Huadong Medicine Co., Ltd. announced positive preliminary results from a Phase I study of HDM2005, an independently developed antibody-drug conjugate (ADC) targeting receptor tyrosine kinase-like orphan receptor 1 (ROR1), in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) or classical Hodgkin lymphoma (cHL). The results demonstrated promising efficacy with a favorable safety and tolerability profile, supporting continued clinical development.
Novel Dual-Mechanism ADC Design
HDM2005 represents a unique approach in the ADC landscape, functioning as both a ROR1 modulator and a tubulin inhibitor through its dual mechanism of action. The drug is composed of a humanized IgG1 monoclonal antibody, a proteolytically cleavable linker, and the cytotoxic payload monomethyl auristatin E (MMAE). ROR1 is a transmembrane protein overexpressed in various cancers, including lymphomas, and plays a role in tumor immune evasion.
In preclinical studies, HDM2005 demonstrated potent anti-tumor activity across multiple lymphoma and solid tumor models, driven by its combination of ROR1 targeting and microtubule disruption.
Phase I Trial Results Show Strong Efficacy
The first-in-human Phase I study (NCT06615193) enrolled patients with relapsed or refractory B-NHL or cHL to evaluate safety, tolerability, determine the maximum tolerated dose (MTD) and recommended Phase II doses (RP2Ds), and perform preliminary efficacy evaluation.
As of July 4, 2025, 29 patients were enrolled across dose cohorts of 0.3, 1.0, 1.8, 2.5, and 2.75 mg/kg, including 17 patients with mantle cell lymphoma (MCL), 8 patients with diffuse large B-cell lymphoma (DLBCL), and 4 patients with cHL. Most patients (72.4%) had received three or more prior lines of anti-tumor therapy.
In the 1.8 mg/kg and 2.5 mg/kg cohorts, the objective response rate (ORR) was 50% (6/12) in MCL patients, including 1 complete response (CR) and 5 partial responses (PR). The ORR was 100% (2/2) in cHL patients with complete responses.
Favorable Safety Profile Addresses ADC Toxicity Concerns
The safety profile of HDM2005 showed notable advantages over existing ADC therapies. In the 1.8 mg/kg and 2.5 mg/kg cohorts, 38.1% of patients (8/21) experienced Grade ≥3 treatment-related adverse events, with the most common being neutrophil count decrease (4 patients, 19.0%). Importantly, no Grade ≥3 gastrointestinal adverse reactions or peripheral neuropathy were reported.
Peripheral neuropathy occurred in only 4 patients (13.8%), all of which were Grade 1 or 2, addressing a common toxicity concern associated with ADC therapies. No patient permanently discontinued treatment due to treatment-related adverse events.
Regulatory Recognition and Market Position
HDM2005 has secured orphan drug designation from the U.S. FDA for its MCL indication, providing critical regulatory advantages including tax credits, expedited review, and seven years of market exclusivity upon approval. This recognition underscores the drug's potential to address a rare but high-unmet-need disease.
The ADC market is highly competitive, with over 400 candidates in development and 15 approved therapies as of 2024. However, HDM2005's focus on ROR1 positions it to capture a significant share in this niche yet important therapeutic area. ROR1 is increasingly recognized as a therapeutic target due to its overexpression in aggressive cancers and its role in immune checkpoint evasion.
Strategic Development Through Partnership
The collaboration between Huadong Medicine and Sanyou Biopharma has accelerated HDM2005's development, with the drug advancing into Phase I trials in 2025. This partnership highlights the technical complexity of ADC development and the strategic importance of leveraging specialized expertise to navigate challenges such as linker stability and payload optimization.
Huadong Medicine's pipeline, including HDM2005, reflects a strategic approach similar to companies that have leveraged niche therapeutic areas to establish market dominance. The company is advancing HDM2005 through Phase 1/2 trials for diffuse large B-cell lymphoma (DLBCL) and expanding into solid tumors, with plans to bring more treatment options to patients through its "science-driven, patient-centered" mission.
