siRNA Therapeutics: Expanding Horizons Beyond the Liver

In a rapidly evolving landscape of RNA interference (RNAi) therapeutics, pharmaceutical companies are pushing the boundaries of small interfering RNA (siRNA) technology. Recent developments indicate a shift from liver-focused treatments to targeting other organs, potentially revolutionizing the treatment of various diseases.

Alnylam's Continued Leadership and Industry Expansion

Alnylam Pharmaceuticals, a pioneer in RNAi therapeutics, has maintained its industry leadership with two recent FDA approvals. In March, the company received clearance for Amvuttra in transthyretin-mediated amyloidosis and, in collaboration with Sanofi, for Qfitlia in hemophilia A and B. These approvals have solidified Alnylam's position and inspired other major pharmaceutical players to enter the field.

Several industry giants, including GSK, AbbVie, Boehringer Ingelheim, and Eli Lilly, are now actively pursuing siRNA-based therapies. This surge of interest has led to significant financial investments, with Boehringer Ingelheim announcing a potential $2 billion agreement with Suzhou Ribo Life Science and Ribocure Pharmaceuticals for developing siRNA treatments for nonalcoholic or metabolic dysfunction-associated steatohepatitis (MASH).

Beyond the Liver: New Frontiers in siRNA Targeting

While all currently approved siRNA therapies target the liver, 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 results in various tissues.

Andrew Adams, Eli Lilly's group vice president and director of the Lilly Institute for Genetic Medicines, highlighted the brain as a particularly interesting target for siRNA therapeutics. Alnylam's candidate mivelsiran, currently in Phase II trials for cerebral amyloid angiopathy and Phase I for Alzheimer's disease, exemplifies this new frontier.

Other tissues showing promise include adipose and lung. Arrowhead Pharmaceuticals has released mouse data on two siRNA candidates designed to reduce body fat while preserving lean muscle mass. The company has also reported 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 potential, siRNA technology faces limitations. It cannot completely knock out gene expression or directly boost protein levels. However, researchers have developed creative solutions, such as Alnylam's Givlaari for acute hepatic porphyria, which targets an upstream enzyme to reduce toxic intermediates.

As the field progresses, siRNA's successes may pave the way for more permanent treatment options, such as gene editing. However, industry experts emphasize the need for extensive long-term data before considering permanent genetic changes.

Myles Minter, a senior biotech analyst at William Blair, summarized the field's outlook: "We're at the precipice where we're waiting, but it's an exciting five to ten years ahead for the field, no doubt."