RNA-Targeting Small Molecules Gain Momentum as Drug Discovery Frontier

A succession of partnerships with biotechs focused on RNA-modulating small molecules have signalled big pharma's growing interest in the space. In 2025 alone, Merck KGaA announced a collaboration with Waltham, Massachusetts-based Skyhawk Therapeutics in a deal worth up to $2bn; Daiichi Sankyo partnered with Seattle, Washington-based Wayfinder Biosciences for use of its drug discovery platform in neurodegenerative disease and Astellas Pharma revealed plans to collaborate with xFOREST to utilise its RNA splicing-targeted drug discovery platform.

While small molecules have long been the cornerstone of the pharmaceutical industry, there is increasingly a demand for innovative precision approaches, often synonymous with biologic therapies. Yet a quiet resurgence in the small molecule sector is building momentum, with its sights set on what was previously considered an "undruggable" target—human RNA.

Traditional protein targets are becoming increasingly saturated, thereby driving interest in alternative approaches. However, RNA-based therapeutics have often been hindered by delivery challenges due to the large, hydrophilic nature of RNA and its susceptibility to degradation. It is argued that RNA-targeted small molecules could offer the same transcription-level intervention, while providing the added benefits of oral availability and scalable manufacturing.

Sector progress has been driven, in part, by the landmark success of Roche's oral SMA drug Evrysdi (risdiplam), which first received FDA approval in 2020. SMA is characterized by deficient SMN protein. Evrysdi binds two sites on exon 7 of the SMN2 pre-mRNA—namely, ESE2 and 5'ss—to promote their inclusion in the mature transcript, thereby increasing functional SMN protein levels.

Beyond xFOREST's collaboration with Astellas, the biotech has also partnered with Daiichi Sankyo, Takeda Pharmaceutical, Otsuka Holdings, and several EU-based global pharma companies. The collaboration can take two forms, supporting RNA-targeted drug discovery from scratch, or advancing lead compounds derived from xFOREST-identified hit molecules.

Clinical-stage Watertown, Massachusetts-headquartered Remix Therapeutics collaborated with Johnson & Johnson for exclusive rights to three specific targets in immunology and oncology, for a $45m upfront payment and other payments potentially exceeding $1bn. In January 2024, Remix formed a partnership with Roche for the discovery and development of small molecule therapeutics modulating RNA processing. The deal included a $30m upfront payment and up to $1.12bn in milestone payments and royalties.

Traditional small molecule drug discovery is predicated on the identification of well-defined binding pockets, which is not conducive to the dynamic nature and relative thermodynamic instability of RNA in comparison with proteins. Nonetheless, advances in the understanding of RNA structural biology and high-throughput screening techniques have allowed for the identification of RNA–small molecule binding interactions. The key challenge has now evolved from identification of RNA binders to enhancing RNA selectivity.

RNA-based therapeutics have garnered much attention in recent years. Ionis Pharmaceuticals' antisense oligonucleotide (ASO) therapy Spinraza (nusinersen) was approved for spinal muscular atrophy (SMA) in 2016 and the first RNA interference (RNAi) therapeutic, Alnylam Pharmaceuticals' Onpattro (patisiran), gained approval in 2018. In addition, the 2024 Nobel Prize in Physiology or Medicine was awarded to the discovery of microRNA (miRNA) and its role in post-transcriptional gene regulation.

Approximately 1% of human DNA is made into protein, while 80% is converted to RNA, highlighting the substantial role of non-coding RNAs in human disease. Tapping into RNA could vastly expand the array of druggable targets.