YolTech Releases Initial Data on YOLT-101 Trial for Familial Hypercholesterolemia Therapy

In a significant development, YolTech Therapeutics Co., Ltd, a company at the forefront of gene editing, has unveiled promising interim clinical results for its novel therapy, YOLT-101, intended to treat heterozygous familial hypercholesterolemia (HeFH). The data, now accessible on medRxiv, suggests that a single administration of YOLT-101 can effectively and safely lower low-density lipoprotein cholesterol (LDL-C) levels in patients. This innovative treatment marks a departure from conventional lipid-lowering methods, which typically require continuous medication or frequent injections, introducing a potential "one-time treatment for lifelong LDL-C reduction."

YOLT-101 is a groundbreaking in vivo base-editing therapeutic created independently by YolTech. This therapy incorporates YolBE, a unique adenine base editor, specifically the hpABE5 version, which consists of nCas9 and a deaminase discovered from Hafnia paralvei. The therapy utilizes a new lipid nanoparticle (LNP) formulation for delivery. Unlike conventional CRISPR/Cas9 techniques that involve DNA double-strand breaks, hpABE5 enables precise single-base modifications without these breaks, significantly decreasing the likelihood of chromosomal abnormalities and off-target effects. Comprehensive preclinical studies have highlighted the therapy's robust safety profile in genome editing.

The therapy is administered via intravenous infusion and is selectively absorbed by hepatocytes, where it induces precise changes in the PCSK9 gene. This targeted gene editing disrupts the production of the PCSK9 protein, enhancing the uptake of LDL-C by LDL receptors on liver cells, thus achieving a significant reduction in plasma LDL-C levels.

The ongoing open-label clinical trial involves patients with HeFH, aiming to evaluate the safety and tolerability of YOLT-101, alongside its preliminary efficacy and pharmacodynamics. As of mid-March 2025, six subjects were involved in the study, across three dose cohorts of 0.2 mg/kg, 0.4 mg/kg, and 0.6 mg/kg. All participants have completed at least 24 weeks of safety monitoring, with some reaching 36 weeks.

YOLT-101 has showcased good safety and tolerability, with no serious adverse events or dose-limiting toxicities reported. The most frequent treatment-related side effect was temporary infusion-related reactions, primarily fever, which resolved within a day. Mild liver enzyme elevations were noted in half of the subjects but improved within a week. These patients exhibited no symptoms, and their bilirubin levels remained normal.

In terms of efficacy, LDL-C levels showed a dose-dependent decrease after treatment. Subjects in the 0.4 mg/kg and 0.6 mg/kg groups experienced sustained LDL-C reductions, starting as early as one week post-administration and reaching maximum effect by week four. The 0.6 mg/kg cohort saw an average LDL-C reduction of about 50% compared to baseline levels, with effects lasting over six months after a single dose. Pharmacodynamic data showed PCSK9 protein levels dropped by over 70% from baseline levels by week four in the 0.6 mg/kg group.

These findings underscore YOLT-101's potential as a transformative therapy for HeFH patients, offering a durable, single-dose solution that could redefine treatment protocols. YolTech Therapeutics remains focused on revolutionizing cardiovascular disease treatment with its advanced base editing technology, aiming to alleviate the lifelong burden of high LDL-C levels in HeFH patients. Future larger-scale clinical trials will be crucial to further validate these promising outcomes and extend benefits to a broader patient population.