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Alnylam Aims Broadly with Hemophilia Drug, Advances HBV Program toward Clinic


NEW YORK (GenomeWeb) – As Phase I testing of its hemophilia therapy ALN-AT3 continues, Alnylam Pharmaceuticals is setting its sights broadly for the program, taking aim at both patients receiving standard medical care as well as those who have become refractory to such treatment, company officials said this week.

"We have a very broad perspective on where this program can go," Alnylam CEO John Maraganore said during a conference call held this week to discuss the firm's third-quarter financial results. "We think it can be very disruptive in the entire hemophilia space."

Meanwhile, development of Alnylam's newly acquired hepatitis B program is proceeding apace as the company works to shift away from the lipid delivery nanoparticles originally used in the program to its GalNAc conjugate technology, which is being used with all of its newer drug candidates.

Alnylam expects to select a lead HBV candidate by the end of the year and submit a regulatory filing to start human testing around the end of 2015, according to Maraganore.


ALN-AT3 comprises siRNAs targeting antithrombin (AT), an endogenous inhibitor of thrombin generation. The drug is the first to take advantage of Alnylam's GalNAc enhanced stabilization chemistry, which the firm says yields increased potency, durability, and a wider therapeutic index than previous versions of the delivery technology.

In May, Alnylam presented top-line data from a Phase I study showing that single sub-pharmacologic doses of ALN-AT3 could silence AT by up to 28 to 32 percent in healthy volunteers. On these data, the company proceeded into the second arm of the trial, in which patients with moderate to severe hemophilia A or B will receive multiple, escalating doses of the drug with the goal of achieving significant AT knockdown.

There are treatments for hemophilia that involve replacement of the missing clotting factors that cause the disease — Factor VIII in the case of hemophilia A and Factor IX in the case of hemophilia B — either as a prophylaxis or as an on-demand therapy during bleeding episodes.

However, in some cases, so-called inhibitor patients develop antibodies against replacement factors making them refractory to such treatment. Meanwhile, there are other rare bleeding disorders caused by deficiencies in other blood coagulation factors including Factor II, V, VII, and X.

Alnylam anticipates ALN-AT3 will be applicable to all of these patient populations, reducing the frequency of bleeding episodes and decreasing the need for on-demand treatment, Maraganore said.

Some patients experience bleeding episodes upwards of 20 or more times a year, he added. "Our goal here would be to reduce that instance of bleeding … to a much smaller number, and that’s where the real value proposition would exist."

Maraganore said that while Alnylam has not provided specific guidance on the timing of future clinical trials of ALN-AT3, "our vision is very broad based with that program and you're going to see us doing multiple Phase II … and ultimately Phase III [studies to] … capture the broadest opportunity with that product."

Complete results from the ongoing Phase I trial are expected to be released in mid-2015.


Alnylam's efforts in HBV are also steadily advancing following the company's acquisition of the program along with Merck's RNAi assets early this year.

Maraganore cited non-human primate data generated by Merck showing that a single 0.25 mg/kg dose of siRNAs against a conserved region of the HBV genome could lead to a greater than two-log reduction in surface antigen, a key marker of active infection.

But he noted that this was achieved using lipid nanoparticles (LNPs), which "we don't think is the right approach" given the need for premedication to address the immune stimulation that these delivery vehicles can trigger.

"From a tolerability standpoint … that just wouldn't work in hep B," he said. "In fact, that's one of the reasons that Merck didn't pursue that approach because of the [pre-medication] challenges with the LNPs."

GalNAc conjugates, which facilitate delivery via uptake through the asialoglycoprotein receptors expressed on the surface of hepatocytes, can overcome that issue, Maraganore added. "So over the course of the year, we've been working to convert the siRNA that was previously encapsulated in the LNP into a GalNAc-conjugate."

Alnylam now expects it will be in a position to begin Phase I testing of an HBV candidate in Europe in late 2015 or early 2016.


For the three-month period ended Sept. 30, Alnylam posted a net loss of $44 million, or $.58 a share, compared with $29.7 million, or $.48 a share, in the same period a year earlier.

Revenues in the quarter were $11 million, up from $9 million a year ago, and included $7.6 million from partners Takeda Pharmaceuticals and The Medicines Company, and $3.4 million from technology licensee Monsanto.

Research and development spending in the quarter rose to $46.3 million from $34.5 million, while general and administrative expenses climbed to $9.9 million from $6.8 million.

At the end of September, Alnylam had cash, cash equivalents, and marketable securities totaling $915.2 million. The company said it expects to end 2014 with over $860 million.