aplitabart (IGM-8444)

The combination of DR5 agonists and commonly used chemotherapeutic agents, such as doxorubicin, can promote cell death...There are currently two ongoing clinical trials focusing on the activation of DR5, namely, IGM-8444 and INBRX-109, which have progressed to phase 2. Further modifications of TRAIL delivery with fusion to single-chain variable fragments (scFv-TRAIL), directed against tumor-associated antigens (TAAs), and in the use of stem cells focus on targeted TRAIL delivery to cancer cells using bi-functional strategies. In vitro, in vivo, and clinical trials, as well as advances in imaging and theranostics, indicate that targeting DR5 remains a valid strategy in the treatment of some relapsed and refractory cancers.

P1, N=272, Active, not recruiting, IGM Biosciences, Inc. | Recruiting --> Active, not recruiting | N=430 --> 272

P1, N=430, Recruiting, IGM Biosciences, Inc. | Trial completion date: Jan 2027 --> Aug 2027 | Trial primary completion date: Nov 2026 --> Jun 2026

P1, N=430, Recruiting, IGM Biosciences, Inc.

P1, N=430, Recruiting, IGM Biosciences, Inc. | Phase classification: P1a/1b --> P1

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.

Indeed, we have demonstrated enhanced anti-tumor efficacy by combining IGM-8444 with chemotherapies such as 5-FU and irinotecan in colorectal cancer models, as well as combining with Bcl-2 inhibitor ABT-199 in hematological malignancy models. In summary, we have evaluated the mechanism by which IGM-8444 agonizes DR5, which potently kills tumor cells without accompanying hepatotoxicity. IGM-8444 is currently being evaluated in a Phase 1 study as a single agent and in combination with chemotherapy-based regimens in patients with solid cancers and NHL (NCT04553692).

Combinations with chemotherapy including cytarabine and doxorubicin or targeted agents such as Bcl-2 inhibitor ABT-199 resulted in synergistic in vitro cytotoxicity in multiple cell lines, as determined by Bliss synergy scores. Conclusions : These data support the clinical development of IGM-8444 in hematological malignancies as a single agent, in combination with standard of care chemotherapy, and in combination with targeted agents that impact the intrinsic signaling pathway such as Bcl-2 inhibitor ABT-199. Initiation of a Phase I clinical study evaluating the safety of IGM-8444 is anticipated in 2020.