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Reporting Positive Data on Conjugate Delivery Tech, Alnylam Preps IND for Subcutaneous ATTR Therapy

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Alnylam Pharmaceuticals this week released new preclinical data on its GalNAc conjugate delivery technology, showing that the approach could permit subcutaneous delivery of siRNAs with a wide therapeutic index.

In light of these “highly promising” data, the company anticipates filing an investigational new drug application for a GalNAc-enabled version of its phase II TTR-mediated amyloidosis treatment ALN-TTR02 by year end.

Separately this week, Alnylam reported its second-quarter financial results, posting a lower net loss amid lower research and development spending and slightly higher revenues.

Since Alnylam unveiled the GalNAc technology, it has touted it as “the future for delivery” of therapeutic siRNAs (GSN 6/2/2011), offering a subcutaneous route of administration for a drug platform that has heretofore been limited to direct and intravenous approaches.

Importantly, the conjugate technology is entirely proprietary, according to Alnylam CEO John Maraganore, which could help the company avoid the kind of ownership dispute that it is facing with partner Tekmira Pharmaceuticals.

As reported by Gene Silencing News, the companies have long collaborated on the use of Tekmira's lipid-based nanoparticles with Alnylam's siRNAs. However, their relationship ran aground after Tekmira accused Alnylam of misappropriating its delivery know-how and claiming it as its own. In early 2011, Tekmira sued Alnylam for misuse of trade secrets and for specifically stealing the delivery technology, dubbed MC3, used in ALN-TTR02 (GSN 3/17/2011).

The case is set to go to trial in October.

During a conference call held this week to discuss the second-quarter results, Maraganore tried to put to rest any concerns over Alnylam's intellectual property position as it relates to the GalNAc technology, stating that it is an entirely “homegrown discovery.”

He said that the conjugate approach makes use of some “background” IP held by Isis Pharmaceuticals that is related to the use of oligonucleotide conjugates, but noted that this is covered by an exclusive licensing arrangement between the firms.

“Beyond those sort of early foundational IP elements from … Isis, this is really a very homegrown Alnylam discovery and development [technology], and one with a lot of IP coverage that [is] Alnylam owned,” Maraganore said. “It’s really exclusively ours, without question.”

Thus far, Alnylam aims to apply the GalNAc technology to ALN-TTRsc, a subcutaneous incarnation of its ATTR therapy, and its hemophilia treatment ALN-AT3.

According to newly presented data, ALN-TTRsc was administered to non-human primates in a loading regimen of once a day for five days, followed by a maintenance regimen of once a week for four weeks. Treatment resulted in a roughly 80 percent reduction of TTR levels at doses as low as 2.5 mg/kg, Alnylam said.

“In single-dose and multi-dose preclinical safety studies in rodents and non-human primates, ALN-TTRsc was found to be generally safe and well tolerated,” the company added. “Specifically, at doses as high as 300 mg/kg, ALN-TTRsc was well tolerated with no clinical signs, no adverse laboratory or histopathologic findings, no elevations in cytokines or complement, and no significant injection site reactions.”

As for the hemophilia program, Alnylam said that rodent experiments showed that weekly subcutaneous administration of ALN-AT3 resulted in potent and durable suppression of its target, the anticoagulant antithrombin.

“Specifically, repeat dosing with ALN-AT3 showed an ED50 for AT plasma protein knockdown of less than 0.75 mg/kg,” Alnylam said. “In addition, subcutaneous administration of ALN-AT3 in non-human primates also resulted in potent, dose-dependent, and durable AT knockdown, with an ED50 for [antithrombin] knockdown of approximately 1 mg/kg after a single dose.”

Jared Gollob, Alnylam's vice president of clinical research, said during this week's conference call that these data support a once a week or twice a month subcutaneous dosing regimen for ALN-AT3, which could become a “game changer for the management of hemophilia patients.”

“In terms of our development progress, we remain on track to advance ALN-AT3 in an IND filing in 2013,” he added.

The Second Quarter

For the three-month period ended June 30, Alnylam's net loss narrowed to $13 million, or $0.25 a share, from a year-ago loss of $13.8 million, or $0.33 a share.

Alnylam's revenues in the period edged up to $20.9 million from $20.6 million, and included $14 million in revenues related to its partnership with Roche, which exited the RNAi therapeutics space in late 2010.

Alnylam's Vice President of Finance Michael Mason noted during the call that the company will recognize a final $9 million payment related to that collaboration in the third quarter.

R&D costs in the second quarter fell to $21.7 million from $25.3 million the year before, in part reflecting the lower clinical trial costs and manufacturing expenses associated with Alnylam's respiratory syncytial virus and liver cancer programs, the future of which remain uncertain.

Alnylam has said that it will only advance the liver cancer drug, ALN-VSP, into phase II testing if it is able to find a partner for it, and that it won't make a decision on the other drug, ALN-RSV01, until it meets with US and European regulators following the recent failure of the agent to meet the primary endpoint of a phase IIb study (GSN 5/31/2012).

General and administrative expenses in the second quarter rose to $11.2 million from $8.4 million, in part due to higher legal expenses tied to the Tekmira dispute.

At the end of the quarter, Alnylam had cash, cash equivalents, and marketable securities totaling $292.8 million. It said it expects to end the year with more than $250 million.

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