aTyr Pharma Revamps Efzofitimod Path With New Phase III Sarcoidosis Trial

Key Points

• aTyr Pharma plans a new Phase III trial of efzofitimod in pulmonary sarcoidosis after FDA feedback, following the prior EFZO-FIT study missing its primary steroid-reduction endpoint.
• The FDA indicated that FVC and KSQ lung are clinically meaningful endpoints, and aTyr now expects FVC to be the primary endpoint with KSQ lung as a key secondary endpoint.
• The proposed study would enroll about 372 patients with moderate to severe progressive pulmonary sarcoidosis and restrictive lung disease, use dosing every three weeks for one year, and target a registrational path while the company looks for capital-efficient financing.

aTyr Pharma NASDAQ: ATYR said it plans to conduct a new Phase III trial of efzofitimod in pulmonary sarcoidosis after receiving feedback from the U.S. Food and Drug Administration at a recent Type C meeting.

President and CEO Dr. Sanjay Shukla said the meeting, held in mid-April with official minutes received last week, was intended to review results from the completed Phase III EFZO-FIT study and determine the next steps for the program. EFZO-FIT missed its primary endpoint of steroid reduction, but Shukla said the study showed “durable benefit” on several prespecified quality-of-life measures, including the King’s Sarcoidosis Questionnaire, or KSQ, lung score, the KSQ general health score and the fatigue assessment score.

Based on the FDA feedback, aTyr plans to submit a protocol next month for a new Phase III trial focused on patients with pulmonary sarcoidosis and restrictive lung disease.

FDA Feedback Focused on FVC and KSQ Lung

Shukla said the FDA indicated that forced vital capacity, or FVC, and KSQ lung are clinically meaningful endpoints in pulmonary sarcoidosis. He said aTyr now views FVC as the more appropriate primary endpoint for the next trial, while KSQ lung will be used as a key secondary endpoint.

According to Shukla, FVC is a direct measure of function and is most relevant for patients with restrictive lung disease. He said the company analyzed EFZO-FIT patients by lung phenotype and found a 124-milliliter difference in change from baseline in FVC between restrictive patients treated with 5 mg/kg of efzofitimod and placebo.

“This demonstrates that patients with impaired lung function clearly benefited from efzofitimod despite being aggressively tapered from steroids,” Shukla said.

The company also has been working with the FDA Division of Clinical Outcome Assessment to validate KSQ lung for regulatory use in a clinical trial setting. Shukla said the FDA acknowledged those efforts and recommended additional symptom measures, including cough severity and wheezing, based on further content validation.

New Phase III Trial Design

The planned study is expected to be a global, randomized, double-blind, placebo-controlled, one-year trial. Shukla said the study will include two parallel cohorts randomized equally to efzofitimod or placebo, with patients receiving 5 mg/kg intravenously once every three weeks for a total of 17 doses.

aTyr intends to enroll approximately 372 patients with moderate to severe progressive pulmonary sarcoidosis with restrictive lung disease. Eligible patients are expected to be receiving a stable dose of daily oral corticosteroids of 5 mg or less and/or a stable dose of background immunosuppressant, with background therapy remaining stable throughout the study.

The primary endpoint will be change from baseline in FVC at week 48. The key secondary endpoint will be change from baseline in KSQ lung score at week 48.

Shukla said key inclusion criteria are intended to ensure that patients are symptomatic and have restrictive lung disease but are not fibrotic. Patients must have a documented history of pulmonary sarcoidosis for at least six months, a dyspnea scale score of at least 2, a KSQ score of 60 or below, FVC between 50% and 80% predicted, and an FEV1-to-FVC ratio of at least 0.7.

Key exclusion criteria include a high-resolution CT fibrosis score greater than 20% and treatment within four months with biologic immunomodulators or antifibrotics, among others.

Dosing and Safety Monitoring

aTyr plans to move from a monthly dosing schedule to dosing every three weeks. Shukla said modeling suggests the revised schedule would increase drug exposure while maintaining a wide safety margin.

He said the FDA suggested additional risk mitigation strategies in light of the proposed dosing update, including continued safety surveillance for the potential development of anti-synthetase syndrome. Shukla said efzofitimod is derived from a splice variant of tRNA synthetase HARS, and that monitoring for this theoretical risk has been part of the company’s program.

“We did not see any development of anti-synthetase syndrome in EFZO-FIT,” Shukla said. He added that the next trial will include prospective monitoring and a data monitoring committee similar to the EFZO-FIT study.

Enrollment, Market Opportunity and Funding

In response to a question from Wells Fargo analyst Derek Archila, Shukla said aTyr believes it can enroll the new trial in about two years, though the company has not provided formal guidance. He said the prior EFZO-FIT trial took about 20 to 21 months to enroll, and that the company expects to benefit from an existing global network of more than 85 centers and prior site experience with efzofitimod.

Shukla said a recent claims analysis suggests nearly 160,000 confirmed diagnosed pulmonary sarcoidosis patients in the U.S., including approximately 90,000 with moderate to severe disease characterized by impaired lung function. He estimated that about 38,000 patients have restrictive disease without advanced fibrosis. Including approximately 24,000 patients with mixed disease without advanced fibrosis, Shukla said the initial target population could range from 38,000 to 62,000 patients in the U.S. alone.

Shukla described the target population as a “multi-billion” dollar opportunity, while noting that the company is exploring ways to finance the Phase III effort and intends to proceed in a capital-efficient manner. Chief Financial Officer Jill Broadfoot was on the call for questions, but Shukla provided the company’s comments on financing.

Other Program Updates

Archila also asked about aTyr’s ongoing efzofitimod trial in systemic sclerosis-associated interstitial lung disease, or SSc-ILD. Shukla said the company remains on track to complete enrollment in the first half of the year and expects the trial to read out approximately seven months after the last patient is enrolled.

During the question-and-answer session, Shukla said aTyr views the planned pulmonary sarcoidosis study as a registrational trial, though he noted that the company will need to evaluate the FDA’s position after the data are available. He also said no interim analysis or futility analysis is currently planned.

Shukla said aTyr intends to keep the next trial focused on the restrictive population to reduce variability and improve the likelihood of demonstrating an FVC benefit. He said regulatory experts advising the company do not believe that approach would necessarily limit the potential label to restrictive patients, citing broader labeling precedents in interstitial lung disease therapies.

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.

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