With delivery remaining the key problem facing the successful development of RNAi therapeutics, an increasing number of players in the field are looking within their own labs for solutions, often using delivery technologies as the foundation upon which to build their businesses.
Although the need for effective delivery approaches has long been recognized, many of the early entrants into the RNAi therapeutics space — companies such as Alnylam Pharmaceuticals, Sirna Therapeutics (now a part of Merck), Atugen (now Silence Therapeutics), and CytRx (which spun out its RNAi drug operations into RXi Pharmaceuticals) — focused much of their initial research and development on the molecules themselves.
But with a greater understanding of how to design and modify functional siRNAs and licenses to key intellectual property now widely available, many RNAi drug firms are making delivery their first priority.
Topping the list is Tekmira Pharmaceuticals, which secured access to one of the RNAi drug field's most important delivery technologies when it merged with Protiva Biotherapeutics about a year ago (see RNAi News, 4/3/2008).
That technology, termed SNALPs, or stable nucleic acid lipid particles, was developed by Protiva and comprises nucleic acids encapsulated by cationic and fusogenic lipids surrounded by a polyethylene glycol coating to prevent the positively charged cationic lipid from clearing the bloodstream.
The technology proved so promising that both Alnylam and Sirna took early licenses, although a lawsuit between Protiva and Tekmira predecessor Inex Pharmaceuticals ultimately led to a restructuring of the arrangement with Sirna. Alnylam, however, continues to use the technology in several of its programs.
The litigation was settled through the Tekmira/Protiva merger, and Tekmira has since attracted a number of additional companies interested in using SNALPs in their own RNAi efforts, including Roche, Johnson & Johnson, and Bristol-Myers Squibb.
With revenues from these and other collaborations, Tekmira has been able to fund its own siRNA drug pipeline, and last month filed an investigational new drug application, its first, for the hypercholesterolemia treatment ApoB SNALP (see RNAi News, 4/16/2009).
Another company defined largely by its delivery approach is Cequent Pharmaceuticals, which has pinned its hopes on its so-called transkingdom RNAi technology.
TkRNAi involves using attenuated Escherichia coli to transcribe therapeutic shRNAs. The bacteria are designed to express the protein invasion on their surface, which allows them to enter a host cell, as well as listeriolysin, which permits the shRNA payload to escape after bacterial entry. Cequent expects the technology will enable oral delivery of RNAi therapeutics.
The company has set its sights on two indications: familial adenomatous polyposis, an inherited, colorectal-cancer syndrome characterized by the growth of colorectal polyps that nearly always become malignant; and inflammatory bowel disease.
Earlier this year, Cequent released non-human primate data demonstrating the safety and gene-silencing ability of its lead FAP candidate, CEQ501, which is expected to enter phase I testing before the end of the year (see RNAi News, 2/12/2009).
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The company also continues to narrow down the list of potential IBD targets, the first of which, optioned to Novartis (see RNAi News, 6/21/2007), is expected to be selected by mid-year.
Also founded on a delivery technology is Arrowhead Research subsidiary Calando Pharmaceuticals, which was originally established to tweak the delivery technology of another Arrowhead unit, Insert Therapeutics, for use in therapeutic RNAi (see RNAi News, 2/25/2005). Those companies were later merged under the Calando banner as part of a cost-cutting strategy (see RNAi News, 10/23/2008).
Calando's core RNAi-delivery technology is the Rondel system, which comprises a linear, cyclodextrin-containing polycation capable of binding to the anionic backbone of an siRNA. When mixed together, the polymer and siRNA self-assemble into nanoparticles that are protected from nuclease degradation in blood serum.
According to Calando, the cyclodextrin in the polymer allows stabilizing agents to be attached to the surface of the particles. These agents have terminal adamantane groups that form inclusion complexes with cyclodextrin and contain polyethylene glycol, which prevents aggregation and degradation. Additionally, ligands to cell-surface receptors can be covalently attached to the adamantane-PEG modifier, which allows the particles to be targeted to tissues of interest.
Using this technology, Calando moved the first formulated siRNA drug, the cancer therapy CALAA-01, into human testing last year (see RNAi News, 6/5/2008). And although it had expected to advance another cancer drug into the clinic this year, Arrowhead recently placed a moratorium on any new INDs from Calando until a cash-making deal can be struck for the subsidiary (see RNAi News, 12/18/2008).
The push for in-house delivery solutions isn't limited to startups, however.
MDRNA, for example, has been building its so-called DiLA2 delivery platform, which allows for the creation of liposomal delivery vehicles from amino acids, as well as the modification of the lipids’ charge, linker, and acyl chains so that delivery can be optimized for specific target tissues.
Although MDRNA was created just last year out of failed nasal drug-delivery shop Nastech Pharmaceuticals (see RNAi News, 6/12/2008), Nastech had been working in the therapeutic RNAi field since 2006 when it acquired the RNAi assets of privately held Galenea (see RNAi News, 2/23/2006).
As it continues to struggle under a cash crunch and deflated stock price, MDRNA has been able to eke some early value from the DiLA2 technology. In March, the firm announced that it had granted Novartis a non-exclusive license to the delivery platform in exchange for an upfront payment of $7.25 million (see RNAi News, 3/26/2009).
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Meanwhile, RXi recently changed up its pipeline for at least the third time to place greater emphasis on an early-stage technology, licensed exclusively from the University of Massachusetts Medical School, that holds promise for oral delivery of siRNA drugs.
Called GERPs, for glucan-encapsulated siRNA particles, the technology comprises hollow, porous, micrometer-sized shells that are loaded with an siRNA payload. Once delivered orally, the GERPs are designed to be taken up by M cells, which are specialized cells in the small intestine that take up antigens and carry them through the intestinal wall so they can be phagocytosed by macrophages.
Under normal conditions, when a macrophage has taken up an antigen, it begins producing cytokines, which in turn triggers inflammation. But a macrophage treated with an anti-inflammatory siRNA would, in theory, lessen inflammation as it migrates from the intestine to other tissues in the body.
As such, RXi said in March that inflammatory disease would be its top focus, leapfrogging other programs in metabolic disease, neurological disorders, and cancer (see RNAi News, 3/26/2009).
Also making a big push for in-house delivery is Roche, which has made some of the biggest investments in therapeutic RNAi of the big pharmaceutical and biotech firms. Last July, the company announced that it would buy Mirus Bio for $125 million in cash in a deal largely driven by Mirus' polymer-based dynamic polyconjugate delivery technology (see RNAi News, 7/24/2008).
Lou Renzetti, vice president and global head of RNA therapeutics at Roche, told RNAi News at the time that the decision to acquire Mirus, rather than just partner with it, would create synergies the Roche Center of Excellence for RNAi Therapeutics Research in Germany, which had been Alnylam Europe before Roche acquired it in mid-2007 (see RNAi News, 7/12/2007).
Last year, Roche also took an equity stake in Tekmira to gain access to that company’s siRNA-delivery technologies.