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Alnylam to Release Phase II ATTR Data, Launch Expansion Trial in Coming Months


Alnylam Pharmaceuticals this week announced that it plans to report initial data from an ongoing phase II trial of its lead drug candidate, the TTR-mediated amyloidosis treatment ALN-TTR02, this summer at an upcoming scientific meeting, and that it will launch an expansion study examining the drug in different treatment regimens.

Meanwhile, the company is on track to release data in the coming months from other pipeline products, including a subcutaneous version of the ATTR therapy called ALN-TTRsc, representing a “very data-rich period” for Alnylam, CEO John Maraganore said.

Alnylam provided the research and development updates along with its first-quarter financial results, which included a decline in revenues as the company recorded the last of the collaboration revenues from Cubist Pharmaceuticals, which dropped out as a development partner for the troubled respiratory syncytial virus drug ALN-RSV01 in 2012.

ATTR is caused by mutations in the TTR gene, which triggers accumulation of abnormal amyloid proteins in the body. ALN-TTR02 comprises siRNAs designed to inhibit both the wild-type and mutant forms of the protein, and is formulated with a lipid nanoparticle technology licensed from Tekmira Pharmaceuticals.

As part of Alnylam’s so-called 5x15 initiative, which aims to have five drug candidates for genetically defined diseases in advanced clinical development by 2015, and with the failure of its RSV drug in a phase IIb study last year (GSN 5/31/2012), ALN-TTR02 has moved to the head of the company’s pipeline.

Last summer, Alnylam released phase I data showing the drug could trigger up to 94 percent reductions in target protein levels after a single dose — a key finding given the close relationship between TTR levels and the disease (GSN 7/19/2012).

A few months later, Alnylam snagged Genzyme as its Asian partner for ALN-TTR02, which had since advanced into a phase II testing (GSN 6/7/2012 & 10/25/2012).

The ongoing phase II trial is designed to evaluate multiple, escalating doses of ALN-TTR02 in approximately 20 ATTR patients, who are dosed every four weeks for two cycles. “Primary objectives of the study are to evaluate the safety and tolerability of multiple doses of ALN-TTR02 and to measure clinical activity based on serial measurements of circulating serum TTR levels,” Alnylam CMO Akshay Vaishnaw said during a conference call held to discuss the first-quarter results.

Initial trial results are slated for presentation this summer at the biennial meeting of the Peripheral Nerve Society being held June 29 to July 3, pending acceptance of the company’s abstract, he added.

Vaishnaw also said that Alnylam is planning to expand the phase II trial with an additional 10 patients at more study sites in order to “explore additional cohorts treated with a once-every-three-weeks dosing regimen and a reduced steroid premedication regimen.”

Data from the additional cohorts will be available later in 2013, and are expected to help Alnylam finalize the dosing regimen for a phase III trial of ALN-TTR02, which will focus on ATTR patients with familial amyloidotic polyneuropathy and start before the end of the year, Vaishnaw said.

He added that Alnylam has wrapped up the long-term, pre-clinical studies required to begin phase III testing, including six-month rat and nine-month non-human primate studies, all of which support chronic dosing of ALN-TTR02 in humans.

Additionally, Alnylam is on track to start an open-label extension study of ALN-TTR02 for patients receiving treatment in the phase II trial, with data available in 2014, he noted.

As part of its effort to shake its reliance on Tekmira’s drug-delivery technologies, which were the subject of an acrimonious legal dispute that ended with a $65 million payout to Tekmira (GSN 11/15/2012), Alnylam is developing ALN-TTRsc, which uses a proprietary conjugation strategy based on the triantennary N-acetylgalactosamine, or GalNAc, ligand.

A phase I trial of that compound, which is set to enroll about 40 healthy volunteers, began in March (GSN 3/21/2013), and Vaishnaw said that Alnylam expects to report data from the study mid-year. A phase II trial in ATTR patients with familial amyloidotic cardiomyopathy is expected to kick off before the end of 2013.

Assuming positive clinical data, a pivotal trial of ALN-TTRsc is expected to start in 2014, he said.

Alnylam also continues to make strides with its earlier-stage candidates, including the bleeding disorder treatment ALN-AT3, which targets antithrombin, an endogenous anticoagulant expressed in the liver. The company plans to file an investigational new drug application for this drug mid-year, with phase I testing starting by year-end.

Preclinical data on ALN-AT3 is scheduled for presentation at the Congress of the International Society on Thrombosis and Haemostasis being held June 29 to July 4.

The company is also working on ALN-AS1, which targets aminolevulinate synthase 1 to treat acute intermittent porphyria, a very rare condition characterized by accumulation of toxic heme precursors.

Vaishnaw said that preclinical data from this effort will be presented in May at the International Congress of Porphyrins and Porphyrias, and phase I testing is expected to begin next year.

Both ALN-AT3 and ALN-AS1 are delivered using the GalNAc technology.

The First Quarter

For the three-month period ended March 31, Alnylam reported a net loss of $9 million, or $0.15 per share, compared with a year-ago net loss of $11.4 million, or $0.25 a share.

Revenues in the period dropped to $18.6 million from $20.6 million, and included payments from collaborators including Genzyme and Cubist. However, Alnylam said that its partnership revenues for the rest of the year will decrease as it will receive no additional funding from Cubist.

Research and development spending edged up to $22.2 million from $21.1 million, primarily due to clinical work on the ATTR drug programs, while general and administrative expenses fell to $6.3 million from $10.4 million as a result of the lower legal costs following the settlement of the Tekmira litigation.

At the end of March, Alnylam had cash, cash equivalents, and marketable securities totaling $400.8 million, which reflects the impact of a $173.6 million stock offering in January.

Looking ahead, Alnylam expects its cash balance to be greater than $320 million at the end of 2013.