Targeting B Cells in Lupus: Efforts Persist Atacicept Lowered Flares in Post-Hoc Analysis

By | July 26, 2016

Atacicept may yet have a role in the treatment of systemic lupus erythematosus, with post-hoc analyses of a phase II/III study showing benefits among patients with high levels of two B-cell biomarkers, researchers reported.

Among patients with high levels of the B-cell stimulating factor known as BLyS and the proliferation-inducing ligand referred to as APRIL, the flare rate over 52 weeks was 32% among those receiving 150-mg subcutaneous atacicept once weekly compared with 50% of those receiving the drug in doses of 75 mg and 75.7% of those given placebo, according to Caroline Gordon, MD, of the University of Birmingham in England, and colleagues.

In addition, time to flare was longer in the high-biomarker group given the 150-mg dose, at 365 days, compared with 275 days in the 75-mg group and 85 days in the placebo group, the researchers reported online in Arthritis & Rheumatology.

“Atacicept is a recombinant fusion protein containing the extracellular, ligand-binding portion of the receptor transmembrane activator and calcium-modulating cyclophilin ligand-interactor and a modified Fc portion of human immunoglobulin (Ig)G,” they explained.

It inhibits BLyS, as does belimumab (Benlysta), but also APRIL, which might increase efficacy because inhibiting APRIL could also target long-lasting plasma cells involved in autoantibody production in lupus, they suggested.

The multicenter study initially enrolled 461 patients with active disease who were autoantibody positive, but before completion two patients in the 150-mg arm died of infections, so that arm was terminated. In the 75-mg group, there were no differences compared with placebo in flare rate (OR 1.15, 95% CI 0.73 to 1.80, P=0.543). However, a preliminary analysis suggested potential flare prevention with the higher dose.

Therefore, with the ongoing unmet need for additional targeted therapies in lupus and the recognition that B cells play an important role in the disease, the study investigators sought to evaluate efficacy and safety outcomes according to biomarkers and drug exposure among patients in the 150-mg dose group who had been randomized more than 52 weeks before termination. These patients would have completed the study if they had no other reason for stopping the treatment, avoiding potential confounding by the termination of that arm of the study.

This potential completer population included 246 patients, with 81 in the 150-mg group, 84 in the 75-mg group, and 81 in the placebo group.

Mean BLyS levels were 1.9 ng/mL in all groups, while mean APRIL levels were 2.2, 2.3, and 2.4 ng/mL in the 150-mg, 75-mg, and placebo groups, respectively.

The investigators divided the patients into subgroups according to levels of BLyS and APRIL. Subgroup 1 included patients whose baseline levels were 1.6 ng/mL or higher for BLyS and 2.2 ng/mL or higher for APRIL (high BLyS/high APRIL), subgroup 2 was high BLyS/low APRIL, and subgroup 3 was low BLyS only.

In subgroup 1, both atacicept groups had lower rates of flare than the placebo group, but the reduction was greater in the higher-dose group. In subgroup 2, only the 150-mg group had a lower flare rate, at 48%, compared with 84.2% in the 75-mg group and 62.5% in the placebo group. No significant reduction in flare rate was seen in subgroup 3, with rates of 48.4%, 51.7%, and 39.3% in the 150-mg, 75-mg, and placebo groups, respectively.

The researchers also looked at treatment responses and other biomarkers such as IgG, IgM, and naive B cells and plasma cells, which were stratified into quartiles, and found that flares were reduced in patients with the greatest reduction in all these markers. They also noted that flare rates were lower among patients with higher serum trough levels of the drug.

The association between treatment response and immunoglobulins and B cells needs further explication, but may relate to a reduction in autoantibody production or errant B cell activity.

No “notable difference” was seen in rates of infection or serious infection in any of the BLyS/APRIL subgroups, the investigators reported. More serious infections occurred in patients with the lowest levels of IgM, but the numbers were small, with five being seen in the top quartile of IgM reduction and none in the lowest quartile.

The two patients who died had IgG levels within the normal range, and their IgM levels remained above 0.34 g/L, while the normal range is 0.4 to 2.3 g/L. They also had “relatively low mean and maximum trough levels of atacicept,” according to the investigators.

“Infections and fatalities in clinical trials must be taken very seriously, and extrapolating from a trial that was ended prematurely has significant limitations, as do all post-hoc analyses,” commented Amit Saxena, MD, of NYU Langone Medical Center in New York City, who was not involved in the study.

“However, the lack of association between atacicept exposure and death allows for the possibility that the drug’s safety profile may be reasonable, which is being studied in a new phase IIb trial. With recent studies showing lack of efficacy with epratuzumab, tabalumab, and atacicept, the question has been raised of how significantly B cell depletion associates with clinical response in SLE,” he told MedPage Today.

“However, subgroup and post-hoc analyses like the one reported here have identified certain patients that respond to these treatments, including those with more active disease and those with elevations in certain biomarkers. Given the way cancer therapeutics are personalized to specific patients, it would seem prudent for the next phase of treatment strategy in lupus to be a similar method of choosing medications based on baseline levels of markers such as B lymphocyte stimulators, interferon, or cytokines,” Saxena said.

Source: Medpage Today

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