PCI-27483: Factor VIIa Inhibitor for Oncology and Thrombosis
Using x-ray structures and rational drug design, PCI-27483 was developed as a small-molecule FVIIa inhibitor with high potency and selectivity for the FVIIa/TF complex. Inhibitors of this complex have the potential to reduce tumor growth and metastases as well as the incidence of venous thromboembolism.
Preclinical studies have demonstrated the anti-tumor and anti-coagulation effects of PCI-27483 both in vitro and in vivo.
Anti-tumor effects in a pancreatic tumor xenograft model
Preclinical studies have shown PCI-27483 to significantly inhibit tumor growth in human pancreatic tumor xenograft models in mice, with or without gemcitabine.
Tumor growth inhibition:
- 16.7% with gemcitabine alone
- 71.3% with PCI-27483 alone
- 89.7% with PCI-27483 plus gemcitabine
Anti-thrombotic effects in an arterial thrombosis model
The anti-thrombotic effects of PCI-27483 were determined in a baboon model of arterial thrombosis. In this model, PCI-27483 showed dose-dependent inhibition of thrombus formation, fibrin accumulation, and prothrombin time, and 4mg/kg PCI-27483 demonstrated comparable anti-coagulation effects as 2mg/kg Lovenox.
Phase I in healthy volunteers
Phase 1 testing of PCI-27483 in healthy volunteers was completed in December 2008. The primary objective of the ascending dose Phase 1 study was to assess the pharmacodynamic and pharmacokinetic profiles of PCI-27483 following a single, subcutaneous injection. The half-life of PCI-27483 was 10 to 12 hours, which compares favorably to the single-dose half-life of the low molecular weight heparins Lovenox (4.5 hours) and Fragmin (3 to 5 hours). In addition, PCI-27483 was well tolerated and no adverse events were observed at any dose level
The International Normalized Ratio (INR) of prothrombin time was used to measure pharmacodynamic effects at varying dose levels of PCI-27483, and INR strongly correlated with drug plasma concentration in patients. A mean peak INR of 2.7 was achieved at the highest dose level. A peak INR response of approximately 3 is being targeted in ongoing clinical studies. Use of INR to assess pharmacodynamic response will allow for personalized dose adjustment to achieve optimal benefit for the patient.
Phase I/II in pancreatic cancer
Pharmacyclics has chosen to study the effects of PCI-27483 in pancreatic cancer receiving a standard regimen of gemcitabine. A Phase I/II study of PCI-27483 in patients with locally advanced and recently diagnosed pancreatic cancer was initiated in November 2009. This study involves two parts: 1) Part A in patients receiving escalating doses of PCI-27483, subcutaneously administered twice a day in combination with gemcitabine has completed enrollment; 2) in Part B, patients are being randomized to receive gemcitabine with or without PCI-27483.
Please refer to the GI Cancer Symposium Presentation for latest clinical data.
Patients and caretakers are invited to visit clinicaltrials.gov for more information regarding PCI-27483 in clinical trials.
Pancreatic cancer, a malignant tumor arising from the tissues in the pancreas, is one of the leading causes of death from cancer worldwide (4th leading cause of death from cancer in the US, responsible for 34,000 deaths each year). Annually, 230,000 individuals are diagnosed with pancreatic cancer worldwide, and more than 43,000 of these diagnoses are within the US. Pancreatic cancer spreads rapidly with minimal symptoms, so many patients are diagnosed in the later stages of the disease. The median survival time of patients being treated for locally advanced or metastatic pancreatic cancer is around five to six months.
Treatment options for pancreatic cancer include surgery, radiation, chemotherapy, and targeted drug therapy. For advanced pancreatic cancer, gemcitabine (a nucleoside analogue) is the standard of care treatment used to improve a patient's quality of life and overall survival. The median overall survival duration for patients treated with gemcitabine was 5.7 months versus 4.4 months for patients dosed with 5 fluorouracil (Burris et al., J Clin Oncol 15:2403-2413, 1997). Recently, erlotinib (a HER1/EGFR tyrosine kinase inhibitor) was approved for use in combination with gemcitabine for the treatment of patients with advanced pancreatic cancer. In a randomized Phase III clinical trial pancreatic cancer patients that received erlotinib plus gemcitabine had a median duration for overall survival of 6.4 months versus 5.9 months for patients that received gemcitabine only (Moore et al., J Clin Oncol 25:1960-1966, 2007). Unfortunately, pancreatic cancer commonly becomes resistant to treatment. Current scientific and clinical efforts are focused combination therapies as a strategy for prolonging patient survival.
Many cancer types show high expression levels of Tissue Factor. In a study reported by Khorana et al. (2007), tissue Factor was expressed in 89% of patients with pancreatic cancer. Pancreatic cancer patients with high Tissue Factor expression had a venous thromboembolism rate of 26.3% compared with 4.5% in patients with low Tissue Factor expression. This study also showed that Tissue Factor expression is an important early event in malignant transformation of the pancreas. The on-going clinical trial with PCI-27483 in patients with pancreatic cancer is designed to assess the potential impact of Factor VIIa/Tissue Factor inhibition on disease progression.