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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A

Objective

To investigate whether treatment with abetimus delays renal flare in patients with lupus nephritis. Secondary objectives included evaluation of the effect of abetimus on C3 levels, anti–double-stranded DNA (anti-dsDNA) antibody levels, use of high-dose corticosteroids and/or cyclophosphamide, and major systemic lupus erythematosus (SLE) flare.

Methods

We conducted a randomized, placebo-controlled study of treatment with abetimus at 100 mg/week for up to 22 months in SLE patients. Three hundred seventeen patients with a history of renal flare and anti-dsDNA levels >15 IU/ml were randomized to a treatment group (158 abetimus, 159 placebo); 298 (94%) were enrolled in the intent-to-treat (ITT) population (145 abetimus, 153 placebo), based on the presence of high-affinity antibodies for the oligonucleotide epitope of abetimus at baseline screening.

Results

Abetimus did not significantly prolong time to renal flare, time to initiation of high-dose corticosteroid and/or cyclophosphamide treatment, or time to major SLE flare. However, there were 25% fewer renal flares in the abetimus group compared with the placebo group (17 of 145 abetimus-treated patients [12%] versus 24 of 153 placebo-treated patients [16%]). Abetimus treatment decreased anti-dsDNA antibody levels (P < 0.0001), and reductions in anti-dsDNA levels were associated with increases in C3 levels (P < 0.0001). More patients in the abetimus group experienced ≥50% reductions in proteinuria at 1 year, compared with the placebo group (nominal P = 0.047). Trends toward reduced rates of renal flare and major SLE flare were noted in patients treated with abetimus who had impaired renal function at baseline. Treatment with abetimus for up to 22 months was well tolerated.

Conclusion

Abetimus at 100 mg/week significantly reduced anti-dsDNA antibody levels but did not significantly prolong time to renal flare when compared with placebo. Multiple positive trends in renal end points were observed in the abetimus treatment group.

There is a substantial body of evidence implicating anti–double-stranded DNA (anti-dsDNA) antibodies in the pathogenesis of lupus nephritis. Anti-dsDNA antibodies are rarely found in individuals without SLE (1–4), and their presence is diagnostic for SLE and prognostic for development of lupus nephritis. The presence of anti-dsDNA antibodies often correlates with active renal disease (5–8). Anti-dsDNA antibodies are concentrated in the kidneys of SLE patients and often have a much higher avidity for dsDNA than do antibodies in the circulation (9, 10). Well-controlled studies have demonstrated a strong correlation between rises in anti-dsDNA antibody levels and subsequent exacerbations of SLE (11–14). Similarly, reductions in anti-dsDNA antibody levels are associated with improved prognosis, in terms of reduced risk of renal flare (15).

The pathogenicity of anti-dsDNA antibodies is related to the formation of immune complexes that either deposit in the kidney glomerulus or form in situ by binding directly to kidney glomerular structures (9, 16–19). Factors that contribute to anti-dsDNA pathogenicity are IgG isotype, the ability to fix complement, cross-reactivity with resident kidney antigens, amino acid composition in the complementarity-determining regions, and high affinity for dsDNA (20–24).

Abetimus sodium (previously called LJP 394) is an investigational drug designed to prevent deterioration of renal function in SLE patients. It is composed of 4 identical strands of dsDNA, each containing 20 bp of unmodified native nucleotides that are covalently linked to a small molecule platform. Abetimus derives its specificity for anti-dsDNA antibodies from this structure and is composed of ∼97% dsDNA (25). Clinical studies have shown that single and repeated intravenous administrations of abetimus result in rapid and sustained reductions of circulating anti-dsDNA antibody levels (26–28). The mechanism of action of abetimus is thought to involve rapid reduction of anti-dsDNA antibody levels mediated by formation and clearance of drug–antibody complexes and a prolonged effect related to tolerizing anti-dsDNA–specific B cells. In BXSB mice, administration of abetimus resulted in a 60–90% reduction in dsDNA antibody–producing B cells, thus suggesting that the drug was able to induce tolerance (25, 29).

A previous phase II/III study of abetimus (the 90-05 trial) examined the effect of treatment with abetimus in SLE patients with a history of renal disease (28). While the prospective analysis from that trial did not reveal a benefit of treatment, a retrospective analysis of patients with high-affinity antibodies to the oligonucleotide epitope of abetimus at baseline revealed that in that subgroup, patients treated with abetimus had significantly better clinical outcomes than those in the placebo group, including longer time to renal flare, fewer rescue treatments with high-dose corticosteroids and cyclophosphamide, fewer renal flares, and fewer major SLE flares. Patients with impaired renal function (serum creatinine ≥1.5 mg/dl) at baseline who received abetimus had fewer renal flares and major SLE flares than did those treated with placebo.

