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Sirna, Nucleonics, CytRx Adjust Drug Timelines; Alnylam Adds to Its Pipeline


Four RNAi-based therapeutics developers provided additional information about their product-development efforts over the past two weeks, with one • Alnylam Pharmaceuticals • announcing the addition of a new drug program, and three • Sirna Therapeutics, Nucleonics, and CytRx • pushing back previously announced timelines.

RNAi News has provided a breakdown of the updates.


Alnylam said this week that it has decided to conduct preclinical development of an siRNA-based treatment for spinal cord injury as part of its partnership with Merck.

In September 2003, the companies signed a 5-year deal under which Merck provides Alnylam with a number of validated drug targets, many of which have been deemed refractory to small-molecule treatment (see RNAi News, 9/12/2003).

Alnylam then designs siRNAs against the targets, giving Merck the opportunity to decide if it wants to participate in additional development and commercialization. Under this arrangement, Alnylam has the right to decide the extent of its role in each deal, and may opt for up to a 50/50 split of costs and profits.

Alnylam said it has decided to work on an siRNA drug against a spinal cord injury target, proposed by Merck, within the Nogo pathway. Once the siRNA has been advanced up to “a defined point in preclinical development,” Merck will make a decision on getting involved in the drug program, Alnylam said.

Nagesh Mahanthappa, senior director of business development and strategy at Alnylam, told RNAi News in an e-mail this week that “the Nogo signaling pathway is … well recognized as playing a very important role in the inhibition of axonal regeneration.

“Various forms of pharmacological intervention in this pathway have resulted in varying degrees of neural regeneration in animal models of spinal cord injury,” he wrote. “Thus we feel that the therapeutic relevance of this pathway has been validated in vivo, and that RNAi therapeutics can be developed that will silence the Nogo pathway in an extremely specific and potent manner.”

Mahanthappa wrote that research indicates the spinal cord is “an excellent site of action for locally administered siRNA molecules. In … proof-of-concept studies, siRNAs have been administered to the spinal cord by intrathecal administration and neuronal targets associated with pain have been successfully silenced. In one recent academic research study, it was demonstrated that components of the RISC complex are present within nerves and that siRNAs can be retrogradedly transported along axons,” he noted.

“Based upon these observations, we are confident that a direct RNAi approach can be applied to the Nogo signaling pathway and may yield significant regeneration of damaged axons after spinal cord injury,” Mahanthappa stated in his e-mail.


Sirna Therapeutics said this week in a released statement that by 2006 it expects to move its age-related macular degeneration drug, Sirna-027, into phase II clinical trials, and three other programs into phase I studies. The announcement comes two weeks after Sirna President and CEO Howard Robin provided analysts and investors development timelines on all its drug programs through phase III at the JPMorgan Annual Healthcare Conference (see RNAi News, 1/14/2005).

While the timelines in the presentation and the release for the most part gibe, a minor change was made to the company’s projections for its AMD program.

In his JPMorgan presentation, Robin indicated that Sirna expected to have phase I data on Sirna-027 ready by the third quarter, with phase II testing beginning before the end of the year. In the press release, however, Sirna stated that results from the trial will be ready by the end of 2005, with a phase II study starting next year.

According to Sirna COO Nassim Usman, the update was made “just to be on the conservative side,” and that there have been no material changes within the drug program.

As for why Sirna kept the details of its press release limited compared with Robin’s presentation, Usman told RNAi News that it had to do with “messaging” • how the company wished to communicate to the investment community attending the JPMorgan conference and the public at large.

The JPMorgan presentation, he said, was designed to “give the investors a sense that there is a progression of events over the next few years that will eventually get [RNAi drugs] into later stage clinical trials,” he said. In this press release, however, the company “wanted to focus on what we actually have a much better understand of, which are the near term phase I and phase II milestones for AMD, only because the other ones are too far out.”

One thing the JP Morgan presentation and press release do have in common is their failure to mention Sirna’s hepatitis C program.

According to Usman, the company’s preclinical work in this area has yielded a clinical candidate, but Sirna has decided to seek a partner • either a big pharma/biotech or an academic lab • before continuing development activities.

“We have [a] liver formulation [of an siRNA-based drug] that we know worked for HBV, and we have the HCV siRNA that we know knocks down the HCV Replicon in cell culture,” he said. “We have to put those two together, and there’re two ways of doing this.” The first, Usman said, is “taking a leap of faith” that the preclinical efficacy observed with the drug candidate in HBV will be seen in HCV in humans. The second is doing more model work.

“We’ve decided we’re going to do more model work with a partner because the risk is a little higher” with the first approach, he said.

Usman said that Sirna is considering doing the additional preclinical research in HCV-infected chimps, but that these are “very difficult to get access to • there aren’t that many of them.”

As such, the company is hoping to find a collaborator, such as a drug maker or NIH lab, that would be able to provide such access.

Alternatively, “we’re [talking] with several academics who have built or are in the process of building very small non-human primate HCV models that would give us the confidence to jump ahead” into the clinic, Usman said.


Last week, Nucleonics President and CEO Robert Towarnicki told RNAi News that the company would not hit its previous goal of filing an investigational new drug application for the hepatitis B treatment HepX during the first quarter of this year. Instead, he expects the company to submit the filing to US regulators before the end of the year.

Towarnicki also said Nucleonics has “fully defined” the multiple dsRNA sequences encoded in HepX, and that the company is in the process of deciding which of three possible delivery technologies to use with its drug. Nucleonics is currently evaluating Novosom’s Smarticles, which are charge-reversible liposome particles; as well as bipuvicaine and spermine technologies acquired from Wyeth (see RNAi News, 9/3/2004).

Towarnicki noted in an e-mail that the company expects to settle on a delivery approach in the late second quarter or early third quarter of this year.


Finally, CytRx CEO Steven Kriegsman provided RNAi News with some insight into the company’s amyotrophic lateral sclerosis program. Last year at the BIO-CEO conference in New York, Kriegsman said that CytRx anticipated filing an IND for an siRNA-based ALS therapy before the end of 2004, with phase I work beginning early this year (see RNAi News, 2/27/2004).

This week, however, he told RNAi News that this timeline has been pushed back in light of the company’s acquisition of the small-molecule arimoclomol, which is being developed for ALS as well. CytRx acquired the drug in October and expects it to enter phase II in the second quarter of this year (see RNAi News, 10/8/2004).

With its attention in ALS now split between RNAi and a small molecule, CytRx has dropped its previous timeline for an siRNA-based treatment. A new one has not been determined.

• DM

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