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Alnylam Steps Back from Huntington's Drug Deal, Sees Two Partnerships by Year-End


Alnylam Pharmaceuticals executives last week disclosed that the company has dropped out of its 50/50 cost- and profit-sharing arrangement with Medtronic for the preclinical RNAi-based Huntington's disease therapy ALN-HTT, opting instead to let its partner incur all expenses associated with the program and receive only milestones and royalties.

Speaking during a conference call held to discuss Alnylam's first-quarter financial results, the officials also gave an update on the company's partnering efforts, indicating that it plans to strike deals for its liver cancer and hypercholesterolemia programs before the end of the year.

ALN-HTT comprises siRNAs against huntingtin, the gene responsible for the disease, and a Medtronic-designed implantable infusion system designed to deliver the RNAi molecules directly to the central nervous system. The companies began their alliance in 2005, agreeing to split the costs of developing the treatment, as well as the profits from its commercialization (GSN 2/11/2005).

In late 2010, the effort got a boost from the non-profit Huntington's disease organization CHDI Foundation, which agreed to take on 50 percent of expenses associated with bringing ALN-HTT up to an investigational new drug application filing (GSN 11/4/2010).

The program has been proceeding apace, with preclinical data slated for presentation later this year. But having slashed its workforce by more than a third to cut costs in January (GSN 1/26/2012), and with a phase I trial of ALN-HTT expected to start in the second half of the year, Alnylam has decided to take a step back from the Huntington's disease alliance in order to focus on other in-house drug candidates.

“It's a program that requires the use of an implantable infusion pump … and therefore … is a much more complicated program than other programs we have in our pipeline,” Alnylam CEO John Maraganore said during last week's call. “It's also a program, in the context of clinical development, [that] doesn't have the types of things we like … namely a very early biomarker that we can measure in phase I.”

According to Maraganore, the move represents a “fundamental business decision” consistent with its efforts to focus in the near term on its phase I transthyretin-mediated amyloidosis drug ALN-TTR02, which is scheduled to enter phase II trials in the second half of 2012, and its preclinical hemophilia therapy ALN-APC, which is on track for phase I in the first half of 2013.

Alnylam President and COO Barry Greene added during that call that “Medtronic has indicated their continued interest … in ALN-HTT and we … are committed to assisting them in these efforts.”

Alnylam's sharpened focus is part of its so-called 5x15 initiative, which aims at moving five drug candidates into “advanced clinical development” by 2015 (GSN 1/6/2011). These include ALN-TTR02 and ALN-APC, as well as the phase I hypercholesterolemia drug ALN-PCS, the preclinical refractory anemia treatment ALN-HPN, and the preclinical hemoglobinopathies therapy ALN-TMP.

As previously announced, Alnylam only plans to run clinical trials of ALN-TTR02 and ALN-APC without the help of partners (GSN 1/12/2012). But Greene last week indicated that the firm may be close to clinching deals for two of its programs.

When discussing Alnylam's goal for the remainder of 2012, he noted that the company is planning on “partnering our ALN-PCS program” as it moves other 5x15 candidates forward.

He also said that Alnylam is slated to present data from an ongoing phase Ib trial of its liver cancer drug ALN-VSP at the upcoming American Society of Clinical Oncology annual meeting in June while “advancing … [the] program into phase II with a partner.”

An Alnylam spokesperson confirmed that the company “expects to form these partnerships in 2012.”

While Alnylam officials did not provide additional details about ALN-VSP, they highlighted ALN-PCS' unique mechanism of action as key to attracting a big pharma partner.

That drug's target, proprotein convertase subtilisin/kexin type 9, has caught the attention of a number of drug developers recently such as Regeneron Pharmaceuticals, which secured a deal with Sanofi for its phase II PCSK9-binding monoclonal antibody.

Unlike antibody-based approaches, however, ALN-PCS “inhibits the synthesis of PCSK9 in liver cells, thereby reducing both its intracellular and extracellular functions, and thus provides a differentiated strategy for PCSK9 antagonism,” Alnylam CMO Akshay Vaishnaw said during the call.

“This mechanism of action results in potent and durable [low-density lipoprotein] cholesterol reductions, enabling once-monthly dosing and potential synergistic effects with statins,” he noted. “In addition, ALN-PCS' novel mechanism enables consistent clinical activity across a wide range of patient PCSK9 plasma levels, including individuals with very high PCSK9 plasma levels.

“We believe these differentiating factors could be very important in the development of PCSK9 agents and will be important to the partnership we intend to form prior to initiating a phase II study,” Vaishnaw said.

Maraganore added that Alnylam expects the next study of ALN-PCS to test multiple doses of the drug in combination with existing cholesterol-lowering statins. And while the company might be able to secure more favorable partnering terms if it waited until after phase II to do a deal, he said, Alnylam needed to make a decision on which programs to prioritize.

“One can continue to invest and make things better and stronger over time, but you have to balance that as a company with the other organizational aspects of what you're doing,” Maraganore explained. “We just can't do everything.”

ALN-APC is expected to enter phase I testing in the first half of next year.

The Financials

For the three-month period ended March 31, Alnylam's revenues slipped slightly to $20.6 million from $20.9 million a year earlier.

Net loss in the quarter dropped to $11.4 million, or $0.25 per share, from a year-ago loss of $16.3 million, or $0.38 per share.

First-quarter research and development spending fell to $21.1 million from $26.3 million, while general and administrative costs edged up to $10.4 million from $10.2 million the year before.

At the end of the quarter, Alnylam had cash, cash equivalents, and marketable securities totaling $316.9 million. The firm said it expects to end 2012 with more than $250 million.