YolTech Completes Dose Escalation in Phase I Trial of YOLT-201 for ATTR

YolTech Therapeutics has released new information regarding their ongoing clinical trial for YOLT-201, an innovative CRISPR/Cas9-based gene-editing therapy aimed at treating ATTR amyloidosis. This trial, which is in its Phase I/IIa stage, has successfully completed dosing in eight participants. These participants include six individuals with ATTR amyloidosis with polyneuropathy (ATTR-PN) and two with ATTR amyloidosis with cardiomyopathy (ATTR-CM). The study was conducted across two distinct dosing cohorts. Importantly, the trial has reported no instances of Grade 3 adverse events, dose-limiting toxicities, or serious adverse events that necessitated the discontinuation of treatment.

Participants with ATTR-PN have completed both the dosing phase and follow-up sessions. Initial findings reveal that those in the higher dosage group experienced a significant reduction—over 90%—in circulating transthyretin (TTR) protein levels. The therapy has shown a strong safety profile and tolerability among participants.

During a Safety Review Committee (SRC) meeting, investigators and the study sponsor concluded that the higher dose constitutes the optimal biologically active dose (OBD) based on current safety and efficacy data. Consequently, the SRC has decided to move forward from the dose-escalation phase for ATTR-PN patients and proceed to the dose-expansion phase. This next phase aims to further explore the therapeutic potential of YOLT-201 in a larger patient cohort.

The YT-YOLT-201-101 study is a multicenter, open-label, single-dose Phase I/IIa clinical trial. The study's objectives are to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic parameters of YOLT-201 in patients suffering from transthyretin amyloidosis polyneuropathy (ATTR-PN) and transthyretin amyloidosis cardiomyopathy (ATTR-CM). The trial consists of two stages: the initial open-label, single-dose, dose-escalation study that identifies the OBD of YOLT-201, followed by a single-dose, dose-expansion study that aims to assess the safety and preliminary efficacy of YOLT-201 at the OBD.

YOLT-201 is an innovative injection that employs lipid nanoparticles (LNP) to encapsulate messenger RNA (mRNA) and single-guide RNA (sgRNA) materials. These nanoparticles are introduced into the body via intravenous injection. Plasma ApoE protein attaches to the LNP particles' surface, allowing liver cells with LDLR receptors to recognize and internalize the LNP through endocytosis. Within endosomes, a decrease in pH fosters electrostatic interactions between ionizable lipids and endosomal membranes, leading to membrane disruption and the release of mRNA and sgRNA. In the cytoplasm, mRNA binds to ribosomes, facilitating the translation of the editor protein. This protein, together with sgRNA, enters the cell nucleus. The sgRNA directs the editor to the TTR gene sequence where the editor protein modifies the target TTR gene, halting its normal transcription into mRNA. This process effectively stops the production of the TTR protein, aiming for a one-time comprehensive cure of ATTR diseases.

YolTech Therapeutics is a leader in gene editing, dedicated to developing transformative gene-editing medicines for serious diseases. The company has established a cutting-edge high-throughput evolution platform and an innovative LNP delivery system. It boasts exceptional capabilities in discovering novel Cas and base editors, along with a strong in-house LNP production capacity for GMP manufacturing, protected by global intellectual property rights and core patents. YolTech's pipeline includes over 10 genetic medicines targeting cardiovascular, metabolic, and infectious diseases, as well as more common and rare conditions. The company has received clinical trial clearance for its leading asset.