LP-108

P1, N=36, Active, not recruiting, Newave Pharmaceutical Inc | Recruiting --> Active, not recruiting

Background: The effectiveness of BCL-2 inhibition in hematologic malignancies has been demonstrated by venetoclax, a globally approved BCL-2 inhibitor that requires weekly dose ramp-up to mitigate the risk of tumor lysis syndrome (TLS) and its efficacy in Chinese patients with non-Hodgkin lymphomas (NHL) is obscure. LP-108 was well tolerated up to 800 mg/day with daily dose ramp-up schedule and showed encouraging antitumor activity in multiple types of B-cell NHL, even in those who had prior BTKi exposure. BCL2, Phase I, Non-Hodgkin's lymphoma, Chronic lymphocytic leukemia

LP-108 is an oral highly potent and selective inhibitor of BCL-2 with comparable or more potent in vitro inhibitory activity compared to the FDA approved oral BCL-2 inhibitor venetoclax. LP-108 as monotherapy and in combination with azacitidine was overall well tolerated with an acceptable safety profile for r/r MDS, CMML, and AML pts. Notably, the combination was associated with encouraging efficacy including ORR and PFS. Swimmers' plot of patients in Arm 1 (A) and Arm 2 (B).

P1, N=36, Recruiting, Newave Pharmaceutical Inc | Trial completion date: Dec 2022 --> Jan 2025 | Trial primary completion date: Dec 2022 --> Jan 2025

P1, N=36, Recruiting, Newave Pharmaceutical Inc | Trial primary completion date: Jun 2022 --> Dec 2022

However, 10–50% of newly diagnosed patients with AML may not respond to venetoclax and HMA or LDAC, and 3–15% patients may not respond to venetoclax with intensive or non-intensive chemotherapy.1–6 In addition, up to 40% of responding patients may relapse with low rates of response of 20% to salvage therapy and poor overall survival of 2 months after relapse.7 Clinical and biological factors associated with primary and acquired resistance to venetoclax include secondary AML, monocytic differentiation, complex cytogenetics, mutations in TP53, BAX, dependence on other anti- apoptotic proteins, altered metabolism of nicotinamide, fatty acids, and oxidative phosphortylation.3,8–14 Several novel inhibitors of BCL-2 are currently being tested in clinic, including BGB 11417, APG-2575, LP-108 and others...There is strong pre-clinical rationale for targeting MCL-1 alone as well as in conjunction with BCL-2 inhibition in AML.15 Recently several selective and highly potent MCL-1 inhibitors have entered pre-clinical and clinical development including S63845, AZD5991, AMG397, and others. Questions remain regarding the therapeutic window of these inhibitors given the important physiologic role of MCL-1 in vital organs and early reports of cardiac adverse events from the AMG176 phase 1 trial.15,16 Multiple pre-clinical studies have expectedly shown synergism between BCL- 2 and MCL-1 inhibition making it a promising path for clinical development of these agents.17,18 Multifactorial challenges in design of specific MCL-1 inhibitors also led to interest in compounds which downregulate MCL-1 expression. Cyclin dependent kinase (CDK) inhibitors including alvocidib, dinaciclib, voruciclib are in various stages of evaluation. Although addition of alvocidib to intensive chemotherapy improved response rates but failed to improve event-free or overall survival.19 Novel CDK inhibitors are currently in early phase trials including AZD4573, CYC065, TG02-101, and others. Inhibition of Nedd8 activating enzyme has complex repercussions for the intrinsic apoptotic pathway with eventual increase in Noxa leading to MCL-1 neutralization.20 Pevonedistat has shown promising early results in AML and myelodysplastic syndrome and is being investigated multiple clinical trials for solid tumors as well. BCL-xL Inhibition Another anti-apoptotic protein BCL-xL had been long recognized as a potential therapeutic target in AML, in particular AML from preceding MPN and AML recurrent post venetoclax failure, but toxicity of earlier inhibitors precluded clinical development.21–23 Recently, AZD0466, a dual BCL-2/xL inhibitor with a favorable therapeutic index and robust activity has been developed and is undergoing pre-clinical development and planned for phase iin hematological malignancies.24 Targeting the Extrinsic Apoptosis Pathway Inhibitor of apoptosis protein (IAP) inhibition: X-linked IAP (XIAP), cellular IAP (cIAP) and survivin have been of long- standing interest in AML. Prior clinical trials with XIAP inhibitor AEG35156, cIAP targeting agent birinapant, and survivin targeting agent LY2181308 have not succeeded in clinc.16,25 ASTX660 is a dual antagonist of XIAP and cIAP which is currently being investigated in phase 1/2 trials in solid tumors and in combination with HMA in relapsed or refractory AML.26,27 TRAIL Agonism Agonists of the TNF-related apoptosis-inducing ligand (TRAIL) receptors have been tested in AML with low response rates.28,29 Previous agents have had limited success in part due to suboptimal clustering of TRAIL receptors.30 Novel antibodies against TRAILR1 and TRAILR2 including an IgM molecule IGM-8444, a tetravalent compound INBRX-109, and HLX56 are currently in phase 1 trials and preclinical data suggests potential synergy with venetoclax.31 FLIP Inhibition FLICE-like inhibitor protein (FLIP or CFLAR) is a key regulator of the death-inducing signaling complex (DISC) involved in the extrinsic apoptotic pathway...This can be augmented by inhibiting p53 degradation via MDM2, which is often upregulated in AML.34 Idasanutlin in combination with venetoclax showed anti- Figure 1 leukemic activity in the dose finding stage in R/R AML.35 Several other inhibitors of MDM2 and dual MDM2/X inhibitors are currently in various stages of pre-clinical and clinical development including HDM-201, KRT-232, BI-9078282, and others.34 Conclusions Opportunities to target the apoptosis machinery in AML has considerably evolved in the last decade. While venetoclax heralded a paradigm shift for patients, we are now faced with challenges in patients who relapse or remain refractory. We have novel clinical stage compounds to methodologically target different facets of the apoptotic pathway and optimize novel combinations with the goal to improve the cure rates in AML patients.