siRNA Therapeutics: Expanding Horizons Beyond the Liver

Alnylam Pharmaceuticals continues to lead the charge in RNA interference (RNAi) therapeutics, with recent FDA approvals and ambitious goals setting the stage for a new era in genetic medicine. As the field gains momentum, major pharmaceutical companies are investing heavily in siRNA technology, aiming to broaden its applications beyond liver-targeted therapies.

Recent Approvals and Industry Momentum

In March, Alnylam secured FDA approvals for two significant treatments: Amvuttra for transthyretin-mediated amyloidosis and Qfitlia, developed in partnership with Sanofi, for hemophilia A and B. These approvals underscore the growing acceptance and potential of siRNA-based therapies in addressing genetic disorders.

The success of Alnylam has sparked intense interest from other industry giants. GSK, AbbVie, Boehringer Ingelheim, and Eli Lilly are among the companies now actively pursuing siRNA-based treatments. This surge in interest has led to substantial financial investments, with Boehringer Ingelheim striking a deal potentially worth over $2 billion with Suzhou Ribo Life Science and Ribocure Pharmaceuticals for MASH treatments. Similarly, GSK invested $1.2 billion in Boston Pharmaceuticals' FGF21 analog efimosfermin alfa, also targeting MASH.

Expanding Beyond Liver Targeting

While current FDA-approved siRNA therapies primarily target liver processes, researchers are making strides in expanding the technology's reach to other organs. Alnylam has set an ambitious goal of targeting siRNA to any organ by 2030, with promising early-stage developments in brain, adipose, and lung tissue targeting.

Myles Minter, a senior biotech analyst at William Blair, noted, "Where we're starting to see innovation—and it still is early stage, although it looks very promising—is trying to deliver to new tissues." This sentiment is echoed by Andrew Adams, Eli Lilly's group vice president, who highlighted brain diseases as a particularly interesting area for siRNA development.

Arrowhead Pharmaceuticals is at the forefront of these efforts, with mouse data on two siRNA candidates designed to reduce body fat while preserving lean muscle mass. The company has also reported encouraging interim results from a Phase I/II study of ARO-RAGE, an siRNA targeting lung tissue for potential asthma treatment.

Challenges and Future Prospects

Despite its promise, siRNA technology faces limitations. It can only knock down gene expression rather than completely knock it out, and it cannot directly boost levels of deficient proteins. However, researchers have developed creative workarounds, such as Alnylam's Givlaari for acute hepatic porphyria, which targets an upstream enzyme to reduce toxic intermediates.

The success of siRNA therapies may also pave the way for more permanent genetic treatments. Adams suggested that once sufficient evidence is gathered on the long-term safety of protein knockdown via siRNA, confidence may grow in pursuing permanent genetic changes through technologies like gene editing.

As the field continues to evolve, the next five to ten years promise to be exciting for siRNA therapeutics. With ongoing research expanding its applications and major pharmaceutical companies investing heavily, siRNA technology stands poised to revolutionize treatment options for a wide range of diseases beyond liver-targeted therapies.