LBL-024 Gains FDA Orphan Drug Status in Neuroendocrine Cancer

• The FDA has granted LBL-024 orphan drug designation (ODD) for the treatment of neuroendocrine cancer.
• LBL-024 is an anti-PD-L1/4-1BB bispecific antibody.
• The agent has already received investigational new drug approvals from the FDA and National Medical Products Administration (NMPA) in China.

The FDA granted ODD to LBL-024, an anti-PD-L1/4-1BB bispecific antibody being evaluated for the treatment of patients with neuroendocrine cancer.¹

LBL-024 is a novel tetravalent bispecific antibody made to simultaneously target 2 critical immune checkpoint pathways: PD-L1 and 4-1BB. The agent works through a dual mechanism of action to enhance anti-tumor immune responses. When used as monotherapy, LBL-024 has shown a favorable overall response rate (ORR) and duration of response (DOR) in patients with previously treated extrapulmonary neuroendocrine cancers (EP-NEC).

Breakthrough therapy designation was granted to the agent in October 2024 by the Center for Drug Evaluation (CDE) of National Medical Products Administration (NMPA) in China. Further, LBL-024 received IND approval from the FDA on July 30, 2021 and the NMPA on September 9, 2021, respectively.

"LBL-024 obtained breakthrough therapy designation from CDE in October this year for the treatment of advanced EP-NEC. Our clinical data to date has been very encouraging, suggesting that LBL-024 could meaningfully improve outcomes of patients living with this devastating disease. The grant of ODD from FDA further underscores the exceptional potential of LBL-024 to address a critical gap in this therapeutic area,” said Charles Cai, MD, PhD, chief medical officer of Leads Biolabs, in a press release.

Microscopic, photorealistic image of neuroendocrine tumor cells - Generated with Google Gemini AI.jpeg

LBL-024 blocks the immunosuppressive PD-1/PD-L1 pathway and selectively costimulates 4-1BB. By lifting the PD-1/PD-L1-mediated immune suppression and intensifying 4-1BB-driven T-cell activation, LBL-024 synergistically boosts the immune system's ability to recognize and destroy tumor cells.

As of July 2024, a single-arm pivotal trial of LBL-024 for EP-NEC is ongoing, marking the first 4-1BB-targeted drug candidate globally to have reached pivotal stage, the company stated in its press release. A phase 1b/2 trial (NCT06157827) in combination with etoposide plus cisplatin or carboplatin in first-line EP-NEC is also ongoing.

Findings from a phase 1/2 trial (NCT05170958) of the agent were previously presented at the 2024 American Society of Clinical Oncology Annual Meeting.² The study evaluated the agent in patients aged 18 years and older with advanced malignant tumors whose disease had progressed on prior standard-of-care therapy, had an ECOG performance status of 0 or 1, and had adequate organ function. In phase 2b of the study, those included must have had EP-NEC as confirmed by central laboratory assessment and have received at least 2 prior lines of chemotherapy.

Results showed that the ORR among patients with advanced EP-NEC who underwent at least 1 tumor assessment (n = 45) was 33.3%.2 All responders had a partial response (PR) and the disease control rate (DCR) was 51.1%.

In the overall population, which consisted of 47 patients, the PR rate was 31.9%, the stable disease rate was 17.0%, and the progressive disease rate was 46.8%, respectively. A total of 4.3% of patients were not evaluable.

When evaluating the recommended phase 2 dose (RP2D) of 15 mg/kg, the ORR was 33.3% and the DCR was 48.5%. At median follow-up of 8.5 months, DOR was a median of 5.3 months. In 26 patients evaluated for PD-L1 expression, patients with negative and positive PD-L1 expression benefited similarly from LBL-024.

Looking at safety, the rates of any-grade treatment-emergent adverse events (TEAEs), treatment-related AEs (TRAEs), serious TEAEs, and serious TRAEs among all treated patients (n = 175) were 92.0%, 77.1%, 33.1%, and 16.6%, respectively. A total of 39.4% of patients had grade 3 or higher AEs, and the rate of grade 3 or higher TRAEs was 20.6%.

Dose interruptions and treatment discontinuation due to TRAEs were seen in 22.3% and 4.0% of patients, respectively. There were no dose-limiting toxicities reported, and the maximum tolerated dose was not reached in phase 1 of the study.

TEAEs that were most common consisted of anemia (any-grade, 33.1%; grade ≥ 3, 5.1%), increased aspartate aminotransferase (32.6%; 1.1%), increased alanine aminotransferase (27.4%; 0.6%), leukopenia (20.0%; 3.4%), hypoalbuminemia (16.6%; 0%), hyponatremia (16.0%; 1.7%), thrombocytopenia (14.3%; 2.3%), hypertriglyceridemia (14.3%; 0%), neutropenia (13.7%; 2.9%), hypokalemia (13.1%; 2.9%), asthenia (13.1%; 1.1%), proteinuria (13.1%; 0%), increased blood bilirubin (12.6%; 1.7%), decreased appetite (10.9%; 1.1%), and pyrexia (10.9%; 0.6%).

"The receipt of ODD for LBL-024 from FDA represents a pivotal milestone in our global strategy. This designation not only enables LBL-024 to receive additional policy support and resource allocation during its development, accelerating its path to market and positioning it as a potential first-in-class therapeutic antibody targeting 4-1BB worldwide, but also provides us with greater market opportunities and avenues for growth on a global scale," said Xiaoqiang Kang, MD, PhD, founder, chairman, and chief executive officer of Leads Biolabs, in a press release.¹

REFERENCES:

1. FDA granted orphan drug designation of LBL-024, an anti-PD-L1/4-1BB bispecific antibody developed by Leads Biolabs, for treatment of neuroendocrine cancer. News release. Nanjing Leads Biolabs Co., Ltd. November 22, 2024. Accessed November 25, 2024. https://tinyurl.com/4pmje975

2. Lu M, Zhang P, Luo S, et al. A novel and uniquely designed bispecific antibody (LBL-024) against PD-L1 and 4-1BB in patients with advanced malignant tumors and neuroendocrine carcinoma: a report of safety and robust efficacy of LBL-024 monotherapy in phase I/II, first-in-human, open-label, multicenter, dose escalation/expansion study. J Clin Oncol. 2024;42(suppl 16):4010. doi:10.1200/JCO.2024.42.16_suppl.4010