Efzofitimod safe, may improve clinical outcomes in patients with sarcoidosis

Key takeaways:

• Various efzofitimod doses given to patients with pulmonary sarcoidosis were well tolerated.
• Lung function and health-related quality of life improved with the largest dose of efzofitimod (5 mg/kg).

Among patients with pulmonary sarcoidosis, efzofitimod was safe through 24 weeks, and it improved measures of lung function and quality of life when given at a higher dosage, according to study results published in CHEST.

“Sarcoidosis is an area of unmet need, with no FDA-approved therapies in over 60 years,” Daniel A. Culver, DO, chair of the department of pulmonary medicine at Cleveland Clinic, told Healio. “Sarcoidosis impacts historically disadvantaged populations, especially Black individuals, disproportionately, and it has not gotten proportionate research or clinical trial focus. This study may help to identify a regulatory pathway that will allow other sponsors to confidently invest in the space, and it may also lead to a new approach to mitigate the toxicities of corticosteroid use and the morbidity of sarcoidosis in affected patients.”

In a randomized, double-blind, placebo-controlled study, Culver and colleagues analyzed 37 patients (mean age, 52.4 years; 54% women; 38% Black) with pulmonary sarcoidosis to assess how three different doses of IV efzofitimod (ATYR1923, aTyr Pharma), a novel immunomodulator, compared with placebo in outcomes including drug-related adverse events, steroid reduction, lung function changes and health-related quality-of-life changes.

Over a span of 20 weeks, patients received either a dose of efzofitimod or placebo every 4 weeks. Of the total cohort, eight patients received the 1 mg/kg dose, eight patients received the 3 mg/kg dose, nine patients received the 5 mg/kg dose and 12 received placebo, according to researchers.

Mean daily steroid dose among 36 patients receiving prednisone and one patient receiving methylprednisolone was 13.2 mg. Patients began a steroid taper on day 15 to a target dose of 5 mg per day by week 8, with additional tapering to less than 5 mg per day after week 16 if feasible.

Twenty-eight patients completed the 20-week treatment period. Nine patients stopped the treatment early, with two patients stopping due to a drug-related adverse event of urticaria (placebo) or alopecia (1 mg/kg dose).

Adverse events, steroid reduction

Researchers found a comparable number of adverse events among the treatment and placebo group. Within the efzofitimod dosage groups, the incidence of adverse events was not found to be connected to a higher dose.

The placebo and 1 mg/kg dose group each had one patient with a serious treatment-emergent adverse event. Notably, no patients died or reported a serious adverse event related to the drug, according to researchers.

Compared with patients receiving placebo, researchers found that patients receiving each of the treatment doses had lower mean daily doses of corticosteroids during the study, at 6.8 mg a day in the 1 mg/kg group, 6.5 mg a day in the 3 mg/kg group and 5.6 mg a day in the 5 mg/kg group vs. 7.2 mg a day in the placebo group.

Those receiving one of the higher treatment doses had greater declines in corticosteroid usage from baseline by the end of the study period than those receiving placebo (3 mg/kg, 48.9% decrease; 5 mg/kg, 58.1% decrease vs. placebo, 45.7% decrease), signaling a dose-dependent relationship, according to the researchers.

Further, daily steroid use was reduced by 5% in the 1 mg/kg group, 9% in the 3mg/kg group and 22% in the 5 mg/kg group after adjusting for baseline measures. Three patients in the 5 mg/kg group achieved total elimination of corticosteroids, according to researchers.

Lung function, quality-of-life changes

The dose-dependent relationship continued when researchers assessed changes in lung function, with the 3 mg/kg and 5 mg/kg doses demonstrating improved but nonsignificant measures of FVC percent predicted and DLCO percent predicted.

Among the four measures of patient reported outcomes for quality of life, researchers found significant improvements in all of them by the end of the study when comparing 5 mg/kg of efzofitimod with placebo: Sarcoidosis Assessment Tool (P = .018), King’s Sarcoidosis Questionnaire lung (P = .022), King’s Sarcoidosis Questionnaire general health (P = .008) and Fatigue Assessment Scale (P = .01). Researchers further noted that improvements in these measures took place prior to the last assessment at week 24.

Compared with placebo, patients receiving 3 mg/kg of efzofitimod also achieved significant improvement in the Sarcoidosis Assessment Test (P = .038).

“It is remarkable to see a consistent dose-effect response across multiple endpoints in such a small study,” Culver told Healio. “This was primarily a safety and tolerability trial, where finding a positive clinical result is unusual due to small sample size, so the consistency of effect was surprising.”

With positive findings in the higher dosage groups of efzofitimod, Culver told Healio this treatment provides valuable insight on an area that can be targeted to help patients with sarcoidosis.

“The study suggests that larger studies should proceed,” Culver said. “It shows that the neuropilin 2 receptor is a potential therapy target in sarcoidosis inflammation, and that using this pathway may be a way to treat sarcoidosis. The study showed reduction of steroid dose in the treated patients, compared with placebo, improved quality of life using several instruments, and a trend toward better lung function. All of these signals were seen despite reduction of background (steroid) therapy.”

In terms of future studies, another trial is already in the works.

“The next trial, EFZO-FIT, is currently underway,” Culver told Healio. “It is the first phase 3 registrational trial in sarcoidosis. The current trial uses a similar design of withdrawing background steroid therapy from patients with pulmonary sarcoidosis to uncover benefits of efzofitimod for management of pulmonary sarcoidosis. Patients will be treated with placebo, 3 mg/kg or 5 mg/kg (1:1:1) efzofitimod for 48 weeks.”

For more information:

Daniel A. Culver, DO, can be reached at culverd@ccf.org.