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Alnylam Pushes Back Development of Flu Drug, Tweaks Other Pipeline Programs

Alnylam Pharmaceuticals’ effort to develop an RNAi-based treatment for pandemic influenza, which is part of the company’s broad alliance with Novartis (see RNAi News, 2/23/2006), has hit a development roadblock, officials from the RNAi firm said last week.
“We are still … committed to our pandemic flu program but do not expect that effort to yield an [investigational new drug application] in 2007,” Alnylam COO Barry Greene said during a conference call held last week to discuss the company’s second-quarter financial results.
The company also tweaked its plans for other drug-development programs, slightly delaying the start of a second phase II trial of its respiratory syncytial virus drug candidate and putting its investigational liver cancer treatment in the running for a possible IND filing this year.
Although Alnylam had been expecting to file an IND on a flu candidate sometime this year — after missing a previously stated goal of filing it in 2006 — the company has delayed plans to begin phase I testing of the drug indefinitely.
Greene attributed the setback to a combination of shrinking interest in “novel treatments for pandemic flu” from the federal government, which in late 2005 provided Alnylam with $240,000 in funding for the program through the US Department of Defense's Defense Advanced Research Projects Agency (see RNAi News, 12/16/2005), and “the need for optimized formulations to achieve the necessary level of in vivo efficacy.”
However, comments made by Alnylam’s President and CEO John Maraganore suggest that the lack of effective, optimized siRNAs is the primary issue holding up the flu program.
“We have just not been satisfied with the level of in vivo efficacy we’re seeing related to specific RNAi effects,” Maraganore said in response to an analyst’s question about the delay during last week’s call. “We’re not going to go ahead until we have a satisfactory dataset around this program, and we’re pushing out the timing of that IND to some [undisclosed] later point.”
When pressed for additional information, Maraganore said that “we don’t truly know” what the issues affecting specificity are, although he noted that they don’t appear to be sequence-specific, but rather relate to “the broad aspects of the flu model” and the use of siRNAs themselves.
“We’re still very committed to [the flu program] and we have a lot of work that’s going on with it, but it’s got to be ready to our satisfaction of scientific quality before we go ahead,” he said.
Greene added that Alnylam’s experiences in developing an RNAi-based flu treatment don’t appear to be unique, based on the literature and details available from other companies’ efforts to develop an RNAi-based flu therapy.
“Data in the published literature and data we’re aware of from other [industry] efforts appear to reflect certain non-specific effects, and we only have an interest in advancing the program based on a solid scientific foundation,” Greene said.
Most notable among the companies developing RNAi-based treatments for influenza is Nastech Pharmaceuticals, which recently modified the timeline for its own flu drug (see related story, this issue).
Officials from neither Alnylam nor Novartis were available for further comment.
Pipeline Shuffle
During the conference call, Greene also noted that Alnylam has pushed back the anticipated start time for the second phase II trial in its RSV program to the first half of 2008 from the second half of 2007.
Earlier this year, Alnylam began a phase II study of its RSV drug candidate, called ALN-RSV01, in healthy adults experimentally infected with the virus (see RNAi News, 6/28/2007). Although the company had anticipated beginning a second phase II trial in naturally infected patients before the end of the year, it now plans to begin that study next year. 
“We want to use the results of the current phase II study that is actively enrolling to guide the design of the next phase II study in naturally infected patients, and therefore we feel it is wise to move the start of that study to the first half of 2008,” he said.
“We’ll have the data from our current phase II trial completed at that point … so we think it’s prudent to start that second study in the first half of next year,” Maraganore added.
Also experiencing a modest change-up is Alnylam’s plan for its preclinical hypercholesterolemia program, which is targeting proprotein convertase subtilisn/kexin type 9, or PCSK9.

“We have just not been satisfied with the level of in vivo efficacy we’re seeing related to specific RNAi effects. We’re not going to go ahead until we have a satisfactory dataset around this program.”

In June, Alnylam’s Director of Research David Bumcrot confirmed that the company was planning to file an IND on a PCSK9 drug before the end of this year (see RNAi News, 6/28/2007). However, the company’s liver cancer drug candidate could fill this slot, Maraganore said last week.
“Both the PCSK9 program and the [liver cancer] program … are in active stages of development right now … [but] it’s too soon to tell which one will come out first” into the clinic, he said during the conference call. “Even though we announced this liver cancer program after the [PCSK9] program, we obviously had been doing quite a bit of work in that area in advance.”
The timing of an IND filing “depends on [results from] the completion of … the studies that support the right dosing regimen in initial clinical studies. That’s really what’s guiding where the timing will go on those programs,” Maraganore added.
Alnylam’s liver cancer drug, called ALN-VSP01, comprises two siRNAs targeting vascular endothelial growth factor and kinesin spindle protein, respectively.
The Financials
For the second quarter, Alnylam’s net loss rose to $12.7 million, or $0.34 per share, from $9.9 million, or $0.31 per share, a year earlier.
Revenues in the quarter jumped to $9.1 million from $6 million and included $4.4 million in cost reimbursement and amortization revenues related to Alnylam’s collaboration with Novartis.
Research and development spending, meanwhile, climbed to $18.8 million in the quarter from $12.6 million in the same period last year reflecting higher external service costs associated with Alnylam’s preclinical programs in hypercholesterolemia, liver cancer, and Ebola, as well as expenses associated with the clinical development of ALN-RSV01.
General and administrative costs in the second quarter edged up to $5.3 million from $4.5 million the year before.
As of June 30, Alnylam had cash, cash equivalents, and marketable securities totaling $194.8 million.
The company expects to finish 2007 with more than $435 million, compared with earlier estimates of more than $180 million, largely as a result of upfront payments and an equity investment by Roche under the firms’ recent collaboration (see RNAi News, 7/12/2007).