YolTech Therapeutics Announces Promising Interim Data for Novel In Vivo Base Editing Therapy YOLT-101 in Heterozygous Familial Hypercholesterolemia (HeFH)

SHANGHAI, April 28, 2025 /PRNewswire/ — YolTech Therapeutics Co.,Ltd, a clinical-stage in vivo gene editing company focused on pioneering precision genetic medicines, today announced encouraging interim clinical data from an investigator-initiated trial (IIT) of YOLT-101 (NCT06458010), with the data now available on medRxiv. YOLT-101 is an investigational in vivo base editing therapy for heterozygous familial hypercholesterolemia (HeFH). Clinical data demonstrate that a single administration of YOLT-101 can safely and effectively reduce low-density lipoprotein cholesterol (LDL-C) levels in HeFH patients. As a next-generation gene-editing therapy, YOLT-101 represents a potential breakthrough in lipid-lowering treatment, moving beyond daily pills and regular injections towards a “one-time treatment for lifelong LDL-C reduction.”

YOLT-101, independently developed by YolTech, is a next-generation in vivo base-editing therapeutic. It utilizes YolBE—a novel, proprietary adenine base editor specifically hpABE5—comprising nCas9 and a newly discovered deaminase from Hafnia paralvei. Delivery is achieved using a novel lipid nanoparticle (LNP) formulation. Unlike traditional CRISPR/Cas9 systems that induce DNA double-strand breaks (DSBs), hpABE5 enables precise single-base editing without DSBs, significantly reducing the risks of chromosomal abnormalities and off-target effects. Extensive preclinical studies have confirmed its excellent genome editing safety profile.

Administered via intravenous infusion, this in vivo base-editing therapy selectively targets hepatocytes, inducing a precise nucleotide conversion within the PCSK9 gene. This targeted edit disrupts PCSK9 protein expression, leading to increased uptake of LDL-C by LDL receptors on hepatocyte surfaces and a subsequent marked reduction in plasma LDL-C levels.

Study Design of the IIT

This open-label clinical trial is evaluating patients with HeFH. The primary objective is to assess the safety and tolerability of YOLT-101, with secondary objectives including preliminary efficacy and pharmacodynamic evaluation. As of March 15, 2025, six subjects have been enrolled: one in the 0.2 mg/kg cohort, two in the 0.4 mg/kg cohort, and three in the 0.6 mg/kg cohort. All subjects have completed at least 24 weeks of safety follow-up, with the longest reaching 36 weeks.

Safety and Tolerability

YOLT-101 has demonstrated good safety and tolerability. As of March 15, 2025, no serious adverse events (SAEs), dose-limiting toxicity (DLT) events, or Grade ≥3 adverse events (CTCAE v5.0) were observed across any dose group. All enrolled subjects are continuing with scheduled follow-up.

The most common treatment-related adverse event was transient infusion-related reactions (5/6, 83.3%), primarily manifesting as fever that resolved within 24 hours. Mild elevations in liver enzymes (3/6, 50.0%) were reported, appearing on Days 4-7 post-administration and typically resolving within 7 days. These patients remained asymptomatic, and their plasma bilirubin levels (key indicators of liver function) remained within normal limits throughout the study. No clinically significant changes were observed in other laboratory parameters.

Efficacy and Pharmacodynamics

LDL-C levels showed a dose-dependent reduction following YOLT-101 administration. Baseline LDL-C was 4.9 ± 0.6 mmol/L. In the 0.4 mg/kg and 0.6 mg/kg cohorts, sustained LDL-C reductions were observed as early as Week 1, reaching maximal effect by Week 4. In the 0.6 mg/kg group, mean LDL-C levels decreased by approximately 50% through the last follow-up with available data compared to baseline. The subject with the greatest response experienced an LDL-C level of approximately 1 mmol/L (maximal percent change from baseline over 74%), with efficacy sustained for over 6 months post-single dose. Pharmacodynamic data showed consistent trends, with plasma PCSK9 protein levels decreasing by over 70% from baseline starting at Week 4 in the 0.6 mg/kg group (maximal individual reduction reached 87%).

Notably, all enrolled subjects in this study were HeFH patients, a population where PCSK9-targeting therapies typically exhibit reduced efficacy compared to the general hypercholesterolemic population. This suggests YOLT-101 may demonstrate even greater lipid-lowering potential in the broader hypercholesterolemic population.

In summary, YOLT-101 demonstrates favorable safety and tolerability in HeFH patients, with mild and transient adverse events. Pharmacodynamic (PCSK9) and efficacy (LDL-C) outcomes in the 0.4 mg/kg and 0.6 mg/kg groups showed durable, dose-dependent reductions, supporting the potential of YOLT-101 to achieve “single-dose, lifelong lipid lowering.”

“We are committed to revolutionizing cardiovascular disease treatment through next-generation base editing technology and groundbreaking single-dose therapies,” said Dr. Yuxuan Wu, co-founder and CEO of YolTech Therapeutics. “Patients with heterozygous familial hypercholesterolemia (HeFH) face a lifelong, genetically driven impairment in LDL-C metabolism, leading to markedly elevated LDL-C levels from birth and a significantly increased risk of premature atherosclerotic cardiovascular diseases. Current lipid-lowering therapies require long-term, continuous administration, and LDL-C levels rebound upon discontinuation. Poor patient adherence and drug intolerance are common challenges, highlighting a critical unmet need for more durable, patient-friendly solutions. The current clinical data for YOLT-101 demonstrates that a single administration can lead to significant and durable reductions in LDL-C levels. By precisely editing key genes regulating LDL-C levels in the liver, YOLT-101 has the potential to be a transformative ‘one-time treatment, lifelong cure’ therapy. We look forward to further confirming its safety and efficacy in larger-scale clinical studies and bringing these benefits to patients worldwide.”

About Familial Hypercholesterolemia (FH)

Familial hypercholesterolemia (FH) is caused by mutations in LDL metabolism-related genes (LDLR, APOB, PCSK9). As a result, patients with FH have markedly elevated low-density lipoprotein cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease (ASCVD). The global prevalence of FH is 1:200-1:250, affecting approximately 34 million people worldwide.

Current FH management strategies include lifestyle modifications, lipid-lowering medications, lipoprotein apheresis, and liver transplantation. The standard of treatment involves pharmacotherapy, with many patients receiving a triple regimen of statins, ezetimibe, and PCSK9 inhibitors. However, current therapies have significant limitations, including suboptimal efficacy, intolerable side effects, and poor long-term adherence. These challenges underscore the urgent need for novel, durable therapies to address the lifelong treatment burden of FH.