The 90-09 study described herein was designed to confirm the preliminary findings obtained in the 90-05 trial. The primary objective was to determine whether treatment with abetimus (100 mg/week) is effective in delaying time to renal flare, compared with placebo. Secondary analyses included evaluation of changes in C3 and anti-dsDNA antibody levels, time to and frequency of high-dose corticosteroid and cyclophosphamide rescue treatment, major SLE flare, and change in health-related quality of life.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A

This multicenter trial was approved by a properly constituted institutional review board or independent ethics committee at all sites (72 sites in North America and 15 in Europe) and performed in compliance with Good Clinical Practice, International Conference on Harmonisation E6 and in accordance with the Declaration of Helsinki. Participating investigators are listed in Appendix A. Written informed consent was obtained from each patient, and from legal guardians of patients who were minors.

Patient population.

Inclusion and exclusion criteria were designed to identify SLE patients with stable renal disease at baseline. Key inclusion criteria for enrollment in the study were age ≥12 years, a confirmed diagnosis of SLE according to the American College of Rheumatology criteria (2), an anti-dsDNA level of ≥15 IU/ml (by Farr assay) at the screening visit, and a history of renal flare within the last 4 years. Key exclusion criteria included increased SLE renal disease within 4 months prior to the study as evidenced by new reproducible hematuria or significant increases in serum creatinine level or proteinuria, treatment with prednisone >20 mg/day, cyclophosphamide, or cyclosporine within 4 months prior to the study, or initiation or increase in dosage of azathioprine, methotrexate, mycophenolate mofetil, or leflunomide within 4 months prior to the study.

Study design.

The LJP 394-90-09 study was a multicenter, double-blind, placebo-controlled trial evaluating weekly intravenous administration of 100 mg abetimus or placebo in patients with a history of SLE renal disease. Following a screening period of∼4–6 weeks, patients were randomized to receive abetimus or matching placebo, at a 1:1 ratio. Placebo consisted of phosphate buffered saline. The maximum duration of treatment was 22 months. At the end of the double-blind treatment period, patients were provided the opportunity to enroll in an open-label extension trial. Patients were followed up for at least 1 month following cessation of treatment, for safety monitoring.

Baseline serum samples from all randomized patients were analyzed in a blinded manner, to determine the affinity of their anti-dsDNA antibodies to the dsDNA epitope of abetimus (30, 31). Baseline affinity assay results were used to define the intent-to-treat (ITT) population as patients with high-affinity antibodies to the oligonucleotide epitope of abetimus (Kd ≤0.8 mg IgG/ml serum). Patients in both study arms could receive standard medical treatment for their disease throughout the trial, as deemed appropriate by the study investigator.

Designation of renal flare.

Designation of renal flare required that at least 1 of the following 3 criteria be met: 1) a reproducible increase in the 24-hour urine protein level to (a) >1,000 mg/24 hours if the baseline value was <200 mg/24 hours, (b) >2,000 mg/24 hours if the baseline value was 200–1,000 mg/24 hours, or (c) >2-fold if the baseline value was >1,000 mg/24 hours; 2) a reproducible increase in the serum creatinine level of >20% or >0.3 mg/dl (whichever was greater), accompanied by proteinuria (>1,000 mg/24 hours), hematuria (≥4 red blood cells/high-power field), and/or red cell casts; or 3) new reproducible hematuria (≥11–20 red blood cells/high-power field) or a reproducible increase in hematuria by ≥2 grades compared with baseline, associated with >25% dysmorphic red blood cells, glomerular in origin, exclusive of menses, accompanied by either a ≥800-mg increase in 24-hour protein excretion or new red cell casts. All laboratory values were determined at a central laboratory. Designation of renal flare also required attribution to SLE by the treating physician, medical monitor, and an independent renal events committee.

Additional end points.

Additional prospective end points studied included incidence of renal flare, incidence of and time to treatment with high-dose corticosteroids (initiation of or increase in prednisone or equivalent of ≥15 mg/day, resulting in a final daily dosage of >20 mg for at least 3 days or any dose >200 mg) and/or cyclophosphamide (at any dosage), major SLE flare, and change in C3 and anti-dsDNA antibody levels. Major SLE flare was defined as the occurrence of any of the following due to manifestations of active SLE: 1) initiation of treatment with high-dose corticosteroids and/or cyclophosphamide, 2) initiation of or increase in treatment with other immunosuppressive drugs, including azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, and leflunomide, 3) hospitalization, or 4) death. Disease activity was additionally evaluated with the SLE Disease Activity Index (32). Health-related quality of life was assessed using the Short Form 36 Health Survey (SF-36) (33).

Statistical analysis.

