Recently, aTyr Pharma announced top-line results from its Phase III EFZO-FIT™ trial evaluating Efzofitimod for the treatment of pulmonary sarcoidosis. The trial results showed that Efzofitimod failed to significantly reduce the mean daily oral corticosteroid (OCS) dose compared to placebo in pulmonary sarcoidosis patients, missing the primary endpoint. Following this announcement, aTyr's stock price plummeted 83%. Based on these results, aTyr plans to engage with the FDA to discuss the future development pathway for Efzofitimod in pulmonary sarcoidosis.
**tRNA Synthetase Therapy**
Efzofitimod is a tRNA synthetase therapy consisting of an immunomodulatory fragment of histidyl-tRNA synthetase (HARS) fused to an Fc domain. It is designed to modulate activated myeloid cells by selectively targeting neuropilin-2, thereby reducing chronic inflammation without causing immunosuppression.
In January 2020, aTyr Pharma entered into a collaboration agreement with Kyorin Pharmaceutical for the development and commercialization of Efzofitimod in Japan. Under the agreement, aTyr is eligible to receive up to $175 million in total payments, including an $8 million upfront payment and $167 million in milestone payments.
In July 2025, Efzofitimod received Breakthrough Therapy Designation (BTD) from the FDA for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD).
**Excessive Placebo Response?**
EFZO-FIT™ was a global, placebo-controlled interventional Phase III clinical trial that enrolled 268 pulmonary sarcoidosis patients. The trial evaluated the safety and efficacy of Efzofitimod at doses of 3.0 mg/kg and 5.0 mg/kg compared to placebo over 48 weeks in patients with pulmonary sarcoidosis. The primary endpoint was the change in mean daily oral corticosteroid (OCS) dose from baseline at week 48.
**Trial Results:**
Primary Endpoint: The 5.0 mg/kg Efzofitimod dose group reduced the mean daily OCS dose in pulmonary sarcoidosis patients to 2.79 mg, while the placebo group achieved 3.52 mg. The difference between the two groups did not reach statistical significance.
Secondary Endpoints: The Efzofitimod (5.0 mg/kg) group showed superiority over placebo in steroid discontinuation rates, lung function questionnaire improvements, and symptom control. Specifically:
- 52.6% of patients in the Efzofitimod (5.0 mg/kg) group completely discontinued steroids, compared to 40.2% in the placebo group. - The Efzofitimod (5.0 mg/kg) group showed a 10.36-point improvement in KSQ-Lung scores from baseline, compared to 6.19 in the placebo group. - The Efzofitimod (5.0 mg/kg) group showed a relative improvement in lung function (FVC) of -1.81 from baseline, compared to -2.11 in the placebo group.
However, since the primary endpoint did not achieve statistical significance, these secondary endpoint p-values can only be considered nominal p-values and cannot be directly used to determine statistical significance.
For this failure, aTyr provided a familiar explanation—an excessively high placebo response rate. aTyr CEO Sanjay Shukla stated during an analyst call that "Efzofitimod performed as we had initially predicted, but the dose reduction effect in the placebo group exceeded our most aggressive model expectations, therefore the trial ultimately failed to achieve statistical significance."
In fact, Efzofitimod previously failed to achieve statistical significance in Phase Ib/II clinical trials for pulmonary sarcoidosis. However, aTyr conducted post-hoc analyses and observed promising results in higher dose groups, leading to the Phase III clinical trial.
Beyond pulmonary sarcoidosis, Efzofitimod is currently being developed for systemic sclerosis-associated interstitial lung disease (SSc-ILD) and is currently in Phase II clinical trials.