Drugs in Clinical Pipeline: PLX3397

PLX3397 [5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine] is a novel, oral small molecule that potently and selectively inhibits Colony-Stimulating-Factor-1 Receptor (CSF1R), KIT, and oncogenic FLT3 kinases.

CSF1R and KIT regulate key components of both the tumor and its microenvironment (macrophages, osteoclasts, mast cells). PLX3397 is being evaluated in several other clinical indications, including breast cancer, pigmented villonodular synovitis (PVNS), glioblastoma, melanoma and Acute Myelogenous Leukemia (AML).

Plexxikon, a member of the Daiichi Sankyo Group since April 2011, is developing PLX3397. In collaboration with partners such as QuantumLeap Healthcare Collaborative, Plexxikon’s is carrying trails for PLX3397. QuantumLeap Healthcare Collaborative will partner in for study in the I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And Molecular Analysis 2). I-SPY 2 is a standing phase 2 randomized, controlled, multicenter trial for women with newly diagnosed, locally advanced breast cancer (minimum of Stage 2) that is designed to test whether adding investigational drugs to standard chemotherapy is better than standard chemotherapy alone in the neoadjuvant setting (prior to surgery).

PLX3397 received Orphan Drug designation by the FDA in February 2014 for the treatment of PVNS and giant cell tumor of tendon sheath. Plexxikon and Daiichi Sankyo plan to initiate a Phase 3 clinical trial in PVNS patients.

Common Name: PLX3397

Synonyms:  PLX-3397; PLX3397; PLX 3397; Pexidartinib; PLX108-01

IUPAC Name: 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl) pyridin-2-amine

CAS Number: 1029044-16-3

Mechanism of Action: Kinase Inhibitor; KIT Inhibitor; Multi-kinase Inhibitor; CSF1R Inhibitor

Indication: Various Cancers; Glioblastomas

Development Stage: Phase I

Company: Plexxikon

What is PVNS?

Pigmented Villonodular Synovitis  (PVNS) is a rare proliferative neoplastic tumor that affects the synovium and tendon sheaths in young and middle-aged adults of both sexes. Patients are commonly diagnosed in their 20s to 50s and can experience severe debility as a result of local growth of tumor within or around a joint. Diffuse PVNS is an aggressive form of the disease, and can affect the entire lubricating membrane of either small or large joints, most commonly the knee. Surgical resection and/or local radiation are the standards of care, and there are no drugs currently approved to treat the condition. The diffuse form has an average annual incidence of 1.8 cases per million, and recurrence following surgery is common. PVNS tumors are known to express high levels of CSF1, which causes proliferation of tumor-associated macrophages, osteoclasts and other CSF1R-dependent cells. By selectively inhibiting CSF1R, PLX3397 should reverse the accumulation of macrophages and reduce PVNS tumor size. PLX3397 previously has been shown to inhibit CSF1R-dependent CD14+/CD16+ pro-inflammatory monocyte cell numbers in cancer patients.

PLX3397 v/s Imatinib

Researchers treated Kit(V558del/+) mice that develop Gastrointestinal stromal tumor (GIST) or mice with subcutaneous human GIST xenografts with imatinib or PLX3397 and analyzed tumor weight, cellular composition, histology, molecular signaling, and fibrosis. In vitro assays on human GIST cell lines were also performed. It was found that PLX3397 was more effective than imatinib in reducing tumor weight and cellularity in both Kit(V558del)(/+) murine GIST and human GIST xenografts. The superiority of PLX3397 did not depend on depletion of tumor-associated macrophages, because adding Colony-Stimulating-Factor-1 Receptor (CSF1R) inhibition did not improve the effects of imatinib. Instead, PLX3397 was a more potent KIT inhibitor than imatinib in vitro. PLX3397 therapy also induced substantial intratumoral fibrosis, which impaired the subsequent delivery of small molecules. PLX3397 therapy has greater efficacy than imatinib in preclinical GIST models and warrants study in patients with GIST. The resultant intratumoral fibrosis may represent one of the barriers to achieving complete tumor eradication [1].

References:
1. Kim, T. S.; et. al. Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor. Clin Cancer Res 2014, 20(9), 2350-2362.