XtalPi Nominates Its First siRNA Preclinical Candidate for IgA Nephropathy Nine Months After Program Initiation

• Preclinical data demonstrate subnanomolar silencing potency, achieving an IC50 tens of times lower than the corresponding values for two clinical-stage reference molecules targeting the same target.
• In non-human primates, a single dose maintained robust target-protein suppression for months, demonstrating a durable pharmacodynamic effect and supporting the potential for extended dosing intervals.
• Using Kodexia™ platform, XtalPi applied generative AI to identify a previously unexplored active target region, jointly optimize the siRNA sequence and chemical modifications, and address freedom-to-operate considerations early in design.

CAMBRIDGE, Mass. and BEIJING, Oct. 15, 2026 /PRNewswire/ -- XtalPi Holdings Limited ("XtalPi," HKEX: 2228), an AI- and robotics-driven drug and materials discovery company, today announced the nomination of its first internally developed small interfering RNA (siRNA) preclinical candidate (PCC) for the treatment of immunoglobulin A nephropathy (IgAN). XtalPi completed the program in nine months using Kodexia™, its proprietary siRNA discovery and development platform, which is the world's first to integrate generative AI and first-principles modeling in a closed loop of computational design, experimental validation, and iterative learning. This milestone demonstrates XtalPi's end-to-end ability to advance AI-guided molecular designs from target-region discovery through PCC nomination, converting its platform capabilities into a proprietary RNA therapeutic asset.

IgAN is one of the world's most common primary glomerular diseases, affecting an estimated 10 million people globally. Driven by the deposition of immune complexes that inflame the kidney's filtering structures, the condition can lead to progressive renal decline and kidney failure. Current care increasingly combines kidney-protective therapy with disease-directed treatments, often over extended periods. Durable disease control, preservation of kidney function, long-term safety, and a manageable treatment burden therefore remain important development goals.

By using the cell's natural RNA interference machinery, siRNA therapeutics can degrade specific messenger RNA (mRNA) to reduce the production of a disease-associated protein. Appropriate chemical modifications can enhance siRNA stability and extend its duration of action, creating the potential for less frequent dosing.

Developing a novel siRNA for this specific IgAN target presented a highly constrained engineering challenge. The target mRNA offered limited viable sequence options, while competing clinical programs and an established patent landscape further narrowed the viable design space. Kodexia™ addressed these constraints by identifying a previously unexplored active target region and jointly engineering the siRNA sequence with sequence-specific chemical modifications. Iterative wet-lab evaluation of the initial AI-generated molecules ultimately produced a candidate distinguished primarily by its potency, durability, and safety profile, while preserving freedom to operate within the scope of the current intellectual property assessment.

In vitro, the resulting candidate achieved subnanomolar silencing potency. Its half-maximal inhibitory concentration (IC50) was tens of times lower than the two clinical-stage reference molecules under corresponding assay conditions, indicating that substantially lower concentrations were required to reach the assay's half-maximal inhibitory response.

In head-to-head non-human primate (NHP) studies, a single dose sustained high-level target-protein suppression over a multi-month observation period, demonstrating greater activity and durability than the reference molecules. Toxicology studies also indicated a broad safety window. Together, the candidate's potency, durability, and safety profile support its best-in-class potential.

This rapid nine-month discovery cycle was executed through Kodexia's closed-loop architecture, which integrates generative AI, first-principles modeling, and automated experimentation. Rather than applying a fixed modification template after sequence selection, Kodexia™ jointly optimizes sequence and chemistry against potency, durability, off-target activity, and safety. This multi-parameter approach has increased molecular design efficiency nearly threefold compared with conventional workflows. More than 50% of the platform's first-round designs tested across multiple programs have demonstrated stronger in vivo activity than their respective positive controls.

XtalPi integrates high-throughput experimentation and robotics into a continuous design–test–learn cycle, enabling hundreds of in vitro experiments and dozens of in vivo experiments each week. The resulting data are fed back into the models to guide successive rounds of molecular optimization. In the IgAN program, the model's predicted activity ranking across the candidate set was confirmed in vivo, demonstrating Kodexia™'s ability to guide candidate selection and direct development resources toward the highest-performing designs.

Moving forward, XtalPi is applying these capabilities to more complex design challenges, including the co-optimization of single-molecule, dual-target siRNAs, and exploring novel conjugate strategies to deliver siRNA therapeutics beyond the liver.

By nominating its first siRNA PCC within nine months, XtalPi has successfully leveraged Kodexia™ to build a proprietary therapeutic pipeline. The Company will continue advancing the IgAN candidate toward clinical development and looks forward to collaborating with global partners to engineer next-generation RNA interference therapies across high-value disease targets.

About XtalPi

XtalPi Holdings Limited (XtalPi, 2228.HK) was founded in 2015 by three physicists from the Massachusetts Institute of Technology (MIT). It is an innovative R&D platform powered by quantum physics, artificial intelligence, and robotics. By integrating first-principles calculations, AI algorithms, high-performance cloud computing, and standardized automation systems, XtalPi provides digital and intelligent R&D solutions for companies in the pharmaceutical, materials science, agricultural technology, energy, new chemicals, and cosmetics industries.

SOURCE XtalPi Inc.