Therapy Areas: Oncology
Sirnaomics Oncology IND Receives Approval from US FDA to Initiate Study for Treatment of Cholangiocarcinoma
17 August 2018 - - The US Food and Drug Administration has approved US-based biopharmaceutical company Sirnaomics' first oncology IND application, the company said.

The IND approval will allow for the study of the company's lead product candidate, STP705, in patients with advanced cholangiocarcinoma.

Sirnaomics' lead product candidate, STP705, is an anti-cancer/anti-fibrosis siRNA (small interfering RNA) therapeutic.

It takes advantage of a dual-targeted inhibitory property and a proprietary polypeptide nanoparticle -enhanced delivery system to target cells in the liver.

STP705 acts by directly inhibiting tumorigenesis through down regulation of Cancer Associated Fibroblast activity and cell proliferation by silencing both TGF-β1 and COX-2 gene expression within the tumor micro-environment.

In 2017, STP705 was granted Orphan Drug Designation from the FDA Office of Orphan Products Development for treatment of Cholangiocarcinoma and Primary Sclerosing Cholangitis. The product has also received both US FDA and Chinese FDA IND approval for Hypertrophic Scar Reduction.

The dual-targeted approach of STP705 is expected to have efficacy across many diseases in multiple therapeutic areas.

Cholangiocarcinoma is the second most common hepatic primary malignancy (accounting for 15-20% of liver cancer). CCA is also known as bile duct adenocarcinoma and biliary tract cancer.

Although it is more common in Asia, its incidence in Europe and North America has increased significantly in recent decades.

CCA is characterised by late diagnosis and fatal outcome with five-year survival ranges from 2-30%. CCA is an epithelial malignancy originating from transformed cholangiocytes, with preclinical studies suggesting hepatic progenitor cells as the 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 and interleukin 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 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. Recent literature indicates that TGF-β1 is directly related to T cell exhaustion, PD-L1 and CTLA-4 upregulation in tumor micro-environment.

These observations suggest that STP705 has the potential for broad application in many fibrotic and oncogenic driven diseases.

Cell culture experiments with an intrahepatic cholangiocarcinoma cell line, HuCCT-1 treated with STP705, have demonstrated a significant target knockdown and tumor cell killing.

HKP enhanced siRNA delivery has demonstrated preferential distribution in liver hepatocytes, liver sinusoidal endothelial cell and hepatic stellate cells.

Following an intravenous administration of HKP/siRNA into mouse models, the enhanced permeability and retention effect results in accumulation in the tumor micro-environment. 

In vivo studies using the HuCCT-1 cell xenograft tumor model in mice treated by STP705 administration, resulted in tumor growth inhibition in a dose-dependent manner.

The Orphan Drug Act from US FDA provides for granting special status to a drug or biological product to treat a rare disease or condition upon request of a sponsor.

This status is referred to as orphan designation.

For a drug to qualify for orphan designation both the drug and the disease or condition must meet certain criteria specified in the ODA and FDA's implementing regulations at 21 CFR Part 316.

Orphan designation qualifies the sponsor of the drug for various development incentives of the ODA, including tax credits for qualified clinical testing.

Sirnaomics is in the discovery and development of RNAi therapeutics, is a Delaware corporation headquartered in Gaithersburg, Maryland, USA, with subsidiaries in Suzhou and Guangzhou, China.
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