ACE723 IND Clearance: Novel GPC3 ADC Enters Clinic With No Clinical Precedent and High Evidentiary Distance

FDA Clears Acepodia's IND for Novel Dual-Payload ADC ACE723

Acepodia announced that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for ACE723. This GPC3-targeted dual-payload antibody-drug conjugate (ADC), developed using Acepodia’s proprietary Antibody-Dual-Drugs Conjugation (AD2C) platform, is intended for the treatment of unresectable or metastatic hepatocellular carcinoma (HCC). The clearance enables Acepodia to advance ACE723 into Phase 1 clinical development, marking a significant milestone for the AD2C platform and bringing its first candidate into the clinic. The planned Phase 1 study will evaluate the safety, pharmacokinetics, and preliminary anti-tumor activity of ACE723 in patients with HCC.

• The FDA's IND clearance for ACE723 signifies a critical milestone for Acepodia's proprietary Antibody-Dual-Drugs Conjugation (AD2C) platform, marking the first candidate generated from this technology to enter clinical development. This advancement underscores the platform's capability to develop innovative, highly effective cell therapies and antibody-drug conjugates for oncology.
• ACE723 is designed as a GPC3-targeted dual-payload antibody-drug conjugate, engineered to deliver two distinct cytotoxic payloads directly to GPC3-expressing tumor cells. This innovative approach aims to address key challenges such as tumor heterogeneity and potential resistance mechanisms often observed with single-payload therapies, offering a differentiated strategy for patients with unresectable or metastatic hepatocellular carcinoma.
• Hepatocellular carcinoma (HCC) represents over 70% of liver cancer cases worldwide, and despite recent advancements in immunotherapy, a substantial unmet medical need remains for patients experiencing disease progression or resistance to existing treatments. ACE723's novel mechanism of action seeks to provide a new, effective therapeutic option for this challenging patient population, potentially improving outcomes where current therapies fall short.

ACE723's Entry into a Dynamic HCC Treatment Landscape

The treatment landscape for unresectable or metastatic hepatocellular carcinoma (HCC) has undergone substantial transformation, driven by the emergence of immune checkpoint inhibitor (ICI)-based combination regimens. Sorafenib and lenvatinib had long anchored first-line systemic therapy, with lenvatinib demonstrated to be non-inferior to sorafenib. The approval of atezolizumab plus bevacizumab marked a pivotal shift, as this combination showed significantly longer overall survival and progression-free survival compared to sorafenib, establishing it as a leading first-line approach for unresectable HCC. Subsequently, durvalumab ± tremelimumab (DT/D) joined atezolizumab/bevacizumab (A/B) as preferred first-line regimens, both sharing an anti-PD-L1 backbone, though differing in their anti-angiogenic mechanisms. The phase 3 CARES-310 trial further expanded the first-line armamentarium, demonstrating that camrelizumab plus rivoceranib significantly improved median progression-free survival (5.6 months vs. 3.7 months; HR 0.52) and median overall survival (22.1 months vs. 15.2 months; HR 0.62) compared to sorafenib, presenting as a new and effective first-line treatment option.

A meta-analysis of eight phase 3 trials — IMbrave150, ORIENT-32, COSMIC-312, CARES-310, LEAP-002, SCT-I10A-C301, HEPATORCH, and APOLLO — encompassing 4,379 patients confirmed that ICI plus targeted therapy (ICI-TT) combination regimens demonstrated significantly improved objective response rate (OR 3.93; 95% CI 2.64–5.85), progression-free survival (HR 0.62; 95% CI 0.54–0.71), and overall survival (HR 0.71; 95% CI 0.62–0.82) compared to sorafenib or lenvatinib monotherapy. The risk of grade 3–5 treatment-related adverse events was not significantly increased with combination therapy (RR 1.13; 95% CI 0.96–1.33), though combination therapy was associated with a significantly higher risk of serious treatment-related adverse events (RR 1.97; 95% CI 1.50–2.60). A network meta-analysis comparing anti-PD-1/L1 plus anti-VEGF antibody (A+A) regimens against anti-PD-1/L1 plus VEGFR-targeted tyrosine kinase inhibitor (A+T) regimens found that A+A carried the greatest probability of delivering the longest overall survival (rank probability 96%), while A+T showed the greatest effect in prolonging progression-free survival and improving objective response rate (rank probability 77%), though without statistically significant differences between the two strategies. Notably, A+A demonstrated a superior safety profile compared to A+T for both all-grade treatment-related adverse events (RR 0.91; 95% CI 0.82–1.00) and grade ≥3 events (RR 0.65; 95% CI 0.54–0.77).

The increasing complexity of first-line options has also intensified scrutiny of differential safety profiles and sequencing strategies. A multicenter retrospective study comparing A/B with DT/D found that overall and high-grade (≥3) bleeding events were more frequent and occurred earlier with A/B — 22.8% vs. 13.3% for any-grade bleeding (p=0.016) and 14.5% vs. 7.3% for high-grade bleeding (p=0.027) — with multivariate regression confirming that A/B treatment was independently associated with increased bleeding risk (p=0.010), an effect attributed to the anti-VEGF component. In the second-line setting, regorafenib, cabozantinib, ramucirumab (for patients with alpha-fetoprotein ≥400 ng/mL), nivolumab, pembrolizumab, and ipilimumab plus nivolumab are approved following sorafenib, though no direct comparisons among these agents exist and inclusion criteria across second-line trials remain heterogeneous. The timing and sequencing of treatment switches are described as key to optimizing patient outcomes, with decisions informed by reasons for discontinuation and disease progression patterns.

