West Coast Editor

Players in the still-hot, and still early stage, zone of RNA interference are starting to mark territories more specifically, or at least make promising noises, with a spate of recent developments.

At the end of last month, CytRx Corp., noting that investors seemed to overlook the value of its RNAi technology, spun that work into a new subsidiary for which the company is casting for a name and initial funding. The motive: to sharpen Wall Street's attention on CytRx's RNAi bid by separating the research from efforts in metabolics and central nervous system disorders.

Others had news, too. Alnylam Pharmaceuticals Inc. raised $66.3 million, selling 5.1 million shares at $13 each, in the wake of word from the U.S. Patent and Trademark Office, allowing a second Alnylam patent application that "broadly covers methods for preparing siRNAs, the molecules that mediate RNAi." Specifically, the patent involved is part of the Tuschl II patent series.

About a week earlier, Alnylam said the USPTO had issued a notice of allowance on a related set of claims in the Tuschl II series, exclusively licensed worldwide to Alnylam for RNAi therapeutics through an agreement with Garching Innovation GmbH, the licensing agent for the Max Planck Society in Germany. The newly allowed claims provide further coverage of methods of making siRNAs to achieve RNAi in mammalian cells.

In June, Alnylam amended its deal with Garching and reinforced Alnylam's continued exclusivity for Tuschl II, while improving the operating flexibility for the company's subsidiary, Alnylam Europe AG. The research behind the Tuschl II series is by one of Alnylam's founders, Thomas Tuschl, and the firm is seeking patents to solidify its position.

Alnylam has multiple programs in its pipeline, all early in research except for a compound against respiratory syncytial virus, which has reached the Phase I stage.

Also in January, Sirna Therapeutics Inc. reported that the USPTO had granted a patent for the chemical synthesis and manufacturing of ribonucleic acids. Sirna's patent "broadly covers a process for the synthesis, deprotection and purification of nucleic acids with one or more ribonucleotides," the company said - a process "critical for the efficient synthesis of RNA at high yields and high purity and is applicable to both small- and large-scale production of oligonucleotides such as [small interfering] RNAs and aptamers."

The patent "further expands Sirna's leadership position in the area of synthesis and manufacturing of [Good Manufacturing Practices]-quality RNA, which is required for both chemically modified and unmodified siRNA-based therapeutics," the company said.

So, who's ahead? In September, Alnylam's leadership vied with Sirna's for the position. Alnylam had just come off a potential $700 million deal with Novartis AG, which is buying almost 20 percent of Alnylam as part of the arrangement. Sirna followed that with a potential $250 million collaboration with Allergan Inc. to develop RNAi drugs for ophthalmic diseases, starting with Sirna's early clinical candidate for age-related macular degeneration. Sirna also has an RNAi oncology partnership with Eli Lilly and Co. (See BioWorld Financial Watch, Sept. 12, 2005.)

Sirna and Allergan aren't alone in the ophthalmic RNAi space. In October, Acuity Pharmaceuticals Inc. started its Phase II program for Cand5, the lead candidate targeting VEGF messenger RNA for the treatment of wet AMD. Nor are Sirna and Lilly alone in oncology. Introgen Therapeutics Inc. in July made a $3 million equity investment in SR Pharma plc, with the investment to be used to develop the latter;s siRNA technology in cancer, including atuPLEX, its delivery system gained recently through the buyout of Atugen AG.

But new patent activity by Alnylam and Sirna might be making some investors think more about where the real RNAi fight could be waged - in the area of intellectual property. Already another player has been involved in a skirmish, albeit overseas. The Australian firm Benitec Ltd. in late 2003 settled a patent dispute with two government organizations.

Benitec, which said it would eventually develop its own RNAi drugs, said the first strategy would involve selling licenses, but by May of last year the firm had identified a clinical candidate for its hepatitis C therapy, noting that efficacy and safety studies had begun in small animal models. Phase I trials were slated to start in the second half of this year.

"I'll give you our standpoint, vs. perhaps how the market sees it," Michael French, Sirna's vice president of corporate development, told BioWorld Financial Watch. "This battle is going to be waged in the clinic," although Sirna has gone far to "ensure we were in a situation where we could take products all the way to the market and not be stopped" due to patent issues.

Although Acuity was the first to put siRNAs into humans, French's firm did the same very soon after, and with Sirna-027 for the same indication, wet AMD. Sirna's compound, though, is chemically modified and targets the VEGF receptor, rather than VEGF itself.

That's important, said Bharat Chowrira, vice president of legal affairs and chief patent counsel for Sirna, who said his firm already has patent rights to unmodified sRNAs, but a license deal or legal battle with Acuity would not happen until the latter gets closer to market - something he doubts will happen, which is why Sirna does not work with unmodified sRNAs in the first place.

When RNAi work first began, he said, "people didn't recognize that you need to significantly stabilize these sRNA molecules, or they get chewed up in no time in the serum, or inside the cells. And unmodified sRNAs are not only unstable but can have side effects."

Alnylam's news about the Tuschl II patents (which involve unmodified sRNAs), Chowrira said, does not mean much, since the Tuschl I group of patents already is co-licensed between Sirna and Alnylam, and "everything in Tuschl II is already covered under Tuschl I - all of the fundamental concepts. But at the end of the day, neither Tuschl I nor Tuschl II will be that important."

French said Sirna believes Alnylam "is going to have to move to more heavily modified sRNAs, but it's hard for us to get wrapped around the axle as to whether they are or they aren't," because everything is early stage. Too early to be talking about patent rights, he added.

"That argument, unfortunately, lies in a couple of single patents, the so-called seminal, dominant, you-can't-do-anything-unless-you-have-these patents," and the argument happens mainly between Alnylam and Sirna, he said. "What the industry is expecting at some point is for Sirna and Alnylam to do a cross-licensing deal, but it's really hard to figure out what we would license from them."

As for Acuity and VEGF, Chowrira said, "Acuity is well aware of what we have. Our patents are going to start issuing in the U.S., and companies like Acuity will have to deal with that."

Sirna is focused on filing an investigational new drug application for its hepatitis C product, deciding on a preclinical candidate in respiratory indications, and getting through a Phase II trial with Sirna-027.

By the time RNAi drugs approach the market, failures and new deals will have changed the playing field, French said. Meanwhile, hopes are pitched high, Chowrira said.

"I've been working in nucleic acids for almost 20 years, and I have never seen so much excitement around gene silencing," he said. "When RNAi came on the scene, it just took over," since the mechanism is endogenous and easy to use.

"It's going to change the way we practice medicine," he said. n

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