aTyr Pharma (NASDAQ:ATYR) CEO Sanjay Shukla outlined the company’s strategy to develop new therapies for inflammation and fibrosis based on tRNA synthetase biology during a presentation at the Leerink Partners Global Healthcare Conference. Shukla focused primarily on efzofitimod, the company’s lead program, including results from a global Phase 3 study in pulmonary sarcoidosis and the upcoming U.S. FDA Type C meeting planned for mid-April.
Platform approach: tRNA synthetase fragments and immune modulation
Shukla said aTyr is translating biology related to tRNA synthetases—enzymes historically known for their role in attaching amino acids to tRNA—into a “new class of medicines.” He said the company’s research has identified that these enzymes can break into fragments that interact with the immune system, creating an opportunity to develop therapies that modulate inflammation and fibrosis.
Efzofitimod mechanism and target indications
Efzofitimod, a tRNA synthetase fragment-based therapy, is being advanced for ILD, with an emphasis on inflammatory phenotypes. Shukla described ILDs as chronic inflammatory diseases that can progress to fibrosis, worsen lung function, and significantly impair quality of life. He also noted that some fibrotic lung diseases have survival rates worse than many common cancers and said existing therapies are often “toxic, not disease modifying or both.”
According to Shukla, efzofitimod is designed to modulate innate immunity at the site of inflammation, primarily by interacting with myeloid cells such as macrophages. He said the drug works upstream through the Neuropilin-2 receptor on macrophages, nudging these cells toward a “less inflammatory phenotype” and downregulating pro-inflammatory and pro-fibrotic signals. He emphasized that the company views the mechanism as restorative and not associated with overt immunosuppression.
Shukla also referenced a publication in Science Translational Medicine that he described as a landmark paper on the mechanism of action.
Phase 3 EFZO-FIT in pulmonary sarcoidosis: topline results and learnings
Shukla reviewed topline data presented in September in Amsterdam from EFZO-FIT, a global Phase 3 trial in pulmonary sarcoidosis conducted at about 90 centers across nine countries. The study compared efzofitimod at 5 mg/kg and 3 mg/kg versus placebo, enrolling 268 patients with a target of about 88 per arm. Patients entered the trial on a stable prednisone regimen (7.5 mg to 25 mg), and the protocol included a rigorous, every-two-week steroid taper based on patient global assessment.
He said discontinuations were low across arms, supporting statistical power. He also highlighted that baseline characteristics were largely balanced, and he pointed to the inclusion of Black patients as evidence that sarcoidosis trials can enroll diverse populations. Participants had longstanding disease (roughly 7–9 years duration on average), and about one-third had extrapulmonary involvement. Average steroid dose at baseline was around 10 mg, he said.
The primary endpoint was steroid reduction. Shukla said efzofitimod showed nearly 80% reductions in steroid use, but the trial did not meet the primary endpoint because placebo patients reduced steroids more than expected, resulting in overlapping curves. He said the company “just missed the p-value by a couple patients,” attributing the outcome to a roughly 40% placebo steroid withdrawal rate that exceeded assumptions used in trial planning.
Despite the primary endpoint miss, Shukla argued the study generated learnings that could affect clinical practice, including how aggressively patients may be tapered off steroids. He relayed an anecdote from a pulmonologist who said she began taking about 40% of her patients off steroids after returning from the European Respiratory Society meeting.
Secondary and composite endpoints: quality of life signal highlighted
Shukla emphasized what he characterized as clear drug activity on quality of life measures. He highlighted results on the King’s Sarcoidosis Questionnaire (KSQ) lung domain, describing a statistically significant improvement for the 5 mg/kg group that emerged around week eight and was maintained across time points. He said other pre-specified measures, including Fatigue Assessment Score (FAS) and KSQ general health, showed consistent and durable benefits, particularly at the higher dose.
He also pointed to pre-specified composite analyses combining steroid withdrawal with symptom improvement. Specifically, he highlighted a composite of being steroid-free and achieving more than an eight-point improvement in KSQ lung, which he said showed a statistically significant result and dose response. Shukla said patients on 5 mg/kg were “more than 2.5x more likely” to be steroid-free and significantly improved versus placebo.
On lung function, Shukla discussed forced vital capacity (FVC), noting that in an aggressive steroid taper setting the expectation would typically be for FVC to decline as prednisone is withdrawn. He said large declines were not observed and characterized the data as suggesting nominal declines with efzofitimod, while placebo showed about a 2%–3% decline. He also said sarcoidosis includes heterogeneous phenotypes and suggested that a more restrictive population might show greater benefit—an area he said is part of discussions with regulators.
Regarding safety, Shukla described efzofitimod as well tolerated, with low serious adverse events and few adverse events leading to discontinuation over one year, and no apparent dose-related safety signal. He also discussed anti-drug antibodies, stating the company did not observe concerning “treatment-boosted” effects.
Regulatory path: FDA Type C meeting in mid-April and potential next trial
Shukla said aTyr has an FDA Type C meeting scheduled for mid-April to review EFZO-FIT results and determine the path forward in sarcoidosis. In Q&A, he said the company believes the program is viable, citing pre-specified analyses showing activity, including steroid weaning alongside improved patient-reported outcomes and preserved lung function. However, he also said filing based on the existing dataset would be “very challenging” because the primary endpoint was not met.
Shukla said the company is preparing for the possibility that FDA may request another study and indicated that any future late-stage trial could emphasize quality of life and potentially pulmonary function, with careful selection of endpoints by patient phenotype (e.g., FEV1, FVC, DLCO). He said the company has built a large natural history database in sarcoidosis and has not presented post-hoc analyses publicly.
On communications, Shukla said the company expects to wait for written FDA correspondence before updating investors, citing the current environment at the agency. He suggested feedback typically arrives about four weeks after the meeting, while noting conditions may not be typical.
Other pipeline updates and financial position
Beyond efzofitimod, Shukla highlighted ATYR0101, another tRNA synthetase fragment that he said modulates myofibroblasts and could have utility in fibrosis. He said he anticipates that program could enter the clinic next year and described it as potentially “a true anti-fibrotic.”
Shukla also provided an update on the ongoing Phase 2 EFZO-CONNECT study in scleroderma-related ILD. He said the company expects to complete enrollment in the first half of the year and expects data roughly six to seven months later. Later in the presentation, he described the scleroderma-ILD trial as a six-month study evaluating fixed doses intended to approximate the weight-based Phase 3 sarcoidosis dosing. He said an interim finding based on early unblinding suggested three of four patients with diffuse skin disease had responded at three months, and he noted that he believes no drug has previously improved skin symptoms in scleroderma. He said enrollment was expected to finish in the first half of 2026, with results anticipated toward the end of the year.
Shukla said the company reported just over $80 million in cash as of year-end and described aTyr as being in a strong position to complete ongoing work and prepare for the upcoming FDA interaction.
About aTyr Pharma (NASDAQ:ATYR)
aTyr Pharma, Inc is a clinical-stage biotechnology company focused on the discovery and development of novel protein-based therapies that modulate the extracellular matrix and immune pathways. Headquartered in San Diego, California, the company applies its proprietary Extracellular Modulation® platform to identify and optimize biologic candidates for the treatment of rare and serious diseases, including pulmonary sarcoidosis, muscular dystrophy, and solid tumors.
The company’s research efforts are centered on harnessing extracellular proteins to regulate tissue remodeling, cell adhesion, and immune signaling.
