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Alnylam Gives Updates on Hemophilia, ATTR Programs; Adds HBV to Pipeline


NEW YORK (GenomeWeb) – Alnylam Pharmaceuticals this week unveiled initial top-line data from an ongoing Phase I study of its siRNA-based hemophilia drug ALN-AT3, which showed the drug is capable of significantly knocking down its target after a single, subcutaneous dose.

Alnylam also announced that it has expanded its pipeline to include a hepatitis B program, which it acquired when it bought the RNAi assets of Merck earlier this year.

Meanwhile, the company continues to lay the groundwork to commercialize its most advanced drug candidate, the Phase III TTR-mediated amyloidosis (ATTR) treatment patisiran, with company officials having recently met with private and government payors over potential pricing schemes.

ALN-AT3 comprises siRNAs targeting antithrombin (AT), an endogenous inhibitor of thrombin generation and takes advantage of Alnylam's flagship GalNAc delivery technology, which facilitates liver delivery via uptake through the asialoglycoprotein receptors expressed on the surface of hepatocytes.

Notably, the drug is the first to use a new version of the GalNAc conjugates that feature so-called enhanced stabilization chemistry (ESC), which the firm said yields increased potency, durability, and a wider therapeutic index than previous versions of the technology.

Earlier this year, the agent moved into a two-part Phase I study. In the first arm, single, escalating sub-pharmacologic doses of ALN-AT3 are administered to 24 healthy volunteers in order to determine its safety and measure its ability to alter AT plasma levels. The maximum allowable level of antithombin knockdown in this part of the study was 40 percent.

The second part will evaluate multiple, escalating doses of ALN-AT3 in 18 patients with moderate to severe hemophilia A or B. The primary objective of this arm of the trial is examine safety and tolerability, as well as clinical activity as determined by the knockdown of circulating antithrombin levels and increase in thrombin generation at pharmacologic doses.

According to the newly released data, which were presented at the World Federation of Hemophilia 2014 World Congress, single 0.03 mg/kg doses of the drug were able to silence its target by up to 28 to 32 percent — a finding that was statistically significant relative to placebo.

This resulted in statistically significant increases in peak thrombin generation, which were "temporally associated and consistent with the degree of AT knockdown," Alnylam said.

"With these results in hand, we are now proceeding to [the second part] of the study," Alnylam Chief Medical Officer Akshay Vaishnaw said in a statement. "Patients will receive three weekly doses, and we fully expect to achieve robust levels of AT knockdown as we dose escalate. In addition, we will aim to evaluate a once-monthly dosing regimen in future clinical studies, as we believe this could provide a highly attractive prophylactic regimen for patients."

Data from the other half of the Phase I trial are expected by year-end.


Separately this week, Alnylam announced that it has added HBV to its drug-development lineup based on the strong non-human primate data generated on the program at Merck.

According to the company, siRNAs targeting a conserved region of the virus' genome were synthesized and formulated into lipid nanoparticles. When administered as a single 0.25 mg/kg dose to chronically infected chimps, the drug led to a greater-than-2-log10 reduction in circulating viral DNA in the highest titer animal.

"In multi-dose, dose-escalation studies in the chronically infected animals, doses of 0.125 to 0.5 mg/kg achieved an over 4 log10 reduction of circulating viral DNA," Alnylam said. In these experiments, treatment also resulted in an up to 2.3 log10 reduction in surface antigen — a marker of actively replicating virus.

Alnylam also noted that some of the treated animals also displayed changes in liver enzyme levels that suggested potential therapeutic flares related to immune clearance of infected hepatocytes.

Arrowhead Research, which has already advanced its own RNAi-based HBV drug into the clinic, also observed indications of such an immune response in non-human primate testing.

Alnylam said that it expects to identify an HBV candidate, which will use its ESC-GalNAc subcutaneous delivery technology, around the end of the year. An investigational new drug application (or IND equivalent) will likely be filed in late 2015, it added.


Although it has now expanded the number of drug candidates in its pipeline into double digits, Alnylam continues to keep a strong focus on patisiran — its nearest-term commercial opportunity. As part of that effort, the firm has been in communication with payors and received positive feedback, company officials said.

Speaking during a conference call held to discuss Alnylam's first-quarter financial results, CEO John Maraganore noted that Alnylam held a meeting last month with representatives from US payor organizations, both public and private. Similar discussions have been held with payors and Europe and elsewhere.

Alnylam President and Chief Operating Officer Barry Greene said during the call that these talks "are going incredibly well," and that there is recognition among payors at ATTR is an orphan disease with "extreme costs to the health care systems."

Greene added that payors also recognize that the disease is tightly linked to levels of the pathogenic TTR protein and have been "quite excited" to see clinical data, even from Phase I studies, showing patisiran's ability to significantly cut target protein levels.

"It's not every day they run across a modality that actually reads out so early in the clinical trials," he said.

Greene added that there is consensus among payors that the endpoints of a recently Phase III trial will be sufficient to justify orphan drug-like pricing — which is typically higher than for drugs treating bigger indications — for patisiran should it reach the market.

But with the Phase III trial just having been initiated, "we're not at a point where we're crafting exact pricing for our drugs," he said.