The primary efficacy end point was time to renal flare, in patients with high-affinity antibodies to abetimus at baseline. The trial design required a minimum of 38 documented renal flares for 80% power to detect a statistically significant difference in time to renal flare at the 2-sided significance level of α = 0.05, assuming a 20% dropout rate and an 18-month renal flare rate of 35% in the placebo group and 14% in the abetimus group. The distribution of time-to-event was plotted using the Kaplan-Meier product limit estimator, and comparison of all time-to-event variables was performed by log rank test. Patients who discontinued treatment without reaching the study end point were considered censored at the time of dropout for time-to-event analyses. Median survival time was estimated from the corresponding incidence rates based on an exponential survival model. All treatment group comparisons were conducted with a significance level of α = 0.05, using 2-tailed tests. All analyses were conducted at the nominal level without correction for multiple end points or multiple testing.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A

Patient disposition.

Of 1,024 patients screened, 298 were enrolled in the ITT population for assessment of efficacy (145 randomized to receive abetimus, 153 placebo), and a total of 317 patients were exposed to one of the study treatments and included in the safety study population (158 abetimus, 159 placebo) (Figure 1). Time of study drug exposure was similar between treatment groups, with a mean duration of treatment of 315 days (range 1–641) in the abetimus group and 336 days (range 1–646) in the placebo group. Baseline characteristics of patients in the abetimus and placebo groups were similar (Table 1). Eighty-three percent of the patients in each group were taking prednisone at baseline (121 in the abetimus group, 127 in the placebo group). At baseline, 69 patients in the abetimus group (48%) and 64 in the placebo group (42%) had been treated with other immunosuppressive agents.

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Figure 1. Disposition of the patients. ITT = intent-to-treat; AE = adverse event.

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Table 1. Baseline characteristics of the systemic lupus erythematosus patients, by treatment group*
 Abetimus (n = 145)Placebo (n = 153)
  • *

    Except where indicated otherwise, values are the number (%). BMI = body mass index; anti-dsDNA = anti–double-stranded DNA.

Sex  
 Female127 (87.6)132 (86.3)
 Male18 (12.4)21 (13.7)
Race  
 White69 (47.6)68 (44.4)
 Asian5 (3.5)10 (6.5)
 Black33 (22.8)43 (28.1)
 Hispanic35 (24.1)26 (17.0)
 Other3 (2.1)6 (3.9)
Age, mean ± SD years37.1 ± 1135.2 ± 9.9
Weight, kg
 Mean ± SD74 ± 2173.4 ± 18.5
 <6039 (26.9)39 (25.5)
 ≥60106 (73.1)114 (74.5)
BMI, kg/m2  
 Mean ± SD28 ± 727 ± 6
 ≤2666 (45.5)78 (51.0)
 >2679 (54.5)75 (49.0)
Serum creatinine, mg/dl  
 Mean ± SD1.1 ± 0.401.1 ± 0.36
 <1.5125 (86.2)130 (85.0)
 ≥1.520 (13.8)23 (15.0)
Creatinine clearance, ml/minute  
 Mean ± SD88.0 ± 43.386.8 ± 36.3
 <304 (2.8)1 (0.7)
 30–5018 (12.4)20 (13.1)
 >50–8038 (26.2)40 (26.1)
 >8062 (42.8)79 (51.6)
Urine protein, mg/24 hours  
 Mean ± SD963 ± 1,3291,131 ± 1,939
 <50067 (46.2)78 (51.0)
 ≥500–≤1,00022 (15.2)21 (13.7)
 >1,000–≤2,00018 (12.4)20 (13.1)
 >2,00020 (13.8)24 (15.7)
C3, mg/dl  
 Mean ± SD87.0 ± 25.483.5 ± 28.2
 <7546 (31.7)62 (40.5)
 ≥7599 (68.3)91 (59.5)
Anti-dsDNA, IU/ml  
 Mean ± SD86.5 ± 137.175.8 ± 69.3
 <75108 (74.5)94 (61.4)
 ≥7537 (25.5)59 (38.6)

Renal flare.

The number of patients at risk of renal flare and the Kaplan-Meier survival plot of time to renal flare are shown in Figures 2a and b. The primary analysis revealed that time to renal flare did not differ significantly between the abetimus and placebo groups. The estimated median time to renal flare was 123 months in the abetimus group and 89 months in the placebo group. The average time to flare in patients with renal flare, excluding data from patients who did not experience a flare, was 310 days and 341 days in the abetimus and placebo groups, respectively. There were 25% fewer renal flares in the abetimus group than in the placebo group (17 of 145 [11.7%] versus 24 of 153 [15.7%]).

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Figure 2. Kaplan-Meier survival plots of time to renal flare and change in anti–double-stranded DNA (anti-dsDNA) antibody levels in the intent-to-treat population, by treatment group. a, Total number of patients at risk of renal flare over the course of the trial. b, Distribution of renal flares by treatment group at 46 weeks (22 in the placebo group, 10 in the abetimus group) and at the end of the trial (24 in the placebo group, 17 in the abetimus group). c, Median percent change from baseline in anti-dsDNA antibody levels. The effect of abetimus on anti-dsDNA antibody levels was significantly different from that of placebo (P < 0.0001). While there was a trend toward a difference between treatment arms during the middle of the study, treatment with abetimus did not significantly prolong time to renal flare when compared with placebo treatment. The substantial reduction in anti-dsDNA antibody levels in the placebo group as the trial progressed paralleled an apparent reduction in risk of renal flare in the placebo group during the second half of the trial.

