LAS VEGAS — Dicerna Pharmaceuticals has selected a target and delivery technology for its first drug candidate, and remains on track to meet its previously stated goal of filing an investigational new drug application by the end of 2013, a company official disclosed this week.
Speaking at the Tides: Oligonucleotide and Peptide Research, Technology, and Product Development conference in Las Vegas this week, Dicerna CSO Bob Brown said that the clinical candidate will combine the company's Dicer-substrate technology with a proprietary lipid-based particle dubbed EnCore.
Dicer-substrates are essentially 27-nucleotide long RNA duplexes that, unlike conventional siRNAs, are processed by the Dicer enzyme for incorporation into RISC. Dicerna has for some time been evaluating different delivery approaches, under development both in-house and externally, that could be used with the molecules, but has settled on its EnCore approach for its cancer drug.
Specific details about the delivery vehicle remain under wraps, but Brown said that it is a “sub-structured particle with distinct internal and surface compositions. It was “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.
He added that Dicerna has synthesized EnCore particles with different targeting moieties ranging from small molecules to antibodies, as well as ones without such additions, and stressed that the final formulation is still being determined.
Thus far, Dicerna has tested different versions of the EnCore particles with Dicer-substrates against various targets in multiple animal models — including ones for colorectal cancer and non-small cell lung cancer, as well as in a variety of liver cancer models — and seen tumor-growth inhibition ranging from 50 percent to 60 percent, Brown said during his Tides presentation.
However, the company has selected the regulator gene Myc as the target for its first clinical candidate, in part because it has been strongly implicated in a wide variety of cancers and because it has proven thus far undruggable by other therapeutic technologies, according to Brown.
He added that in in vivo testing, inhibition of Myc has not resulted in any toxicities or adverse events.
Given Dicerna's 2013 IND-filing goal, Brown said that the company expects to finalize its choice for a Dicer-substrate payload and EnCore formulation this year, with IND-enabling studies in non-human primates slated to start in the third quarter.
The non-human primate data is expected too give Dicerna guidance on, among other things, the dose range that will be tested in the planned phase I, repeat-dosing study, which will enroll around 36 patients with hepatocellular carcinoma and with metastatic liver lesions associated with other cancers., and will examine escalating doses of the drug with the goal of determining safety and tolerability, he said.
The primate work will also allow Dicerna to confirm target knockdown in liver tissue obtained from sacrificed animals.
Previously, Dicerna had said that it is aiming to ink at least one corporate partnership during 2012 (GSN 12/22/2011). Brown confirmed this week, however, that the company does not need to do so in order to move forward with its phase I trial.