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Alnylam CEO Touts Advances with Lipid, Conjugate Delivery Approaches


By Doug Macron

Alnylam Pharmaceuticals' CEO last week pitched the company's delivery technology-development efforts to investors, citing advancements made with both second-generation lipid nanoparticles, as well as conjugate-based approaches, which he said are “the future for delivery of small interfering RNAs.”

During his presentation at ThinkEquity's annual healthcare conference, CEO John Maraganore also highlighted the company's delivery collaborations with the Massachusetts Institute of Technology and Canadian startup AlCana, but notably made no mention of partner Tekmira Pharmaceuticals, which recently sued Alnylam for allegedly misappropriating technology and trade secrets.

Lipid nanoparticles have long been a staple of Alnylam's delivery technology portfolio, with first-generation nanoparticles developed by Tekmira Pharmaceuticals forming the foundation for Alnylam's phase I liver cancer drug ALN-VSP01 and phase I TTR amyloidosis drug ALN-TTR01.

But it was the next generation of LNPs, which boost improved pharmacodynamic and pharmacokinetic profiles, that Maragnore focused on during his ThinkEquity presentation. In doing so, however, he conspicuously made no mention longtime collaborator Tekmira.

“Our first-generation lipid nanoparticle platform … has been improved dramatically to show ED50 for target gene knockdown in the range of 10 to 30 micrograms per kilogram,” and “Alnylam has led the way [in the development of these molecules] in collaboration with both MIT and … AlCana,” he said.

Alnylam has been collaborating with the labs of Robert Langer and Daniel Anderson at MIT since 2007 to develop so-called lipidoids for siRNA delivery (GSN 5/10/2007). Though producing promising data, the arrangement has not yielded delivery agents that have made it into any of Alnylam's clinical or late-stage preclinical programs.

The RNAi shop's dealings with AlCana have been less straightforward. In 2009, Alnylam first announced that it was working with the company, but it wasn't until Tekmira filed its lawsuit earlier this year that details about Alnylam's arrangement with AlCana were made public.

In March, Tekmira sued Alnylam for allegedly misusing trade secrets and other confidential information about its lipid nanoparticle technology, including for the development of its own delivery systems (GSN 3/17/2011).

“Alnylam abused its collaborator status and access to [the] confidential information by improperly using this information for its own internal purposes and to replicate a competing technology in ways that were unauthorized and without our consent,” Tekmira President and CEO Mark Murray said at the time. He also said that Alnylam “stole” a delivery technology called MC3, which is expected to be used in Alnylam's upcoming hypercholesterolemia candidate ALN-PCS.

The next month, Alnylam filed counterclaims against Tekmira, denying the allegations and charging that the lawsuit violates conflict-resolution provisions in the companies' agreements (GSN 4/7/2011).

In legal filings, Alnylam also revealed that a number of former Tekmira scientists had founded AlCana, and alleged that Tekmira was attempting to improperly gain control of AlCana technology through the litigation.

Since that time, neither company has made much mention publicly of the other as the legal wrangling proceeds. But Maraganore's comments during last week's presentation suggest that Alnylam has not backed away from its position that it owns its second-generation LNP technology.

“We are leading the advances on lipid nanoparticle delivery of siRNAs,” he said. “We are doing this in our collaboration with AlCana, [which] has been the leader in the discovery of novel lipids that we have been generating in the form of lipid nanoparticles.

“And of course we have additional research we are doing at Alnylam and in collaboration with MIT,” he added.

Maraganore also touched on Alnylam's research with conjugate-based delivery approaches, stating that they represent “a simple approach for the delivery of small interfering RNAs that we think will ultimately be the leading approach for delivery of RNAi therapeutics.”

In preclinical studies, Alnylam has used GalNAc-conjugated siRNAs, which take “advantage of the asialoglycoprotein receptor ... present on hepatocytes,” to knock down transthyretin — the target of ALN-TTR —
in a dose-dependent fashion with an ED50 of 5 mg/kg.

“We also achieve a very durable … silencing of the transthyretin gene that lasts for weeks after a single, subcutaneous injection,” Maraganore said. “This type of improvement in delivery, we think, is game-changing going forward.

“We think conjugates will be the future for delivery of small interfering RNAs,” he added.

Have topics you'd like to see covered in Gene Silencing News? Contact the editor
at dmacron [at] genomeweb [.] com

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