Press Release.
Arrakis Therapeutics Unveils Data for its Lead, Rationally Designed, RNA-Targeted Small Molecule (rSM) Drug Program Demonstrating Disease-Modifying Binding to RNA to Treat Myotonic Dystrophy
Preclinical data presented at Cell Symposia conference show a small molecule directed at a pathogenic RNA achieved reversal of myotonia in an animal model of myotonic dystrophy Type 1 (DM1)
Supports additional product development with Company’s multi-modality rSM drug platform, broadening the reach of genetic medicine and offering the potential to treat diseases at their root cause with oral medicines
Waltham, Mass., December 4, 2024 – Arrakis Therapeutics, a biopharmaceutical company pioneering the discovery of a new class of small molecule medicines that directly target RNA, today announced the first presentation of data for its RNA-targeted small molecule (rSM) drug program for the treatment of myotonic dystrophy type 1 (DM1), a form of muscular dystrophy. These preclinical data demonstrate Arrakis’s leading-edge capability to rationally design a disease-modifying RNA-targeted small molecule, using its pioneering and comprehensive drug discovery platform. The data are being presented today at the Cell Symposia conference Chemical Biology in Drugging the Undrugged, taking place in San Francisco, CA on December 2-4, 2024.
The preclinical data from in vivo animal studies demonstrated the reversal of myotonia with Arrakis rSMs binding the target pathogenic CUG repeat RNA element responsible for DM1. Arrakis molecules selectively bind the CUG repeat, disrupt the formation of nuclear aggregates, release sequestered splicing factors, specifically Muscleblind-Like Splicing Regulator 1 (MBNL1), and correct splicing defects responsible for myotonia. Arrakis’s proprietary RNA‐specific chemical, biological, and structural methods and RNA-directed medicinal chemistry enabled structure-based small molecule drug design targeting the trinucleotide (CUG) repeat expansion in the mRNA of DMPK (myotonic dystrophy protein kinase) that drives DM1 pathology. The methodologies applied to the DM1 drug program are being used by Arrakis to advance its pipeline of proprietary and partnered rSM drug candidates for a range of other diseases.
“While there have been serendipitous discoveries of small molecule drugs that bind to RNA, we believe this is one of the clearest examples of a rationally designed small molecule that has been purpose-built to address an RNA disease target,” said Michael Gilman, PhD, Chief Executive Officer of Arrakis Therapeutics. “With the many tools we’ve built and lessons we’ve learned along the way, we believe that our DM1 program is the first of many potential RNA-targeted small molecule drug candidates that will emerge from our platform in coming years.”
Dr. Gilman added, “From the beginning, we have believed in the power of targeting RNA and committed to deeply understand RNA sequence, structure and function. rSMs combine the specificity, validation, and impact of genetic medicines with the well understood benefits of small molecule drugs, including systemic biodistribution, oral delivery, and more streamlined and cost-efficient supply chains. With our platform now built and scaled, we look forward to advancing our pipeline and vastly expanding the reach of RNA-targeted medicines by deploying our industry’s most established drug modality, oral small molecules.”
A presentation at Cell Symposia describes results from several preclinical studies. Highlights include:
- High-resolution X-ray structures revealing the interaction of multiple Arrakis rSMs bound to the CUG RNA repeat.
- Arrakis rSMs selectively bind the target RNA and displace MBNL1, a splicing factor sequestered in nuclear aggregates caused by CUG RNA repeats associated with DM1.
- Arrakis rSMs neutralize repeat aggregates and correct splicing defects in DM1 patient-derived myocytes.
- Arrakis rSMs modulate splicing and reverse myotonia in the HSALR mouse, the gold standard murine model of muscle dysfunction in DM1.
The presentation from Cell Symposia is available here on Arrakis’s website.
“We are pleased to share data on our DM1 program. For the first time, we are showing how our in silico, wet lab, and structural biology capabilities enable Arrakis to identify druggable RNA target sites and to rationally design and optimize small molecules that selectively bind to an RNA structure to modify its function,” said Jennifer Petter, PhD, Founder and Chief Scientific Officer at Arrakis Therapeutics and presenter of the data at Cell Symposia. “While there are promising muscle-directed oligonucleotide therapies in clinical development for the treatment of DM1, our rSMs have the potential to address the full systemic manifestations of the disease and represent a new class of genetic medicine that use small molecules to directly address the genetic basis of disease by targeting pathogenic RNA.”
About the rSM Program to Treat Myotonic Dystrophy Type 1 (DM1)
Myotonic dystrophy type 1 (DM1) is a form of muscular dystrophy and a genetic neuromuscular disease affecting at least 1 in 8,000 people worldwide or approximately 45,000 people in the United States. It is a multi-system disease, affecting the skeletal muscle, heart, diaphragm, central nervous system, and gastro-intestinal tract. DM1 is caused by a trinucleotide (CUG) repeat expansion of the RNA encoding DMPK (myotonic dystrophy protein kinase), resulting in the formation of nuclear aggregates that bind and sequester splicing factors important for cellular function. Arrakis’s rSM selectively binds to CUG repeats, disrupting aggregate formation in cells, liberating splicing factors, and correcting splicing defects in genes that drive DM1 pathology, including myotonia.
About Arrakis Therapeutics
Arrakis Therapeutics is a biopharmaceutical company pioneering the discovery of a new class of medicines that directly target RNA. Arrakis is building a proprietary pipeline of RNA-targeted small molecule (rSM) medicines focused on genetically validated targets and numerous disease areas. The company brings together scientific leaders in RNA structure, chemistry and biology, along with a highly experienced management team and the backing of leading life sciences investors. The company is located in Waltham, Massachusetts. For more information, please visit www.arrakistx.com and engage with us on LinkedIn.
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