However, the novel immunomodulatory fusion protein was found to be safe and well-tolerated.
The results from the largest randomised trial ever conducted in pulmonary sarcoidosis are in.
Efzofitimod, a novel immunomodulatory fusion protein which targets the neuropilin 2 receptor,has failed to demonstrate a significant steroid-sparing benefit in patients with pulmonary sarcoidosis, despite some encouraging improvements in patient-reported outcomes.
Pulmonary involvement occurs in more than 90% of people with sarcoidosis, a heterogeneous multisystem granulomatous disorder. Oral corticosteroids remain standard first-line treatment, but prolonged use can cause substantial toxicity, including weight gain, insulin resistance, hypertension, cardiovascular disease, osteoporosis, and increased susceptibility to infection.
Existing steroid-sparing treatments, including methotrexate and infliximab, can be limited by tolerability and accessibility. Some international experts have argued that corticosteroids should ideally be used as bridging therapy for no longer than three to four months, highlighting the need for effective alternatives.
The phase 3 EFZO-FIT trial, involving 268 patients across 85 centres in nine countries, found no significant difference in corticosteroid dose reduction at 48 weeks between the treatment and placebo group. Mean age was 53·8 years, 43% were female, and 64% identified as White.
Participants received monthly intravenous infusions of efzofitimod at 3mg/kg (n=89), 5mg/kg (n=88), or placebo (n=91), alongside a protocol-directed corticosteroid taper. The primary endpoint was the change in mean daily oral corticosteroid dose at week 48.
Across the study population, the mean daily corticosteroid dose fell from 10.7mg at baseline to 2.9mg at week 48. However, the reduction was similar across all three groups.
Compared with placebo, the adjusted difference in corticosteroid dose reduction was 0.02mg/day with efzofitimod 3mg/kg (95% CI -1.49 to 1.52) and 0.73mg/day with the 5mg/kg dose (95% CI -2.21 to 0.75). Both of these differences were not statistically significant.
The substantial reduction in corticosteroid use among placebo recipients was a notable finding, with the group achieving an average 63% reduction in daily dose over the study period.
By week 48, 40% of placebo recipients were steroid-free, compared with 52% in each of the efzofitimod groups. The difference between the 5mg/kg dose and placebo did not reach statistical significance (OR 1.69; 95% CI 0.92–3.09).
Around a quarter of participants in the placebo group were also able to remain off corticosteroids for at least 180 days. This suggested that a substantial proportion of patients could tolerate a structured reduction in steroid treatment, irrespective of whether they received efzofitimod.
Related
The researchers noted that many patients treated with corticosteroids could be managed on substantially lower doses following a prescribed withdrawal protocol.
Although the primary endpoint was not met, the higher efzofitimod dose was associated with improvements in several exploratory patient-reported outcomes.
At 48 weeks, patients receiving 5mg/kg had significantly greater improvements than placebo recipients in scores on the King’s Sarcoidosis Questionnaire lung and general health domains, as well as the Fatigue Assessment Scale.There was no significant difference in cough-related quality of life.
A composite endpoint combining corticosteroid-free status with an eight-point improvement in the lung questionnaire score was achieved by 30% of patients receiving 5mg/kg, 28% receiving 3mg/kg, and 14% receiving placebo.
However, these were secondary or exploratory findings and did not change the negative result for the primary endpoint. No significant placebo-adjusted improvement in forced vital capacity was observed.
The safety profile of efzofitimod was broadly comparable with placebo, with similar proportions of participants experiencing treatment-emergent adverse events and serious adverse events.
Headache, sinusitis, wheezing, and increased aspartate aminotransferase were more frequently reported in the efzofitimod groups, although most events were mild or moderate.
Two participants in the 3mg/kg group died during the study, but neither were considered related to treatment. There were no serious opportunistic infections, and no cardiorespiratory events were reported in the efzofitimod groups.
The researchers concluded that efzofitimod did not produce a significant reduction in corticosteroid use compared with placebo, but was safe and well-tolerated.
EFZO-FIT was the largest randomised trial conducted in pulmonary sarcoidosis to date. Its results provide evidence that a structured corticosteroid taper can achieve substantial dose reductions in many patients, but do not establish that efzofitimod offers additional benefit.
The trial authors acknowledged several limitations, including the absence of predefined physiological or patient-reported thresholds to guide corticosteroid tapering and escalation. Decisions were instead informed by investigator and patient global assessments, reflecting the combination of clinical information used in routine practice but potentially introducing variability between participants.
The findings leave the need for effective, well-tolerated steroid-sparing treatments in pulmonary sarcoidosis unresolved.
