In addition to the unpredictable and highly variable symptoms that affect patients with systematic lupus erythematosus (SLE), they often experience serious side effects from medications such as immunosuppressants and corticosteroids. There is a need for novel treatments that would decrease the need for these drugs while reducing mortality and end-organ damage. A new study reported in Arthritis & Rheumatology describes a post-hoc analysis to determine if specific biomarkers were predictive of treatment outcomes in response to the recombinant fusion protein atacicept.1
SLE patients who are unresponsive to standard care “are increasingly considered for targeted biological treatments directed at B-cell activating factors, B and T cells, and cytokines,” wrote the authors of the current study. “Blockade of B cells is of specific importance since lupus autoantibodies play a key role in the pathophysiology of the disease,” they explained.
The human monoclonal antibody belimumab has been shown to effectively treat SLE with an acceptable safety profile. Like belimumab, atacicept inhibits B lymphocyte stimulator (BLyS), while also targeting a proliferation-inducing ligand (APRIL), another B-cell stimulating factor.
High Yield Data Summary
- Post-hoc analysis of patients with SLE who received atacicept revealed a dose-response relationship between drug concentrations, immunoglobulin reductions, and number of SLE flares; baseline BLyS and APRIL biomarkers appear to identify likely drug responders
The simultaneous inhibition of BLyS and APRIL–both of which are increased in SLE patients–may have the additional advantage of decreasing production of antibodies by acting on long-lived plasma cells, compared with blockade of BLyS alone.
Results of a phase II/III trial of atacicept in Generalized Systemic Lupus Erythematosus (APRIL-SLE study, ClinicalTrials.gov Identifier NCT00624338), published last year found no difference in flare rates with a 75 mg dose vs placebo.2
However, though the 150 mg treatment arm was terminated after 2 patients developed fatal infections, analysis suggested efficacy of the higher dose in preventing flare (P = .002) vs placebo.
Investigators of the current study conducted a post-hoc analysis of data collected during the APRIL-SLE trial to explore associations between response to atacicept treatment, various patient biomarkers, and safety outcomes.
Adult patients with moderate-to-severe SLE had been randomly assigned to receive a placebo or subcutaneous atacicept 75 mg or 150 mg twice per week for 4 weeks initially, and then once per week for 48 weeks.
The analysis revealed the following results:
- Higher concurrent levels of BLyS and APRIL (≥1.6 ng/ml and ≥2.2 ng/ml, respectively), at baseline were associated with greater treatment response: flare rates of 75.7% with placebo vs 50% with atacicept 75 mg and 32% with atacicept 150 mg
- Reduced flare rates were linked with increased atacicept exposure: 60.5% with placebo vs. 63.4–29.3% in the lowest to highest quartiles of exposure
- Greater reductions in immunoglobulin (Ig) and mature B cells correlated with reduced flare rates
- Similar rates of infection were observed regardless of baseline biomarkers or atacicept serum trough concentration
Summary and Clinical Applicability
These findings suggest that patients with elevated levels of BLyS and APRIL may have the greatest response to atacicept. Future research should investigate whether these biomarkeres can help predict the likelihood of a response and further explore the efficacy of the 150 mg dosage.
Limitations and Disclosures
The observed associations may be limited by the small sample size.
Caroline Gordon, MD, FRCP, reports consultation fees from Bristol-Myers Squibb, Merck Serono, Parexel and UCB; lecturing fees from Eli Lilly and UCB; and a research grant from UCB. David Wofsy, MD, reports consultation fees from Genentech Inc., Anthera Pharmaceuticals, Biogen Idec, GlaxoSmithKline, and Aurinia Pharmaceuticals Inc. David Isenberg, MD, reports honoraria from Merck Serono, Eli Lilly, GlaxoSmithKline, Roche, UCB and Pfizer, which he donated to a local arthritis charity. Stephen Wax, PhD and Yong Li, MHS, PhD are employed by EMD Serono, a business of Merck KGaA in Darmstadt, Germany. Claudia Pena Rossi, MD, PhD, is employed Drugs for Neglected Diseases Initiative in Geneva, Switzerland, and was employed by Merck Serono S.A. (now Merck Biopharma) during the study.
1. Gordon C, Wofsy D, Wax S, Li Y, Pena Rossi C, Isenberg D. Post-hoc analysis of the Phase II/III APRIL-SLE study: Association between response to atacicept and serum biomarkers including BLyS and APRIL. Arthritis Rheumatol. 2016; doi: 10.1002/art.39809.
2. Isenberg D, Gordon C, Licu D, Copt S, Rossi CP, Wofsy D. Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial). Ann Rheum Dis. 2015; 74(11):2006-15.