News & Events
ASH Joint Program Committees have selected two LP-168 clinical abstracts in NHL and MCL, and one LP-118 preclinical study in MCL for poster presentations at the 65th ASH Annual Meeting and Exposition, December 9-12, 2023, in San Diego, California. LP-168 is a novel next generation BTK inhibitor, and LP-118 is a new generation dual Bcl-2/Bcl-xL inhibitor invented by Guangzhou Lupeng Pharmaceutical Co., Ltd.. Abstracts are available on the ASH website.
LP-168 clinical presentation details (by presentation time)
【Title】Safety and Efficacy Results from the Phase I Study of a Novel Dual Covalent and Non-Covalent Next Generation Inhibitor of Bruton’s Tyrosine Kinase LP-168 in Patients with Relapsed/Refractory Mantle Cell Lymphoma
【Publication Number】3033
【Session】623. Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster II
【Time & Location】Sunday, December 10, 2023: 6:00 PM-8:00 PM, Halls G-H (San Diego Convention Center)
【Presenter】Dr. Yuqin Song
【Abstract highlight】
Methods: This is a Phase 1 first-in-human multi-center open-label study of LP-168 enrolling Chinese patients with B cell Non-Hodgkin Lymphoma (NHL) who have progressed after at least 1 or 2 prior treatments. The study has two parts: Phase 1a: "3+3" dose escalation and Phase 1b: dose expansion in disease-specific cohorts (e.g. R/R MCL, R/R MZL, etc.).
Results: By 31 May 2023, 33 R/R MCL patients who received at least one dose were enrolled and received LP-168 100 mg (n=8), 150 mg (n=24), and 200 mg (n=1) QD, respectively. Median lines of prior therapies were 2 (range, 1-11) with 24.2% refractory to the last prior treatment. All patients have received rituximab or a rituximab-containing regimen. 19 (57.6%) subjects have received at least a cBTKi or cBTKi-containing regimen.
The most common treatment emergent adverse events (TEAEs) were platelet count decreased (30.3%), neutropenia and anemia (27.3% each) and COVID-19 (24.2%), most of which were Grade 1. Serious AE (SAE) occurred in 3 (9.1%) subjects. Dose interruptions due to AE occurred in 7 patients (21.2%)，but no AE has led to dose adjustment, drug discontinuation or death.
Of 31 efficacy evaluable subjects, 24 (77.4%) achieved response including 12 (38.7%) complete metabolic response or complete response (CMR/CR). More importantly, of 17 subjects who had prior cBTKi exposure, 12 (70.6%) responded to LP-168 and 6 (35.3%) achieved CMR. LP-168 also showed efficacy in 2 subjects who have received ≥ 2 cBTKi treatments.
Conclusion: In this Phase 1 trial, the novel BTK inhibitor LP-168 demonstrated a high CR rate and durable response in heavily pre-treated R/R MCL with favorable safety profile. Moreover, LP-168 could effectively overcome the acquired resistance to prior cBTKi. Based on the safety, PK and preliminary efficacy data from the Phase 1 study so far, we have determined the recommended phase 2 dose (RP2D) for MCL as 150 mg QD. A phase 2 trial of LP-168 in R/R MCL is currently ongoing (NCT05716087).
【ASH website link】
https://ash.confex.com/ash/2023/webprogram/Paper180694.html
【Title】A Novel Dual Covalent and Non-Covalent Next Generation Inhibitor of Bruton’s Tyrosine Kinase LP-168 in Patients with Relapsed/Refractory B Cell Non-Hodgkin Lymphoma: Safety and Efficacy Results from a Phase 1 Study
【Publication Number】4400
【Session】623. Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster III
【Time & Location】Monday, December 11, 2023: 6:00 PM-8:00 PM, Halls G-H (San Diego Convention Center)
【Presenter】Dr. Yuqin Song
【Abstract highlight】
Methods: This multi-center Phase 1 study contains a “3+3” dose escalation part (Phase 1a) followed by a dose expansion part (Phase 1b). Subjects with R/R B-NHL are eligible to receive LP-168 once daily treatment until disease progression or unacceptable toxicity.
Results: By 31 May 2023, 68 subjects (33 MCL, 14 diffuse large B cell lymphoma [DLBCL], 15 marginal zone lymphoma [MZL], 3 CLL/SLL, 2 follicular lymphoma [FL] and 1 primary mediastinal large B cell lymphoma [PMBCL]) were enrolled. Cohorts of 100 mg (N=13) 150 mg (N=40) and 200 mg (N=15) taken QD were treated respectively. The median number of prior therapies was 2 (range, 1-10) and 25 (36.8%) subjects had received at least a cBTKi-containing regimen. The median follow-up was 4.5 (0.3-21.3) months with 46 subjects remaining on treatment.
