Population Pharmacokinetic Modeling of Certepetide in Human Subjects With Metastatic Pancreatic Ductal Adenocarcinoma

Abstract

Certepetide (aka LSTA1 and CEND-1) is a novel cyclic tumor-targeting internalizing arginyl glycylaspartic acid peptide being developed to treat solid tumors. Certepetide is designed to overcome existing challenges in treating solid tumors by delivering co-administered anticancer drugs into the tumor while selectively depleting immunosuppressive T cells, enhancing cytotoxic T cells in the tumor microenvironment, and inhibiting the metastatic cascade. A population pharmacokinetic (PK) analysis was conducted to characterize the concentration-time profile of patients with metastatic exocrine pancreatic cancer receiving certepetide in combination with nab-paclitaxel and gemcitabine, and to investigate the effects of clinically relevant covariates on PK parameters. The PK of certepetide was characterized by a 2-compartment model with linear elimination and a proportional residual error structure. Body weight and baseline creatinine clearance (CrCL) were found to have statistically significant effects on central and peripheral volume (Vc and Vp) and clearance (CL) parameters, respectively, during model development and were included as covariate effects in the final PK model. Forest plots demonstrated a potentially clinically meaningful impact of high body weight (100 kg) on certepetide exposure (steady-state maximum concentration [C_max,ss] and area under the concentration-time curve [AUC_ss]), as well as low and high CrCL (50 and 150 mL/min) on AUC_ss. Exposure predictions illustrated a relationship between certepetide exposure (AUC_ss) and renal function, with increasing exposure and decreasing CL of certepetide observed with worsening renal function. Modeling will strengthen the understanding of certepetide’s PKs and will inform dose optimization in ongoing drug development activities.

It is well recognized that treatment for solid tumors is suboptimal and there is an urgent need for novel therapies. Treatment of solid tumors remains a significant challenge for 2 main reasons, solid tumors are surrounded by a dense cellular barrier called the stroma which inhibits anticancer agents from effectively penetrating the tumor and solid tumors have an immunosuppressive tumor microenvironment that hinders the immune system from recognizing and attacking the cancer.¹ Unfortunately, prolonged and/or escalated conventional anticancer therapies do not overcome these challenges and often lead to intolerable off-target side effects.

Pancreatic ductal adenocarcinoma (PDAC) is a solid tumor with a hostile tumor microenvironment and abundant stroma that compromises drug delivery and may explain the significant morbidity and mortality therein.² By 2030, it is believed that pancreatic cancer will have become the second leading cause of cancer-related death in the United States.³ Despite the advances in knowledge regarding tumor biology and treatment of PDAC, the prognosis for these patients remains poor, with a 5-year survival rate of only 12%.⁴

PDAC is often associated with elevated levels of CA19-9, a tumor biomarker measured in the serum. CA19-9 levels often correlate with the stage of disease, with higher levels of CA19-9 more commonly seen in advanced stages of PDAC. Once diagnosed with pancreatic cancer, regular CA 19-9 tests can be used to monitor treatment response and detect potential recurrence.⁵

Certepetide (aka LSTA1 and CEND-1) is a novel 9-amino acid cyclic tumor-targeting internalizing arginyl glycylaspartic acid peptide (molecular weight 989.1 g/mol) designed to overcome the challenges in treating solid tumors. Certepetide selectively targets and enhances the penetration of coadministered anticancer drugs and modifies the tumor microenvironment.^6–8 Specifically, the arginyl glycylaspartic acid motif of certepetide binds to αvβ3/5-integrins which are upregulated on tumor endothelium.⁶ On binding and subsequent proteolytic cleavage, the resulting 5 amino-acid linear C-end-Rule peptide binds to neuropilin-1, which is also overexpressed on tumor vascular endothelial cells and tumor cells.⁹ This process triggers an active transport mechanism to deliver anticancer drugs into the tumor.^8, 10, 11 Due to the nature of the transport mechanism, penetration is enhanced for small molecules,¹² monoclonal antibodies,^10, 13 and larger moieties such as nanoparticles¹⁴ and cell therapies.^9, 15 Certepetide also selectively depletes immunosuppressive T cells, enhances cytotoxic T cells, and inhibits the metastatic cascade.^16–18

Certepetide is administered as a slow intravenous push over 1 minute shortly after the administration of chemotherapy and/or immunotherapy. Certepetide is thought to be metabolized into its component amino acids, as expected for small peptides. Autoradiography has demonstrated that certepetide primarily undergoes renal elimination (data on file). Certepetide does not bind to plasma proteins (data on file).

Preliminary analysis of the safety, tolerability, PK, and biological activity of certepetide including 31 patients with unresectable metastatic PDAC receiving first-line treatment with certepetide in combination with nab-paclitaxel and gemcitabine has already been published.^19, 20 Investigators and associated Human Research Ethics Committees are provided in Table S1. The majority of patients were male (65%) and Caucasian (87%). No patients had any prior cancer medication, radiation, or pancreatic cancer surgery and 84% of patients had elevated cancer antigen 19-9 (CA19-9). The median age of all patients was 62 years.

Certepetide exposure concentrations were observed to be consistent throughout the course of the study. The mean baseline CA19-9 concentration was 23,469 U/mL. Nearly all patients (20 out of 22) had a ≥50% reduction in CA19-9 at cycle 5, day 1.

All 31 patients in this phase 1 trial had ≥1 treatment-emergent adverse event, 94% had adverse events (AEs) of severity grade 3 or 4, and 71% had serious adverse advents. The most common AEs observed were neutropenia, anemia, leukopenia, and pulmonary embolism. The 3.2 and 1.6 mg/kg dose groups were comparable in the number and severity of AEs observed. There were no dose-limiting toxicities associated with the study drug. The adverse event profile of patients in this study was comparable to that of subjects with pancreatic cancer treated with gemcitabine and nab-paclitaxel. A total of 10 deaths occurred during the study period: 9 deaths were due to metastatic pancreatic cancer disease progression and 1 death was due to left middle cerebral artery stroke due to disease progression (not attributed to certepetide).

Preliminary efficacy results were summarized as follows: investigator-assessed overall response rate was 59%, disease control rate at 16 weeks was 90%, 50% of patients in the 1.6 mg/kg dose group and 61.5% of patients in the 3.2 mg/kg dose group had a partial response or complete response, median progression-free survival after 33.2 months was 9.7 months, median overall survival after 26 months was 13.2 months, and median overall survival from treatment start was 12.8 months.

In this work, the population pharmacokinetics (PKs) of certepetide in a first-in-human trial involving patients with metastatic exocrine pancreatic cancer was investigated. Additionally, potential nonlinearity in certepetide PK was examined and the influence of patient-specific factors (age, body weight, sex, and CrCL) on its PKs was evaluated.