LP-118

P1, N=100, Recruiting, Newave Pharmaceutical Inc | Trial completion date: Aug 2024 --> Oct 2025 | Trial primary completion date: Aug 2024 --> Oct 2025

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 in clinic. Conclusion LP-118 showed encouraging anti-MCL activity as single agent and in combination with standard of care agents in vitro and in vivo, warranting further evaluation of these combinations in clinical trials.

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.

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).

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 hematological malignancies. Future in vitro and in vivo animal studies will continue to evaluate drug combinations that best overcome drug resistance to anti-apoptotic treatment.

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).

P1, N=76, Recruiting, Guangzhou Lupeng Pharmaceutical Company LTD. | Not yet recruiting --> Recruiting

P1, N=100, Recruiting, Newave Pharmaceutical Inc | Not yet recruiting --> Recruiting

P1, N=76, Not yet recruiting, Guangzhou Lupeng Pharmaceutical Company LTD.

P1, N=100, Not yet recruiting, Newave Pharmaceutical Inc | Initiation date: May 2021 --> Aug 2021