News & Events
ASH Joint Program Committees have selected LP-168 preclinical and clinical abstracts for oral 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 invented by Guangzhou Lupeng Pharmaceutical Co., Ltd.. Abstracts are available on the ASH website.
LP-168 clinical presentation details:
【Title】Initial Results of a Phase 1 Dose Escalation Study of LP-168, a Novel Covalent and Non-Covalent Next-Generation Inhibitor of Bruton’s Tyrosine Kinase
【Publication Number】328
【Session】642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: New Inhibitors and Cellular Therapies for Treatment of Relapsed CLL
【Time & Location】Saturday, December 9, 2023: 4:00 PM-5:30 PM, Grand Hall D (Manchester Grand Hyatt San Diego)
【Presenter】Dr. Jennifer Woyach
【Abstract highlight】
Methods: NCT04775745 is a multicenter phase 1 dose escalation study of LP-168 monotherapy in patients with relapsed/refractory B-cell malignancies and ≥2 prior therapies. Dose escalation was performed using “3+3” design with expansion at multiple doses.
Results: By Jul 10, 2023, 43 DLT-evaluable patients were enrolled, including 35 with CLL, at doses 100-300 mg daily as well as 150 mg twice daily. CLL patients enrolled had received a median of 3 prior therapies, with 94% received one and 11% received one ncBTKi, respectively.
In this study, no DLT has been observed, and most AE have been low grades. Serious AE were seen in 11 patients. AE frequency did not increase with increasing doses. Overall response rate (ORR) at all dose levels was 54.5% (18/33), and all were partial response (PR) or partial response with lymphocytosis (PR-L). When evaluating patients at doses of 200 mg or higher, the ORR was 66.7% (10/15). In the subgroup of patients who had received only one prior BTKi at all dose levels, the ORR was 77.8% (14/18). In the subgroup of patients with both BTK C481 and T474 mutations at doses of 150 mg BID or 300 mg QD, the ORR was 75% (3/4). At the time of this report, only 5 patients with CLL have been off the study for progressive disease.
Pharmacokinetics showed that plasma exposure of LP-168 was increased dose-dependently. BTK occupancy is nearly at 100% at dose all tested levels, with little variation among different patients. Collective review demonstrates optimal Cmax to be achieved at either 200 or 300 mg dosed daily.
Conclusions: LP-168 has been well tolerated in this study, with no DLTs identified at doses up to 300 mg daily. Preliminary efficacy was observed in high risk CLL patients, including those treated with one or more BTKi. Considering safety, efficacy, and PK/PD, dose expansion will occur at 200 mg and 300 mg daily following the FDA Project Optimus guidelines to determine the recommended phase 2 dose. A separate cohort will enroll patients with BTK gatekeeper mutations to further explore efficacy. Updated biomarker, safety, and efficacy data will be presented at the meeting.
【ASH website link】
https://ash.confex.com/ash/2023/webprogram/Paper186432.html
LP-168 preclinical presentation details:
【Title】Targeting Covalent and Non-Covalent BTKi-Resistant CLL Using the Dual Irreversible/Reversible 4th Generation BTK Inhibitor LP-168
【Publication Number】416
【Session】605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Targeted Therapy in Lymphoid Leukemia
【Time and Location】Sunday, December 10, 2023: 9:30 AM-11:00 AM, Grand Hall B (Manchester Grand Hyatt San Diego)
【Presenter】Dr. Britten Gordon
【Abstract highlight】
Background: Treatment of chronic lymphocytic leukemia (CLL) has been transformed with targeted therapies including inhibitors of Bruton’s tyrosine kinase (BTKi) but most patients eventually relapse. LP-168 is a novel ultra-selective 4th generation BTKi with an active warhead capable of covalent interaction with WT BTK or non-covalent binding when a BTK C481 mutation is present.
Results:LP-168 demonstrated selectivity towards BTK. LP-168 displayed nanomolar potency towards both WT BTK (IC50=0.11 nM) and C481S BTK (IC50=1.0 nM). Irreversible binding of BTK was confirmed. LP-168 inhibited BCR signaling in primary CLL B cells at increasing concentrations, demonstrated by reduced phosphorylation of BTK (92%, p<0.0001, n=8) and its immediate downstream target PLCγ2 (41%, p=0.0013, n=8). Migration capacity of primary CLL cells towards CXCL12 and CXCL14 was also found to decrease with LP-168 (52%, p<0.001, n=10 and 51%, p<0.001, n=10, respectively). LP-168 was able to induce cytotoxicity of primary CLL cells alone and in co-culture with HS-5 stromal cells in a dose-dependent manner, with similar or improved efficacy to other BTKi. LP-168 decreased CLL cell production of CCL3 and CCL4 chemokines (CCL3: 93%, p<0.001, n=8; CCL4: 93%, p<0.001, n=8). LP-168 also demonstrated modest cytotoxicity towards TMD8 cells harboring either C481S BTK (24%, p=0.0008, n=3) or T474I BTK (13%, p=0.0690, n=3), as well as decreased production of CCL3 (C481S: 95%, p<0.0001, n=3; T474I: 99%, p<0.0001, n=3) and CCL4 (C481S: 97%, p<0.0001, n=3; T474I: 98%, p<0.0001, n=3) (Figure 1A). Further, we observed inhibition of downstream BCR signaling in primary CLL B cells harboring C481S via immunoblotting and cytokine production. Finally, to evaluate the in vivo efficacy of LP-168 in both the Eµ-TCL1 and Eµ-MTCP1 models. We treated mice daily via oral gavage and found that 50 mg/kg of LP-168 significantly improved survival in the Eµ-TCL1 model when compared to vehicle (median 51 vs 44 days; p=0.0018) or ibrutinib at 50 mg/kg (median 51 vs 45 days; p=0.0098) and the Eµ-MTCP1 model when compared with vehicle (median 122 vs 62 days; p<0.0001) or ibrutinib at 50 mg/kg (median 122 vs 96 days; p=0.0162)
Conclusions: Collectively, our data demonstrate that LP-168 is a potent and selective inhibitor of BTK with activity against CLL, even in the presence of mutations that mediate resistance to cBTKi and ncBTKi. These data support the continued preclinical and clinical investigation of LP-168.
【ASH website link】
https://ash.confex.com/ash/2023/webprogram/Paper178259.html