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Intradigm Drops Lead Cancer Rx Candidate As It Focuses on New Targets, Delivery Tech

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Intradigm has shelved its lead cancer therapeutic ICS-283, which had been projected to enter phase I testing this year, in order to focus on developing RNAi drugs against undisclosed targets that are currently undruggable by other technologies, RNAi News has learned.
 
At the same time, the company has closed a $2.9 million final tranche of its $21.4 million Series B round of financing, which will help it re-build its pipeline and continue developing its proprietary delivery technology.
 
Intradigm has also made its second major change in leadership since it was founded in 2001, appointing Phil Haworth to be its new CEO. Haworth, formerly Intradigm’s vice president of business development, replaces Mohammad Azab, who remains on Intradigm’s board.
 
Details about Azab’s resignation were not available.
 
ICS-283 is an siRNA targeting vascular endothelial growth factor that is delivered using Intradigm’s so-called nanoplex technology, which consists of an RNAi payload surrounded by a polyethylene glycol coat and decorated with targeting ligands.
 
As early as 2004, Intradigm officials had been saying the drug was on the cusp of entering human testing (see RNAi News, 5/7/2004). After a series of delays and a sweeping corporate reorganization in 2006 (see RNAi News, 11/22/2006), the company pushed that clinical timeline back to some time in 2009 (see RNAi News, 10/18/2007).
 
According to Haworth, however, Intradigm eventually deemed RNAi drugs targeting VEGF as not commercially promising enough to warrant further development.
 
VEGF was “a rational target at the time” ICS-283 was originally developed, he told RNAi News this week. “We have now re-thought how to use [RNAi] technology on what we consider to be previously undruggable targets.” He did not provide specifics about these targets, but noted that the company plans to keep its in-house focus on oncology.
 

“We didn’t cease developing [ICS-283] because the [delivery] nanoparticles don’t work but because the molecular target was inappropriate in the current commercial context.”

With a well-validated role in a variety of diseases including certain cancers and ocular disorders, VEGF has been a popular target for many RNAi drug candidates including Opko Health’s phase III wet age-related macular degeneration drug bevasiranib.
 
At the same time, VEGF and related growth factors are targets for a number of non-RNAi drugs, both on the market and under development, such as Genentech’s antibody-based cancer drug Avastin.
 
It was that very popularity that led to ICS-283’s demise, Haworth said.
 
“The real value of siRNA and our delivery technology is to develop drugs that treat diseases whose targets are not accessible through antibodies or small molecules,” he said. “VEGF’s value was that it was validated through antibodies and small molecules.” Therefore, the target “loses the real benefit of a siRNA approach.”
 
“There are many drugs ahead of our technology that inhibit angiogenesis through VEGF” or VEGF receptors, he added. “We were too late to come to the market with a product that went through that particular intervention strategy.”
 
The work done on ICS-283, however, wasn’t a wasted effort, Haworth stressed. The drug “validated two things for us: that we could get in vivo knockdown and we could deliver systemically to the tumor,” he said. In the end, though, “we don’t believe, with the 140 drugs ahead of us in the clinic, that there is a commercial rationale for developing a drug” that targets VEGF.
 
With that decision, Intradigm is left with the task of building up an empty pipeline, while broadening the utility of the nanoplex technology. But with $21.4 million in the bank from the Series B, Haworth said that Intradigm is in a good position to do just that.
 
In October, Intradigm announced that it had closed an $18.5 million Series B round (see RNAi News, 10/2/2008). But this week, the company said that a new investor, Astellas Venture Management, and an existing investor, Lilly Ventures, had ponied up an additional $2.9 million.
 
As a result, “we have sufficient money to run our operations for the plan we have in place,” he said.
 
In terms of new drug candidates, Haworth said that Intradigm is currently evaluating “a whole group of new targets that were previously undruggable.” He declined to provide any timelines for Intradigm’s new drug-development activities, but noted that an investigational new drug application is “not a 2009 goal.”
 
When it comes to the nanoplex technology, Haworth said that Intradigm is working to expand the technology’s capabilities “so that it applies solid tumors, liquid tumors, and other disease conditions,” which would not only expand the number of indications the company could pursue by itself, but also help attract potential collaborators.
 
“We recognize there are many potential applications … outside our own biological and development expertise [in cancer] that a partner would like to pursue with their resources [using] our delivery platform,” he noted.
 
But as with its pipeline, Intradigm’s partnership plans are early-stage since any kind of corporate tie-up won’t likely happen until the company has a strong data package in hand.
 
To Haworth, the goal isn’t “just getting a deal done, [but] a deal where we get proportional value for what we have to give up,” he said. “The more data we have and the stronger the demonstration of our capabilities is, the more attractive those deals become.”
 
Despite Intradigm’s interest in further developing the nanoplex technology, Haworth noted that the delivery approach is already effective enough to be used for siRNA drug delivery and may be incorporated into upcoming drug candidates.
 
In the case of ICS-283, “we didn’t cease developing it because the [delivery] nanoparticles don’t work, but because the molecular target was inappropriate in the current commercial context,” he said.

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