After the REGENCY trial yielded positive results in lupus nephritis, the ALLEGORY study does the same for systemic lupus erythematosus.
A new international study has reported that obinutuzumab is safe and effective in patients with systemic lupus erythematosus, adding to previous data showing similar outcomes in lupus nephritis.
The study, published in the New England Journal of Medicine, suggests that the humanised glycoengineered type II anti-CD20 antibody outperformed placebo across a range out outcomes.
“In this trial involving adults with active SLE, obinutuzumab plus standard therapy led to a significantly higher percentage of patients with clinically meaningful reductions in disease activity across the primary end point… and key secondary end points than placebo plus standard therapy,” the authors concluded.
Three hundred and three patients who had been diagnosed with SLE as per the 2019 EULAR-ACR classification criteria for at least 12 weeks prior to screening were eligible.
In addition, participants were required to have a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of at least 8 (excluding points for alopecia, headache or fever), at least one domain A score or at least two domain B scores on the British Isles Lupus Assessment Group 2004 index (BILAG-2004) and a Physician’s Global Assessment Score (PGA) of 1.0 or more on a three-point visual analogue scale.
Patients were randomised to receive either 1000mg of obinutuzumab (n = 151) or placebo (n = 152) via infusion at day 1 and at weeks 2, 24 and 26. Premedication treatment included 80mg of IV methylprednisolone, 650 to 1000mg of acetaminophen or paracetamol and 50mg of diphenhydramine. Disease activity and safety outcomes were assessed every four weeks for 52 weeks.
After 52 weeks 76.7% of patients who received obinutuzumab were responders on the SLE Responder Index 4 (the primary outcome), a composite end point comprised of a minimum four-point reduction in SLEDAI-2K score from baseline, no worsening of the BILAG-2004 and PGA scores and no intercurrent events (e.g., requiring rescue medication, lack of efficacy or adverse events).
The five key secondary outcomes also favoured obinutuzumab over placebo.
Significantly more patients in the active treatment group displaying a BILAG-based Composite Lupus Assessment response at week 52 (62.0% versus 40.1%), reducing their glucocorticoid dose to ≤ 7.5mg/day and sustaining this reduction from week 40 to week 52 (80.0% versus 54.1%), having an SRI-4 response at week 40 and sustaining it to week 52 (72.0% versus 46.4%) and achieving an SRI-6 response at week 52 (68.9% versus 38.9%).
Finally, the median time to fist BILAG flare from week 52 onwards could not be calculated in the obinutuzumab group but was 52.3 for the placebo group.
Obinutuzumab led to a reduction of peripheral CD19-positive B cells after the first infusion, with 98.5% of patients receiving the active treatment displaying complete B-cell depletion after the second week of treatment.
For comparison, only 5.6% of patients in the placebo group had complete B-cell completion at the same timepoint.
Related
A greater proportion of patients in the obinutuzumab group experienced adverse events than in the placebo group (88.7% versus 81.5%), as well as grade 3 or higher adverse events (16.6% versus 13.9%), serious adverse events (15.9% versus 11.9%) and infusion-related reactions (11.9% versus 3.3%).
The most common serious adverse events among the obinutuzumab group were pneumonia (2.0%), upper respiratory tract infections (1.3%) and urinary tract infections (1.3%), but the authors were not overly concerned by this finding.
“Although the incidence of infections was higher among patients who received obinutuzumab than among those who received placebo, they were overall manageable, and the safety data were consistent with the known safety profile of obinutuzumab or underlying disease of the patient population,” they said.
The authors said their findings were complementary to those of the phase 3 REGENCY trial, which also found obinutuzumab was associated with clinically meaningful improvements in patients with active proliferative lupus nephritis.
“The high incidence of responses to obinutuzumab could be attributed to several factors, including modern refinements to trial design, but a growing body of evidence suggests that robust B-cell depletion is a major contributor to enhanced clinical responses in autoimmune diseases,” they wrote.
However, the authors also highlighted the ever-present need for ongoing research.
“Although administration of obinutuzumab resulted in rapid and durable peripheral B-cell depletion, further investigation is needed to evaluate tissue-level B-cell depletion and correlations with clinical responses.”
