Researchers have demonstrated the clinical efficacy and safety of sifalimumab in inhibiting interferon-α in patients with moderate-to-severe active systemic lupus erythematosus (SLE).
Munther Khamashta, MD, PhD, of the Graham Hughes Lupus Research Laboratory at King’s College, Rayne Institute at St. Thomas’ Hospital in London, along with several colleagues, conducted a randomized, double-blind, placebo-controlled phase IIb study (ClinicalTrials.gov identifier NCT01283139) to determine the safety and efficacy of sifalimumab therapy for moderate-to-severe active SLE.
Conducted at 107 sites across 20 countries between 2011 and 2014, the study included a 52-week randomized, double-blind, placebo-controlled, parallel-group treatment phase, followed by a 22-week safety follow-up phase. Eligible participants (n=431) were between 18 and 75 years of age and fulfilled ≥4 of the 11 American College of Rheumatology (ACR) SLE classification criteria. Participants were also required to score ≥6 on the SLE Disease Activity Index 2000 (SLEDAI-2K), ≥1A or ≥2B on the British Isles Lupus Assessment Group (BILAG)-2004, and ≥1 on the Physician’s Global Assessment (PGA) disease activity scale.
High Yield Data Summary
- Patients in all sifalimumab groups experienced reductions in all measures of disease activity scores.
The study’s primary efficacy end point was the percentage of patients achieving SLE Responder Index (SRI)-4 response at 52 weeks (defined as a 4-point improvement in SLEDAI-2K), as well as no clinically significant worsening of PGA or BILAG-2004 scores.
Secondary efficacy end points included the percentage of patients prescribed decreased oral prednisone doses, a ≥4-point reduction in the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), and a >3-point improvement in Functional Assessment of Chronic Illness Therapy-Fatigue score. Safety end points included rates of reported adverse events, laboratory assessments, and patient vital signs.
Researchers randomized study participants 1:1:1:1 to receive either intravenous placebo (n=108) or sifalimumab 200 mg (n=108), 600 mg (n=109), or 1200 mg (n=107) on days 1, 15, and 29 of the study, and on a monthly basis thereafter. At 52 weeks, data showed that greater numbers of patients in the sifalimumab groups were achieving the primary end point vs those in the placebo group (P =.053). This effect was found across all sifalimumab dosages (see Table below), although improvements peaked at 24 weeks.
Table. Percentage of Patients Achieving the Primary End Point at 52 Weeks
|200 mg||58.3% (P =.057)|
|600 mg||56.5% (P =.094)|
|1200 mg||59.8% (P =.031)|
All participants in the sifalimumab group showed maximum improved CLASI scores at 20 to 24 weeks; additionally, these patients achieved a ≥4-point reduction in SLEDAI-2K scores and more frequently had positive BILAG-based Combined Lupus Assessment (BICLA) responses. Improvements in both frequently (mucocutaneous and musculoskeletal) and less frequently involved SLEDAI organ systems (hematological, renal, and vascular) were also reported in this group. In the 600- and 1200-mg sifalimumab groups, rates of new disease flares resulting in an increased oral corticosteroid dose were lower compared with placebo.
Post hoc analyses of patients with severe joint involvement (≥8 swollen and tender joints) at baseline found an increase in the percentage of patients who experienced a ≥50% decrease in affected joints, as well as a dosage-related increase in the percentage of patients who exhibited clinically meaningful reductions of SLEDAI response, particularly in the 600- and 1200-mg sifalimumab groups.
Rates of adverse events—serious or leading to discontinuation—were similar across all groups. Most commonly, patients experienced worsening of SLE symptoms, urinary tract infections, and nasopharyingitis. Five deaths were reported during the double-blind period (2 in the placebo group, 1 in the sifalimumab 600-mg group and 2 in the 1200-mg sifalimumab group); 1 additional death was reported in the sifalimumab 600-mg group during the follow-up period.
One patient in the sifalimumab 1200-mg group was diagnosed with active tuberculosis, but responded well to treatment. Serious infections were reported in 7.4% of patients in the placebo group and 22.3% of the patients in all sifalimumab groups. Herpes zoster was reported in 0.9% of placebo patients vs 5.9% of sifalimumab patients, with all patients responding to antiviral treatment and 1 patient (sifalimumab 200 mg) experiencing a relapse and 1 patient (sifalimumab 1200 mg) discontinuing study participation due to the infection.
No clinically important changes were noted in patients’ hematology, urinalysis, vital signs, lipids levels, or electrocardiographic results in any treatment group during the study or follow-up periods.
Summary and Clinical Applicability
“This phase IIb study demonstrated greater efficacy with [interferon]-α pathway blockade thank placebo in treatment of patients with moderate-to-severe active SLE and an inadequate response to standard-of-care treatments,” wrote Dr Khamastha and colleagues, noting the “acceptable safety profile” of the drug.
“These potentially promising results are important in early drug development, but are not definitive until prospectively replicated in larger studies with a more stringent statistical significance level,” the researchers concluded.
Limitations and Disclosures
- The authors noted that larger studies are required to confirm “the safety of this treatment and to define those at highest risk of complications.
Disclosures: Dr Khamastha reports receiving a grant for this study from MedImmune /AstraZeneca, grants for other work from Bayer, and personal consultancy fees from INOVA Diagnostics, MedImmune, GlaxoSmithKline, and UCB. Dr Merrill reports receiving grants from Genentech/Roche. Drs Merrill, Werth, Furie, Kalunian, Illei, Drappa, Wang, and Greth report receiving personal fees from MedImmune/AstraZeneca; Drs Gerth and Illei report holding stocks in AstraZeneca/MedImmune, and are employees of MedImmune along with Drs Wang and Drappa. Dr Werth holds a patent for the CLASI copyright, owned by the University of Pennsylvania.
Khamashta M, Merrill JT, Werth VP, et al, on behalf of the CD1067 study investigators. Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomized, double-blind, placebo-controlled study. Ann Rheum Dis. 2016;75:1909-1915. doi: 10.1136/annrheumdis-2015-208562 [Epub ahead of print].