Persistent Unmet Needs in Advanced HCC Treatment

Despite meaningful advances in first-line immunotherapy-based regimens, several critical gaps in patient management for unresectable or metastatic hepatocellular carcinoma (HCC) have emerged over the past three years. These gaps span treatment sequencing, patient subgroup optimization, and the identification of predictive biomarkers to guide individualized therapy.

• Optimal second-line sequencing after immunotherapy progression. As atezolizumab plus bevacizumab has become a standard first-line regimen, evidence on subsequent therapies remains limited. Real-world data from the CHIEF cohort show that only 42.1% of atezolizumab-bevacizumab-treated patients accessed second-line therapy following progression, and comprehensive head-to-head comparisons to establish the ideal treatment sequence are lacking. Most evidence guiding second-line therapy has been derived from post hoc analyses, real-world data, and select prospective studies, primarily based on phase II designs.

• Patients with impaired liver function (Child-Pugh B/C). Patients with advanced cirrhosis represent a persistently underserved population. ICI-based therapies conferred a survival benefit primarily in patients with preserved liver function (Child-Turcotte-Pugh A: OS HR = 0.82; 95% CI: 0.71–0.95; PFS HR = 0.76; 95% CI: 0.63–0.92), while patients with impaired liver function (CTP B/C) did not receive significant benefit. Real-world data confirm that Child-Pugh B patients show similar objective response rates but shorter OS and PFS compared to patients with preserved liver function.

• Non-viral and HCV-related HCC. Subgroup analyses reveal that ICI-based regimens provide significant survival benefit in HBV-related HCC (HR = 0.70; 95% CI: 0.60–0.82), while no statistically significant advantage was observed in HCV-related or non-viral HCC. The heterogeneity in outcomes by viral etiology underscores the need for personalized treatment approaches based on the viral background of HCC patients.

• HCC with portal vein tumor thrombosis (PVTT). PVTT occurs in 21% of HCC patients at one year and 46% at three years and is consistently associated with poor prognosis. There is a lack of global consensus or established protocols regarding the optimal management of HCC with associated PVTT, and AFP >400 ng/mL has been identified as an independent predictor for the presence of PVTT (OR, 4.08; 95% CI, 2.34–7.12; P < 0.001).

• Predictive biomarker development. The neutrophil-to-lymphocyte ratio (NLR), with a ROC-optimised cut-off of 3.20, has been identified as the strongest independent predictor of objective response rate and PFS with atezolizumab plus bevacizumab, and AFP >400 ng/mL is an independent predictor of survival in patients receiving any form of therapy (HR = 2.23; 95% CI = 1.19–4.18, P = 0.012). Nonetheless, the search for an ideal biomarker in HCC continues, with ongoing research investigating novel targets including fibroblast growth factor 19 and glypican-3.

• Patients ineligible for standard systemic therapies. A subset of patients with unresectable HCC are ineligible for or intolerant to conventional treatments. Real-world data on agents such as icaritin-based regimens suggest certain efficacy and a favorable safety profile in this population, with combination therapy achieving a disease control rate of 93.8%, a median PFS of 5.7 months, and a median OS of 10.6 months, though evidence remains limited to small retrospective analyses.

Dual-Payload ADC Enters Clinic for HCC: A New Frontier

The recent IND clearance for Acepodia's ACE723 marks a significant step forward in the pursuit of more effective treatments for unresectable or metastatic hepatocellular carcinoma (HCC), a disease with substantial unmet medical needs. ACE723 is notable for being a Glypican-3 (GPC3)-targeted dual-payload antibody-drug conjugate (ADC), representing an evolution in targeted therapy design.

Research into dual-payload strategies, whether with ADCs or small-molecule drug conjugates (SMDCs), suggests a promising path to enhance therapeutic efficacy. Studies indicate that these multi-payload constructs can offer superior cytotoxicity and improved tumor suppression compared to their single-payload counterparts. This approach aims to address critical challenges in cancer therapy, such as tumor heterogeneity and the development of resistance, by potentially delivering a more potent and comprehensive attack on cancer cells while minimizing off-target diffusion and systemic toxicity. The successful progression of ACE723 into Phase 1 trials also serves as a crucial validation for Acepodia's proprietary AD2C platform, signaling its potential to generate a pipeline of innovative targeted therapies.

However, the path forward is not without its complexities. While GPC3 is widely recognized as an attractive target due to its high expression in HCC, existing literature presents a nuanced picture. One study, for instance, found that GPC3 positivity was associated with decreased overall survival and lower objective response rates in HCC patients treated with atezolizumab-bevacizumab. This suggests that the role of GPC3 as a predictive biomarker for response to targeted therapies may require careful consideration and patient stratification. Furthermore, ACE723 enters a competitive landscape, with other GPC3-targeted modalities, including CAR T-cell therapies and alpha-therapies, already in various stages of clinical development. Early-phase CAR T-cell trials in heavily pretreated advanced HCC patients have shown preliminary anti-tumor activity but with modest objective response rates, underscoring the challenge of achieving significant clinical benefit in this difficult-to-treat population. The Phase 1 study for ACE723 will be critical in establishing its safety profile and preliminary anti-tumor activity, providing essential insights into whether this novel dual-payload approach can truly expand the therapeutic window and offer a meaningful advantage for patients with advanced HCC.