XTALPI (02228) announced today that PEP08, a next-generation PRMT5 inhibitor discovered with its assistance for PharmaEngine, Inc., has achieved a significant clinical development milestone. PEP08 recently received clinical trial approvals from Australia's Human Research Ethics Committee (HREC), Australia's Therapeutic Goods Administration (TGA), and Taiwan's Food and Drug Administration (TFDA), marking the imminent launch of Phase I clinical trials. Based on this progress, XTALPI confirmed receipt of milestone payment for this project.
PRMT5 (Protein Arginine Methyltransferase 5) is a key enzyme overexpressed in multiple cancers that promotes tumor growth, and represents a popular synthetic lethality target in cancer therapy. In tumors with homozygous MTAP (Methylthioadenosine Phosphorylase) deletion (approximately 10-15% of human cancers), inhibiting PRMT5 activity can produce a "synthetic lethality" effect, potentially achieving highly effective and safe targeted cancer treatment. These 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. However, traditional PRMT5 inhibitors often suffer from toxicity issues due to poor selectivity, representing a significant unmet clinical need.
Following project initiation, XTALPI leveraged its intelligent drug discovery platform that integrates physical models, AI algorithms, and robotic experiments, combined with PharmaEngine's expert experience, to rapidly conduct rational drug design. XTALPI generated a million-scale molecular library for this project and precisely screened a batch of lead compounds with outstanding drug activity and selectivity, featuring 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 completed preclinical development by PharmaEngine.
As a second-generation PRMT5 inhibitor, PEP08 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 PRMT5 inhibition that specifically kills MTAP-deficient tumor cells while minimizing impact on normal cells, demonstrating tremendous clinical development potential.
Preclinical research data indicate that compared to first-generation non-selective PRMT5 inhibitors, PEP08 shows significant advantages in toxicity and safety, possessing good blood-brain barrier penetration capability and ideal comprehensive drug-like properties. At lower doses across multiple animal efficacy models, PEP08 demonstrated powerful in vivo therapeutic effects. Compared to other second-generation PRMT5 inhibitors currently in clinical development, PEP08's comprehensive pharmaceutical properties show potential best-in-class effects and broad potential for combination with other therapies.
Related research findings have been presented by PharmaEngine at the 2025 American Association for Cancer Research (AACR) Annual Meeting.
PEP08's successful receipt of clinical trial permits from regulatory authorities in both regions and achievement of milestone payment represents an important staged accomplishment in the collaboration between XTALPI and PharmaEngine, once again validating XTALPI's platform capability to efficiently enable drug innovation delivery. XTALPI will continue supporting its partners to bring high-quality and effective treatment options to more patients.