Deaths mar atacicept trial for lupus, but research continues

PARIS – A randomized trial of two doses of atacicept for systemic lupus erythematosus was interrupted after two deaths occurred in patients taking 150 mg of the drug.

However, since a post hoc analysis concluded that the 150-mg dose was more effective at reducing flares than was the 75-mg dose, research on it continues, Dr. Caroline Gordon said at the annual European Congress of Rheumatology.

Additionally, said Dr. Gordon, professor of rheumatology at the University of Birmingham, England, the 150-mg dose was significantly more effective than was the 75-mg dose or placebo at reducing mucocutaneous and musculoskeletal flares (9% vs. 18%).

"This finding, and the suggestion that atacicept may have a steroid-sparing effect, allows for assessing its safety and efficacy further," she said.

EMD Serono, a subsidiary of Merck, is now recruiting for a 24-week trial comparing the 75- and 150-mg doses in patients with systemic lupus erythematosus (SLE).

Atacicept is an investigational, fully human recombinant fusion protein that inhibits B-lymphocyte stimulator (BLyS) and the A proliferation-inducing ligand (APRIL). Both proteins stimulate B-cell production and are elevated in patients with lupus.

At the congress, Dr. Gordon reported the results of the APRIL-SLE study, which randomized 461 patients to atacicept at either dose or placebo. Its primary endpoint was the rate of new flares in patients with lupus. Secondary endpoints included changes in disease activity scores, overall safety, biomarkers, and pharmacodynamics. The full results of the study were published after the congress (Ann. Rheum. Dis. 2014 [doi:10.1136/annrheumdis-2013-205067]).

Patients had to achieve stable condition before being randomized. After screening, they were assigned to a 10-week corticosteroid taper. If they had improved to a score of C or D on the British Isles Assessment Group (BILAG) scale, they were randomized. After the 52-week treatment period, there was a 24-week safety observation period.

Most patients in the placebo and 75-mg groups completed the study (70%). In the 150-mg arm, 43% completed the trial. After the two deaths, 38% patients in the 150 mg-arm stopped treatment. Both patients died of pneumonia complicated by pulmonary hemorrhage.

One of these was a 22-year-old man from the Philippines on week 42 of treatment, who had complicating comorbidities of systemic sclerosis and may have had leptospirosis as well, Dr. Gordon said. "There may have also been some delays in getting him treated, although we are not sure of that."

The other was a 30-year-old woman on treatment week 22. She developed a pneumococcal pneumonia "and deteriorated rapidly," Dr. Gordon said.

There were no withdrawals because of infection or any other adverse events in any of the treatment groups.

The patients had a mean age of 39 years, and most were women (93%). The mean disease severity by BILAG score was A (severe) in 31% and B (moderate) in the remainder.

In the primary intent-to-treat analysis, there was no significant difference between placebo and 75 mg in flare rate. The 150-mg dose was associated with significantly fewer flares than was placebo (40% vs. 55%), but the difference between it and the lower dose was not statistically significant. Both doses prolonged the time to first flare significantly more than placebo.

The investigators also conducted a post hoc, potential completer analysis to examine the effect in all patients who had completed the entire 52 weeks of treatment. Atacicept 75 mg was not significantly better than placebo, but the 150-mg dose was, reducing the odds of a flare by 51% (flare rate 43% vs. 60%) – a finding similar to the intent-to-treat analysis.

The largest portion of flares (about 23%) was in the mucocutaneous and musculoskeletal systems. The 150-mg dose halved the occurrence of these flares relative to placebo.

The study was not powered to detect flare severity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). However, another post hoc analysis concluded that, compared with placebo, the 150-mg dose reduced the chance of a severe flare by 55% on SLEDAI scoring.

