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At BIO Investor Forum Meeting, Intradigm Breaks Out Drug Development Timeline

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As it prepares to begin its second round of financing following a major restructuring, Intradigm has begun publicly disclosing a timeline for the development of its long-delayed lead RNAi drug that includes a planned investigational new drug application filing in the third quarter of 2008.
Speaking last week at the Biotechnology Industry Organization Investor Forum in San Francisco, Intradigm President and CEO Mohammad Azab also indicated that the company would be in a position to take its drug candidate — a therapy for solid tumors called ICS-283 — through phase I on its own, should the upcoming financing effort hit its goal of $30 million.
 
Once a prominent player in the nascent RNAi drugs field, Intradigm slipped off the radar in recent years amid a corporate shakeup that included the departure of essentially all of the company’s prior management, including CEO John Spears, as well as co-founders Martin Woodle, Patrick Lu, and Puthupparampil Scaria. Additionally, Intradigm moved its headquarters from Maryland to Palo Alto, Calif. (see RNAi News, 11/22/2006).
  
Under new leadership, the company closed a $16 million Series A financing round that funded its move and gave it enough resources to add about 10 employees, bringing the total number of staffers to 27.
 
Now, according to Azab, Intradigm is planning a Series B round that is slated to begin in earnest late this year or early next year, and pull in between $25 million and $30 million.
 
“We believe that within a year [of filing an IND on ICS-283] we can achieve a proof of concept of the delivery [system] and the drug,” a milestone that Intradigm can reach on its own with the addition of the Series B money, Azab said during his presentation at last week’s meeting, which was webcast.
 
More specifically, Intradigm’s new development timeline for ICS-283 slates process development and scale-up of the drug’s manufacture for animal studies to begin in the first half of next year. IND-enabling preclinical work, drug manufacturing for human trials, and an IND filing are scheduled for the third quarter of 2008.
 
The first human dosing of ICS-283 is expected to begin by the fourth quarter of 2008, with clinical proof of concept possible by the end of 2009.
 
At the same time as this work is occurring, Azab said that Intradigm is also looking to expand its pipeline to include other RNAi-based cancer treatments — work that should be expedited as the company optimizes its delivery approach.
 

“The pipeline opportunities are tremendous. Once you perfect the delivery vehicle, you can just change … the siRNA payload in the particle and you have a new product in a matter of a few months as opposed to several years.”

Intradigm’s so-called nanoplex delivery technology essentially consists of an RNAi payload surrounded by a polyethylene glycol coat. Binding ligands on the surface of the particle are used to direct it to specific tissues.
 
In the case of ICS-283, the nanoparticles are constructed with pegylated polyethyleneimine and decorated with Arg-Gly-Asp (RGD) peptide ligands that target the drug to tumor neovasculature. The details about the RNAi payload of the drug have not been disclosed, but Azab said at the BIO meeting that it includes multiple siRNA against VEGF and VEGF receptors.
 
“The pipeline opportunities are tremendous,” he noted. “Once you perfect the delivery vehicle, you can just change … the siRNA payload in the particle and you have a new product in a matter of a few months as opposed to several years,” as with traditional new drug development.
 
Azab was not available for additional comment.
 
Targeting VEGF
 
During his presentation at last week’s investor meeting, Azab also provided a glimpse at some preclinical data from experiments evaluating the ability of its delivery technology to knock down targets in the VEGF pathway in mouse models.
 
In the first set of experiments, mice were injected with tumor cells and Matrigel, and then received intravenous doses of nanoplexed siRNA against VEGF, VEGFR-1, or VEGFR-2, or a combination of siRNA.
 
“Then we harvest the Matrigel … to look at [its] morphology … and, more importantly … [to count] the blood vessels” to evaluate angiogenesis, he said. The data showed that the siRNA treatment resulted in significantly lower rates of angiogenesis compared with negative control siRNA.
 
“More importantly, the siRNA treatments “produced anti-angiogenic activity similar to the positive control,” which was Genentech’s gold-standard colon cancer treatment Avastin
 
In another set of experiments, Intradigm evaluated the ability of nanoplex-delivered siRNA to reduce tumor size in HT-29 tumor xenograft mice, which are a “known colon-cancer tumor xenograft model,” Azab said.
 
After the tumor was allowed to grow, the mice received intravenous injections of either negative control siRNA, Avastin, or nanoplexed siRNA against VEGF and VEGF receptors.
 
“The negative control had no response; the tumor kept growing,” he said. The positive control, meanwhile, led to a significant reduction in tumor size — an effect similarly achieved by one of the nanoplexed siRNA treatments.

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