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Alnylam Execs Highlight Conjugate Delivery Tech as Lipid-Enabled TTR Drug Advances

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Officials from Alnylam Pharmaceuticals last week provided updates on the company’s pipeline programs, highlighting efforts involving its GalNAc conjugation technology, which enables subcutaneous siRNA delivery, and a fledgling effort in complement-mediated diseases.

Also last week, Alnylam released its second-quarter financial results, posting a higher net loss alongside a drop in revenues and a rise in research and development spending.

Although its lineup of clinical candidates has long been enabled by lipid nanoparticles developed by Tekmira Pharmaceuticals, the once-close relationship between the companies began to sour over the years, and in early 2011 Tekmira sued its partner for allegedly stealing trade secrets regarding its delivery technology.

In late 2012, the companies settled their legal war, with Alnylam agreeing to pay Tekmira $65 million and provide it will the rights to certain disputed intellectual property while retaining the rights to continue using Tekmira’s lipids with some of its drugs.

With Alnylam officials declaring that there would be “no relationship” with Tekmira going forward, the RNAi drug shop began focusing on its GalNAc technology, which facilitates liver delivery of siRNAs via uptake through the asialoglycoprotein receptors expressed on the surface of hepatocytes.

The most advanced pipeline program incorporating the GalNAc approach is ALN-TTRsc — a subcutaneous version of the phase II TTR amyloidosis treatment ALN-TTR02, which uses Tekmira’s lipid nanoparticles.

Last month, Alnylam reported top-line data from an ongoing phase I study of ALN-TTRsc, showing that the drug could knock down serum levels of its target protein by more than 80 percent (GSN 7/11/2013).

“We believe these clinical results with ALN-TTRsc establish human translation for RNAi therapeutics employing our GalNAc/siRNA conjugate delivery platform with implications for the entirety of our … preclinical pipeline, which now employs a clinically validated subcutaneous delivery approach,” Alnylam CEO John Maraganore said during a conference call last week.

“Indeed, we see our proprietary GalNAc conjugate platform as the path forward for execution on our … pipeline, and believe that it now represents the best-in-class approach for knockdown of liver-expressed disease genes across the industry,” he added.

In regards to ALN-TTRsc, Alnylam anticipates releasing final phase I data next month and starting a phase II trial in ATTR patients with cardiac manifestations of the disease, known as familial amyloidotic cardiomyopathy, by the end of 2013.

“Assuming positive results, the start of a pivotal phase III trial for this subcutaneously administered RNAi therapeutic [will occur] in 2014,” Jared Gollob, vice president of clinical research at Alnylam, said during the call.

“These results have important implications for the entirety of our preclinical … pipeline, since all of these programs utilize the GalNAc-siRNA conjugate approach employed in [ALN]-TTRsc,” he added.

Indeed, amid positive results with ALN-TTRsc, Alnylam has three GalNAc-enabled candidates poised to enter human trials including ALN-AT3, an antithrombin-targeting treatment for hemophilia and other bleeding disorders that now set to move into phase I in early 2014 following a slight delay in pre-investigational new drug application studies. Also on deck with GalNAC is ALN-AS1, which is designed to silence aminolevulinic acid synthase-1 in order to treat the enzyme disorder porphyria and is expected to yield an IND in early 2014.

But it was Alnylam’s complement-mediated disease treatment ALN-CC5, which targets complement component 5 that received much of the attention during last week’s conference call, with Maraganore stating that it would be advanced “expeditiously.

He said that Alnylam is working with a lead molecule that has demonstrated “very impressive” knockdown of complement component 5, or C5, in rodent models and is currently being tested in non-human primates.

The compound requires further optimization before being declared an official development candidate, he noted, but all signs indicate that it will allow for weekly subcutaneous dosing with target knockdown of over 90 percent.

This level of inhibition, Maraganore added, is on par with the effect of eculizumab, a C5-binding monoclonal antibody marketed by Alexion Pharmaceuticals as Soliris and the first drug approved by US regulators for the rare blood disease paroxysmal nocturnal hemoglobinuria, or PNH.

“Clearly this type of performance with a [subcutaneously] administered drug could be a very compelling product in a very broad range of different complement-mediated diseases including PNH amongst others,” Maraganore said of ALN-CC5.

A final development candidate from the C5 program is expected to be chosen by year-end.

While work progresses with its GalNAc programs, Alnylam also continues to make progress with its ALN-TTR02, which remains its most advanced research and development effort.

In July, Alnylam presented phase II data showing the intravenously administered drug to be capable of reducing serum TTR levels by as much as 93 percent in a rapid, dose-dependent, and durable manner (GSN 7/3/2013).

Gollob said that the enrollment in the study is nearly complete, and that final phase II data are slated for release at the International Symposium on Familial Amyloidotic Polyneuropathy in November.

Alnylam President Barry Greene noted that the presentation will include “full TTR knockdown data for about 30 ATTR patients, and will also include important safety data on [a] reduced and simplified pre-medication regimen.”

Meanwhile, a previously disclosed open-label extension study is set to begin “in the coming weeks,” with data available next year, he said.

Assuming positive phase II results, Alnylam is set to launch a phase III trial of ALN-TTR02 by the end of this year.

“It will be randomized, double-blind, placebo-controlled, global study with two-to-one randomization of active drug ALN-TTR02 to placebo,” Gollob said.

“We anticipate enrolling anywhere from 150 to 200 patients, dosing at 0.3 milligram per kilogram every three or four weeks,” he continued. “The primary endpoint for this study will be a change in a composite neurologic impairment score [at] either 12 to 18 months. … There will also be key secondary endpoints [including] TTR levels, quality of life, level of disability, motor function assessments, as well as nutritional status.”

Maraganore said that the phase III study, which would mark the first time Alnylam has advanced a drug into the final stage of clinical development, is expected to take between two and a half and three and a half years to complete.

Second-quarter Financials

For the three-month period ended June 30, Alnylam’s net loss climbed to $18.2 million, or $0.29 a share, from a year-ago loss of $13 million, or $0.25 a share.

Revenues in the quarter sank to $8.7 million from $20.9 million, a decline that Alnylam Vice President of Finance Michael Mason attributed to the completion of amortization of gross overhead deferred revenue during 2012.

R&D spending rose to $24.2 million from $21.7 million in the second quarter, while general and administrative costs dipped to $5.8 million from $11.2 million, in part reflecting a decrease in legal expenses following the end of the Tekmira litigation.

Alnylam said that it expects to end 2013 with more than $320 million in cash, cash equivalents, and marketable securities.

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