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Alnylam to File IND Next Year for Either Its Liver Cancer or Cholesterol Candidates

Alnylam Pharmaceuticals last week provided some new details on its preclinical systemic RNAi therapeutics programs, indicating that it will file an investigational new drug application with US regulators for either its liver cancer or hypercholesterolemia drug candidates sometime next year.
Speaking during a conference call to discuss the company’s third-quarter financial results, Alnylam officials also reiterated their expectation that the next phase II trial of its respiratory syncytial virus drug candidate would begin in the first half of 2008.
However, no mention was made of Alnylam’s pandemic influenza program, which apparently has hit a major development roadblock based on comments made by the RNAi shop’s management earlier in the year.
This summer, an Alnylam researcher said that the company expected to file an IND this year for its cholesterol drug, which targets proprotein convertase subtilisn/kexin type 9 (see RNAi News, 6/28/2007).
A couple of months later, however, the company backed off this timeline and didn’t offer a new one (see RNAi News, 8/16/2007). It also said that its liver cancer therapeutic candidate, called ALN-VSP01, could potentially reach human testing before the hypercholesterolemia drug.
Now, Alnylam appears confident that it will file an IND on at least one of its two systemic therapies in 2008.
“We remain encouraged by the results [in our systemic RNAi program] that we have seen to date, but we must advance these programs in a high-quality manner,” Alnylam President and CEO John Maraganore said during last week’s call. “We now expect to file an IND for our first systemic RNAi therapeutic program in 2008.”
He declined to offer a more specific timeline or indicate which of the two systemic therapies might be first filed with the US Food and Drug Administration, but said that the company plans to provide additional guidance early next year.
As for its RSV program, Maraganore said that enrollment in a phase II study of the drug, ALN-RSV01, in healthy adult volunteers experimentally infected with the virus is “progressing very well” and on track for completion in December.
Alnylam expects to release top-line results from that trial early in the first quarter of 2008, he added.
The company also plans to use the findings from this study to help it design a planned phase II trial of the drug in naturally infected adult patients. The firm expects this study to begin in the first half of next year, Akshay Vaishnaw, vice president of clinical research at Alnylam, added during the conference call.
When asked for details by an analyst on why Alnylam decided to examine ALN-RSV01 in adults in the natural infection study, rather than pediatric patients, Maraganore said that the company felt that the “significant population” of RSV-infected adults “could represent a fast-to-market opportunity for us.”
However, the company remains focused on “advancing this program ultimately toward the pediatric marketplace,” he added.
Maraganore said that Alnylam is reviewing its options for testing the drug in a pediatric population ― for instance, whether to conduct the trials in parallel with, or staggered between, adult studies ― and said a final decision will “be driven by our ongoing discussions” with the FDA.
“We are looking forward to discussions with the agency at the appropriate time to discuss our pediatric study,” he said. “We’ll give further guidance when we know more.”
One area where Alnylam didn’t offer guidance was its flu program, which was once poised to enter human testing in 2006.
In August, Alnylam officials suggested that the lack of effective, optimized siRNAs was holding up development of the drug.
“We have just not been satisfied with the level of in vivo efficacy we’re seeing related to specific RNAi effects,” Maraganore said during a conference call at the time. “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.”
An Alnylam spokesperson confirmed that there has been no change in the status of the flu program since this summer. Company officials were not available for additional comment.
From Partners to Rivals
Barry Greene, Alnylam’s COO, also took last week’s third-quarter conference call as an opportunity to shed some new light on why the company’s collaboration with Merck was terminated. Chief among them was the fact that efforts by the big pharma to invalidate certain of Alnylam’s intellectual property in European turned the partners into competitors.
Though Merck and Alnylam had been early collaborators in the RNAi drugs space (see RNAi News, 9/12/2003 and 7/2/2004), their relationship became rocky after Alnylam began pursuing deals with other big pharmas.
Among them was a deal penned in late 2005 with Novartis, which signed a broad drug-discovery and -development deal with Alnylam that included the Swiss drug maker buying a nearly 20 percent equity stake in the RNAi drugs shop (see RNAi News, 9/9/2005).
Shortly thereafter, Alnylam said it was shelving its AMD candidate amid increased competition in the AMD field. Coincidentally, one of the biggest players in the AMD field is Novartis, which markets Lucentis as a treatment for the eye disease.  