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The survival plot (Figure 2b) suggested that the risk of developing a renal flare was greater in the placebo group than in the abetimus group for the much of the study period. More than 90% of the total renal flares in the placebo group (22 of 24) were observed during the first 46 weeks of exposure, compared with 59% of the total renal flares (10 of 17) occurring during this same period in the abetimus group. The apparent reduction in risk of renal flare in the placebo group in the second half of the trial was unexpected and was concurrent with a substantial reduction in anti-dsDNA levels in this treatment group (Figure 2c).

Of the patients in the abetimus group who developed renal flares, 8 (versus 18 in the placebo group) were judged to have renal flare based on proteinuria, 4 (versus 0 in the placebo group) based on hematuria, and 5 (versus 6 in the placebo group) based on serum creatinine level. There were 5 renal flares among the patients with low-affinity antibodies to abetimus (4 of 13 patients [30.8%]) in the abetimus treatment group and (1 of 6 [16.7%]) in the placebo group. This difference was not statistically significant. The median duration of exposure to study treatment among patients in the low-affinity antibody population was 468 days in the abetimus group and 88 days in the placebo group.

Therapeutic intervention was required in patients with renal flare. Among the 41 patients with renal flares in this study, 15 (37%) received cyclophosphamide and 33 (80%) received high-dose corticosteroids; 22 (54%) were hospitalized.

High-dose corticosteroid and/or cyclophosphamide treatment.

There was no evidence of treatment effect on time to initiation of treatment with high-dose corticosteroids and/or cyclophosphamide. The median time to institution of these treatments was 59 weeks in the abetimus group and 57 weeks in the placebo group (P not significant). Of the 69 patients who started treatment with high-dose corticosteroids, cyclophosphamide, or both, 33 were in the abetimus group and 36 in the placebo group.

Major SLE flare.

The composite end point major SLE flare was developed to provide a more comprehensive assessment of the impact of treatment with abetimus on SLE disease. The incidence of major SLE flare was 21% lower in the abetimus group (35 of 145 patients [24%]) than in the placebo group (47 of 153 patients [31%]). The estimated median time to major SLE flare was 55 months in the abetimus-treated group and 42 months in the placebo-treated group. The difference in time to major SLE flare between the abetimus and placebo groups was not statistically significant.

Treatment effects in patients with impaired renal function at baseline.

Renal impairment, defined as a serum creatinine level of ≥1.5 mg/dl, was assessed at baseline, and the subgroup of 43 patients with renal impairment at baseline was analyzed prospectively. Twenty of these patients were in the abetimus treatment group and 23 in the placebo group. In this subpopulation, abetimus-treated patients appeared to benefit more than placebo-treated patients, on multiple outcome measures. They had fewer renal flares (2 patients [10%] in the abetimus group versus 6 [26%] in the placebo group), a lower frequency of initiation of high-dose corticosteroid or cyclophosphamide treatment (4 patients [20%] in the abetimus group versus 6 [26%] in the placebo group), and fewer major SLE flares (4 patients [20%] in the abetimus group versus 7 [30%] in the placebo group). However, these differences were not statistically significant, due in part to the small number of patients.

Proteinuria.

A retrospective evaluation of the effect of abetimus on 24-hour urine protein levels was conducted for all ITT patients who had 24-hour urine collections both at baseline and at 1 year. A larger proportion of patients in the abetimus treatment group had at least a 50% reduction in proteinuria compared with the placebo group (26 of 63 patients [41.3%] versus 23 of 81 patients [28.4%]; nominal P = 0.047) (Table 2). The effect of treatment was evident across the range of baseline proteinuria levels.

Table 2. Patients with a ≥50% reduction in 24-hour urine protein level from baseline, at week 52*
Baseline urine protein, mg/24 hoursAbetimus (n = 145)Placebo (n = 153)
No. of patientsNo. (%) with ≥50% reduction at week 52No. of patientsNo. (%) with ≥50% reduction at week 52
  • *

    Analysis includes all patients in the intent-to-treat population who completed 1 year of study treatment and had a protocol-specified 24-hour urine protein collection at 1 year.

  • Nominal P = 0.047 by logistic regression.

≤5003511 (31.4)345 (14.7)
>500–1,00095 (55.6)135 (38.5)
>1,000–2,00085 (62.5)175 (29.4)
>2,000–3,00063 (50.0)83 (37.5)
>3,00052 (40.0)95 (55.6)
Total6326 (41.3)8123 (28.4)

SLEDAI.

There was a trend toward improved SLEDAI scores over the course of the study in the abetimus group compared with the placebo group (Figure 3a). The impact of abetimus treatment on the SLEDAI appeared to be progressively greater over time and was statistically significant at several time points.

