LP-118 / Lupeng Pharma - LARVOL DELTA

Pre-Clinical Evaluation of a New-Generation Orally Bioavailable Dual Bcl-2/Bcl-Xl Inhibitor LP-118 in Mantle Cell Lymphoma (ASH 2023) - "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...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...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..."

IO biomarker • Preclinical • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • Solid Tumor • BCL2 • BCL2L1

Trial in progress: A Phase I/II study to investigate the combination of LP-118, ponatinib, vincristine and dexamethasone (LPVd regimen) in relapsed/refractory T-ALL/lbl (ASH 2025) - P1/2 | "A previousphase 1b/2 study of venetoclax, navitoclax and chemotherapy in R/R T-ALL showed 50% CR rate.Therefore, we anticipate a CR rate of 30% in our study, which combines LP-118 with similarchemotherapy backbone. We will include 6 patients from phase 1 portion in our efficacy analysis.Several correlative studies are planned to identify biomarkers of response and resistance, including BH3profiling, molecular genetic profiling (DNA- and RNA-seq), and pre-TCR signaling activity in baseline vsrelapse samples. This investigator-initiated trial is funded by the Leukemia Lymphoma Society AcademicClinical Trials grant."

IO biomarker • P1/2 data • Acute Lymphocytic Leukemia • Anorexia • Constipation • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Rare Diseases • T Acute Lymphoblastic Leukemia • BCL2 • BCL2L1 • TRB

Genome-Wide CRISPR/Cas9 Knockout Screen Reveals Novel LP-168 (Rocbrutinib) Combinations Targeting BCL-2 Protein Members for Chronic Lymphocytic Leukemia (ASH 2024) - "As BCL-2 interacts with both pathways, and was amongst the top-ranking genes depleted, we chose to target it with either venetoclax (BCL-2i) or with LP-118, a dual BCL-2/-xL inhibitor currently under investigation for R/R hematological malignancies. Conclusions : These data show combined use of LP-168 with pharmacological inhibitors targeting BCL-2 and BCL-xL display synergistic activity in CLL, even in the presence of mutations that mediate resistance to BTKi and BCL-2i. These data are consistent with clinical data showing dual targeting of BTK, with previous generation inhibitors, and BCL-2 has been effective in the clinic, with many patients achieving uMRD and prolonged remission off therapy and supports continued preclinical and future clinical investigation of LP-168 with inhibitors of BCL-2 and BCL-2/-xL."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BCL2 • BCL2L1

A Study of LP-118 in Patients With Advanced Tumors (clinicaltrials.gov) - P1 | N=96 | Active, not recruiting | Sponsor: Guangzhou Lupeng Pharmaceutical Company LTD. | Trial primary completion date: Jan 2025 ➔ Jul 2025

Trial primary completion date • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • BCL2

A Study of LP-118 in Patients with Advanced Tumors (clinicaltrials.gov) - P1 | N=96 | Active, not recruiting | Sponsor: Guangzhou Lupeng Pharmaceutical Company LTD. | Recruiting ➔ Active, not recruiting | Trial completion date: Jul 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2023 ➔ Jan 2025

Enrollment closed • Metastases • Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • BCL2

LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclax-resistant chronic lymphocytic leukemia. (PubMed, Haematologica) - "Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax responsive and relapsed CLL."

IO biomarker • Journal • Chronic Lymphocytic Leukemia • Leukemia • Lymphoma • Oncology • BCL2 • BCL2L1

Study of Oral Administration of LP-118 in Patients With Relapsed or Refractory CLL, SLL, MDS, MDS/MPN, AML, CMML-2, MPN-BP, ALL, MF, NHL, RT, MM or T-PLL. (clinicaltrials.gov) - P1 | N=100 | Recruiting | Sponsor: Newave Pharmaceutical Inc | Trial completion date: Aug 2024 ➔ Oct 2025 | Trial primary completion date: Aug 2024 ➔ Oct 2025

Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Non-Hodgkin’s Lymphoma • Oncology • Prolymphocytic Leukemia • Richter's Syndrome • Small Lymphocytic Lymphoma • BCL2

Targeting Bcl-2/Bcl-xl for small cell lung cancer treatment with LP-118 (AACR 2024) - P1 | "Overall, LP-118 is more potent than ABT-263 in Bcl-2 or Bcl-2/Bcl-xl co-dependent cell lines, and it is relatively less active in Bcl-2/Bcl-xl/Mcl-1 co-dependent cell lines, such as NCI-H69 (IC50: 169.7 nM). In addition, combinations of LP-118 and SN-38 (the active metabolite of irinotecan), topotecan, or etoposide, induced strong synergist effects in both NCI-H69 and NCI-H146 cell lines, suggesting that LP-118 could enhance the cytotoxicity of these drugs...Moreover, LP-118 plus carboplatin or topotecan dramatically inhibited tumor growth of NCI-H526 xenograft models and has significantly better efficacy than either carboplatin or topotecan alone...Clinical trials are ongoing to further evaluate the safety and efficacy of LP-118 in hematological cancers and solid tumors, including SCLC. Additional studies are also underway to develop predictive biomarkers for facilitating patient stratification in the clinic."

