LP-118 / Lupeng Pharma - LARVOL DELTA

A Study of LP-118 in Patients With Advanced Tumors (clinicaltrials.gov) - P1 | N=68 | Completed | Sponsor: Guangzhou Lupeng Pharmaceutical Company LTD. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2025 ➔ Jul 2025

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

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

Profiling drug sensitivity in CLL B cells after BTK inhibitor progression using a novel drug panel (ASH 2025) - " Using the Mayo Clinic CLL Database and the Mayo Clinic CLL Tissue Bank, we identified 47 patients with RR CLL, all of whom experienced disease progressionon a BTKi (35 ibrutinib +/- CD20 antibody, 10 acalabrutinib +/- CD20 antibody, 2 other)...We also observed that RR CLL cohort exhibited significantly increased drug resistance to most of the tested drugs in the presence of BMSCs with corresponding increases in IC50s (with vs. without BMSCs, fold-change respectively): LP-118 3.92-fold, venetoclax 1.98-fold, carfilzomib 2.58-fold, TP-0903 1.65-fold, panobinostat 204.23-fold, TCIP1 1.91-fold, crenolanib 1.31-fold, idasanutlin 1.69-fold, belinostat 6.14-fold, LP-168 1.29-fold, eprenetapopt 3.44-fold and GTE 1.08-fold (11 out of 12 with p -values <0.05 except for GTE which was not significant, Mann-Whitney U test)... Our results highlight the spectrum of currently available drugs that show promise for therapeutic use in patients with RR CLL who experience disease..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • AXL • BCL2 • STAT6 • TP53

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

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