aTyr Pharma has announced a significant scientific validation of its lead therapeutic candidate efzofitimod in a peer-reviewed publication in Science Translational Medicine. The publication details the drug's unique mechanism of action in reducing inflammation and fibrosis through targeting the neuropilin-2 (NRP2) receptor.
The article, titled "A human histidyl-tRNA synthetase splice variant therapeutic targets NRP2 to resolve lung inflammation and fibrosis," presents comprehensive preclinical data supporting efzofitimod's development from concept to clinic.
Novel Mechanism of Action Revealed
Efzofitimod represents a first-in-class immunomodulator derived from a splice variant of histidyl-tRNA synthetase (HARS). According to the publication, this protein is naturally enriched in human lung tissue and upregulated by inflammatory cytokines in both lung and immune cells.
The research demonstrates that efzofitimod binds specifically and selectively to neuropilin-2 (NRP2), a cellular receptor highly expressed by myeloid cells at active inflammation sites. Through this interaction, the drug inhibits the expression of pro-inflammatory receptors and cytokines, effectively downregulating inflammatory pathways in macrophages.
"This peer-reviewed publication in a highly regarded journal such as Science Translational Medicine validates the immunomodulatory activity and extracellularly mediated mechanism of efzofitimod in reducing inflammation and fibrosis," said Leslie A. Nangle, Ph.D., Vice President of Research at aTyr.
Implications for Interstitial Lung Disease Treatment
The publication provides strong scientific rationale for efzofitimod's ongoing clinical development program in interstitial lung disease (ILD), particularly in targeting these conditions during their inflammatory stages.
Sanjay S. Shukla, M.D., M.S., President and Chief Executive Officer of aTyr, emphasized the significance of this research: "This scientific work along with the compelling clinical proof-of-concept generated for efzofitimod in pulmonary sarcoidosis supports the ongoing clinical development program in interstitial lung disease."
The mechanism identified could potentially disrupt the cycle of chronic inflammation and fibrosis that characterizes many forms of ILD, offering a new therapeutic approach for conditions with limited treatment options.
Current Clinical Development Status
Efzofitimod is currently being investigated in two major clinical trials:
- The global pivotal Phase 3 EFZO-FIT™ study in pulmonary sarcoidosis, a major form of ILD
- The Phase 2 EFZO-CONNECT™ study in systemic sclerosis (SSc, or scleroderma-related ILD)
The drug has received orphan drug designation in the U.S., E.U., and Japan for sarcoidosis, as well as Fast Track designation in the U.S. for pulmonary sarcoidosis. Additionally, it has secured orphan drug designation in the U.S. and E.U. for SSc and Fast Track designation in the U.S. for SSc-ILD.
Broader Implications for tRNA Synthetase Platform
Beyond efzofitimod's specific applications, this validation strengthens the potential of aTyr's proprietary tRNA synthetase platform. The company focuses on unlocking therapeutic intervention points by uncovering signaling pathways driven by domains derived from all 20 tRNA synthetases.
"This validation considerably expands the basis for the application of efzofitimod in chronic inflammatory conditions, as well as encourages the potential development of other tRNA synthetase-based therapeutics for disease intervention," noted Dr. Nangle.
For patients with ILD, who currently face limited therapeutic options, efzofitimod represents a potential disease-modifying treatment that could improve outcomes without the broad immunosuppression associated with current therapies.
The publication marks a significant milestone in aTyr's drug development program and provides strong scientific support for the continued clinical investigation of efzofitimod in inflammatory and fibrotic lung conditions.
