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RNAi Upstart Galenea Baffled as Alnylam -- a Possible Partner -- Morphs Into Rival

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Alnylam Pharmaceuticals' announcement last week that it was pursuing development of an RNAi-based drug for the treatment and prevention of highly pathogenic influenza (see RNAi News, 5/27/2005) caught many people's attention for a number of reasons, not least of which are the company's high profile in the RNAi space and the growing concern over a possible human outbreak of avian flu.

But it was the economic implications of Alnylam's move into the flu space that were felt most acutely by RNAi startup Galenea, which has made the development of an influenza therapy the sole focus of the RNAi portion of its operations since it was founded two years ago.

Given Galenea's focus on the flu market, and the fact that the company has held discussions over a possible partnership with Alnylam in the past, Galenea CEO John Oyler told RNAi News this week that it came as a shock that Alnylam decided to position itself as a direct competitor to his company.

"The siRNA we have has been shown to work effectively against highly pathogenic strains [of the flu virus, and] Alnylam has seen all of our initial IP under non-disclosure," he said. "They have every disease known to mankind to potentially work on, and they chose the one our company has talked about working on."

When asked why he believes Alnylam made its decision, Oyler said that the company has "seen the tremendous results we've had. Anyone who looks at the data that are published can see there're interesting results in the flu area. It's just a question of whether you choose to invest the limited resources you have trying to pursue that business or not," he said.

"I know as a fact that Alnylam is full of brilliant scientists that are experts in their field, and it's surprising that they aren't choosing to address an unmet medical need for which there isn't already a solution," Oyler said. "There's already a solution for pandemic flu -- Galenea has it."

Galenea was established to develop and commercialize siRNA-based drugs for respiratory disorders -- at this point an influenza treatment developed by MIT researcher and company co-founder Jianzhu Chen -- as well as calcineuron-related therapeutics for cognitive disorders stemming from the work of the company's other co-founders.

Chen's published work in the field extends back at least to March 2003, when he co-authored a paper in The Proceedings of the National Academy of Sciences showing that siRNAs targeting conserved regions of the influenza virus' genome could inhibit virus production in cell lines and embryonated chicken eggs. The siRNAs, specific either for nucleocapsid or a component of the RNA transcriptase, also knocked down targeted mRNA, as well as virion RNA and its complementary RNA, according to the paper.

About a year later, Chen published in PNAS data showing that siRNAs could be used to prevent and treat influenza infection in the lungs of mice when delivered either intravenously or intranasally.

At this point, the company has settled on a lead siRNA molecule for development and is in the process of "doing a little bit of lead optimization," according to Oyler.

"Basically, [we're] still playing around a little bit with [pharmacokinetic] properties and formulation to try to get the best characteristics to be sure we have that before we do our formal" toxicology experiments, he said. He added that next on the company's agenda is to begin testing its flu therapy in ferrets, and that Galenea is currently expecting to file an investigational new drug application to begin human studies of an intravenous formulation of the drug in the fourth quarter of 2007.

"We're doing delivery both IV and direct-to-lung, [and] we have good results with both," Oyler said. "The IV we're doing for critical care patients … [since] it's just easier to administer … in a hospital setting. In terms of direct-to-lung, that's clearly for a much broader audience, and we're going down that path for other applications" outside of the hospital setting, he said.

According to Oyler, Galenea has data showing that its siRNA is effective against pathogenic strains of the flu virus, and that as far as he is aware, Alnylam has neither conducted similar experiments nor "disclosed any information that would indicate they have a sequence that does that.

"Galenea has tried hundreds of [siRNA] sequences, [and] has identified which ones work and which ones don't," he said. "We've run hundreds to thousands of … animal model [experiments] and are the true expert in this area. To our knowledge, [Alnylam doesn't] have an operating flu model … at this point."

Alnylam President and CEO John Maraganore told RNAi News in an e-mail this week that his company decided to pursue development of a drug for highly pathogenic flu because "our demonstrated success in developing siRNAs for [respiratory syncytial virus] has logically led to an extension of this effort for other major respiratory infectious diseases."

As for where Alnylam's efforts in the field stand, Maraganore said that Alnylam provides "details on our scientific progress in peer-reviewed meetings and publications. We expect to update people on our progress regarding our flu research in the future," he wrote. "In fact, the research led by our collaborator Mark Tompkins, now at the University of Georgia, has already resulted in one of the first papers to document the efficacy of siRNAs in models of flu. We are optimistic about the extension of this work."

