The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to Zai Lab Limited's ZL-1310, a first-in-class delta-like ligand 3 (DLL3) antibody-drug conjugate (ADC), for the treatment of small cell lung cancer (SCLC). This regulatory decision aims to support the development of ZL-1310 by providing incentives such as fee waivers, tax credits, and potential seven-year market exclusivity upon approval, addressing a critical unmet need in SCLC treatment.
ZL-1310: Targeting DLL3 in SCLC
ZL-1310 is designed to target DLL3, an antigen overexpressed in neuroendocrine tumors and associated with poor clinical outcomes. This ADC comprises a humanized anti-DLL3 monoclonal antibody linked to a novel camptothecin derivative, a topoisomerase 1 inhibitor, as its payload. The drug utilizes Zai Lab's TMALIN technology platform, designed to leverage the tumor microenvironment to overcome challenges associated with first-generation ADCs, such as off-target payload toxicity.
According to Rafael G. Amado, MD, President and Head of Global Research and Development at Zai Lab, the orphan drug designation recognizes ZL-1310's potential to treat SCLC patients who urgently need innovative treatment options. He noted the promising objective response rates and favorable safety profile demonstrated in the ongoing Phase 1 trial of ZL-1310 in patients with recurrent SCLC.
Clinical Trial Data and Ongoing Evaluation
The FDA's decision is supported by data from an ongoing Phase 1a/1b clinical trial evaluating ZL-1310 as a monotherapy and in combination with atezolizumab (Tecentriq) for patients with extensive-stage SCLC (ES-SCLC) who have previously undergone at least one platinum-based chemotherapy regimen. Preliminary data presented at the EORTC-NCI-AACR (ENA) Symposium 2024 indicated a favorable pharmacokinetic and safety profile for ZL-1310, with early clinical activity observed at the first dose level.
The Phase 1a/1b trial enrolled patients with metastatic or extensive-stage SCLC who had received one to three prior platinum-based chemotherapy regimens. In the dose-escalation phase, patients received ZL-1310 at doses of 0.8 mg/kg, 1.6 mg/kg, 2.0 mg/kg, or 2.4 mg/kg intravenously every three weeks. Preliminary results showed a 74% objective response rate (ORR) among response-evaluable subjects, including partial responses in 3 of 4 patients. Notably, there were no dose-limiting toxicities or treatment-related adverse events of grade 3 or higher observed.
Significance of Orphan Drug Designation
The Orphan Drug Designation provides ZL-1310 with significant development incentives, potentially accelerating its path to market. SCLC, representing approximately 15% of the 2.5 million annual lung cancer diagnoses globally, is an aggressive disease with high relapse rates and poor prognosis. The median survival for ES-SCLC patients is approximately 12 months following initial therapy, with a 5-10% overall five-year survival rate. The ODD underscores the urgent need for new, effective treatments for this challenging cancer.
