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Novartis Says 'No' on Alnylam IP Option as Alternate RNAi Approaches Gain Traction

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By Doug Macron

Alnylam Pharmaceuticals last week disclosed that long-time partner Novartis has decided not to acquire broad, non-exclusive access to the RNAi drug shop's intellectual property and technologies — a transaction that would have been worth $100 million to Alnylam.

Concurrent with the announcement, Alnylam said that it was cutting between 25 percent and 30 percent of its workforce, which is expected to cost up to $3 million in one-time charges this year but save the company $25 million in 2011.

During a conference call last week, Alnylam officials put a positive spin on the news, stating that the end of the Novartis alliance gives the firm greater freedom in pursuing other collaborations and that Novartis may chose to strike additional deals with the firm on a target-by-target basis down the road.

But the emergence of new RNAi chemistries and technologies in recent years, and big pharma's growing interest in building up its own capabilities, suggest that Alnylam's status as the go-to partner in the field may be waning.

Alnylam and Novartis first joined forces in 2005 (GSN 9/9/2005). Under the terms of the three-year deal, the companies worked together to optimize siRNA-based drugs for up to 31 disease targets that Novartis would own and take through the clinic and onto the market. Novartis also acquired a 19.9 percent stake in Alnylam, although that has since fallen to about 13.4 percent.

Novartis had the option to extend the arrangement for two additional one-year periods, which it did, most recently last summer (GSN 7/23/2009). The deal also gave Novartis the option to pick up at the end of the alliance the non-exclusive rights to use Alnylam's IP and know-how to design siRNAs against any target it chose.

While many in the industry had expected Novartis to do so, the Swiss drugs giant has decided not to.

Instead, Alnylam said, Novartis has chosen for now to limit itself to 31 targets, only some of which Alnylam has designed siRNA constructs against. For the others, Novartis will handle siRNA design. Alnylam still stands to receive milestones and royalties on all products developed.

During the conference call, Alnylam CEO John Maraganore noted that Novartis "fully selected the 31 targets [although] they didn't contractually need to do that," and added that the decision against exercising its license option was "based on their recognition that they will be very … busy working on [these] targets in the many years to come."

Maraganore also pointed out that Novartis has built up strong RNAi capabilities since 2005, with "about 100 people [in Cambridge, Mass., who] are focused on this technology." With this team in place, "they simply made a financial decision at the end of the day … and said, 'With 31 targets that we're going to work on, we're going to be very busy.'"

And Novartis is fully expected to work on all 31 targets, he noted.

"They have been very clear to us that they plan to diligently advance their RNAi efforts on these targets … and they are very committed to RNAi," Maraganore said. At the same time, Novartis is bound by "diligence provisions" in its agreement with Alnylam that "make it important" for Novartis to advance the 31 RNAi therapeutic programs.

"When the agreement was formed, it was very important for us to make sure that they just didn't put these targets on a list someplace and not do anything with them," he said.

Should Novartis decide down the road that it wants to develop RNAi drugs against other targets not included on its list of 31 already selected, "they will need to come back to Alnylam," Maraganore added.

But whether Novartis would really need to do so is not so clear.

While Alnylam touts its IP estate as "required for the development and commercialization of all RNAi therapeutics," a growing number of companies in the space have developed technologies they claim are independent of any patents held by Alnylam.

For example, last month Silence Therapeutics CEO Philip Haworth told Gene Silencing News that his company has developed novel siRNA constructs and thereby "worked our way around the requirements to license" Alnylam's technology (GSN 8/12/2010).

Additionally, Dicerna Pharmaceuticals' Dicer-substrates, RXi Pharmaceuticals rxRNAs, and Marina Biotech's transkingdom RNAi approach, which it picked up through the acquisition of Cequent Pharmaceuticals, all are based on technologies their owners claim do not fall under other companies' IP.

Even Novartis has been taking an interest in these new RNAi approaches in recent years. In 2007, it acquired an option to one of Cequent's inflammatory bowel disease programs, which it could exercise next year (GSN 6/21/2007 & 4/8/2010).

More recently, Novartis took an option to Quark Pharmaceuticals' phase II p53 inhibitor QPI-1002, a deal Quark's CEO told Gene Silencing News was a validation of its freedom to operate in RNAi without IP licenses from other firms (GSN 8/19/2010).

To Alnylam, however, its IP remains a necessity for developing RNAi-based drugs, and Maraganore noted during the conference call that "If I were in [Novartis'] shoes, I would have done the [technology] adoption license" in addition to selecting the 31 targets.

"But I'm not in their shoes," he said.

'Not Alone'

As a result of the completion of the Novartis arrangement, Alnylam said it had decided to shed 25 percent to 30 percent of its workforce, which comprised 182 employees as of June 30.

The layoffs will save Alnylam $25 million next year and are "an important step in building our company for the long term," he said.

Alnylam's President Barry Greene added that "we are certainly not alone in this current environment in making a decision to optimize our overall cost structure for better productivity."

Patricia Allen, Alnylam's vice president of finance, said during the call that while the headcount reduction will result in one-time charges of as much as $3 million, the majority of which is expected to be recorded in the third quarter of this year, it is "likely" to be less.

She also said that Alnylam has re-affirmed its year-end cash guidance of greater than $325 million.

Although the loss of Novartis as a partner is a blow to Alnylam's pocketbook — Maraganore noted that funding received under the alliance paid for roughly 25 Alnylam employees annually — the RNAi firm views it as an opportunity, as well.

"The planned completion of the Novartis alliance allows us to transition our activities away from service-based research activities … toward higher-value activities for our people such as the advancement of our own pipeline," Maraganore said last week.

"Further, with Novartis now behind us, we have significantly greater freedom as it relates to future partnerships," he added.

Specifically, the Novartis deal included "some provisions related to the right of first offer mechanism and the right of first negotiation mechanism that essentially changed with this agreement now expired," he said. "That absolutely gives us greater freedom as to how we work with partners going forward."

Meanwhile, the layoffs will have "zero impact" on Alnylam's ability to form and support future partnerships, Maraganore said. "We have made a prudent business decision about the restructuring, [which was made with] … full recognition of existing discussions we have with potential … partners, as well as our current partnerships."

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