- Prolonged steroid use is linked to excess morbidity and mortality, but corticosteroids remain the first-line treatment for sarcoidosis.
- The novel immunomodulatory agent efzofitimod failed to reduce steroid use in pulmonary sarcoidosis, a phase III trial showed.
- However, the fact that the protocol for steroid tapering worked for a large proportion of placebo- and study drug-treated patients emphasized the need for more aggressive steroid reduction in clinical practice.
The novel immunomodulatory agent efzofitimod failed to reduce steroid use in pulmonary sarcoidosis, a phase III trial showed.
Monthly infusions of the fusion protein targeting the neuropilin 2 receptor had no impact on placebo-adjusted change in daily oral corticosteroid dose from baseline to 48 weeks whether at the 3-mg/kg dose (0.02 mg, 95% CI -1.49 to 1.52, P=0.98) or the 5-mg/kg dose (-0.73 mg, 95% CI -2.21 to 0.75, P=0.33), Daniel A. Culver, DO, of the Cleveland Clinic, and colleagues reported in the Lancet Respiratory Medicine.
While efzofitimod was designed as a steroid-sparing agent, the researchers found that corticosteroid tapering was possible in 40-52% of patients across treatment groups.
“[T]he data indicate that a large proportion of patients treated with corticosteroids and implementing a prescribed steroid withdrawal protocol can be managed with substantially lower doses of steroids for a period of up to 32 weeks,” the researchers concluded, pointing to “mounting evidence” tying prolonged steroid use to excess morbidity and mortality.
Alternatives to corticosteroids have been hard to come by in the field, leaving them as the first-line treatment, although guidelines have relied “largely on common sense rather than high-quality evidence,” noted an accompanying editorial by Marlies Wijsenbeek, MD, PhD, of the Center of Expertise for Interstitial Lung Diseases and Sarcoidosis at Erasmus Medical Centre in Rotterdam, the Netherlands.
The researchers noted that “successful steroid reduction in the placebo group demonstrates that steroid reduction is unlikely to be a useful endpoint in future pulmonary sarcoidosis trials, although it could be a part of the trial design to unmask biological effectiveness of a proposed intervention.”
Wijsenbeek agreed, pointing also to the recent PREDMETH and RESOLVE trials that both aimed at corticosteroid avoidance or minimization in pulmonary sarcoidosis.
“All three of these trials underscore that the door to corticosteroid reduction as (part of) a primary endpoint is closed,” she wrote. “In EFZO-FIT, oral corticosteroid could be tapered irrespective of treatment group. In both EFZO-FIT and RESOLVE, the number of patients with disease relapse after oral corticosteroid tapering within 1 year was too low to be a good endpoint. Finally, PREDMETH strengthens the case for using less corticosteroids in the first place.”
EFZO-FIT included 264 participants with pulmonary sarcoidosis who were randomly assigned to efzofitimod 3 mg/kg, efzofitimod 5 mg/kg, or placebo. All three groups had protocolized 16-week oral corticosteroid tapering with the target of discontinuation.
Average corticosteroid duration was 4.6 years at baseline, with 53% on a dose of 10 to under 20 mg a day (mean 10.7 mg/day) and only 38% on steroid-sparing therapies. By the primary endpoint assessment at week 48, the average dose had dropped to 2.9 mg per day across the whole trial cohort. Both efzofitimod groups had 52% of patients become steroid-free by that point, as did 40% on placebo, without a significant difference between groups.
“These data illustrate that even when guidelines advise corticosteroid tapering and steroid-sparing therapies, reality is different,” Wijsenbeek said. “Besides investing in novel therapies, we should optimize and standardize how we use the existing ones first. Protocolized corticosteroid tapering seems a realistic and cheap win for many patients. This study teaches us that using simple tools as a patient global assessment numerical scale combined with investigator assessment (stable, improved, or worsened) could be easily implemented to taper corticosteroids.”
Drug developer aTyr Pharma announced another planned phase III trial for efzofitimod focused on the subset of chronic, symptomatic pulmonary sarcoidosis with restrictive lung disease based on a post hoc unpublished analysis from EFZO-FIT. In patients with forced vital capacity (FVC) percent predicted ≤80% with a normal FEV1/FVC ratio, 5 mg/kg of efzofitimod yielded a “clinically meaningful” benefit in FVC and improvements in multiple patient-reported outcomes, including the King’s Sarcoidosis Questionnaire (KSQ)-Lung score, compared to placebo. The primary endpoint will be FVC rather than steroid sparing.
Wijsenbeek expressed skepticism that even this endpoint would be met, as the consensus FVC response threshold of at least 10% predicted change has not been achieved in any recent sarcoidosis trial.
“Both phase II and III efzofitimod studies showed a positive effect on patient-reported outcomes. It seems a missed opportunity that these were not positioned higher in the endpoint hierarchy,” she wrote.
In EFZO-FIT, efzofitimod improved health-related quality of life measures, including scores on the KSQ-Lung, KSQ general health status, and Fatigue Assessment Scale.
The drug appeared well-tolerated, according to the researchers. Serious treatment-emergent adverse event rates were similar between groups. More treatment-emergent events occurred with efzofitimod in terms of headache, sinusitis, wheezing, and increased aspartate aminotransferase. Two deaths in the efzofitimod 3-mg/kg group (one respiratory failure and one incarceration of a pre-existing inguinal hernia) were deemed not causally related to the treatment.
