Sirnaomics, Inc., a biopharmaceutical company engaged in the discovery and development of RNAi therapeutics against cancer and fibrotic diseases, announced today dose administration for the first patient in a Phase 1 U.S. clinical study for liver cancer treatment, with the company’s siRNA (small interfering RNA) drug candidate, STP705. STP705 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.

This Phase 1 trial is a multicenter, open-Label, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of STP705, with an intratumoral administration. In this “basket study” of up to 50 subjects suffering from cholangiocarcinoma, hepatocellular carcinoma, or liver metastases from colorectal cancer, the patients with advanced/metastatic or surgically unresectable solid tumors and are refractory to standard therapy will be treated with STP705. This therapeutic regimen is designed to take advantage of a dual-targeted inhibitory property of siRNAs and polypeptide nanoparticle (PNP)-enhanced delivery to directly knock down both TGF-β1 and COX-2 gene expressions. Early pre-clinical and clinical studies using STP705 have shown an increase of active T cell infiltration into the tumor microenvironment. In addition, knocking down TGF-β1 and COX-2 gene expressions in animal fibrosis tissue can activate fibroblast apoptosis with significant antifibrotic efficacy.

“Advancing STP705 from skin cancer to liver cancer is a major milestone for Sirnaomics’ clinical programs, especially with a basket study design that consists of multiple tumor types. We are particularly interested in learning whether the mechanism of action validated in the skin cancer clinical study can be further verified in this liver cancer study,” said Patrick Lu, Ph.D., founder, President and Chief Executive Officer of Sirnaomics. “We are expecting that the combination of anti-fibrotic effects and enhanced tumor immunity will provide a novel approach for the treatment of cholangiocarcinoma and hepatocellular carcinoma using our novel siRNA therapeutics. Sirnaomics is committed to advancing our polypeptide nanoparticle delivery system for innovative RNAi-based cancer therapy.”

“Liver cancer is a devastating disease for patients with high mortality and high unmet medical need,” stated Michael Molyneaux, MD, Chief Medical Officer of Sirnaomics. “The company is excited to announce first dosing, as we hope to gain important insight into the potential safety and efficacy of STP705 in this Phase 1 trial and build on the data from this study to expand into other oncology indications.”

Sirnaomics expects to report initial clinical data from the Phase 1 trial in the second half of 2021. Additional information about this clinical trial is available at clinicaltrials.gov using the identifier: NCT04676633

About Liver Cancer

Liver cancer is a global health problem, with liver neoplasms representing the second-most frequent cause of cancer-related death. There are many different types of liver cancers including hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), liver angiosarcoma, hepatoblastoma and others. Additionally, liver is a highly metastasis-permissive organ. It is the most frequently afflicted organ by metastasis and liver metastases are much more common than primary hepatic tumors. The distinctive biology of the liver renders it intrinsically susceptible to metastases. The true prevalence of liver metastasis is unknown, but between 30% and 70% of patients dying of cancer have liver metastases and most patients with liver metastases will die of their disease. 

STP705 and Liver Cancer

Over expressions of TGF-β1 and COX-2 have been well-characterized as playing key regulatory roles in tumorigenesis. TGF-β is produced by different liver cells and is demonstrated to induce tumor cell migration and survival. TGF-β has been found to be overexpressed in metastatic HCC tissues. Overexpression of TGF-β is generally accepted to be associated with metastasis and poor prognosis. COX-2 is reported to be highly expressed in cancer stem cells and promotes cell migration in HCC cell lines. Additionally, inhibition of COX-2 suppresses cell migration and induces apoptosis. As such TGF-β1 and COX-2 are excellent therapeutic targets for treatment of liver cancer. 

STP705 is composed of two siRNA oligonucleotides targeting TGF-β1 and COX-2 mRNA respectively and formulated in nanoparticles with a proprietary Histidine-Lysine Co-Polymer (HKP) peptide. Each individual siRNA has demonstrated the ability to inhibit the expression of their target mRNA and combining the two siRNAs produces a synergistic effect that diminishes pro-fibrogenic, pro-inflammatory, and pro-tumorigenic factors. Sirnaomics has completed several pre-clinical studies that demonstrate that inhibition of TGF-β1 and COX-2 is expected to result in the inhibition of tumor growth and provide an alternative approach for the treatment of various liver cancers. Molecular analyses of the effects of administering the combination demonstrated that the inhibition of these targets had effects on downstream gene products associated with numerous oncology targets.

Additional immunohistochemistry and image analyses of the liver and tumor tissues demonstrated that animals treated with STP705 resulted in increased CD4⁺ and CD8⁺ T cell infiltration within the tumor microenvironment.  Using STP705 for treatments of hepatocellular carcinoma and cholangiocarcinoma have been designated as Orphan Drug indications by U.S. FDA. STP705 has also been evaluated in a Phase 2a clinical trial for treatment of Non-melanoma skin cancer.

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Sirnaomics, Inc., a leading privately held biopharmaceutical company for discovery and development of RNAi therapeutics, is a Delaware corporation headquartered in Gaithersburg, Maryland, USA, with subsidiaries in Suzhou and Guangzhou, China. The Company’s mission is to develop novel therapeutics to alleviate human suffering and advance patient care in areas of high unmet medical need. The guiding principles of the company are: Innovation, Global Vision with a Patient Centered focus. Members of the senior management team have a great deal of combined experience in the biopharmaceutical industry, financial, clinical and business management in both the USA and China. The company is supported by funding from institutional investors and corporate partnerships. Sirnaomics has developed a strong portfolio of intellectual property with an enriched product pipeline. The therapeutic areas of focus include oncology and anti-fibrotic therapeutics. Learn more at www.sirnaomics.com.