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Lilly Tells Investors That Antisense Will Help Fuel Growth; RNAi Falls to the Wayside

Drugs giant Eli Lilly last week said that two of its antisense-based cancer drug candidates are key to the company’s future growth as it embraces biotechnology in order to help fill out its pipeline.
"Lilly has invested more than $1 billion in its biotech R&D capabilities just in this decade … and bioproducts comprise fully one-third of our pipeline,” Steven Paul, executive vice president of science and technology, said during the company’s annual corporate update meeting with investors.
Part of that one-third includes two antisense drugs licensed from Isis Pharmaceuticals: LY2181308, which is on track to enter phase II before the end of the year, and LY2275796, which continues to advance through phase I testing.
Both drugs are so-called second-generation antisense oligos, incorporating recently developed backbone modifications designed to boost efficacy and stability.
“We believe that second-generation [antisense] chemistry pharmacologically will make a better drug and has a higher chance of succeeding” than earlier antisense oligonucleotides, Chris Slapak, a Lilly distinguished scholar and director of the company’s early-phase oncology group, told RNAi News this week. “We think they can potentially overcome some of the issues we saw with the first-generation molecules.”
Despite Lilly’s enthusiasm for antisense, however, it appears that the company has not embraced all gene-silencing technologies as promising therapeutic modalities.
In January 2004, Lilly formed one of the RNAi space’s earliest collaborations, establishing an 18-month partnership to evaluate siRNAs generated by Sirna Therapeutics against undisclosed oncology targets (see RNAi News, 1/30/2004). 
But since then, little has been said about the arrangement by the companies, and the alliance apparently ended without yielding any promising therapeutic candidates.
Wherefore Antisense?
“Whether one employs ASOs or RNA interference, knocking down the target gene is a prerequisite for any therapeutic effect,” Paul said during Lilly’s investment meeting. “Recently published work by several groups has now unequivocally demonstrated the ability of ASOs to knock down key genes and their proteins in vivo, such as clusterin in prostate cancer.”
Among that work are a number of papers co-authored by Martin Gleave, a Vancouver General Hospital researcher and CSO of OncoGenex, showing that targeting the cytoprotective chaperone clusterin with antisense agents can boost the efficacy of chemotherapy in various cancers while also inhibiting angiogenesis. (OncoGenex is developing all three of its antisense-based drug candidates, including a clusterin-targeting agent, in collaboration with Isis.)
In light of these and other data, antisense agents “show promise in reducing the expression of genes and proteins involved in human cancer growth,” Paul added.
After expanding in 2002 an antisense drug-discovery partnership with Isis to include cancer, Lilly selected as its first therapeutic candidate LY2181308, which targets the apoptosis inhibitor survivin.
According to Isis, in preclinical studies LY2181308 has demonstrated anti-tumor activity associated with selective inhibition of survivin and has been shown to boost the effect of certain chemotherapeutic agents.
“Survivin is over-expressed in 80 to 90 percent of tumors, but it is virtually non-existent in healthy tissue,” Paul said. “Based on successful phase I trials, we have selected the dose to advance into phase II … based on the presence of significant levels of the ASO in the tumor and the drug’s ability to knock down its target in biopsy specimens.”

“We believe that second-generation [antisense] chemistry pharmacologically will make a better drug and has a higher chance of succeeding” then earlier antisense agents.

Specifically, Lilly aims to begin the first of several phase II trials of LY2181308 in liver cancer patients later this month. In 2007, the company plans to start additional phase II studies in prostate cancer, acute myelogenous leukemia, ovarian cancer, and non-small cell lung cancer, Paul said.
Meanwhile, he added, Lilly remains committed to continuing development of LY2275796, which targets eukaryotic initiation factor-4E, a protein over-expressed in a variety of cancers and associated with tumor angiogenesis, growth, and survival.
Whither RNAi?
Though Lilly jumped into the RNAi arena early, the company has yet to incorporate the technology into its drug-development efforts in a significant way.
According to Slapak, Lilly is “still very interested in the potential for RNAi,” but has doubts about whether it is ready for clinical applications.
While three RNAi-based drugs developed by other companies are already in human trials — Acuity Pharmaceuticals’ bevasiranib, which is in phase II for age-related macular degeneration, Sirna’s phase I AMD therapy Sirna-027, which has been licensed to Allergan (see RNAi News, 10/7/2005), and Alnylam’s respiratory syncytial virus drug ALN-RSSV01, which is slated to enter phase II trials next year — all are delivered directly to the disease site.
While several firms are planning to begin clinical studies of systemic RNAi drugs in the coming year, on the delivery front antisense continues to be “further advanced right now,” Slapak noted.

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