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Figure 3. Changes in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores and anti–double-stranded DNA (anti-dsDNA) levels in the intent-to-treat population, by treatment group (▴ = placebo; ⧫ = abetimus). a, Mean percent change from baseline in SLEDAI scores. There was a progressive improvement in SLEDAI scores in the abetimus group compared with the placebo group. ∗ = P < 0.05; ∗∗ = P < 0.005, versus placebo. b and c, Median percent change from baseline in anti-dsDNA antibody levels among patients who were taking azathioprine (b) (38 of 145 patients [26%] in the abetimus group, 36 of 153 patients [24%] in the placebo group) or mycophenolate mofetil (c) (20 of 145 patients [14%] in the abetimus group, 22 of 153 patients [14%] in the placebo group) at baseline. The effect of abetimus on anti-dsDNA antibody levels was additive with the effect of these immunosuppressive agents.

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Anti-dsDNA antibody and C3 levels.

The effect of treatment on anti-dsDNA antibody levels is shown in Figure 2c. Values for anti-dsDNA antibody levels measured after initiation of high-dose corticosteroid or cyclophosphamide treatment are excluded because these treatments can decrease anti-dsDNA antibody levels and increase C3 levels, potentially confounding the evaluation of study drug effects on these parameters. Treatment with abetimus was associated with a statistically significant decrease in anti-dsDNA antibody levels from baseline compared with the effect observed with placebo (P < 0.0001). The maximal effect of abetimus 100 mg/week on anti-dsDNA levels was achieved after ∼3 months of treatment and maintained for the 22-month duration of the study.

As can be seen in Figure 2c, a progressive decline in anti-dsDNA antibody levels in the placebo group was observed. This finding was unexpected since all previous trials with abetimus showed either no change or modest increases in anti-dsDNA levels in placebo-treated patients over durations that extended to 18 months of treatment (26–28). Several potential causes were examined, including differential utilization of concomitant medications. However, no definitive explanation for the reduction in anti-dsDNA levels in the placebo group is available at this time.

An effect of abetimus on anti-dsDNA antibody levels was also observed in patients receiving concomitant immunosuppressive therapy. Abetimus-treated patients taking azathioprine or mycophenolate mofetil showed significant reductions in anti-dsDNA antibody levels when compared with placebo-treated patients receiving these medications (Figures 3b and c).

There was a statistically significant inverse correlation between anti-dsDNA antibody levels and C3 levels, with correlation coefficients of −0.337 and −0.453 in the abetimus and placebo groups, respectively (nominal P < 0.0001 for both groups). By week 24, 7 of 23 patients (30%) in the abetimus group who had low C3 levels (<75 mg/dl) at baseline showed a ≥25% increase in C3 levels; at week 48, C3 levels had increased ≥25% in 6 of 14 abetimus-treated patients (43%) with low baseline C3 levels. This compared favorably with findings in placebo-treated patients with low C3 levels at baseline, among whom 7 of 37 (19%) and 6 of 21 (29%) had at least a 25% increase in C3 levels at week 24 and week 48, respectively.

Health-related quality of life.

Results from previous trials showed improvement in the abetimus treatment group in selected domains measuring health-related quality of life, including evaluations obtained at the time of renal flare (34, 35). In the present trial, maintenance or improvement in health-related quality of life as assessed with the SF-36 was evaluated at weeks 24 and 48, at the termination visit, and following a renal flare. Meaningful improvements were not consistently demonstrated within the abetimus treatment group or between the abetimus and placebo groups. The analysis of patients with available SF-36 data from the periods preceding and following a documented renal flare, however, demonstrated less deterioration in several domains of the SF-36 in the abetimus treatment group compared with the placebo group.

Safety.

The safety analysis population included all 317 patients (158 in the abetimus group, 159 in the placebo group) who received at least 1 dose of study medication. It included the ITT population of 298 patients with high-affinity antibodies at baseline, and the 19 patients who had low-affinity antibodies at baseline. The mean duration of treatment exposure was 315 days (range 1–641) in the abetimus treatment group and 336 days (range 1–646) in the placebo group.

Abetimus appeared to be well tolerated, with no apparent differences in the overall incidence of adverse events between abetimus-treated and placebo-treated patients. One hundred thirty-nine patients (88%) in the abetimus group experienced at least 1 adverse event, compared with 142 patients (89%) in the placebo group. The most frequently reported events were in the body-as-a-whole system, followed by the digestive system and the skin/appendages. The most common adverse events in the abetimus treatment group that were considered by the investigators to be related to study drug were headache, dizziness, and rash. There were 3 infections considered by the investigators to be related to study drug administration (2 in the abetimus group and 1 in the placebo group). Adverse events seen in ≥3% of abetimus-treated patients and more frequently in abetimus-treated than in placebo-treated patients are shown in Table 3.

