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Alnylam ATTR Program on Track as Company Explores Subcutaneous Delivery for Cholesterol Drug

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Alnylam Pharmaceuticals this week provided new guidance on its key drug-development programs, noting that its flagship transthyretin-mediated amyloidosis therapy ALN-TTR02 remains poised to enter phase III testing by the end of next year, and that the development of a subcutaneous version of its hypercholesterolemia treatment ALN-PCS has given a boost to partnership discussions around the drug.

Speaking during a conference call held to discuss Alnylam's third-quarter financial results, company officials also indicated that other pipeline efforts remain on track, although they reiterated the possibility that the beleaguered respiratory syncytial virus drug ALN-RSV01 could end up being shelved permanently.

ALN-TTR02 comprises siRNAs that inhibit expression of the protein transthyretin, which is mutated in ATTR, and formulated with a second-generation lipid nanoparticle technology. Recently, Alnylam reported phase I data showing that the drug could lower target levels by 94 percent after a single dose (GSN 7/19/2012).

Around that time, Alnylam also initiated a phase II dose-escalating study examining ALN-TTR02's clinical activity, safety, and tolerability in approximately 20 ATTR patients who will receive the drug once every four weeks for two cycles (GSN 6/7/2012). Enrollment in that trial continues, Alnylam said this week, with data expected to be available for release by mid-2013, with a phase III trial beginning before the end of that year.

Meantime, work continues on a subcutaneous version of ALN-TTR02, which takes advantage of Alnylam's GalNAc conjugate technology and has proven to trigger a roughly 80 percent reduction in transthyretin levels at doses as low as 2.5 mg/kg in non-human primates. An investigational new drug application filing for this agent, dubbed ALN-TTRsc, is slated for sometime this year.

Alnylam has also extended its work with the GalNAc technology to certain of its other programs, notably ALN-PCS. The intravenous drug, which targets proprotein convertase subtilisn/kexin type 9, performed well in a recent phase I study demonstrating the ability to significantly and durably lower levels of its target and low-density lipoprotein cholesterol, but has been put on hold until Alnylam can find a partner for it (GSN 4/26/2012).

Looking to improve its chances of wooing a partner, Alnylam has been exploring a subcutaneous route of administration for ALN-PCS, and last week presented data at the Oligonucleotide Therapeutics Society's annual meeting showing that this formulation could potently knock down the PCSK9 gene with an ED50 below 0.3 mg/kg in humanized transgenic mice after a single dose.

“We expect this new subcutaneous program will be an important part of a partnership that we aim to form to advance our ALN-PCS program into phase II,” Alnylam Chief Medical Officer Akshay Vaishnaw said during this week's conference call.

Alnylam is also aiming to use its GalNAc conjugates with ALN-AT3, which is being developed to treat hemophilia. Preclinical data on this candidate show that subcutaneous administration of the compound, which inhibits antithrombin, results in potent, dose-dependent, and durable target silencing in both mice and non-human primates with an ED50 for antithrombin plamsa protein levels of about 1 mg/kg after a single dose.

An IND for ALN-AT3 is on track for 2013.

As this work continues, however, the future of the RSV program remains in doubt.

Once a major part of Alnylam's pipeline, ALN-RSV01 was showing promising activity in clinical testing, with preliminary data from a phase II trial showing the drug to be safe and well-tolerated in adult lung-transplant patients (GSN 7/23/2009).

On such findings, Alnylam secured Cubist Pharmaceuticals as its worldwide partner for the agent, except in Asia where Kyowa Hakko took the rights.

However, by late 2009, Cubist had backed out of its original deal and instead took the rights to a follow-on candidate, ALN-RSV02, which was to be developed for RSV infection in pediatric patients. Ultimately, Alnylam decided to stop work on ALN-RSV02 as part of a portfolio decision, with Cubist maintaining an option to co-develop ALN-RSV01 in the future.

Since that time, the path forward for ALN-RSV01 has not been a smooth one, with the biggest setback coming earlier this year when Alnylam disclosed that the drug failed to meet the primary endpoint of a phase IIb trial that was aimed at validating “exploratory” signs of efficacy in the phase II study (GSN 5/31/2012).

Specifically, the phase IIb study did not show a reduced incidence of new or progressive bronchiolitis obliterans syndrome, a non-reversible obstructive lung disease associated with RSV. Alnylam officials at the time said that the company was planning to meet with US and European regulators about the data in order to figure out how to proceed with ALN-RSV01, if at all.

During this week's conference call, Alnylam CEO John Maraganore said that Alnylam has scheduled meetings with the regulatory agencies, and offered some general guidance on the possible fate of the RSV program.

“There are a range of different options that could occur,” he said. “One … is that, after discussing the results with regulators … we and our partners … decide that it's not necessarily worth proceeding.

“The other outcome is that we clearly define and delineate a path forward for approval … and that Cubist and [Kyowa Hakko] make the commitment to proceed with that,” he said. “Those are the bookends.”

The Third Quarter

For the three-month period ended Sept. 30, Alnylam's net loss rose to $19.5 million, or $0.38 a share, from a year-ago loss of $13.2 million, or $0.31 a share.

Revenues dropped to $16.8 million from $20.8 million, and include $9.3 million related to its one-time collaboration with Roche, which in 2010 exited the RNA drugs space and sold off its related assets to Arrowhead Research. Alnylam said that, going forward, it expects its collaboration revenues to decrease after completion of the amortization of Roche/Arrowhead deferred revenue.

Research and development spending in the third quarter slipped to $22.1 million from $24.3 million, while general and administrative costs climbed to $12.8 million from $9 million in the same period a year earlier.

Looking ahead, Alnylam said that it expects its cash, cash equivalents, and marketable securities to total more than $280 million at the end of 2012. This represents a $30 million increase over previous guidance, reflecting the impact of new alliances with Monsanto in ag-bio (GSN 9/6/2012) and Genzyme on ATTR (GSN 10/25/2012).

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