Discussion
discontinuations, sarcoidosis, myalgia, aggressiveness, depression, deaths, toothache
SARCOIDOSIS, PULMONARY SARCOIDOSIS
The results from the present study suggest that efzofitimod is safe and well tolerated in patients with pulmonary sarcoidosis, with no clear dose relationship regarding the incidence of TEAEs. Specifically, no apparent trends overall, within or across efzofitimod treatment groups, were seen regarding change from baseline in clinical laboratory test results, and no notable differences from placebo were observed. No deaths and or discontinuations occurred because of serious AEs in efzofitimod-treated patients. Overall, a low rate of serious or related AEs were noted, with no dose-dependent relationship between AE frequency and increased dose. The nonserious Grade 3 AEs reported after efzofitimod treatment (depression, toothache, and myalgia) were deemed by the investigator to be unlikely to be related to the study drug and did not result in hospitalization or threat of hospitalization. No immunogenicity was reported, as supported by the low incidence of patients with IRRs (n = 1) and the lack of antidrug antibody induction after repeat infusions.All efzofitimod treatment groups showed a lower corticosteroid use at week 24 compared with the placebo group, which seemed to be dose dependent, with the largest difference observed in the 5 mg/kg treatment group. Four patients were able to taper off prednisone completely (one patient in the placebo group and three patients receiving 5 mg/kg). However, the patient receiving placebo could not be maintained off prednisone for more than 8 weeks because of worsening sarcoidosis and required resumption of prednisone to 10 mg/d. Overall, corticosteroid tapering was possible in all groups, consistent with prior data showing that patients with sarcoidosis in clinical trials can taper corticosteroid successfully over a span of several months.Compared with placebo, the highest doses of efzofitimod resulted in improvements in FVC % predicted and DChanges in QOL have been considered a major priority for treatment of sarcoidosis.The major limitation of this study is the small sample size, and as such the results will need to be confirmed in a larger study. Operational site difficulties imposed by the COVID-19 pandemic accounted for most of the dropouts. Because of the size, baseline imbalances were present for several of the key end points and the CIs are fairly wide, which limits our ability to draw firm conclusions. However, statistical analyses when adjusted for baseline value demonstrated that the major end points exhibited directionality in favor of a beneficial effect of efzofitimod, suggesting that a larger sample may solidify the findings. We also acknowledge that statistical adjustment for multiple hypothesis testing and power analysis were not performed because of the exploratory nature of the study. Most patients in this study were receiving > 10 mg of prednisone; therefore, further improvement in FVC % predicted was not likely to be demonstrated. However, the current findings suggest a corticosteroid-sparing effect and improved QOL beyond the MCID. Another limitation is the absence of a rigid corticosteroid tapering protocol based on defined thresholds for measurable physiologic indexes or PROs. Variability in corticosteroid tapering aggressiveness may introduce residual bias in the results, but in general this effect likely would tend to reduce the chances of positive findings, rather than increase them, because the patients were randomized. Allowing some investigator discretion about corticosteroid tapering more accurately mirrors usual practice. It is also not possible to determine whether improvements in QOL scores directly reflect efzofitimod activity or occurred indirectly because efzofitimod allowed a greater reduction of prednisone, which has been associated with worse QOL as measured by the Short-Form 36 (SF-36) and St. George’s Respiratory Questionnaire (SGRQ).