The study was sponsored by EMD Serono, a subsidiary of Merck. Dr. Gordon disclosed that she received personal remuneration from Merck Serono during the study. The three coauthors were Merck employees.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

PARIS – A randomized trial of two doses of atacicept for systemic lupus erythematosus was interrupted after two deaths occurred in patients taking 150 mg of the drug.

However, since a post hoc analysis concluded that the 150-mg dose was more effective at reducing flares than was the 75-mg dose, research on it continues, Dr. Caroline Gordon said at the annual European Congress of Rheumatology.

Additionally, said Dr. Gordon, professor of rheumatology at the University of Birmingham, England, the 150-mg dose was significantly more effective than was the 75-mg dose or placebo at reducing mucocutaneous and musculoskeletal flares (9% vs. 18%).

"This finding, and the suggestion that atacicept may have a steroid-sparing effect, allows for assessing its safety and efficacy further," she said.

EMD Serono, a subsidiary of Merck, is now recruiting for a 24-week trial comparing the 75- and 150-mg doses in patients with systemic lupus erythematosus (SLE).

Atacicept is an investigational, fully human recombinant fusion protein that inhibits B-lymphocyte stimulator (BLyS) and the A proliferation-inducing ligand (APRIL). Both proteins stimulate B-cell production and are elevated in patients with lupus.

At the congress, Dr. Gordon reported the results of the APRIL-SLE study, which randomized 461 patients to atacicept at either dose or placebo. Its primary endpoint was the rate of new flares in patients with lupus. Secondary endpoints included changes in disease activity scores, overall safety, biomarkers, and pharmacodynamics. The full results of the study were published after the congress (Ann. Rheum. Dis. 2014 [doi:10.1136/annrheumdis-2013-205067]).

Patients had to achieve stable condition before being randomized. After screening, they were assigned to a 10-week corticosteroid taper. If they had improved to a score of C or D on the British Isles Assessment Group (BILAG) scale, they were randomized. After the 52-week treatment period, there was a 24-week safety observation period.

Most patients in the placebo and 75-mg groups completed the study (70%). In the 150-mg arm, 43% completed the trial. After the two deaths, 38% patients in the 150 mg-arm stopped treatment. Both patients died of pneumonia complicated by pulmonary hemorrhage.

One of these was a 22-year-old man from the Philippines on week 42 of treatment, who had complicating comorbidities of systemic sclerosis and may have had leptospirosis as well, Dr. Gordon said. "There may have also been some delays in getting him treated, although we are not sure of that."

The other was a 30-year-old woman on treatment week 22. She developed a pneumococcal pneumonia "and deteriorated rapidly," Dr. Gordon said.

There were no withdrawals because of infection or any other adverse events in any of the treatment groups.

The patients had a mean age of 39 years, and most were women (93%). The mean disease severity by BILAG score was A (severe) in 31% and B (moderate) in the remainder.

In the primary intent-to-treat analysis, there was no significant difference between placebo and 75 mg in flare rate. The 150-mg dose was associated with significantly fewer flares than was placebo (40% vs. 55%), but the difference between it and the lower dose was not statistically significant. Both doses prolonged the time to first flare significantly more than placebo.

The investigators also conducted a post hoc, potential completer analysis to examine the effect in all patients who had completed the entire 52 weeks of treatment. Atacicept 75 mg was not significantly better than placebo, but the 150-mg dose was, reducing the odds of a flare by 51% (flare rate 43% vs. 60%) – a finding similar to the intent-to-treat analysis.

The largest portion of flares (about 23%) was in the mucocutaneous and musculoskeletal systems. The 150-mg dose halved the occurrence of these flares relative to placebo.

The study was not powered to detect flare severity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). However, another post hoc analysis concluded that, compared with placebo, the 150-mg dose reduced the chance of a severe flare by 55% on SLEDAI scoring.

The study was sponsored by EMD Serono, a subsidiary of Merck. Dr. Gordon disclosed that she received personal remuneration from Merck Serono during the study. The three coauthors were Merck employees.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

PARIS – A randomized trial of two doses of atacicept for systemic lupus erythematosus was interrupted after two deaths occurred in patients taking 150 mg of the drug.

