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Alnylam Sees a Return to Big Indications amid Advances in Rare Diseases

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NEW YORK (GenomeWeb) – Although Alnylam Pharmaceuticals has focused on rare, genetically defined diseases in recent years, the company sees opportunities to someday move back into the broader indications that once populated its research and development initiatives, a top company official said last week.

Still, the RNAi shop anticipates that any such programs will remain centered around targets in the liver, where the RNAi space has had the most success overcoming delivery challenges, and would likely be pursued only through partnerships, Alnylam Chief Business Officer Laurence Reid said.

Speaking at the Leerink Partners Rare Disease Roundtable, Reid also fielded questions about some of Alnylam's existing drug candidates including the hemophilia treatment ALN-AT3, allaying concerns about that compound's therapeutic window.

Alnylam, which was founded in 2002, began with an ambitious pipeline that included programs in major indications such as influenza, age-related macular degeneration (AMD), cancer, respiratory syncytial virus (RSV), and Parkinson's disease.

Yet none of those programs has advanced beyond Phase II development, either because of technical challenges — as in the case of Alnylam's flu effort, which was dropped due to unsatisfactory in vivo efficacy — or competitive ones — the company bowed out of the AMD space, for instance, citing the dominance of newly approved antibody-based therapies.

Alnylam's liver cancer drug ALN-VSP and RSV treatment ALN-RSV01 technically remain active and are licensed to Ascletis Pharmaceuticals and Kyowa Hakko Kirin, respectively, in certain Asian markets. However, Alnylam has said it would only work on their development for other markets through an alliance.

In early 2011, Alnylam announced that it had undertaken a new strategy through an initiative dubbed "5x15" (pronounced five by 15), which called for the company to have five RNAi drug programs in the clinic by 2015. Notably, these would involve drug candidates against "genetically defined targets and disease … [with the] potential to have a major impact in a high unmet need population."

The result has been a robust pipeline covering rare diseases such as transthyretin-mediated amyloidosis (ATTR), hemophilia, complement-mediated disorders, porphyria, preeclampsia, beta-thalassemia, and alpha-1 antitrypsin deficiency. The ATTR program remains Alnylam's most advanced, with one compound — the lipid nanoparticle-formulated patisiran — in Phase III testing and another — ALN-TTRsc, which uses a proprietary GalNAc conjugation technology to enable subcutaneous delivery — set to enter pivotal testing later this year.

Despite its current interest in rare diseases, Alnylam recently added hepatitis B to its R&D roster, having acquired the program when it bought the RNAi assets of Merck earlier this year. Meanwhile, in collaboration with The Medicines Company it has been steadily working on a version of its hypercholesterolemia drug, which uses the GalNAc technology instead of lipid nanoparticles for delivery.

To Reid, these two programs "represent the beginning of a strategy outside of the rare disease space," he said during a webcast presentation at the Leerink Partners event.

As Alnylam continues to generate human pharmacology and safety data for its current programs, and as information becomes available about dosing and tolerability of the GalNAc technology, opportunities are opening up for "Alnylam to participate in chronic diseases and diseases outside of the rare disease space," Reid said.

He added that "those are going to continue to be driven by targets in the liver," and will likely be in the areas of infectious disease and cardiometabolic disorders.

Tackling those bigger indications, however, will require that Alnylam consider "the risk and cost of participating … in the commercialization and development in those areas," particularly in regards to their market potential and the level of validation for different therapeutic targets, Reid said. This, he added, must also be weighed against other rare disease opportunities that the company has not yet begun pursuing in earnest.

In the end, Alnylam expects that it will continue going after "rare disease opportunities with great genetically driven targets in the liver" with partner Genzyme, which inked a $700 million tie-up with Alnylam in January, he said. "We … will probably take more of a partnering approach [when it comes] to moving into … bigger disease areas."

Safety in hemophilia

Also at the Leerink Partners conference, Reid discussed Alnylam's hemophilia therapy ALN-AT3, which comprises siRNAs targeting antithrombin (AT), an endogenous inhibitor of thrombin generation, and uses a new version of the GalNAc technology that Alnylam claims offers increased potency, durability, and a wider therapeutic index than previous versions.

Earlier this year, ALN-AT3 entered the first portion of a two-part Phase I study. Initially, the trial will test single, escalating sub-therapeutic doses of ALN-AT3 in 24 healthy volunteers. The maximum allowable level of AT knockdown in this arm of the trial is 40 percent.

The second part of the trial will evaluate multiple, escalating doses of ALN-AT3 in 18 patients with moderate to severe hemophilia A or B.

During the rare disease meeting, Reid noted that one of the concerns with ALN-AT3 is that suppressing AT might result in thrombophilia, or abnormal blood coagulation, which could lead to thrombosis.

Alnylam views the "ablation of their AT3 phenotype is incredibly safe," he said. Further, based on the company's expectation that its findings in animal studies can be translated to humans, it believes that it will be able to achieve "supertherapeutic doses and very significant AT knockdown with no clotting problems," Reid added.

He said that the company expects patients can be treated with doses "perhaps two logs or below [those] that have been administered to hemophilic animals with no side effect problems."

"We are very confident there will be a significant therapeutic window in which we will be able to operate very safely," he said, cautioning, however, that "obviously, we need to clarify that in human beings."

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