“We remain encouraged by the results [in our systemic RNAi program] that we have seen to date, but we must advance these programs in a high-quality manner. We now expect to file an IND for our first systemic RNAi therapeutic program in 2008.”

Then, last summer, Merck and Alnylam revamped their alliances into a single partnership, dropping ocular diseases altogether and giving Merck the option to participate in the earlier stages of research (see RNAi News, 7/6/2006).
Finally, last November, Merck agreed to acquire Alnylam rival Sirna Therapeutics in a bid to secure control of what was considered one of the RNAi drugs field’s most important IP estates. In doing so, Merck set itself up as a direct competitor of Alnylam (see RNAi News, 11/2/2006).
When the termination of the alliance became public, Maraganore said in a statement that it was “fundamentally in our best interests to terminate our Merck collaboration.”
Alnylam officials at the time would not elaborate. But during last week’s call, Greene said that “over the last year, Merck chose to be a competitor and to actually oppose our issued European patents [for which] we had granted them a license.
“We found this to be an unacceptable foundation for a partnership,” he added. “Accordingly … we’ve chosen to distance ourselves from Merck and deny them access to our intellectual property and know-how.”
Greene added that although “we wish Merck the best of luck … to be clear, we believe anyone developing and commercializing RNA therapeutics will need a license to Alnylam intellectual property.”
The Financials
During the call, Alnylam also provided an overview of its third-quarter financials, which included a sharp increase in net loss, which jumped to $52.8 million, or $1.35 per share, from $7.4 million, or $0.23 per share, in the same period the year before.
Contributing to the increase were “a number of unique, deal-related expenses” that included a $27.5 million license fees the company paid to its licensors as a result of an alliance penned during the summer with Roche, Patricia Allen, vice president of finance for Alnylam, said during the conference call. Also contributing to the net loss were $7.9 million in increased stock-based compensation expenses.
“Excluding charges related to our Roche alliance, our net loss was completely in line with management expectations,” she noted.
The terms of Alnylam’s deal with Roche, which could be worth up to $1 billion, (see RNAi News, July 12, 2007), included Alnylam’s granting of a non-exclusive license to fundamental RNAi IP to Roche, an RNAi drug discovery alliance between the companies, and the sale of Alnylam’s German subsidiary to the Swiss pharmaceutical and diagnostics giant.
Some of the IP included in that license had been previously licensed by Alnylam from other companies, primarily Isis Pharmaceuticals, and Alnylam was required to pay a percentage of its fees from Roche to those other firms. The company also incurred a one-time $5.3 million expense related to the divestiture of the German unit.
Alnylam’s revenues in the quarter nearly doubled to $16.3 million from $8.2 million a year earlier, and included $6.4 million in revenues from the company’s collaboration with Roche, as well as $3.5 million in deferred revenues related to the terminated Merck alliance.
Alnylam said that it expects its revenues to continue to increase in the fourth quarter of 2007 as it records the first full quarter of revenues related to the Roche deal, which are being recognized over a five-year period.
However, revenues in the fourth quarter will be impacted by costs related to employees at Alnylam’s former German subsidiary, which are still under contract to Alnylam, Allen said.
“We expect the costs for these employees will decrease significantly in the first half of 2008, and by June of 2008 our transition services with [the German site] will be completed,” she added. “We would then expect to report approximately $14 million in revenues from our Roche alliance in each quarter going forward.”
Research and development spending in the quarter rose to $59.6 million from $12.7 million in the third quarter of 2006, reflecting payments to licensors resulting from the Roche alliance and the costs associated with the firm’s RSV program.
As of Sept. 30, Alnylam had cash, cash equivalents, and marketable securities totaling roughly $468.4 million.
Looking ahead, the company said it expects to have more than $435 million in cash, cash equivalents, and marketable securities at the end of 2007. Alnylam has also boosted its alliance-based revenue goal for the year to $45 million from $25 million.

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