WOBURN, Mass. — Rgenta Therapeutics, a clinical-stage biotechnology company pioneering the development of a new class of oral small molecules targeting RNA and RNA regulation for oncology and neurological disorders, announced today that preclinical data from its new Huntington’s disease (HD) drug candidate targeting PMS1, RGT-0474060, were presented at the 21st Annual HD Therapeutics Conference being held this week in Palm Springs, CA. The data, generated in a model of Huntington’s disease (HD), demonstrate robust efficacy and well tolerated in vivo safety. The pharmacokinetics of RGT-0474060 track with reduction in PMS1 RNA and protein levels, and a dose-dependent suppression and inhibition of somatic CAG-repeat expansion associated with HD.
“Targeting somatic CAG repeat expansion in the HTT gene, the mutation that causes HD, through a reduction of PMS1 is a promising strategy for treating HD and potentially transformative in our care of patients with this devastating disease,” said Sarah Tabrizi, M.D., Ph.D., professor of Clinical Neurology at University College London and co-founder of the UCL Huntington Disease Centre. “For our Huntington’s disease patients there are no disease modifying therapies yet available and existing therapies are limited to alleviating symptoms without addressing the underlying disease or its devastating progression. With future therapies, like RGT-0474060, we hope to have treatments that have the potential to slow, and possibly halt, disease progression.”
Travis Wager, Ph.D., co-founder and chief scientific officer of Rgenta added, “The mechanism of RGT-0474060 is a direct, on-target hit to the underlying cause of HD and a testament to the power of our RNA-targeting small molecule discovery platform, which continues its proven successful record in uncovering promising development candidates against traditionally undruggable targets. Specifically, RGT-0474060 has an emerging profile that supports favorable safety, pharmacokinetics, and pharmacodynamic properties that make it an ideal drug candidate.”
“In just six years since our founding, we have identified and advanced two new innovative drug candidates using our platform,” said Simon Xi, Ph.D., co-founder and chief executive officer of Rgenta. “Our pipeline is expanding with drug candidates in multiple disease areas with high unmet medical needs and we look forward to advancing RGT-0474060 into the clinic in HD. Separately, we continue to advance our ongoing Phase 1a/b clinical trial of RGT-61159 in patients with relapsed or refractory adenoid cystic carcinoma and colorectal cancers, and we look forward to broadening that program into adults with AML/high risk myelodysplastic syndromes.”
In an oral presentation titled “Targeting repeat-expansion at its source: Discovery of RGT-0474060, a PMS1 RNA splice modulator for Huntington’s disease and beyond,” Nandini Patel, Rgenta senior director, head of MedChem, reviewed the company’s discovery platform capabilities to identify and target RNA and RNA binding proteins to regulate gene expression, particularly in repeat expansion diseases. Selection of RGT-0474060 involved the alignment of multiple clinically translatable attributes: robust mechanism-linked functional activity for PMS1 reduction, dose-dependent pharmacokinetics, oral, brain-penetration, and clinically relevant reduction of PMS1 in brain tissues with a well-tolerated safety profile. The data showed that RGT-0474060 is an effective agent to halt CAG expansion and targets the root cause of the disease. Further, the presentation highlighted the potent, highly selective and dose-dependent elimination of PMS1 by RGT-0474060 in NHP and human cell lines that express PMS1, demonstrating on-target therapeutic activity of this orally available small molecule. Furthermore, as a brain penetrant molecule, RGT-0474060 showed effective mRNA knockdown and PMSI inhibition in brain tissue.
About RGT-0474060
RGT-0474060 is an oral bioavailable small molecule designed to inhibit PMS1 RNA and protein expression, effectively to modulate splicing of CAG (cytosine-adenine-guanine) repeat expansion known to cause Huntington’s disease. Preclinical data have demonstrated robust mechanism-linked functional activity for PMS1 reduction, dose-dependent pharmacokinetics, oral, brain-penetration, and clinically relevant RNA reduction in brain tissues with a well-tolerated safety profile.
About Huntington’s Disease (HD)
Huntington’s disease (HD) is a rare inherited, progressive disorder that causes nerve cells (neurons) in the brain to gradually break down and die. The disease attacks areas of the brain that help to control voluntary (intentional) movement, as well as other areas. People living with HD develop uncontrollable movements (chorea) as well as problems with behavior, emotion, thinking, and personality. The disease is caused by a defective mutation, a CAG repeat expansion gene, which produces a toxic form of the Huntington protein (mHTT) that leads to neuronal loss. PMS1 (postmeiotic segregation increased 1) is a DNA mismatch repair gene that drives somatic CAG repeat expansion, particularly in neurons, and has been identified as a key genetic modifier of HD. People with HD are born with the defective gene, but symptoms don’t usually appear until middle age. In the U.S., it is estimated that approximately 41,000 people are living with Huntington’s disease, with an additional 200,000 estimated to carry the mutant gene. While therapeutics companies are researching HD, there currently is no cure or treatment to stop HD.
About Rgenta Therapeutics
Rgenta Therapeutics is a clinical stage biotechnology company developing a pipeline of oral RNA-targeting small molecule medicines with an initial focus on oncology and neurological disorders. Our proprietary platform mines the massive genomics data to identify targetable RNA processing events and design small-molecule glues to modulate the interactions among the spliceosome, regulatory proteins, and RNAs. Our lead programs and unique approach are unlocking the therapeutic potential of historically undruggable targets in human diseases. Learn more at: http://www.rgentatx.com.
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