No dose-limiting toxicities (DLTs) were observed during dose escalation from 100mg QD, 150mg QD to 200mg QD, and the maximum tolerated dose (MTD) was not reached. The most common treatment-emergent adverse events (TEAEs) occurring in ≥20% subjects included neutropenia, platelet count decreased and anemia, most of which were Grade 1 or 2. Only 9 (13.2%) subjects experienced Serious Adverse Event (SAE). No major bleeding, hypertension, or atrial fibrillation was observed in this study. Dose reduction occurred in only 1 subject due to AE. No TEAE led to drug discontinuation.
Of 60 efficacy-evaluable subjects, overall response rate (ORR) was 65.0%. In particular, ORR in R/R MCL (N=31) was 77.4% with a CR of 38.7%, non-GCB DLBCL (N=10) had an ORR of 70.0% with a CR of 40.0% and MZL (N=11) had an ORR of 72.7% with a CR of 9.1%.
LP-168 steady state plasma exposure increases dose-dependently with limited accumulation at 100 to 200 mg. Plasma concentration peaks at approximately 2 to 3 hours at fasted state, the average terminal half-life was 15.1 hours, supporting once daily dosing.
Conclusion: The current results of the Phase 1 study showed that LP-168 was well tolerated at 100-200 mg QD with favorable PK profile and has demonstrated encouraging efficacy in multiple B-cell malignancies, including those who had progressed on prior cBTKi.
【ASH website link】
https://ash.confex.com/ash/2023/webprogram/Paper180485.html
【Title】Pre-clinical Evaluation of a New-Generation Orally Bioavailable Dual Bcl-2/Bcl-xL Inhibitor LP-118 in Mantle Cell Lymphoma
【Publication Number】3640
【Session】802. Chemical Biology and Experimental Therapeutics: Poster II
【Time & Location】Sunday, December 10, 2023: 6:00 PM - 8:00 PM, Halls G-H (San Diego Convention Center)
【Presenter】Dr. Bing Dai
【Abstract highlight】
Methods: In vitro cell viability assay was performed with CellTiterGlo method in MCL cell lines REC-1 and Granta519 to examine cellular activity of LP-118. To determine the synergy of the combinations of LP-118 with standard of care agents, matrix combinations were performed with different concentrations of LP-118 and different drugs including vincristine, bendamustine, cytarabine, docetaxel, doxorubicin, cisplatin, and bortezomib. The data were analyzed using SynergyFinder (2.0), an online program for synergy scores. For in vivo experiments, Granta519 and REC-1-derived xenograft models were established and treated with different regimens: for Granta519 model, mice were treated with vehicle, BR (bendamustine, 25mg/kg, iv, day 1 and rituximab, 10mg/kg, iv, day 1), LP-118 (75mg/kg, po, qd, 28 days) in combination with BR. For REC-1 models, mice were treated with vehicle, LP-118 (50mg/kg, po, qd, 28 days) plus a BTK inhibitor LP-168 (25mg/kg, po, bid, 28 days), or ABT-199 (50mg/kg, po, qd, 28 days) plus ibrutinib (25mg/kg, po, qd,13 days, then bid, 28 days), and tumor growth/remission were examined to determine the in vivo anticancer activity.
Results: LP-118 is highly active in cell viability assays with Granta519 and REC-1 cells, with IC50 of 0.6 nM and 1.96 nM, respectively. And compared to venetoclax, LP-118 is 8 to18 times more potent in REC-1 and Granta519 cells. In the matrix combination studies with REC-1 cells, combinations of LP-118 with SOC agents showed synergistic anticancer effects with all the tested drugs, including vincristine, bendamustine, cytarabine, docetaxel, doxorubicin, cisplatin, and bortezomib. Moreover, the combination of LP-118 with BR induced complete tumor regression of Grana519 xenografts in all mice (7/7) at day 45 with no significant body weight changes, whereas no complete tumor regression was observed in the BR group, indicating that combination of LP-118 with BR was more effective than the treatment with BR alone. Similarly, the combination of LP-118 with LP-168 (BTKi) also resulted in complete tumor regression in REC-1 xenograft models at day 40, while the combination of ABT-199 plus ibrutinib showed no significant tumor growth inhibition, suggesting that combination of LP-118 and LP-168, a new generation BTKi currently also in clinical trial, might be more effective against MCL than the combination of ABT-199 plus ibrutinib in clinic.
【ASH website link】
https://ash.confex.com/ash/2023/webprogram/Paper180190.html