PT886 Granted Orphan Drug Designation for Pancreatic Cancer
The FDA has granted Orphan Drug designation to PT886 for the treatment of pancreatic cancer. PT886 is a first-in-class bispecific antibody targeting claudin 18.2 (CLDN18.2) and cluster of differentiation 47 (CD47) being developed for patients with pancreatic cancer, as well as gastric and gastroesophageal cancers. The goal of the bispecific antibody is to block the CD47-SIRP[alpha] interaction, stimulate phagocytosis of tumor cells by macrophages, and deliver robust effects mediated by the functional Fc of the bispecific antibody.
Findings presented at the 2022 American Association for Cancer Research meeting showed PT886 to have high affinity monovalent binding to cell surface CLDN18.2 and low affinity monovalent binding to cell surface CD47. By doing so, PT886 can preferentially bind to tumor cells, which overexpress CLDN18.2 and CD47, and reduce its binding to normal cells that exclusively express CD47.
However, PT886 exhibits higher activity to tumor cells expressing CLDN18.2 and close to no activity toward normal cells that do not express CLDN18.2. This was shown in a phagocytosis assay as PT886 stimulates stronger phagocytosis in the presence of CLDN18.2 binding in vitro.
Along with targeting CLDN18.2 and CD47, PT886 has a fully functional Fc to directly recruit the tumor cell killing activities of NK cells and macrophages. The anti-tumor activity of PT886 was potent and demonstrated in vivo in a pancreatic cancer xenograft model. Here, treatment with PT886 resulted in a complete tumor clearance at doses as low as 1 mg/kg.
In NHP studies, PT886 also demonstrated a good safety profile. These data support the Phase I clinical trial of the bispecific antibody planned for 2022.
Belzupacap Sarotalocan for Non-Muscle Invasive Bladder Cancer
The FDA granted Fast Track designation for belzupacap sarotalocan, a VDC product candidate, for the treatment of non-muscle invasive bladder cancer. A planned Phase I clinical trial with belzupacap sarotalocan in this indication will evaluate the safety and early proof of mechanism, as well as assess distribution, local necrosis, and evidence of immune activation. Researchers expect to initiate the trial in the second half of 2022, with initial Phase I data expected in 2023.
U.S. Biologics License Application for PD-1 Inhibitor Tislelizumab in 2L ESCC
The FDA has deferred action on the Biologics License Application (BLA) for tislelizumab as a second-line treatment for patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC). The FDA has been unable to conduct required inspections in China due to COVID-19-related travel restrictions. As a result, the FDA is deferring action on the application until the inspections are complete.
In the letter, the FDA cited only travel restrictions and the inability to complete inspections as the reason for the deferral. The application remains under review, and the FDA did not provide a new anticipated action date as they continue to monitor the public health situation and travel restrictions.
In September 2021, the FDA accepted the BLA for tislelizumab in second-line ESCC and provided a Prescription Drug User Fee Act (PDUFA) goal date of July 12, 2022. The evidence base for the BLA submission includes results from RATIONALE-302, a randomized, open-label, multi-regional, Phase III trial that enrolled 512 patients from Europe, U.S., and Asia. It included safety data on 1,972 patients who received tislelizumab as a monotherapy from seven clinical trials. The trial demonstrated a 30 percent reduction in the risk of death (HR=0.70, 95% CI: 0.57-0.85, p=0.0001) and extended median overall survival by 2.3 months compared to chemotherapy in people with unresectable recurrent locally advanced or metastatic ESCC who had received prior systemic therapy (J Clin Oncol 2022; doi: 10.1200/JCO.21.01926).
Tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody specifically designed to minimize binding to Fc-gamma (Fc[gamma]) receptors on macrophages, helping to aid the body's immune cells to detect and fight tumors. In pre-clinical studies, binding to Fc[gamma] receptors on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of effector T cells.
Tislelizumab is being developed internationally as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. The global tislelizumab clinical development program includes more than 9,000 subjects enrolled to date in more than 35 countries and regions. Researchers have initiated or completed more than 20 potentially registration-enabling clinical trials, including 17 Phase III trials.
FDA Nod to Begin Phase II Trial of LP-300 in Biomarker-Defined NSCLC
The FDA gave permission to begin a Phase II trial of the investigational drug LP-300 plus chemotherapy in patients with biomarker-defined advanced non-small cell lung cancer (NSCLC). The trial, called Harmonic, is slated to begin enrollment in the third quarter or 2022 and will involve 90 patients who will receive either LP-300 with chemotherapy or chemotherapy alone. Eligible NSCLC patients must be never smokers, have prior treatment with tyrosine kinase inhibitors, and harbor alterations in MET exon 14, ALK, EGFR, or NTRK.
LP-300 is a cysteine-modifying agent that can modulate multiple cellular pathways simultaneously, including ALK, EGFR, MET, and ROS1. The drug has also shown in previous studies to reduce toxicities associated with chemotherapy and help sensitize patients to chemotherapy treatment.
The drug failed to meet its primary endpoint in a Phase III study in an all-comer population of advanced NSCLC patients, but it showed activity in a smaller subset of patients with certain genomic mutations. Researchers used the RADR machine learning platform to identify patients most likely to benefit from treatment with the drug.
Orphan Drug & Fast Track Designations of Novel Sonodynamic Therapy for Brain Cancer
The FDA granted both Orphan Drug and Fast Track designations to CV-01 delivery of sonodynamic therapy (SDT) as a potential treatment for patients with recurrent glioblastoma and other malignant gliomas. Northwell Health's North Shore University Hospital in Long Island, NY, is currently enrolling patients in the multi-center Phase I clinical trial. The first-in-human trial will evaluate the safety, optimal dosage, and efficacy of the SDT platform in patients with recurrent high-grade glioma.
"The diffuse nature of glioblastomas, often across the hemisphere, makes it an extremely challenging disease to treat. There are very few effective options, leading to poor patient outcomes and a universally fatal disease," commented Michael Schulder, MD, Director of the Brain Tumor Center and primary investigator for the clinical trial at Northwell Health's Institute for Neurology and Neurosurgery. "Sonodynamic therapy enables non-invasive, diffuse treatment across the hemisphere. It has the potential to change the landscape of high-grade glioma therapy and we are excited to be part of this important study."
This proprietary, investigational SDT treatment is an innovative, non-invasive drug-device combination that targets cancer cells throughout the entire hemisphere using low-intensity, diffuse ultrasound. The SDT is administered in an outpatient setting and does not require imaging. The multi-center trial (NCT05362409) is designed to study the safety and optimal application of the SDT treatment, as well as efficacy, and is planned to enroll up to 33 patients.