ozekibart (INBRX-109)

P1, N=321, Recruiting, Inhibrx Biosciences, Inc | N=240 --> 321 | Trial completion date: Jul 2026 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Jun 2026

Among new approaches, DR5 agonists such as INBRX-109 have shown single-agent efficacy, with minimal toxicity, opening possibilities for use in combination therapies to improve outcomes...The integration of multi-targeted approaches could enhance efficacy, address tumour heterogeneity, and overcome resistance, presenting a hopeful direction for systemic therapy in this challenging cancer. The investigation of combination regimens with IDH inhibitors, immunotherapy and DR5 agonists hold promise for transforming the management of advanced chondrosarcoma.

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.

P2, N=201, Recruiting, Inhibrx, Inc. | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Feb 2024 --> Dec 2024

P1, N=240, Recruiting, Inhibrx, Inc. | Trial completion date: Dec 2024 --> Jul 2026 | Trial primary completion date: Aug 2024 --> Dec 2025

INBRX-109 demonstrated encouraging antitumor activity with a favorable safety profile in patients with unresectable/metastatic chondrosarcoma. A randomized, placebo-controlled, phase 2 trial (ChonDRAgon, NCT04950075) will further evaluate INBRX-109 in conventional chondrosarcoma.

Irinotecan (IRI) and temozolomide (TMZ) are frequently used in the relapsed setting, but prognosis remains poor. INBRX-109+IRI/TMZ led to high response rates in pts with EWS (71%) and DSRCT (33%), with an ORR of 60% in cohort C3; no grade ≥2 hepatotoxicity or significant AEs leading to discontinuation were observed. Our findings support further evaluation of INBRX-109+IRI/TMZ in these tumors. Cohort C3C is now enrolling (n≈10) at the RP2D of 3 mg/kg.

Herein, we report that SDH-def tumors are sensitive to TMZ, which induces ER stress and upregulates DR5, a pro-apoptotic receptor that can be targeted by INBRX-109 (Figure 1). In turn, TMZ+INBRX-109 additively/synergistically reduces SDH-def GIST cell viability in vitro. These data provide the preclinical evidence for a Phase I clinical trial (3+3 dose escalation design with two dosing cohorts, NCT03715933) to study the safety/tolerability of TMZ+INBRX-109 in patients with aggressive SDH-def cancers, including GIST (Figure 2).

Designed to achieve a best-in-class therapeutic index, INBRX-109 induces robust apoptosis of cancer cells in vitro and in vivo while sparing healthy tissues. INBRX-109 was well tolerated and had anti-tumor activity in unresectable/metastatic conventional chondrosarcoma in a phase I study and is currently being evaluated in a blinded, placebo-controlled pivotal phase II trial.

INBRX-109 demonstrated anticancer activity in unresectable or metastatic CS, regardless of IDH mutation status, with a longer median PFS compared with limited historical data (7.6 vs < 4 mo). Such tumor reductions are rarely observed in this indication, which lacks an effective systemic therapy. The observed safety profile was favorable and consistent with prior results.

Additionally, INBRX-109 used in combination with SN-38, the active metabolite of irinotecan (IRI), demonstrated synergistic activity across multiple ES model cell lines...Initiation of an ES expansion cohort to explore INBRX-109 combined with IRI and temozolomide (IRI/TMZ) is under way. A 3-part, phase 1 study (NCT03715933) evaluating the safety and efficacy of INBRX-109 in patients with advanced/metastatic solid tumors was initiated in November 2018 (Figure)... This is a trial in progress. No conclusions can be drawn at this time.

This is a trial in progress. No conclusions can be drawn at this time.

Based on this encouraging pre-clinical data, we are planning to initiate an Ewing sarcoma expansion cohort to explore the combination of INBRX-109 with irinotecan and temozolomide (IT). Encouraging pre-clinical anti-cancer activity warrants further investigation of INBRX-109 in unresectable or metastatic Ewing sarcoma in combination with irinotecan based chemotherapy. The Ewing sarcoma cohort is planned to start in 2H 2021 and any clinical updates if available will be shared at the CTOS meeting in November 2021.

Encouraging early anti-cancer activity supports the continued investigation of INBRX-109 in unresectable or metastatic conventional chondrosarcoma. In January 2021, the U.S. Food and Drug Administration (FDA) granted Fast Track designation to INBRX-109 for the treatment of patients with unresectable or metastatic conventional chondrosarcoma. A randomized, blinded, placebo-controlled, Phase 2 trial of INBRX-109 in this indication is planned to open for enrollment in the 2nd half of 2021 in the U.S. Clinical trial applications in select European countries and the UK are planned to be filed later in 2021.

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.