IO biomarker • Endocrine Cancer • Hematological Malignancies • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • BCL2 • BCL2L1 • MCL1

LP-118, a Novel BCL2 Inhibitor, Shows Potent in Vitro Anti-Myeloma Activity (ASH 2022) - P1 | "LP-118 is a novel BCL-2/BCL-XL inhibitor, which has a modified structure with fine-tuned BCL-XL activity that minimizes platelet toxicity, associated with other BCL-XL inhibitors, such as navitoclax...In cell lines with acquired venetoclax resistance, the combinations of LP-118 with bortezomib or dexamethasone also showed promising synergistic activity, but requiring higher doses of both compounds in comparison to their venetoclax-sensitive counterparts. Based on recent literature showing a direct link of venetoclax sensitivity to electron transport chain activity, co-treatment with IACS-010759, a mitochondrial complex I inhibitor, was also tested, showing moderate enhancement of anti-BCL-2 activity. However, best results were seen when targeting the compensatory upregulation of MCL-1 with S63845, an MCL-1 inhibitor...An ongoing phase 1 dose-escalation trial (NCT04771572) is underway evaluating safety and tolerability in patients with relapsed or refractory..."

IO biomarker • Preclinical • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • ANXA5 • BCL2L1

LP-118, a Selective Bcl-2 Inhibitor with Tuned Bcl-Xl Activity, Causes Myeloid Differentiation and Cell Death in Acute Myeloid Leukemia (AML) (ASH 2022) - P1 | "After 60 days, the median OS of LP-118+gilteritinib (15.24 mg/kg PO daily) was not reached and showed increased OS compared to azactidine+gilteritinib and venetoclax+azacitidine. Finally, LP-118 induces myeloid differentiation, to our knowledge a novel mechanism of action of bcl-2/bcl-xL inhibition in AML. These data support the recently initiated AML clinical trial (NCT04771572)."

IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2A1 • BCL2L1 • BCL2L2 • CASP3 • CD34 • ITGAM • MCL1 • PTPN11

Characterization of LP-118, a Novel Small Molecule Inhibitor of Bcl-2 and Bcl-Xl in Chronic Lymphocytic Leukemia Resistant to Venetoclax (ASH 2021) - P1 | "LP-118 was rationally designed to have an enzymatic IC 50 for Bcl-xL at 10.1 nM which was in-between venetoclax (62.2 nM) and navitoclax (2.9 nM) to prevent the on-target effects of platelet toxicity. 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)."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL2L1 • CD19 • CD5 • MCL1 • TP53

Targeting Apoptosis with Novel BH3 Mimetics in T-Lineage Acute Lymphoblastic Leukemia (ASH 2022) - P1 | "A phase 1 study of venetoclax (BCL-2 inhibitor) plus navitoclax (BCL-2/BCL-XL inhibitor) and chemotherapy resulted in a complete remission rate of 53%, considerably higher than historic controls. Our data show maturation stage-specific differences in antiapoptotic protein dependencies in ETP- vs T-ALL, that correlate with their responses to individual BH3 mimetics. Based upon this work, we believe that dual targeting of BCL-2 and BCL-XL is a promising approach for further clinical development in both types of T-lineage ALL. Additionally, the dose limiting toxicity of myelosuppression observed with navitoclax may be overcome with the novel dual inhibitor, LP-118."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • Thrombocytopenia • BCL2L1 • CD34 • CD7

A phase I/Ib study evaluating the safety, pharmacokinetics, and preliminary efficacy of LP-118 in subjects with relapsed or refractory haematological malignancies (ESMO 2022) - P1 | "2017) The inhibitory effect of LP-118 on the targets BCL-2 and BCL-XL is carefully adjusted to be between that of navitoclax and venetoclax with the aim of minimizing BCL-XL on-target platelet toxicity while retaining and improving antitumor efficacy. The safe starting dose of LP-118 calculated from non-clinical toxicity studies is 50 mg/d. To mitigate risk of TLS, an accelerated step-up dosing schedule of LP-118 will be used to reach the target dose for each cohort."

Clinical • IO biomarker • P1 data • PK/PD data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • BCL2L1