Table 3. Adverse events occurring with a frequency of ≥3% in the abetimus group and occurring more frequently in the abetimus group than in the placebo group, in the safety study population*
System and eventAbetimus (n = 158)Placebo (n = 159)
  • *

    Values are the number (%) of patients.

Any adverse event139 (88.0)142 (89.3)
Adverse events by system  
 Body as a whole  
  Pain40 (25.3)29 (18.2)
  Headache39 (24.7)33 (20.8)
  Accidental injury21 (13.3)21 (13.2)
  Allergic reaction16 (10.1)9 (5.7)
  Chest pain14 (8.9)13 (8.2)
  Facial edema6 (3.8)3 (1.9)
  Chills5 (3.2)5 (3.1)
  Neck pain5 (3.2)4 (2.5)
 Cardiovascular  
  Migraine8 (5.1)8 (5.0)
  Hemorrhage6 (3.8)3 (1.9)
 Digestive  
  Vomiting14 (8.9)13 (8.2)
  Dyspepsia7 (4.4)6 (3.8)
  Gingivitis7 (4.4)2 (1.3)
  Gastrointestinal distress5 (3.2)5 (3.1)
 Hematic/lymphatic  
  Anemia15 (9.5)10 (6.3)
  Ecchymosis12 (7.6)8 (5.0)
  Leukopenia5 (3.2)4 (2.5)
 Metabolic/nutritional  
  Hypokalemia11 (7.0)6 (3.8)
  Dehydration5 (3.2)1 (0.6)
 Musculoskeletal  
  Joint disorder6 (3.8)0 (0.0)
  Spontaneous bone fracture5 (3.2)3 (1.9)
  Leg cramps5 (3.2)4 (2.5)
 Nervous  
  Paresthesia8 (5.1)7 (4.4)
  Depression6 (3.8)5 (3.1)
  Vertigo6 (3.8)1 (0.6)
  Anxiety5 (3.2)2 (1.3)
 Respiratory  
  Pharyngitis25 (15.8)17 (10.7)
  Increased cough21 (13.3)18 (11.3)
  Bronchitis13 (8.2)8 (5.0)
  Dyspnea13 (8.2)7 (4.4)
  Pneumonia7 (4.4)6 (3.8)
 Skin/appendages  
  Rash24 (15.2)21 (13.2)
  Alopecia13 (8.2)11 (6.9)
  Herpes zoster10 (6.3)5 (3.1)
  Skin ulcer5 (3.2)4 (2.5)
  Urticaria5 (3.2)4 (2.5)
  Maculopapular rash5 (3.2)2 (1.3)
 Special senses  
  Conjunctivitis13 (8.2)7 (4.4)
  Otitis media5 (3.2)4 (2.5)
 Urogenital  
  Urinary tract infection21 (13.3)19 (11.9)
  Vaginal Monilia7 (4.4)4 (2.5)
  Cystitis6 (3.8)3 (1.9)

Serious adverse events were reported in a total of 62 patients (30 of 158 patients in the abetimus group and 32 of 159 in the placebo group [19% and 20%, respectively]). The only serious adverse events observed in >2 patients in the abetimus group were pneumonia (3 of 158 patients in the abetimus group [1.9%] and 4 of 159 in the placebo group [2.5%]) and nephritis (4 of 158 patients in the abetimus group [2.5%] and 4 of 159 in the placebo group [2.5%]). Three serious adverse events were considered by the investigator to be possibly related to drug administration: 2 in the abetimus group (angioedema and nephritis) and 1 in the placebo group (fever). There were 25 serious adverse events with an infectious etiology (9 in the abetimus group and 16 in the placebo group). These serious adverse events included sepsis (2 in the abetimus group, 2 in the placebo group), cellulitis (1 in the abetimus group, 2 in the placebo group), abscess (2 in the abetimus group, 1 in the placebo group), osteomyelitis (0 in the abetimus group, 1 in the placebo group), infection (0 in the abetimus group, 3 in the placebo group), pneumonia (3 in the abetimus group, 4 in the placebo group), urinary tract infection (1 in the abetimus group, 1 in the placebo group), cystitis (0 in the abetimus group, 1 in the placebo group), and pyelonephritis (0 in the abetimus group, 1 in the placebo group).

Four deaths were reported during study treatment or within 30 days of discontinuation of study drug: 3 in the abetimus group and 1 in the placebo group. The deaths in the abetimus-treated patients were caused by sepsis subsequent to pulmonary embolism and pneumonia, sepsis subsequent to cellulitis fasciitis, and cytomegalovirus pneumonitis in a patient positive for human immunodeficiency virus. The death in the placebo-treated patient was due to septic shock subsequent to pneumonia. One additional patient in the abetimus treatment group, with a history of pulmonary hypertension and mitral valve regurgitation, died of cardiac arrest 59 days after discontinuing treatment. No deaths were considered by investigators to be related to the study drug. The incidence of serious thromboembolic events was similar between treatment groups (2 of 158 abetimus-treated patients [1.3%] and 4 of 159 placebo-treated patients [2.5%]).