However, since a post hoc analysis concluded that the 150-mg dose was more effective at reducing flares than was the 75-mg dose, research on it continues, Dr. Caroline Gordon said at the annual European Congress of Rheumatology.

Additionally, said Dr. Gordon, professor of rheumatology at the University of Birmingham, England, the 150-mg dose was significantly more effective than was the 75-mg dose or placebo at reducing mucocutaneous and musculoskeletal flares (9% vs. 18%).

"This finding, and the suggestion that atacicept may have a steroid-sparing effect, allows for assessing its safety and efficacy further," she said.

EMD Serono, a subsidiary of Merck, is now recruiting for a 24-week trial comparing the 75- and 150-mg doses in patients with systemic lupus erythematosus (SLE).

Atacicept is an investigational, fully human recombinant fusion protein that inhibits B-lymphocyte stimulator (BLyS) and the A proliferation-inducing ligand (APRIL). Both proteins stimulate B-cell production and are elevated in patients with lupus.

At the congress, Dr. Gordon reported the results of the APRIL-SLE study, which randomized 461 patients to atacicept at either dose or placebo. Its primary endpoint was the rate of new flares in patients with lupus. Secondary endpoints included changes in disease activity scores, overall safety, biomarkers, and pharmacodynamics. The full results of the study were published after the congress (Ann. Rheum. Dis. 2014 [doi:10.1136/annrheumdis-2013-205067]).

Patients had to achieve stable condition before being randomized. After screening, they were assigned to a 10-week corticosteroid taper. If they had improved to a score of C or D on the British Isles Assessment Group (BILAG) scale, they were randomized. After the 52-week treatment period, there was a 24-week safety observation period.

Most patients in the placebo and 75-mg groups completed the study (70%). In the 150-mg arm, 43% completed the trial. After the two deaths, 38% patients in the 150 mg-arm stopped treatment. Both patients died of pneumonia complicated by pulmonary hemorrhage.

One of these was a 22-year-old man from the Philippines on week 42 of treatment, who had complicating comorbidities of systemic sclerosis and may have had leptospirosis as well, Dr. Gordon said. "There may have also been some delays in getting him treated, although we are not sure of that."

The other was a 30-year-old woman on treatment week 22. She developed a pneumococcal pneumonia "and deteriorated rapidly," Dr. Gordon said.

There were no withdrawals because of infection or any other adverse events in any of the treatment groups.

The patients had a mean age of 39 years, and most were women (93%). The mean disease severity by BILAG score was A (severe) in 31% and B (moderate) in the remainder.

In the primary intent-to-treat analysis, there was no significant difference between placebo and 75 mg in flare rate. The 150-mg dose was associated with significantly fewer flares than was placebo (40% vs. 55%), but the difference between it and the lower dose was not statistically significant. Both doses prolonged the time to first flare significantly more than placebo.

The investigators also conducted a post hoc, potential completer analysis to examine the effect in all patients who had completed the entire 52 weeks of treatment. Atacicept 75 mg was not significantly better than placebo, but the 150-mg dose was, reducing the odds of a flare by 51% (flare rate 43% vs. 60%) – a finding similar to the intent-to-treat analysis.

The largest portion of flares (about 23%) was in the mucocutaneous and musculoskeletal systems. The 150-mg dose halved the occurrence of these flares relative to placebo.

The study was not powered to detect flare severity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). However, another post hoc analysis concluded that, compared with placebo, the 150-mg dose reduced the chance of a severe flare by 55% on SLEDAI scoring.

The study was sponsored by EMD Serono, a subsidiary of Merck. Dr. Gordon disclosed that she received personal remuneration from Merck Serono during the study. The three coauthors were Merck employees.

msullivan@frontlinemedcom.com

On Twitter @alz_gal