Scribe Therapeutics, an Alameda, California-based biotechnology company, has received clearance from the Australian Therapeutic Goods Administration (TGA) to begin a Phase I STX-1150 clinical trial in adults with elevated LDL-C and increased cardiovascular risk — marking the first time the company's proprietary epigenetic silencing platform will be tested in humans. The announcement indicates STX-1150 is a potential single-dose alternative to the chronic lipid-lowering regimens that currently define standard of care for hypercholesterolemia.
The open-label, single ascending dose study will enroll up to 64 participants across sites in Australia and New Zealand, with the first site at Monash Health's Victorian Heart Hospital in Clayton, Victoria. Endpoints include safety, tolerability, pharmacokinetics, and pharmacodynamics, with participants monitored for one year post-treatment. The study is led by principal investigator Stephen Nicholls, MBBS, Ph.D., director of the Victorian Heart Institute at Monash University.
Disease biology and the PCSK9 rationale
PCSK9 functions as a negative regulator of the LDL receptor on hepatocytes. By binding to the receptor on the cell surface and directing it toward lysosomal degradation, PCSK9 reduces the number of LDL receptors available to clear circulating LDL-C. Suppressing PCSK9 expression reverses this process, increasing receptor recycling and enhancing LDL-C clearance from the bloodstream.
The target's clinical validity rests on unusually strong human genetic evidence. Naturally occurring loss-of-function variants in PCSK9 are associated with lifelong low LDL-C and, in one landmark study, up to an 88% reduction in coronary heart disease risk — with no identified adverse health consequences. This effectively constitutes a decades-long human experiment demonstrating that sustained PCSK9 suppression is both safe and cardioprotective.
Despite the availability of statins, ezetimibe, PCSK9 monoclonal antibodies, and inclisiran (Leqvio, Novartis), a substantial proportion of high-risk patients remain above guideline-recommended LDL-C targets in real-world practice. The core problem is not efficacy but durability and adherence. PCSK9 monoclonal antibodies such as evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi/Regeneron) require subcutaneous injection every two to four weeks indefinitely. Inclisiran, an siRNA that silences PCSK9 mRNA, requires twice-yearly dosing. None of these approaches offer sustained disease control from a single administration, and real-world adherence to chronic injectable regimens remains poor.
The recently approved lerodalcibep (Lerochol, LIB Therapeutics), a once-monthly adnectin-based PCSK9 inhibitor approved by the US FDA in December 2025, and Merck's enlicitide decanoate (MK-0616), an oral macrocyclic peptide currently in Phase III development, represent incremental improvements in convenience but do not resolve the fundamental durability gap.
STX-1150 uses Scribe's ELXR (Epigenetic Long-Term X-Repressor) platform — a nuclease-inactivated, CasX-derived CRISPR protein fused to epigenetic effector domains — to install histone and DNA methylation marks at the PCSK9 gene promoter in hepatocytes. The result is transcriptional silencing without cutting or permanently altering the DNA sequence. Delivered via a liver-tropic lipid nanoparticle carrying an mRNA encoding the ELXR protein and a single guide RNA targeting PCSK9, the therapy is designed to achieve sustained LDL-C reduction following a single dose.