With the exception of the decreases in anti-dsDNA antibody levels in patients who received abetimus, changes in laboratory parameters and vital signs were comparable between treatment groups. Premature discontinuations of study treatment were also similar in the 2 groups, as seen in Figure 1. The most common reason for premature discontinuation was patient request to be withdrawn, followed by intolerable adverse events.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A

Abetimus is a novel therapeutic agent designed to specifically reduce anti-dsDNA antibody levels and thereby provide prophylactic treatment in SLE patients at risk of renal disease. The compound is highly effective at decreasing levels of anti-dsDNA antibody (26–28). In the present study, in spite of a consistent reduction in anti-dsDNA antibody levels in the abetimus-treated patient group over the entire 22 months of treatment, the primary end point of time to renal flare in the abetimus group was not significantly different from that in the placebo group. These observations raise the question of whether reduction of anti-dsDNA is not an effective means of prolonging time to renal flare, or whether the effect size obtained with the 100-mg weekly dosage of abetimus was inadequate to observe a statistically significant benefit given the design parameters of the trial.

Several observations suggest that a reduction in anti-dsDNA antibody levels in response to abetimus treatment may have a positive effect on renal disease in patients with lupus nephritis. There were 25% fewer renal flares in the abetimus group versus the placebo group at the end of the trial, with ∼50% fewer flares in the first year of the trial. Favorable trends were also observed with regard to major SLE flare. Improvements in proteinuria were observed in the abetimus treatment group at 1 year, and patients with low C3 levels showed improvement at 24 weeks and 48 weeks. The favorable findings in the entire ITT population were mirrored in the population of patients who had serum creatinine levels of ≥1.5 mg/dl at baseline. Thus, the abundance of distinct, related findings in favor of abetimus treatment supports the possibility that this treatment may have a beneficial effect, and that the effect size observed with the 100-mg weekly dosage level was inadequate to demonstrate statistical significance under the design constraints of the trial.

The finding that treatment with abetimus was associated with a 50% reduction in 24-hour urine protein levels after 1 year of treatment is important since it indicates that reducing the anti-dsDNA antibody burden can potentially improve renal function, while also preventing renal deterioration due to renal flare. We conducted a retrospective examination of the phase II/III 90-05 study results for evidence of reduction in proteinuria at 1 year, and the results were nearly identical to those reported here from the current 90-09 study (in the former study, at 1 year, 44% and 18% of patients in the abetimus group and the placebo group, respectively, had a ≥50% reduction from baseline in the 24-hour urine protein level [nominal P = 0.002]) (Cardiel MH, et al: unpublished observations). The importance of reducing proteinuria in patients with glomerular disease is well recognized (36). The glomerular filtrate is normally relatively free of protein, and protein in the renal tubules can lead to activation of inflammation mediators (37, 38). Although obtained retrospectively in one study, the observation that abetimus improved renal function, as measured by reduction in proteinuria, in two independent trials provides further evidence of the potential clinical benefit associated with reducing anti-dsDNA antibody levels in patients with lupus nephritis.

The reduction in anti-dsDNA antibody levels in the placebo group was associated with a substantial decrease in the risk of renal flare in that group in the second year of the trial. At the 1-year time point there had been approximately twice as many renal flares in the placebo group as in the abetimus treatment group. However, as the anti-dsDNA antibody levels continued to decline in the placebo group, the apparent risk of renal flare also decreased. Overall, 22 of 24 renal flares in the placebo group were observed in the first 52 weeks, with only 2 occurring in the subsequent 10 months. This association between reduction in anti-dsDNA antibody levels and reduction in risk of renal flare is consistent with observations showing that reduction in anti-dsDNA levels is associated with clinical benefit (15, 34, 35).

The inclusion of major SLE flare as an end point permits evaluation of a broad spectrum of SLE manifestations. In the present study, treatment with abetimus resulted in a 21% lower incidence of major SLE flares and improved SLEDAI scores over time, compared with placebo. Taken together, the major SLE flare data and the SLEDAI data suggest the potential for extrarenal benefit associated with reduction in anti-dsDNA antibody levels. These results are also consistent with observations that subsets of anti-dsDNA antibodies may mediate extrarenal symptoms, including cognitive impairment and depression (39–41).

The safety profile of abetimus was similar to that of placebo and did not reveal any safety considerations associated with treatment, similar to the findings in the previous phase II/III trial (28). The apparent lack of toxicity of abetimus is likely related to its DNA-based structure, since there is substantial metabolic requirement for processing of dsDNA associated with normal cell turnover. In addition, the overall systemic exposure is limited based on weekly dosing, a half-life of ∼1 hour, and a low volume of distribution, indicating that the compound is primarily confined to the vascular compartment.

