NEW YORK (GenomeWeb) – As it shifts toward the use of conjugates for drug delivery to the liver, Dicerna Pharmaceuticals disclosed yesterday that it would use Tekmira Pharmaceuticals' lipid nanoparticle (LNP) technology with its primary hyperoxaluria type 1 (PH1) candidate rather than its own EnCore lipid delivery vehicles.
The EnCore technology was originally designed for cancer drug delivery and is being used in the company's Phase I solid tumor drug DCR-MYC. Dicerna had considered adapting it for liver delivery for use in the PH1 program, but opted to go with Tekmira's more advanced delivery technology because it had already decided that its future liver-targeting drugs would eschew LNPs altogether, CEO Douglas Fambrough told GenomeWeb.
That decision made liver-directed EnCore LNPs a "one-off," he said, adding that "it didn't make sense to assume the risk and take on all the additional work involved [with optimizing the technology for the liver] if we were only going to do it once" for PH1.
Fambrough also noted that although Dicerna's conjugate technology is entirely proprietary even though it is based on the same biological processes as Alnylam Pharmaceuticals' GalNAc conjugates, which have become that company's go-to delivery modality.
Further, he said that modifications made to Dicerna's RNAi molecules to enable conjugate delivery result in a novel drug entity that is not covered by any intellectual property held by other organizations, relieving the company of certain royalty obligations and giving it clear freedom to operate.
These new molecules, he said, will be used in all upcoming drug programs.
PH1 is a rare, inherited autosomal-recessive condition characterized by the liver's inability to metabolize a precursor of oxalate due to disruption of an enzyme called alanine-glyoxylate aminotransferase 1 (AGT1). As a result, calcium oxalate builds up in renal tubules causing kidney stones and fibrosis.
Dicerna's candidate, DCR-PH1, is designed to inhibit HAO1, a gene that produces glycolate oxidase, which is an enzyme upstream of AGT1. As the company announced yesterday, the drug will employ Tekmira's LNPs based on the successful mouse and non-human primate testing the companies conducted together.
In exchange for the rights to Tekmira's LNPs, Dicerna will pay $2.5 million upfront and up to $22 million in potential development milestones. It will also owe Tekmira mid-single-digit royalties on sales of DCR-PH1.
Fambrough said that the deal not only gives Dicerna access to Tekmira's already-scaled up LNP manufacturing, but also the use of a delivery technology that has been proven safe in humans in multiple studies — both of which are expected to "streamline" the development of DCR-PH1.
Dicerna, however, has not formally adjusted its guidance on the development of its PH1 drug, which remains on track to enter Phase I testing sometime in 2015, with initial human data available before the end of that year.
Notably, DCR-PH1 will be the first of Dicerna's drug candidates to feature a modified design that falls outside of the IP covering its earlier compounds, Fambrough said.
Dicer-substrates, or DsiRNAs, are asymmetrical double-stranded molecules, with the passenger strand 25 nucleotides in length and the guide strand 27 nucleotides long. On one side of the molecule the strands lie flush with each other, while on the other side there is a two-base overhang, which is recognized by Dicer.
According to Fambrough, Dicerna has found that the addition of an extension to the other side of the guide strand — the part that is eventually cleaved off by Dicer to create an siRNA — offers a number of advantages.
In the case of DCR-PH1, modifications can be put on the extensions of these so-called DsiRNA-EX molecules to suppress immunological activity and enhance stability. But it can also be used to enable conjugate delivery through the attachment of N-acetylgalactosamine (GalNAc) ligands.
GalNAc ligands have a high affinity for the asialoglycoprotein receptors expressed on the surface of hepatocytes. While the concept of using the ligands to facilitate the delivery of drugs into the liver has been around for years, doing so has been difficult. Recently, however, Alnylam has found success with the approach and is using GalNAc conjugates with all of its new candidates.
Fambrough said that Dicerna, too, is developing GalNAc conjugates, which enable both subcutaneous and intravenous administration, and expects to have its technology ready for use in upcoming liver disease programs. The company has said that its next pipeline candidate will be for a rare liver disease, but will not provide additional details until it is officially announced next year.
He added that although Dicerna's GalNAc conjugates are based on the same ligand receptor system as Alnylam's, it involves a unique chemistry that makes it "a totally different approach from an IP perspective."
Fambrough also stressed that the DsiRNA-EX molecules themselves are covered by novel IP that is entirely controlled by Dicerna — something that has both near-term and potentially long-term implications.
In the near term, by using DsiRNA-EX molecules in its PH1 program, Dicerna is eliminating the need to pay a royalty to the City of Hope (COH), where the original DsiRNAs were invented.
Under its license with COH, Dicerna is required to pay an undisclosed royalty on products based on the DsiRNA technology. With DCR-PH1, Dicerna no longer has that obligation, which Fambrough noted helps offset royalties that will be owed to Tekmira.
The use of DsiRNAs puts Dicerna outside of any IP held by other companies, Fambrough said. Longer term, this could remove any doubt that may arise about the company's freedom to operate.
Indeed, the COH IP licensed to Dicerna is also held by Arrowhead Research, which acquired it when it bought the RNA assets of Roche in 2011. Roche previously sublicensed the IP from Marina Biotech, which picked it up years ago when it was still known as Nastech Pharmaceuticals.
A bigger potential threat to Dicerna's freedom to operate may be Alnylam, which announced earlier this year that it had received noticed of allowance from the US Patent and Trademark Office for two patent applications that it claims cover Dicer-substrate RNAi triggers.
But to Fambrough, the DsiRNA-EX molecules fall outside of Alnylam's IP for the same reasons that they are not covered by the COH patents.
"If you have the [guide strand] extension, it clearly falls outside of those claims," he said.
While DCR-PH1 and Dicerna's other planned programs will all use DsiRNA-EX technology, DCR-MYC and a preclinical cancer drug under development with Kyowa Hakko Kirin use the standard DsiRNA molecules covered by the COH IP.