As far as Oyler is concerned, however, whether Alnylam is able to develop an effective RNAi-based flu drug is beside the point because of Galenea's IP position in the indication.

"Galanea has filed IP … that covers the entire flu genome," he said. "Whether [Alnylam has] a sequence or not, we believe any siRNA developed towards influenza is covered by the IP which we have." (See chart below.)

Oyler fell short of suggesting that an IP showdown with Alnylam was inevitable, but it's unclear how such a situation might be avoided. According to Oyler, "we're going to be successful and they're going to be successful, and we're sure that any siRNA used to treat influenza, whether it's a virulent strain or a non-virulent strain, is covered by the IP that Galenea has."

He added that any sort of out-licensing arrangement for Galenea's IP is unlikely, given that the company's "intellectual property … is very narrow and very tight, and it's based on influenza and the specific sequences that work with influenza. We haven't described IP that is very broad and very applicable in lots of different areas, and I'm not sure what is left for Galenea … if we out-license flu," he said.

Maraganore noted in his e-mail, however, that "Alnylam has the broadest, and what we believe to be the clearly dominant, IP estate covering fundamental aspects of short-interfering RNAs, including issued patents in both the US and EU. We are not aware of any impediment to our ability to develop and commercialize our products. Indeed, the reverse is the case as evidenced by multiple partnerships we have already concluded as well as many other ongoing discussions involving IP for RNAi therapeutics," he stated.

Even though previous talks with Alnylam did not produce a collaboration, Oyler said that Galenea would still welcome the possibility of a partnership, and would be "happy to work with anybody in any way, shape, or form that makes sense for both parties. Alnylam could very well be one of those parties."

But despite his diplomatic overtures, Oyler still pointed out that "it was surprising to us and not viewed favorably that [Alnylam] would choose to [pursue flu], and there's some question as to what [the company's] motivation is."

When asked to elaborate on this point, Oyler said, "I think I would leave it at that."

It seems clear, however, that the vast money-making potential of the influenza therapy market played a role in Alnylam's decision.

For instance, Roche's Tamiflu has become a huge seller for the pharmaceutical giant, pulling in $357 million in the first quarter of this year alone amid concerns about avian flu outbreaks in humans and a flu vaccine shortfall in the US last season. The drug could see even better numbers should Roche secure a contract with the World Health Organization for stockpiles of Tamiflu.

And in April, Alnylam's President and CEO John Maraganore told Reuters that his company is in discussions with the US government over a contract to develop an RNAi-based avian flu drug. Such an arrangement would likely mean significant research and development dollars from the government for Alnylam, all of which would be in addition to any future revenues from product sales.

Regardless of whether Alnylam's foray into the flu area would cut into Galenea's ability to market an RNAi-based flu treatment or secure R&D funding, Oyler said that his company is not in need of capital in the "short term."

Indeed, Galenea announced in February that it had formed a collaboration, covering both its RNAi and small molecule programs, with Japanese drug firm Otsuka Pharmaceutical. The deal included an equity investment that a source close to the transaction, speaking on the condition of anonymity, told RNAi News totaled about $50 million. Galenea officials declined to comment on this issue, but in October last year Chen told RNAi News that the investment was likely to be in "the tens of millions" of dollars (see RNAi News, 10/15/2004).

Additionally, Galenea has been approved for an SBIR grant, Oyler said, adding that "on June 1, we have an RO1 grant [application] that's going in. We'll have several others in that area that are all geared towards addressing flu or bioterrorism."

-- Doug Macron ([email protected])

Select US IP Held by Galenea
(As provided by the company)
IP
Date Filed
Title
Provisional patent application, No. 60/414,457
Sept. 28, 2002
"Influenza Therapeutic"
Provisional patent application, No. 60/446,377
Feb. 10, 2003
"Influenza Therapeutic"
Patent application,
No. 10/674,159
Sept. 29, 2003
"Influenza Therapeutic"
Patent application,
No. 10/674,087
Sept. 29, 2003
"Compositions and
Methods for Delivery of Short-Interfering RNA and Short Hairpin RNA".
Provisional patent application, No. 60/549,070
March 1, 2004
"RNAi-Based Therapeutics for Allergic Rhinitis
and Asthma"
Provisional patent application, No. 60/664,580
March 22, 2005
"Influenza Therapeutic"
Patent application,
No. 11/102,097
April 8, 2005
"Influenza Therapeutic"

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