Dicerna Presents New Data From Multiple Tumor Models

Dicerna Pharmaceuticals, Inc. recently announced promising new in vivo data for CTNNB1 DsiRNA in multiple patient-derived xenograft (PDX) and other models of diverse tumor types. CTNNB1 DsiRNA is an extended Dicer substrate short interfering RNA (DsiRNA-EX) therapeutic targeting beta-catenin delivered using Dicerna’s proprietary next generation EnCore lipid nanoparticle (LNP) technology. Beta-catenin, encoded by the CTNNB1 gene, is a well-studied oncology target that is validated by human genetic and functional evidence in a variety of cancers, including hepatocellular carcinoma (HCC), colorectal carcinoma (CRC), and intrahepatic cholangiocarcinoma (IHCC).

The data was presented at the 2015 RNA & Oligonucleotide Therapeutics Meeting at Cold Spring Harbor Laboratory, held April 8-11, 2015, in Cold Spring Harbor, NY. The findings were presented in an oral presentation entitled Advances in Delivery of Dicer Substrate siRNAs (DsiRNAs) to Tumors and were also presented in a poster presentation entitled Delivery of Dicer-substrate siRNAs (DsiRNAs) to Patient-Derived Xenograft Tumors.

The findings demonstrate CTNNB1 DsiRNA’s favorable pharmacokinetic (PK) and biodistribution properties as well as robust messenger RNA (mRNA) knockdown and tumor exposure in models of HCC, CRC, melanoma, leukemia, genetic hepatoblastoma, and other tumor types, including PDX models.

“Dicerna’s second-generation EnCore LNP system has been further refined and is more broadly active than the first-generation EnCore technology,” said Douglas M. Fambrough, PhD, Chief Executive Officer of Dicerna. “As a result, Dicerna is now able to show consistent gene knock down in an even wider range of tumor types, greater efficiency of tumor delivery, and delivery to both subcutaneous and orthotopic tumors. These findings provide us with a deeper understanding of the parameters that drive EnCore-mediated tumor delivery and will help to inform our clinical development strategy as we move forward.”

In an orthotopic HCC PDX model, a single dose of CTNNB1 DsiRNA yielded up to 90% knockdown of CTNNB1 and downstream effectors. Furthermore, Dicerna scientists observed rapid dampening of Wnt signaling in the tumor cells, but not in the adjacent normal liver tissue.

In addition to the HCC findings, Dicerna showed mRNA knockdown in models of hepatoblastoma, melanoma, leukemia, and CRC, providing further insights into the efficacy and delivery of EnCore-mediated CTNNB1 DsiRNA in other tumor types. In one example, CTNNB1 DsiRNA delivery resulted in robust tumor growth inhibition in beta-catenin-dependent CRC tumors.

Dicerna continues to advance its EnCore LNP platform through extensive structure-function analyses to identify advanced formulation components and manufacturing processes. These advances have yielded a greater mechanistic understanding of tumor delivery, improved potency, and up to 10-fold improvements in tumor-specific delivery.

Dicerna’s proprietary RNAi molecules are known as Dicer substrates, or DsiRNAs, so called because they are processed by the Dicer enzyme, which is the initiation point for RNAi in the human cell cytoplasm. Dicerna’s discovery approach is believed to maximize RNAi potency because the DsiRNAs are structured to be ideal for processing by Dicer. Dicer processing enables the preferential use of the correct RNA strand of the DsiRNA, which may increase the efficacy of the RNAi mechanism, as well as the potency of the DsiRNA molecules relative to other molecules used to induce RNAi. Dicerna’s DsiRNA Extended (DsiRNA-EX) molecules resemble DsiRNA molecules but have an extended region at one end of the molecule, which is engineered to provide additional functionality to the DsiRNA-EX molecules. Dicerna can also use this extended region to generate its DsiRNA-EX-Conjugates, where a drug delivery agent is linked directly to the extended region of the DsiRNA-EX molecule, enabling the ability to deliver DsiRNA-EX Conjugates to patients through a subcutaneous injection.

Dicerna Pharmaceuticals, Inc. is a biopharmaceutical company focused on the discovery and development of innovative treatments for rare, inherited diseases involving the liver and for cancers that are genetically defined. The company is using its proprietary RNA interference technology platform to build a broad pipeline in these therapeutic areas. For more information, visit www.dicerna.com.