XtalPi Achieves Clinical Milestone as PharmaEngine's Novel Synthetic Lethality Drug PEP08 Receives Phase I Trial Approvals

XtalPi (2228.HK) announced today that the new generation PRMT5 inhibitor PEP08, which it assisted PharmaEngine Inc. in discovering, has reached a significant clinical development milestone. PEP08 was recently approved by the Australian Human Research Ethics Committee (HREC),Australian Therapeutic Goods Administration (TGA)and Taiwan, China “Approval from the "Taiwan Food and Drug Administration (TFDA)" for the Phase I clinical trial of solid tumors. XtalPi confirms receipt of the milestone payment for this project.

PRMT5 (Protein Arginine Methyltransferase 5) is a key enzyme that is overexpressed in various cancers and promotes tumor growth, and it is also a popular synthetic lethal target in cancer. In MTAP (Methionyl-tRNA synthetase) Homozygous deletion of tumors (accounting for approximately 10-15% of human cancers), inhibition of PRMT5 activity can produce a "synthetic lethal" effect, which is expected to achieve efficient and safe targeted cancer therapy. Such tumors are commonly found in non-small cell lung cancer (NSCLC), mesothelioma, pancreatic cancer,Glioblastoma (GBM), head and neck cancer, esophageal cancer, and bladder cancer, among others. However, traditional PRMT5 inhibitors often lead to toxicity issues due to poor selectivity, representing a significant unmet clinical need.

After the project was launched, XtalPi, with its intelligent drug discovery platform that integrates physical models, AI algorithms, and robotic experiments, combined with the expert experience of the PharmaEngine team, quickly initiated rational drug design. XtalPi generated a molecular library of millions for this project and precisely screened out a group of lead compounds with outstanding drug activity and selectivity as well as novel molecular scaffolds. After multiple rounds of ADMET property evaluation and iterative optimization combining physical and AI models, PEP08 was ultimately identified as the preclinical candidate compound (PCC) and the preclinical development was completed by PharmaEngine.

PEP08, as a second-generation PRMT5 inhibitor, features a novel structure with high activity and selectivity. It can bind to PRMT5 through an MTA cooperative binding mode, forming a stable ternary complex, thereby achieving highly selective inhibition of PRMT5. It specifically targets and kills MTAP-deficient tumor cells while minimizing the impact on normal cells, demonstrating significant potential for clinical development.

Preclinical study data show that, compared with first-generation non-selective PRMT5 inhibitors, PEP08 demonstrates significant advantages in toxicity and safety, with excellent blood-brain barrier penetration and ideal overall drug-like properties. In multiple animalEfficacyIn the model, PEP08 demonstrated robust in vivo efficacy. Compared with other second-generation PRMT5 inhibitors currently in clinical development, PEP08’s comprehensive pharmaceutical properties exhibit potential best-in-class effects and broad potential for combination with other therapies. The related成果 poster was presented by PharmaEngine Inc. at the 2025 American Association for Cancer Research (AACR) Annual Meeting.

PEP08 Successfully Obtains Clinical Trial Approval from Regulatory Authorities in Two Regions and Achieves Milestone Payment, Marking an Important Phase Achievement in the Collaboration between XtalPi and PharmaEngine Inc.Once again, XtalPi's platform has demonstrated its efficient capability to empower and deliver drug innovation.XtalPi will continue to leverage its AI + robotics drug discovery platform to help more partners accelerate the discovery of innovative drugs with market potential and differentiated competitiveness, bringing more patients high-quality and efficient treatment options.

● AboutPharmaEngine Inc. ● 

PharmaEngine Inc. began operations in February 2003. The concept behind PharmaEngine’s establishment was to focus on new drug development through international strategic alliances using the "Virtual Pharmaceutical Company Business Model" to reduce the risks associated with new drug development. PharmaEngine's marketed anticancer drug, ONIVYDE®, has been launched in multiple countries and regions including the United States, Europe, South Korea, Singapore, Japan, and China. Among the company’s pipeline drugs, one project, PEP07, is a cell damage regulatory enzyme inhibitor currently undergoing Phase I clinical trials. Another project, PEP08, is an MTA-Cooperative PRMT5 inhibitor, which is also about to enter Phase I clinical trials. Additionally, through international collaboration or licensing agreements, PharmaEngine is advancing several early-stage drug development projects. Leveraging its extensive experience in project management, the company aims to expand its R&D pipeline and accelerate the timelines for drug development and commercialization.