AbbVie's investigational antibody-drug conjugate ABBV-706 has received orphan drug designation from the U.S. Food and Drug Administration for the treatment of small cell lung cancer (SCLC), marking a significant regulatory milestone for this novel SEZ6-targeting therapy. The designation, granted on October 29, 2024, highlights the drug's potential in addressing a rare and highly aggressive form of cancer with limited treatment options.
Clinical Trial Results Show Promise
At the May 2024 ASCO meeting, AbbVie presented encouraging early data from the first-in-human dose-escalation study of ABBV-706 monotherapy. The results demonstrated an overall objective response rate (ORR) of 43.8% among 48 evaluable patients. Notably, the response rate was particularly strong in SCLC patients, reaching 60.9%, compared to 28% in the neuroendocrine tumor (NET) group.
The safety profile showed manageable toxicities, with the most common Grade ≥3 treatment-emergent adverse events including neutropenia (42%), anemia (42%), and leukopenia (28%). These findings provide strong support for ABBV-706 as a potential treatment option for patients with this challenging malignancy.
Novel Mechanism Targets SEZ6 Protein
ABBV-706 is an antibody-drug conjugate that specifically targets SEZ6 (Seizure-related 6 homolog), a protein that plays a key role in dendritic formation and neural signaling. Studies have shown that SEZ6 is overexpressed in SCLC and is closely associated with tumor cell proliferation and invasion, making it an attractive therapeutic target.
The drug is engineered with a topoisomerase 1 inhibitor (TOP1i) payload linked via a valine-alanine linker, with a drug-to-antibody ratio (DAR) of 6. ABBV-706 specifically targets SEZ6-expressing tumor cells, rapidly internalizes, and delivers the cytotoxic payload directly to cancer cells. Preclinical studies have demonstrated significant antiproliferative activity across various SCLC cell lines and sustained tumor regression in SCLC patient-derived xenograft (PDX) models.
Addressing Critical Unmet Medical Need
Small cell lung cancer accounts for approximately 15% of all lung cancers and is characterized by high malignancy, rapid progression, and a high recurrence rate, making it particularly challenging to treat. Currently, chemotherapy and radiotherapy remain the primary treatment options, but they offer limited survival benefits and poor prognosis for patients.
ABBV-706 represents the only SEZ6-targeting ADC currently in development for SCLC, positioning it as a potentially important addition to the limited therapeutic arsenal for this disease. The drug's progress is drawing significant industry attention as researchers seek novel targeted therapies to enhance treatment efficacy and improve patient survival.
Comprehensive Development Program
The Phase 1 clinical trial is evaluating ABBV-706 both as a monotherapy and in combination with other agents. The combination studies include pairing ABBV-706 with the PD-1 inhibitor Budigalimab (ABBV-181), as well as with standard chemotherapy agents carboplatin or cisplatin.
This comprehensive approach reflects the growing trend in oncology to explore combination strategies that may enhance therapeutic efficacy. Compared to traditional chemotherapy and radiotherapy, ADC drugs offer significant advantages in treating refractory/relapsed SCLC by precisely targeting specific antigens found in SCLC, reducing damage to normal cells while enhancing cytotoxic effects.
Regulatory Progress Continues
The FDA orphan drug designation follows earlier regulatory progress for ABBV-706. On July 25, 2024, China's Center for Drug Evaluation (CDE) approved AbbVie's clinical trial application for ABBV-706 lyophilized powder for injection, enabling the company to expand its clinical development program internationally.
The orphan drug designation provides AbbVie with several benefits, including market exclusivity, tax credits for clinical trial costs, and fee waivers for regulatory submissions. This designation further validates SEZ6 as an effective therapeutic target for SCLC and underscores the significant unmet medical need in this patient population.
