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Alnylam Officials Tout End of Novartis Alliance as Opportunity to Focus on Pipeline

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By Doug Macron

Officials from Alnylam Pharmaceuticals last week struck an optimistic note regarding the end of the company's longstanding alliance with Novartis, which prompted a 25 percent workforce reduction, stating that it is now positioned to focus more on its in-house drug-development initiatives.

Among those efforts is a preclinical program in hypercholesterolemia, which remains on track to yield an investigational new drug application filing next year and will incorporate a new lipid-nanoparticle delivery technology developed in collaboration with Tekmira Pharmaceuticals, they said.

In September, Alnylam disclosed that Novartis opted not to take a license for broad, non-exclusive access to the RNAi shop's intellectual property and technology estate (GSN 9/30/2010).

Novartis did select 31 disease targets against which to develop siRNA drugs using Alnylam's technology — the maximum permitted under the partnership — in exchange for up to $75 million in milestones, as well as royalties. However, its decision against the licensing transaction, which would have been worth $100 million to Alnylam, effectively ended the companies' five-year partnership (GSN 9/9/2005).

As a result, Alnylam cut its staff by about 25 percent, which the company said would save $25 million next year. Alnylam had 161 employees as of the end of October.

But the "difficult decisions" made as part of the reorganization "were important … in building our company for the long term," Alnylam CEO John Maraganore said last week during a conference call held to discuss the company's third-quarter financial results. It also "allows us to transition certain historical service-based resource allocation activities toward a more product-focused and higher-value commitment of efforts."

Alnylam President and COO Barry Greene said during the call that although "we certainly hoped to benefit financially in this option for a broader license," the restructuring "will enable us to optimally position our company for continued growth, success, and focus on the highest-value activities such as the advancement of our own pipeline."

"Progress on our clinical pipeline remains the critical determinant in our company's value-creation strategy," Maraganore added. "We remain very focused on this activity accordingly.

"In short, it's all about the pipeline and human data," he said.

Alnylam currently has three drugs in the clinic: a phase II treatment for respiratory syncytial virus called ALN-RSV01, the phase I liver cancer therapy ALN-VSP, and the phase I TTR amyloidosis drug ALN-TTR01

Next year, "we expect to have two or more additional programs in clinical development," Maraganore said.

The first of these is Alnylam's hypercholesterolemia program, which centers around ALN-PCS, an siRNA targeting proprotein convertase subtilisn/kexin type 9. Last year, Maraganore highlighted the role of PCSK9 in regulating low-density lipoprotein-receptor levels and the ability to accelerate plasma LDL clearance by PCSK9 silencing (GSN 5/14/2009).

At the time, he also touted PCSK9's superiority as a hypercholesterolemia target over apolipoprotein B, a protein associated with cholesterol metabolism that is silenced by Tekmira's RNAi drug TKM-APOB and Isis Pharmaceuticals' antisense agent mipomersen.

"In the case of our PCSK9 program, we are on track for a 2011 [investigational new drug application] filing," Akshay Vaishnaw, Alnylam's senior vice president of clinical research, said during last week's conference call. In contrast to monoclonal antibodies, RNAi therapeutics that inhibit the target, "represent the optimal strategy to silence both the intracellular and extracellular PCSK9 levels, thereby phenotyping the human genetics where loss-of-function PCSK9 mutations have been associated with low LDL cholesterol levels and protection from coronary artery disease."

Notably, ALN-PCS will be the first of Alnylam's drug candidates to use next-generation nanoparticles formulated with a novel lipid called MC3.

This summer, Alnylam reported data showing that siRNA-containing MC3 nanoparticles "achieve effective in vivo gene silencing activity at single-digit microgram per kilogram dose levels," Vaishnaw said. "This is the best in the industry by far."

Alnylam is also including in its pipeline guidance a hepatitis C drug targeting microRNA-122 under development by its Regulus Therapeutics joint venture with Isis Pharmaceuticals (GSN 9/13/2007).

Greene also said that the restructuring will give Alnylam "greater degrees of freedom as it relates to future partnerships," and that the firm has "active" negotiations ongoing with potential collaborators.

The company aims to "form additional new alliances across our efforts at Alnylam, Regulus, and its biologics manufacturing initiative Alnylam Biotherapeutics," which was established about a year ago (GSN 11/19/2009).

However, he did not provide guidance on the number of deals Alnylam expects to forge, a position the company has taken since missing guidance last year. Still, in a corporate update released in January, Alnylam said it is committed to meeting the guidance it provided in 2008 under its so-called RNAi 2010 plan (GSN 1/10/2008), which requires the company to establish at least three new alliances this year.


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