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Alnylam Adds New Program to Pipeline as It Shelves Anemia Candidate

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Alnylam Pharmaceuticals this week provided an update to its research and development activities, adding a new preclinical program to its pipeline with ALN-AS1 for acute intermittent porphyria while dropping its refractory anemia drug ALN-HPN in order to focus on “higher priority” efforts.

Notably, the ALN-AS1 program will take advantage of Alnylam's GalNAc conjugate liver-delivery strategy, reflecting the company's growing focus on conjugates, which CEO John Maraganore described in 2011 as “the future for delivery of small interfering RNAs.”

Acute intermittent porphyria, or AIP, is a rare genetic disease caused by loss-of-function mutations in porphobilinogen deaminase, an enzyme in the heme biosynthesis pathway that can lead to the accumulation of toxic heme precursors, Alnylam said. Symptoms include severe abdominal pain, neuropathy, and neuropsychiatric disturbances such as hallucinations and anxiety.

ALN-AS1 is designed to silence ALAS-1, a liver-expressed rate-limiting enzyme upstream of porphobilinogen deaminase, the company said. Inhibition of ALAS-1 has been shown to reduce the accumulation of heme precursors that cause AIP's clinical manifestations.

Alnylam said it expects to select a clinical candidate for the program in late 2013, with phase I testing beginning in 2014, and that it will handle the drug's commercialization in North and South America and Europe on its own.

Meanwhile, Alnylam has shelved ALN-HPN indefinitely and added another drug candidate to the list of products that it will only develop with the help of a partner.

Previously, Alnylam said that its preclinical hemoglobinopathy treatment ALN-TMP, its phase I hypercholesterolemia agent ALN-PCS, and its phase I liver cancer drug ALN-VSP would only be advanced in collaboration with another company. (Although ALN-VSP has been licensed to Ascletis in China, it remains unpartnered in the rest of the world.)

Now it said that ALN-AAT, a preclinical drug targeting the mutant Z-allele in alpha-1-antitrypsin deficiency for the treatment of AAT deficiency-associated liver disease, will also remain in a holding pattern until it is partnered.

Alnylam also said that it had met with US and European regulators over its respiratory syncytial virus drug ALN-RSV01, which failed in a phase IIb trial recently (GSN 9/6/2012), but that it would not comment on the drug's fate until later this year. Cubist Pharmaceuticals holds an option to the agent after backing out of a deal to develop a different version called ALN-RSV02.

Elsewhere in Alnylam's pipeline, things remain on track.

The company said that it continues to advance ALN-TTR02, an intravenously delivered treatment for TTR-mediated amyloidosis, through an ongoing phase II trial in approximately 20 patients, with results ready by mid-year.

It said that it plans to begin an extension study for the drug around the same time to examine longer-term treatment of ATTR patients, and that it will evaluate a number of exploratory clinical endpoints beyond the circulating serum TTR levels being measured in the ongoing trial. Results from this trial are expected in 2014.

Assuming positive results from the phase II work, Alnylam said a phase III trial of ALN-TTR02 in ATTR patients with familial amyloidotic polyneuropathy, a clinical manifestation of the disease, is slated to begin before the end of the year, in line with previous guidance.

A subcutaneous version of the drug called ALN-TTRsc, which uses the GalNAc technology, is also on track to enter phase I testing in the UK early this year. Alnylam noted this week that a phase II trial in ATTR patients with familial amyloidotic cardiomyopathy, another clinical manifestation of the condition, will begin toward the end of this year pending positive phase I data.

Alnylam intends to handle commercialization of ALN-TTR02 and ALN-TTRsc in North and South America, as well as Europe.

Finally, Alnylam said that its investigational hemophilia and bleeding disorder drug ALN-AT3, which is delivered using the GalNAc conjugates and silences the anticoagulant antithrombin, is still expected to enter phase I testing in late 2013, with data ready by the following year.

As with its ATTR and AIP drugs, Alnylam plans to handle the drug's commercialization in North and South America, and in Europe.

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