STP705 Granted Orphan Designation for Treatment of Cholangiocarcinoma

Sirnaomics announced the Office of Orphan Product Development division of the FDA has granted Orphan-drug designation to its leading therapeutic candidate, STP705, for the treatment of Cholangiocarcinoma (CCA).

STP705, is an siRNA (small interfering RNA) therapeutic which takes advantage of a dual-targeted inhibitory property and polypeptide nanoparticle (PNP)-enhanced delivery to directly knock down both TGF-β1 and COX-2 gene expression. The product has also received both US FDA and Chinese FDA IND approval for Hypertrophic Scar Reduction and it is expected to have efficacy in many diseases across multiple therapeutic areas. The Orphan Drug application was supported by recent results of in vitro and in vivo studies using a human cholangiocarcinoma cell line and its xenograft tumor in a mouse model.

"We are very pleased to reach this significant milestone and we are very excited to develop our lead product candidate for this oncology indication," stated Dr. Patrick Lu, founder and CEO. "This is the fourth major clinical milestone we have achieved in the past twelve months including our FDA and CFDA IND approval for STP705 for the treatment of Hypertrophic scar as well as our Orphan Drug Designation approval for Primary Sclerosing Cholangitis.  The antifibrotic and antitumorigenic properties of STP705 may bring an alternative therapeutic approach for treatment of devastating cancers such as cholangiocarcinoma and others."

Cholangiocarcinoma's (CCAs) are cancers that arise from cells that line the bile duct. CCA is also known as bile duct adenocarcinoma and biliary tract cancer. CCA is the second most common hepatic primary malignancy (accounting for 15-20% of cases).  Although it is more common in Asia, its incidence in Europe and North America has significantly increased in recent decades. CCA is characterized by late diagnosis and fatal outcome with 5-year survival ranging from 2-30%.  CCA is an epithelial malignancy originating from transformed cholangiocytes, with preclinical studies suggesting hepatic progenitor cells as cells of origin. Inflammation and cholestasis are key factors in cholangiocarcinogenesis.  Studies have shown high expression of TGF-β1 which is thought to become an oncogenic factor that induces invasion, angiogenesis, proliferation, and, in certain cases, metastasis.  Cyclooxygenase-2 (COX-2) also plays a role in the pathogenesis of CCA, activating growth factors that promotes cholangiocyte growth, such as MAPK, epidermal growth factor receptor (EGFR) and interleukin 6 (IL-6).

STP705 is composed of two siRNA oligonucleotides, targeting TGF-β1 and COX-2 mRNA respectively, and formulated in nanoparticles with Histidine-Lysine Co-Polymer (HKP) peptide. Each individual siRNA was demonstrated to inhibit the expression of their target mRNAs and combining the two siRNA's produces a synergistic effect that diminishes pro-fibrogenic and pro-inflammatory factors. Molecular analyses of the effects of administering the combination demonstrated that the inhibition of these targets had effects on downstream gene products associated with fibrosis including: α-SMA, Col1A1, and Col3A1. Additional data suggests that reductions in TGF-β1 and COX-2 led to proapoptotic effects in fibroblasts. These observations suggest that STP705 has the potential for broad application in many inflammatory and fibrotic driven disease states. Cell culture experiments with a human intrahepatic cholangiocarcinoma cell line, HuCCT-1, have demonstrated significant target knockdown and reduction in tumor cell viability. Further in vivo studies in mice using the HuCCT-1 cell xenograft tumor model results in tumor growth inhibition in a dose-dependent manner when treated by STP705 injection.