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Silence Considers Testing GI Cancer Drug In Lung Cancer as it Preps for Phase I

Silence Therapeutics is considering expanding a planned phase I study of its lead RNAi drug candidate, the gastrointestinal and pancreatic cancer therapy Atu-027, to examine whether the drug can also be used to treat lung cancer, a company official told RNAi News last week.
Also last week, Silence issued a letter to its shareholders containing an overview of the company’s recent activities, including discussions with possible collaborators, in hopes of addressing marketplace rumors the company said have been hurting its stock price recently.
Atu-027 is a preclinical, systemically administered drug comprising modified, blunt-ended siRNA that target PKN-3, a protein kinase that company researchers have linked to tumor growth and metastases, and formulated with a mixture of cationic and fusogenic lipids.


Silence had originally planned to test the drug as a treatment for gastrointestinal and pancreatic cancers, while at the same time developing an inhaled formulation of the agent under the name Atu-093 for non-small cell lung cancer. However, recent animal data suggest that the drug might be more effective for lung cancer when formulated for intravenous administration — as Atu-027, essentially.
“Even though we have Atu-093 still in the pipeline, it’s very likely that … it makes more sense to dose systemically rather than trying to go through an alternate form of delivery such as inhalation” for treating lung cancer, Silence CEO Jeffery Vick told RNAi News. As such, a lung cancer therapeutic is likely to move forward, “but not necessarily as a separate formulation” from Atu-027.
About a year ago, Silence announced that it had completed preclinical toxicology work on Atu-027, setting the stage for a mid-year phase I study of the drug (see RNAi News, 2/1/2007). However, by that spring the company had pushed this timeline back to 2008, citing the need to “optimize the risk/benefit ratio in acutely ill patients” (see RNAi News, 5/3/2007).


According to Vick, that optimization is ongoing as the company works to establish the appropriate dose levels and regimens in order to “make sure that we move forward into the clinic … with an appropriate program with good chance of success.”
As that work continues, he noted, Silence is also following up on data from toxicology studies that suggested Atu-027 could be effective at lower-than-expected doses and possibly as treatment for lung cancer.
In a letter issued to shareholders last week, Silence Chairman Iain Ross said that 28-day preclinical studies of Atu-027 using multiple dosing schedules showed “on-target activity at all doses, including the lowest dose, not only in the target tissues but also in the lung.”
“What we’ve found is that at the lower dose … we still had [the] full level of knockdown activity [and] full biological response,” Vick added. “So now we’re seeing how far down we can push the dose” for testing in phase I as recommended by the European Medicines Agency.

“Our preliminary thinking … is that in fact it’s likely a phase I program for Atu-027 could potentially support multiple indications.”

“One of the big challenges in the delivery of oligonucleotides in general, whether it’s RNAi or antisense, is that the delivery systems themselves tend to have some toxicity,” he explained. “What we are looking at now is widening the range between the toxic level of the delivery system and the effective level of the drug itself.”
At the same time, Silence is conducting additional non-human primate experiments to determine whether the phase I study of the drug for gastrointestinal and pancreatic cancers, which is slated to begin in Europe later this year, should also include lung cancer.
“It’s actually much more interesting to have a single formulation that can be used in multiple settings,” Vick said. It is “quite exciting to us that we have the possibility of using the same formulation not only for GI cancer or pancreatic cancer, but also lung cancer and potentially other forms of cancer, as well.
“Our preliminary thinking … is that in fact it’s likely a phase I program for Atu-027 could potentially support multiple indications,” including lung cancer, Vick said. As a result, the future of Atu-093 is now tied to Atu-027. “It would be most interesting” to Silence to use Atu-027 for both gastrointestinal and lung cancers, he added.
Damage Control
In the company’s letter to its shareholders, which can be viewed here, Ross said that he was attempting to “correct any misconceptions that may have arisen as a result of inaccurate reports” that surfaced around the end of 2007.


“As a result of the low level of news flow, we have been the subject of a variety of inaccurate reports circulating in the market in recent weeks,” he wrote. “This, coupled with the high liquidity of our stock [and] the recent volatility in the financial markets, has resulted in a decline in our share price, which … is unwarranted.”
Over the past several months, shares of Silence have sharply declined, falling from around 150 pence per share to about 58 pence per share as of Thursday.
Silence CEO Jeffery Vick told RNAi News last week that these reports were primarily rumors among “smaller retail shareholders who have their own speculation that then takes on a life of its own.”
He noted that few of these shareholders have contacted the company for additional information, making the rumors difficult to address directly.
Instead, Silence issued the letter, which touched on the preclinical data regarding delivery of Atu-027 to the lung, and also noted that the company is in “discussions with a number of possible partners” about entering into research and development collaborations and licensing deals.
Most recently, Silence signed an siRNA-based drug-discovery deal with AstraZeneca that initially focuses on respiratory diseases (see RNAi News, 7/12/2007). But whether any new deal is on the horizon is unclear.


“We take very seriously … the need to establish the best quality business relationships,” Ross wrote in the letter. “In short, we will only sign up to collaborations that provide us with real opportunity to create a sustainable increase in shareholder value.
“We intend to sign further collaborations, but recognize that, in a very competitive environment, we need to secure the right deal at the right time,” he added.

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