Dicerna Pharmaceuticals this week released preclinical data from three studies demonstrating the therapeutic potential of its core RNAi and drug-delivery technologies in liver cancer — the company's lead indication.
As reported by Gene Silencing News, Dicerna aims to file an investigational new drug application for the liver cancer candidate by the end of next year. The drug will comprise Dicer-substrate, or DsiRNA, molecules — essentially 27-nucleotide long RNA duplexes that are processed by the Dicer enzyme for incorporation into RISC — formulated with the firm's proprietary EnCore lipid nanoparticles.
Little has been publicly disclosed about the EnCore technology, but Dicerna CSO Bob Brown described it earlier this year as involving sub-structured particles with “distinct internal and surface compositions” (GSN 5/24/2012). The vehicles were “built by design to have an interior that allows maximum RNAi loading and consistent size,” he added, while its surface is optimized for bio-distribution, tumor accumulation, cellular entry, and cytoplasmic release.
Meantime, Dicerna continues to advance its second pipeline candidate, a prostate cancer treatment targeting androgen receptor. The agent also combines the EnCore and Dicer-substrate technologies, and could be poised for a 2014 IND filing, according to a company official.
The liver cancer candidate is specifically designed to silence Myc, a regulator gene that is mutated in a variety of cancers and which has proven to be undruggable by conventional small-molecule therapies.
In a poster presented at the International Liver Cancer Association's annual meeting in Berlin, Dicerna reported that DsiRNAs against Myc were able to trigger picomolar target mRNA inhibition when transfected into human liver cells. Additionally, when formulated with the EnCore technology and delivered intravenously, the RNAi molecules inhibit tumor growth in two different mouse models of liver cancer.
The knockdown of tumor-derived Myc was “sufficient for anti-tumor activity,” Dicerna noted in the poster, and such activity was dose-dependent and observed with multiple, distinct DsiRNAs. Meantime, reductions in Myc mRNA and protein, as well as protein levels of a gene downstream of Myc, all correlated with the anti-tumor activity.
Dicerna also tested the effects of anti-Myc DsiRNAs in combination with the approved liver cancer treatment sorafenib, and found that the combination was well tolerated, with no significant weight loss or changes in spleen or liver weight associated with the combination therapy.
These data, Dicerna said, provide a rationale for the clinical development of a Myc-targeting DsiRNA in patients with advanced hepatocellular carcinoma.
In a separate poster, Dicerna also described the identification of potent DsiRNAs against CTNNB1, a gene that encodes for beta-catenin and has been linked to a variety of cancers, and their use both in vitro and in vivo.
As in the previous poster, Dicerna demonstrated that a variety of tested DsiRNAs could result in picomolar beta-catenin inhibition in liver cells, noting that 80 percent of the molecules identified through its screening process achieved greater than 90 percent knockdown.
When formulated with EnCore, distinct DsiRNAs were able to significantly reduce tumors in established orthotopic cancer models, and they were well tolerated when combined with sorafenib. Additionally, the lower levels of beta-catenin mRNA and protein correlated with the observed anti-tumor activity.
These results, Dicerna said, suggest that DsiRNA inhibition of beta-catenin “may prove to be a promising option” for treatment of advanced liver cancer.
Lastly, Dicerna presented a poster at the ILCA meeting describing the use of its DsiRNA technology in a mouse model of liver fibrosis. Specifically, the company found that a single administration of EnCore-formulated DsiRNAs was able to inhibit target gene expression potently and in a dose-dependent manner in the animals without any elevation in liver enzymes, indicating that they are well tolerated even in the presence of liver damage.
The fibrosis data also “suggests new indications that we can go into outside of oncology,” Dicerna CEO Douglas Fambrough told Gene Silencing News this week. But before going after such diseases, he noted, the firm is first aiming to move ahead with its prostate cancer program.
Prostate cancer has long been a focus for Dicerna, but the effort was put to the side in recent months so that the company could “lock down the Myc program,” he noted.
Now, with a lead liver cancer candidate selected and GLP non-human primate toxicology studies slated to begin early next year, Dicerna has been able to “cycle back to prostate” cancer, Fambrough said.
He declined to provide specific guidance on the timing of the prostate cancer program, but said that he anticipates being at least as far along with the effort as Dicerna is with its liver cancer program at this time next year.