
We have a world-class MedChem team, mainly pursue clinically validated targets with significant unmet needs, challenging medicinal chemistry, and strong interests from big pharma , particularly the targets with strong synergy with Bcl-2 pathway. Our drug design team dedicate to the rational drug design of proprietary drug candidates with strong differentiations.
Our clinical teams have deep understanding and rich experience in rapid and cost-effective completion of clinical proof-of-concept (POC) and pivotal studies both in China and US. We strive to bring newest generation medicines to cancer patients worldwide.