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Alnylam Focuses on Two Lead Programs, Won't Advance Others without Partners

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By Doug Macron

Alnylam Pharmaceuticals this week re-organized its pipeline to focus on its drug-development programs in transthyretin-mediated amyloidosis and hemophilia, opting to advance its other programs only through partnerships.

"As we effect our transformation from a platform company to a product company, now is the time to focus our near-term efforts on what we believe to be our highest value opportunities with accelerated clinical development plans,” Alnylam CEO John Maraganore said in a statement.

The move marks a change in strategy for the company, which just one year ago had said that it planned to handle US commercialization for five products — the TTR amyloidosis and hemophilia candidates, as well as therapies for hypercholesterolemia, anemia, and hemoglobinopathies — while only looking for partners in “other global territories.”

This claim came as part of the company's year-old 5x15 initiative, which promises five drug candidates in “advanced clinical development” by 2015 (GSN 1/6/2011).

Now leading Alnylam's pipeline is ALN-TTR02, which comprises siRNAs against the wild-type and mutant forms of the transthyretin gene associated with TTR amyloidosis and which is delivered using second-generation lipid nanoparticles.

Late last year, the company reported data from a phase I trial of ALN-TTR01, which uses a delivery technology developed by Tekmira Pharmaceuticals, showing that the therapy could safely trigger statistically significant reductions in serum levels of a target protein (GSN 12/01/2011).

Alnylam said this week that this study will conclude in the first quarter of this year, with interim data being released before mid-year, but noted that ALN-TTR02 will be the compound that it intends to bring to market. Although Alnylam has said that it fully owns the delivery technology used in the newer drug, it is embroiled in a lawsuit with Tekmira over the matter (GSN 11/10/2011).

Alnylam added that it has filed an application to begin testing ALN-TTR02 in the UK in a 32-patient, phase I study, which will evaluate single doses of the drug at levels ranging from 0.01 mg/kg to 0.5 mg/kg. This trial is expected to begin by the middle of 2012, with initial data available in the third quarter. A multiple-dose phase II trial is slated to begin in the second half of the year, with a phase III study beginning as early as 2013.

Alnylam said that it also plans to move a subcutaneously delivered version of the drug into human testing before the end of 2012. This compound will be delivered using the company's GalNAc conjugates and “represents an attractive opportunity for product differentiation” in a clinical setting, the firm said.

Meantime, Alnylam said its hemophilia treatment ALN-APC, which targets the natural anticoagulant protein C, is on track to enter the clinic in the first half of next year. The company is weighing both systemic administration via lipid nanoparticles, as well as subcutaneous delivery using GalNAc conjugates for the agent.

Importantly, Alnylam said that all other programs in its pipeline will only move forward through partnerships. These include its phase I hypercholesterolemia drug ALN-PCS, its preclinical refractory anemia treatment ALN-HPN, and the newly unveiled hemoglobinopathies therapy ALN-TMP, all of which are covered under the 5x15 effort.

ALN-PCS comprises siRNAs against proprotein convertase subtilisn/kexin type 9 that are delivered using the so-called MC3 lipid nanoparticle technology. Earlier this month, Alnylam released phase I data showing the drug could inhibit its target and trigger dose-dependent reductions in LDL cholesterol (GSN 1/5/2012). Alnylam said it would not begin phase II development of the drug until it has been partnered.

ALN-HPC is designed to inhibit transferrin receptor subtype 2, an approach that has shown to be effective for treating anemia in animal models. Alnylam had previously said that it expects to file a new drug application for the compound this year, but noted this week that human trials would only start once a partner for the drug has been signed.

ALN-TMP comprises siRNAs that target transmembrane protease, serine 6 as a treatment for hemoglobinopathies including beta-thalassemia and sickle cell anemia, according to Alnylam. The company said that pre-clinical animal model studies have shown the drug to have “corrective effects on iron overload, in addition to broader disease modifying effects including improvements in hemoglobin levels and spleen histopathology.”

As with its anemia therapy, Alnylam will only move ALN-TMP into clinical testing with a partner.

Alnylam said it will also seek partners for earlier-stage preclinical programs including efforts in erythropoiesis, alpha-1-antitrypsin deficiency-associated liver disease, severe hypertriglyceridemia, and acute intermittent porphyria.

Alnylam also said this week that it continues to search for a partner for its phase I liver cancer drug ALN-VSP, and reiterated its intention not to begin phase II testing until it has done so. Meantime, its Huntington's disease program, already partnered with Medtronic, is moving toward an IND filing in the second half of the year.

The company said that it is nearing completion of a phase IIb trial of its respiratory syncytial virus treatment ALN-RSV01 in lung-transplant patients, but provided no guidance on when additional human studies would be initiated.

The drug is licensed to Kyowa Hakko Kirin in Asia, while Cubist Pharmaceuticals holds an option to the drug for the lung-transplant indication in all other markets.


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