aTyr Pharma (NASDAQ:ATYR) outlined its revised development strategy for efzofitimod in pulmonary sarcoidosis during a presentation at a Jefferies event, emphasizing a new Phase 3 trial design following recent discussions with the U.S. Food and Drug Administration.
The company said efzofitimod remains its lead program and described the drug as a first-in-class immunomodulator targeting neuropilin-2, a receptor the company said is expressed in sarcoidosis granulomas. The presentation focused on pulmonary sarcoidosis, an orphan disease characterized by granulomas that occur largely in the lung and can progress to fibrosis in a subset of patients.
FDA feedback shifts next trial toward lung function endpoint
The company said the next study will differ from EFZO-FIT, its prior pulmonary sarcoidosis trial, by using forced vital capacity, or FVC, as the primary endpoint at week 48. The King’s Sarcoidosis Questionnaire lung score, or KSQ Lung, is expected to serve as a key secondary endpoint.
The company said the trial will focus on patients with a restrictive lung phenotype, because FVC is most relevant for that population. The planned study is expected to enroll approximately 372 patients, with a target treatment effect of about 80 milliliters. The company said that level would be clinically meaningful and would allow for statistical significance even if the observed effect is lower.
EFZO-FIT data inform new design
The company described EFZO-FIT as the largest interventional pulmonary sarcoidosis trial conducted to date, involving about nine countries and nearly 90 centers. That trial focused on steroid reduction, but aTyr said substantial steroid reduction occurred across all study arms, including placebo, which contributed to the study not meeting its primary endpoint.
The company said EFZO-FIT nevertheless showed consistent signals across patient-reported outcomes. It highlighted statistically significant improvement in KSQ Lung at week 48, along with benefits in general health and fatigue measures. The company said these outcomes reflected improvements in cough, shortness of breath, fatigue and broader quality-of-life measures.
aTyr also highlighted a pre-specified analysis of 44 restrictive patients from EFZO-FIT. The company said that group showed a 124 milliliter treatment effect in FVC slope analysis, which it characterized as larger than expected and clinically meaningful. The company said the result was notable because patients in the trial were aggressively tapered off steroids, which would typically be expected to pressure FVC measurements.
Dosing and background therapies to change
The company said it presented pharmacokinetic data to the FDA supporting a shift to dosing every three weeks. According to aTyr, the new regimen could provide about 30% more drug exposure, increasing annual dosing to 17 doses from 12 without moving to a higher dose.
The planned Phase 3 study will not include a steroid taper. aTyr said it expects many patients in the next trial to be on 0 to 5 milligrams of steroids, reflecting changing treatment patterns following EFZO-FIT. Background immunomodulatory therapies are expected to remain stable during the trial to avoid confounding the FVC endpoint.
The company said key inclusion criteria will focus on patients with a restrictive pulmonary function profile, including FVC percent predicted between 50% and 80%, as well as symptoms such as dyspnea and lower KSQ scores. Patients with more than 20% fibrosis are not expected to be included, with the company saying those patients should be treated with an anti-fibrotic rather than enrolled in this study.
Safety and market opportunity
aTyr said efzofitimod has shown a favorable safety profile compared with steroids, methotrexate and other off-label immunomodulators used in sarcoidosis. In EFZO-FIT, adverse events were mostly mild or moderate, with no concerning serious adverse event signals and low immunogenicity, according to the company.
The company estimated that the restrictive pulmonary sarcoidosis population in the U.S. includes about 40,000 patients, compared with a broader group of roughly 90,000 patients it previously considered for a more frontline approach. It also said mixed diffusion-limited patients could eventually be candidates for therapy, though the next trial will focus on restrictive patients to reduce variability in FVC.
aTyr said efzofitimod could represent a large market opportunity in interstitial lung disease, with potential up to $5 billion. The company said prior pricing assumptions were in the range of $150,000 to $200,000 and that updated estimates may move toward the higher end because the targeted population is sicker and has fewer treatment options.
Other pipeline updates
Beyond pulmonary sarcoidosis, the company said it expects to complete enrollment around mid-year in a small proof-of-concept trial of efzofitimod in systemic sclerosis, focused primarily on skin and inflammatory and fibrotic markers. aTyr also said its ATYR0101 program, described as a potential anti-fibrotic therapy from its tRNA synthetase platform, is expected to enter the clinic next year.
The company said its current strategic focus is completing the Phase 3 redesign for efzofitimod and advancing the program in a capital-efficient manner.
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.