In summary, weekly administration of 100 mg abetimus resulted in significant and persistent reductions in anti-dsDNA antibody levels. This did not result in a significant prolongation in time to renal flare, although 25% fewer renal flares occurred in the abetimus group compared with the placebo group throughout the trial. These combined observations leave open the possibility that abetimus in higher doses may be effective in prolonging time to renal flare. The current weekly administration of 100 mg for up to 22 months was well tolerated and did not appear to be associated with any drug-related toxicity.

Single doses of abetimus of up to 2,400 mg have been well tolerated, suggesting that the potential clinical benefit of treatment at a weekly dosage level of >100 mg should be evaluated. There is an ongoing clinical efficacy trial evaluating the ability of abetimus treatment at weekly doses of 300 mg and 900 mg to prolong time to renal flare (ClinicalTrials.gov identifier: NCT00089804). That trial should provide definitive information regarding whether reductions in anti-dsDNA antibody levels result in a prolongation of time to renal flare in patients with lupus nephritis.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A

Dr Linnik had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Cardiel, Furie, Joh, Linnik.

Acquisition of data. Cardiel, Tumlin, Furie, Wallace, Joh, Linnik.

Analysis and interpretation of data. Cardiel, Tumlin, Furie, Wallace, Joh, Linnik.

Manuscript preparation. Cardiel, Tumlin, Furie, Wallace, Joh, Linnik.

Statistical analysis. Wallace, Joh, Linnik.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A

The authors gratefully acknowledge Nancy L. Carteron, MD, FACP, Antonio Guasch, MD, and Rodanthi C. Kitridou, MD for expert assistance in adjucating renal flares as part of the independent renal event committee; Kenneth Heilbrunn, MD, Irina Yushmanova, MD, and Toni Foster for tireless efforts in coordinating the execution of the trial; Shaw-Ling Wang, PhD and Jay Hu, PhD for providing expert and insightful statistical help; and Jonathan Fishbein, MD and Ayman Farahat, MD for expert monitoring of the trial.

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  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A
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APPENDIX A

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
  9. APPENDIX A

LJP 394-90-09 INVESTIGATOR CONSORTIUM

Members of the LJP 394-90-09 Investigator Consortium are as follows: Micha Abeles, MD, Jacob Aelion, MD, Gerald B. Appel, MD, Cynthia Aranow, MD, Stanley Ballou, MD, Michael A. Becker, MD, H. Michael Belmont, MD, Eugene P. Boling, MD, Stefano Bombardieri, MD, James Brodeur, MD, Jill Buyon, MD, Mario H. Cardiel, MD, John J. Condemi, MD, Mary E. Cronin, MD, John J. Cush, MD, Raphael DeHoratius, MD, Deborah Desir, MD, John Donohue, MD, Michael Edwards, MD, Mohamed A. El-Shahawy, MD, Paul Emery, MD, FRCP, Stephanie Ensworth, MD, Luis R. Espinoza, MD, Maria Fondal, MD, Paul Fortin, MD, Richard A. Furie, MD, Thomas Geppert, MD, Gary S. Gilkeson, MD, Ellen Ginzler, MD, Peter Gorevic, MD, Jose Granda, MD, Jennifer Grossman, MD, Falk Hiepe, MD, Paul Howard, MD, Claudia E. Hura, MD, Adrian Jaffer, MD, James Jakes, MD, Joachim R. Kalden, MD, Gary M. Kammer, MD, Mariana J. Kaplan, MD, Stanley Kaplan, MD, Robert Katz, MD, Alastair Kennedy, MD, Howard M. Kenney, MD, Munther Khamashta, MD, PhD, Alan J. Kivitz, MD, Christine Kovacs, MD, Mahesh Krishnan, MD, Neil A. Kurtzman, MD, Michael Liebling, MD, Seth H. Lourie, MD, James Loveless, MD, Carl V. Manion, MD, Susan Manzi, MD, MPH, Kevin Martin, MD, James McKay, DO, Phillip J. Mease, MD, Joan T. Merrill, MD, Larry W. Moreland, MD, Charles Moritz, MD, C. Michael Neuwelt, MD, Michelle Petri, MD, MPH, Bryan C. Pogue, MD, Robert J. Quinet, MD, Rosalind Ramsey- Goldman, MD, Arnold Roth, MD, Naomi Rothfield, MD, Nicholas Scarpa, MD, Matthias Schneider, MD, William J. Shergy, MD, Yvonne Sherrer, MD, Jean Sibilia, MD, Moges Sisay, MD, Douglas Smith, MD, Bruce Spinowitz, MD, FACP, Moses Spira, MD, Michael P. Stevens, MD, Gunnar Sturfelt, MD, PhD, William Surbeck, MD, Elizabeth A. Tindall, MD, Arnaldo Torres, MD, James A. Tumlin, MD, Ronald van Vollenhoven, MD, Anitha Vijayan, MD, Miguel Vilardell-Tarres, MD, Daniel J. Wallace, MD, Cynthia Weaver, MD, Gary W. Williams, MD, PhD, Michael Zummer, MD.