A phase 3 trial of aTyr Pharma’s efzofitimod in a lung disease has missed its primary endpoint. With a multibillion-dollar market in its sights, the biotech is planning to talk to the FDA about a path forward despite the failure and the skepticism of investors.
The biotech planned to position the immunomodulator efzofitimod as a steroid-sparing agent for people with moderate-to-severe forms of the inflammatory lung disease pulmonary sarcoidosis. Reflecting that goal, the biotech ran a phase 3 trial to compare the effect of 48 weeks of dosing with efzofitimod and placebo on the mean daily oral corticosteroid (OCS) dose.
Efzofitimod performed no better than placebo, causing the trial to miss its primary endpoint. The change from baseline in mean daily OCS dose reduced to an average of 2.79 mg for the high dose of efzofitimod versus 3.52 mg for placebo. ATyr CEO Sanjay Shukla, M.D., blamed the failure on the placebo response rate.
“We assumed that patients on efzofitimod would taper from baseline to an average daily prednisone dose between 1 to 4 milligrams, with placebo expected to taper to between 4 to 7,” Shukla said on a call with analysts. “The drug performed accordingly to what we projected. However, we did not achieve statistical significance as the placebo tapering outperformed even our most aggressive modeling.”
Shukla voiced a positive take on the data, telling analysts that the study demonstrated that patients with chronic symptomatic sarcoidosis “can be managed with substantially lower steroid doses than previously thought without the fear of worsening disease.”
The CEO added that, despite a higher than anticipated placebo response, aTyr “found that treatment with efzofitimod was associated with a greater amount of steroid reduction including steroid withdrawal, a clinical improvement in the quality of life for these patients and a maintenance of lung function.”
ATyr used a hierarchical statistical analysis, meaning the failure on the primary endpoint made all other p values nominal. Even so, the biotech claimed a clinical improvement on the KSQ-Lung patient-reported measure of health-related quality of life, with a 10.36-point change on the high dose playing off against a 6.19-point change on placebo.
The company also highlighted a responder analysis of people who achieved complete steroid withdrawal and improved on KSQ-Lung as a positive of the trial. Complete steroid withdrawal was achieved in 52.6% of patients treated with the high dose of efzofitimod and 40.2% of people on placebo. The proportions of people who also reported KSQ-Lung improvement were 29.5% on efzofitimod and 14.4% on placebo.
Shukla cited the fact that the analyses were prespecified as a driver of its belief it has the evidence to support talks with the FDA. Given the lack of effective therapies in the indication, Shukla predicted that the FDA will be “a collaborative partner.”
Shares in aTyr fell 80% to $1.21 in premarket trading.
Analysts at Leerink Partners had previously been positive heading into the readout. The analysts wrote, "We were wrong," in a Sept. 15 note.
"The study was ultimately doomed by a higher than expected placebo effect, a known risk heading into the readout," according to Leerink Partners. "We are moving to the sidelines given uncertainty on this."
Editor's note: This article was updated at 11:50 a.m. ET on Sept. 15 to include analyst insight.