Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial

On Study Day -14, patients commenced MMF (500 mg, twice daily, orally) and prednisone/prednisone equivalent (the lesser of 0.8 mg/kg/day or 60 mg/day, orally). MMF dose was increased to 1,000 mg twice daily at Day -7, thereafter up to a maximum of 1.5 g twice daily by Day 1. Day -14 to Day 1 was defined as the screening period. Patients fulfilling all entry criteria were randomized (1:1) on Day 1 to placebo or atacicept, 150 mg subcutaneously, twice weekly for 4 weeks, then 150 mg weekly for a planned 48 weeks. The CS dose was to be tapered starting at Week 5 by 5 mg/day/week, to 10 mg/day by Week 12. Assessments were scheduled post Day 1 at Weeks 2 and 4, then every 4 weeks to Week 52. Following the discontinuation of the study drug (completion of 52 weeks of treatment or early termination), follow-up visits were scheduled 4, 12 and 24 weeks after the last dose.

Key inclusion criteria were: SLE diagnosis satisfying ≥ 4 of the 11 American College of Rheumatology criteria [4]; positive antinuclear antibody test (Hep-2 antinuclear antibody ≥ 1:80) and/or antibodies against double-stranded DNA ([anti-dsDNA] ≥ 30 IU/ml); renal biopsy within the 12 months preceding study entry, with histological findings consistent with active LN (International Society of Nephrology/Renal Pathology Society class III or IV LN); active LN, defined by proteinuria (urine protein:creatinine ratio [UPr:Cr] > 1.0 mg/mg) and hematuria (> 10 red blood cells [RBCs]/high-powered field [hpf] with or without RBC casts): all other causes of hematuria of non-glomerular origin were excluded. Key exclusion criteria were: renal disease unrelated to SLE; calculated glomerular filtration rate ([GFR] based on the Modification of Diet in Renal Disease equation) ≤ 30 ml/min/1.73 m² at screening; comorbidities requiring CS; progressive disease (25% decrease in GFR or doubling of UPr:Cr between screening and randomization). The Institutional Review Board or Ethics Committee at each center approved the study; written informed consent was obtained from each patient or their legal representative, according to the Declaration of Helsinki.

Key criteria for discontinuation were: 25% decrease in calculated GFR or doubling of UPr:Cr compared with baseline; IgG level < 3 g/L; minimal or no improvement in renal parameters at Week 24.

At the time of termination, six patients from four centers in the US had been randomized: two to receive placebo and four to receive atacicept (Table 1). Four patients were women and two men; the age range was 18 to 54 years.

The courses of the four atacicept-treated patients are described here. Three patients developed serum IgG levels below the protocol-defined discontinuation criterion. Patient #3 had an IgG level of 2.9 g/l on Day 29 and developed Haemophilus influenzae pneumonia complicated by empyema, septicemia and pneumothorax; treatment was discontinued on Day 30. Patient #13 had an IgG level of 2.5 g/l on Day 30; treatment was discontinued on Day 33 and the patient was diagnosed with Legionella pneumophila pneumonia on Day 34. Patient #14 had an IgG of 2.5 g/l and was discontinued on Day 18. At Week 12 of the safety follow-up period, this patient developed Bacillus bacteremia. Patient #5 had atacicept administered until Day 230, when the study was discontinued. Her IgG level decreased from a baseline of 20.1 to 4.7 g/l at Week 12, and then gradually increased to 6.9 g/l at approximately Week 34 (when atacicept was terminated along with the study).

In both placebo-treated patients, IgG levels fell between Days 1 and 15, declining to nadirs at Weeks 4 and 8 above the lower limit of normal [LLN] (11.9 g/l in Patient #2; 10.2 g/l in Patient #8), before gradually increasing. Patient #2 discontinued study participation due to leukocytoclastic vasculitis, 148 days post randomization. Patient #8 continued until the time of study termination, 85 days post randomization.

The study was terminated early as a result of the above safety events and, thus, none of the patients reached full treatment to Week 52. Enrollment ceased and study drug administration stopped in all patients. All patients completed a 24-week post-treatment follow-up period. Table 1 provides demographic and disease history characteristics, study treatment duration, and reasons for discontinuation.

Immunoglobulin levels across the study period are shown in Figure 1. Serum IgG levels were normal or elevated in all patients at screening. Following the initiation of MMF and CS, a marked reduction in IgG (up to 57%) was observed by Day 1 (Table 2; Figure 1A). The decreases were largest in those patients who were subsequently randomized to atacicept. Serum IgG levels continued to decline between Days 1 and 14, by up to 47% versus Day 1 and 72% versus Day -14 (Table 2). Neither IgA nor IgM levels showed a consistent decrease among enrolled patients (Table 2; Figures 1B, C).

At screening, the patients subsequently randomized to atacicept presented with more severe proteinuria (UPr:Cr ≥ 3.0 versus ≤ 2.3 mg/mg) and a lower mean GFR (52.1 versus 76.1 ml/min/1.73 m²) compared with those who were randomized to placebo on Day 1. Baseline GFR was particularly low in Patients #13 and #14, and remained so on Days 1 and 14. Whereas UPr:Cr had fallen below 1.0 mg/mg in Patient #2 on Days 1 and 14, and in Patient #8 on Day 14 (Day 1 reading unavailable), it remained high on Days 1 and 14 in patients randomized to atacicept (range 5.6 to 18.0 mg/mg, with the exception of a value of 1.0 mg/mg in Patient #5 on Day 1). At the end of the study period, both placebo-treated and two atacicept-treated patients (Patients #5 and #13) had UPr:Cr ratios that were lower than baseline values. In a third atacicept-treated patient (Patient #3), the ratio was approximately the same as at baseline, and in Patient #14 it was higher than at baseline.

Patients entered the study with wide variations in counts of white blood cells (WBCs), absolute neutrophils, and absolute lymphocytes (Table 3). During the study, WBCs fluctuated in all patients but were within the normal range by the 24-week follow-up visit in all except Patient #5. Neutrophilia was common at screening and Day 1. Lymphocyte concentrations at screening were below or at the lower end of the reference range (0.9 to 4.3 × 10⁹/l) in all patients (Table 3). In Patients #3 and #13, lymphocyte counts declined from a baseline (Day -14) level within the reference range (0.9 and 1.5 × 10⁹/l, respectively) to Grade 2 lymphopenia by Day 1 (0.7 × 10⁹/l in both). After addition of atacicept, lymphocytes continued to decline in both patients, with Grade 3 lymphopenia developing in Patient #3 on Day 29 (0.5 × 10⁹/l), coincident with H. influenzae pneumonia, and in Patient #13 on Days 15 and 30, the latter (0.5 × 10⁹/l) coincident with development of L. pneumophila pneumonia. CD4⁺ counts (not measured at screening) were also low on Day 1, in all patients measured.

On Day 1, one placebo- and three atacicept-treated patients had C3 levels below the LLN (Table 3). C3 and C4 levels rose during treatment in all patients, but started and remained below the LLN in Patient #14 (on atacicept), and were below the LLN at Day 1 and at end of treatment in Patient #2 (on placebo), having risen above the LLN during treatment. C3 levels were within the normal range at end-of-treatment assessments in the remaining three patients on atacicept and one on placebo (Table 3).