Delivering on Promise of RNAi Therapeutics

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Delivering on Promise of RNAi Therapeutics
August 11, 2006
Carolyn Riley Chapman, PhD
Drug Discovery and Development
In 1998, scientists discovered that RNA not only acts as a simple intermediary between genes and proteins, but that it also carries out regulatory activities of its own. The discovery of RNA interference (RNAi) by Fire and Mello was breathtaking for two reasons: first, researchers hadn?t known about it before, and second, it had amazing potential as a research tool and even as a new class of therapeutics. With the sequence of the human genome in hand, RNAi essentially allows scientists to knock down the activity of any protein at will by causing mRNA degradation.
Indeed, RNAi has become a standard technique for basic and drug discovery research (see July DD&D). Today, it seems probable that RNAi drugs will eventually make it to the market. While there is no question the mechanism works, "it is not yet a clinically validated technology," cautions Paul Johnson, PhD, senior vice president of research and development and chief scientific officer at Nastech Pharmaceutical Co., Bothell, Wash.
To receive approval from the FDA, small interfering RNA (siRNA) drugs still need to demonstrate efficacy and safety in humans, even those that take advantage of local administration and delivery paradigms. But for RNAi to become a broader platform applicable to all therapeutic areas, the systemic delivery challenge, or getting siRNAs into appropriate cells within humans, must be solved.
A small group of biotech companies, both public and private, is actively pursuing the discovery and development of RNAi therapeutics, and some pharmaceutical companies have allied with them. For example, Novartis, Basel, Switzerland, and Merck, Whitehouse Station, N.J., have partnered with Alnylam Pharmaceuticals, Cambridge, Mass. And Eli Lilly, Indianapolis, Ind., and GlaxoSmithKline, London, are working with Sirna Therapeutics, San Francisco. But while there is a great deal of work going on, perhaps the biggest barrier to new entrants in the field is the intellectual property associated with RNAi technologies, an area of considerable complexity. "Usually those issues don?t get resolved until a drug comes to market," says Steven Kriegsman, president and chief executive officer of CytRx Corp., Los Angeles.
Despite the intellectual property issues, there is now substantial progress in the development of RNAi therapeutics. There are currently three RNAi drug candidates in the clinic. One is Bevasiranib, Cand5, from Acuity Pharmaceuticals, Philadelphia, which is in phase II trials for age-related macular degeneration (AMD) and diabetic macular edema. In addition, there are Sirna-027 from Sirna, which is also for macular degeneration, and Alnylam?s ALN-RSV01 for pediatric RSV. Acuity?s Bevasiranib, which targets vascular endothelial growth factor (VEGF), was the first siRNA to enter both phase I and II clinical trials. "The challenge of being first is like being the first person in a bike race, or the first person breaking through snow if you?re hiking through snow," says Sam Reich, co-founder and vice president of research and development at Acuity.
Targeting VEGF
Dale Pfost, PhD, Acuity?s chairman, president and chief executive officer, says his company?s approach was to use the breakthrough technology of siRNA to silence a clinically-validated target. "VEGF, the protein, is central to the angiogenesis and the leakage that causes these diseases. We have seen time and again now that an anti-VEGF approach is a fruitful one to pursue. So, therefore, translating that into an siRNA strategy was really quite appropriate," says Pfost. For example, Macugen and Lucentis, drugs for AMD from OSI Pharmaceuticals, Melville, N.Y., and Genentech, San Francisco, respectively, are both VEGF antagonists. Macugen is a pegylated aptamer and Lucentis is a humanized therapeutic antibody. In that respect, it is important to recognize that siRNA drugs will compete not only with other siRNA drugs, but with many different types of therapies, including small molecules and antibodies.
So far, results with Bevasiranib have been promising. In phase I trials, more than 100 patients were exposed to the drug, and Reich points out that the approval of two phase II protocols is validation of the safety findings from phase I. But he adds that "one of the safety advantages we have is lack of systemic exposure to a potent VEGF inhibitor." Bevasiranib is administered by intravitreal injection, and without modifications to increase its stability, it quickly degrades in serum.
Sirna, in collaboration with Allergan, Irvine, Calif., is also pursuing a siRNA drug, Sirna-027, for the treatment of AMD, and it is now in phase I clinical trials. But Roberto Guerciolini, MD, the company?s chief medical officer, expresses even more excitement about Sirna-034, "because we switch now from local administration to systemic administration." Sirna expects to file an IND for intravenous administration of Sirna-034 for the treatment of chronic hepatitis C by the end of 2006. Guerciolini believes Sirna-034 meets the chemical stabilization, modification, and delivery challenges associated with a systemic RNAi therapy. He says Sirna-034 combines two different RNA sequences in a proprietary nanoparticle formulation that preferentially delivers RNA into hepatocytes.
One way Sirna improves the stability of its siRNA drugs is by removing ribose from the molecules so they become "siNAs" or small interfering nucleic acids instead of ribonucleic acids. Sirna-034 has been significantly modified to maintain stability in extracellular and intracellular environments, says Guerciolini, but it still retains some riboses
Designing siRNA Therapeutics
Since siRNAs are now routinely used by academic, pharmaceutical, and biotech investigators for basic and drug discovery research, it?s interesting to note that there are big differences in how companies go about designing siRNA therapeutics versus siRNA tools. "You certainly can?t just buy an off-the-shelf siRNA and expect it to be therapeutically relevant. It won?t be; it will degrade in seconds," says Rebecca Robinson, senior director of corporate strategy, Sirna Therapeutics, San Francisco. "It?s a sexy area right now. Folks are interested in it, but it?s also a challenging one, and it takes a lot of expertise and understanding." siRNAs, particularly ones that will be administered systemically, are modified and formulated to enhance their drug-like properties.
Nagesh Mahanthappa, PhD, senior director of business development and strategy at Alnylam Therapeutics, points out fundamental distinctions between siRNA design for therapeutic use and research use. "If you?re involved in genome-wide screening, obviously you?re up against an economic barrier. You can?t make hundreds of different siRNAs for every gene in the human genome. For that reason, you?re quite reliant on algorithms that will maximize specificity and potency." In contrast, Alnylam relies heavily on brute force, wet lab testing to empirically identify siRNAs for select therapeutic targets of interest, he says, and has not become overly tied to algorithms for siRNA design because of their inherent limitations.
Mahanthappa characterizes Alnylam?s siRNA design and selection process as a funnel with attrition, pointing out that Alnylam doesn?t run all assays on all siRNAs. They start off by synthesizing a set of siRNAs that pass two major filters. First, they eliminate any sequences that are identical to sequences in off-target genes.