Repository Corticotropin Injection for Active Rheumatoid Arthritis Despite Aggressive Treatment: A Randomized Controlled Withdrawal Trial

Abstract

Introduction: The objective of this study was to assess efficacy and safety of repository corticotropin injection (RCI) in subjects with active rheumatoid arthritis (RA) despite treatment with a corticosteroid and one or two diseasemodifying antirheumatic drugs (DMARDs). Methods: All subjects received open-label RCI (80 U) twice weekly for 12 weeks (part 1); only those with low disease activity [LDA; i.e., Disease Activity Score 28 joint count and erythrocyte sedimentation rate (DAS28-ESR) \ 3.2] were randomly assigned to receive either RCI (80 U) or placebo twice weekly during the 12-week double-blind period (part 2). The primary efficacy endpoint was the proportion of subjects who achieved LDA at week 12. Secondary efficacy endpoints included proportions of subjects who maintained LDA during weeks 12 through 24 and achieved Clinical Disease Activity Index (CDAI) B 10 at weeks 12 and 24. Safety was assessed via adverse event reports. Results: Of the 259 enrolled subjects, 235 completed part 1; 154 subjects (n = 77 each for RCI and placebo) entered part 2, and 127 (RCI, n = 71; placebo, n = 56) completed. At week 12, 163 subjects (62.9%) achieved LDA and 169 (65.3%) achieved CDAI B 10 (both p \ 0.0001). At week 24, 47 (61.0%) RCI-treated and 32 (42.1%) placebo-treated subjects maintained LDA (p = 0.019); 66 (85.7%) RCI-treated and 50 (65.8%) placebo-treated subjects maintained CDAI B 10 (p = 0.004). No unexpected safety signals were observed. Conclusions: RCI was effective and generally safe in patients with active RA despite corticosteroid/DMARD therapy. By week 12, [ 60% of patients achieved LDA, which was maintained with 12 additional weeks of treatment. Most

Distinct binding and signaling activity of Acthar Gel compared to other melanocortin receptor agonists

“…hypertension, hyperglycemia, headache, weight gain, edema) [48]. In particular, bone turnover markers were stable, suggesting minimal further impact of Acthar Gel on bone metabolism in patients already receiving corticosteroids [48]. Treatment with Acthar Gel has also been effective in patients with rheumatoid arthritis or glomerular diseases that have been resistant to corticosteroid treatment, further confirming a mechanism of action that is independent of cortisol production [48,49].…”

“…In particular, bone turnover markers were stable, suggesting minimal further impact of Acthar Gel on bone metabolism in patients already receiving corticosteroids [48]. Treatment with Acthar Gel has also been effective in patients with rheumatoid arthritis or glomerular diseases that have been resistant to corticosteroid treatment, further confirming a mechanism of action that is independent of cortisol production [48,49]. Thus, these data, in combination with preclinical and clinical studies [24][25][26]28,48,49], suggest that Acthar Gel may provide benefit in the treatment of inflammatory disease through mechanisms beyond the induction of steroids.…”

“…In support of this, a recent clinical study in patients with rheumatoid arthritis treated with Acthar Gel reported little to no incidence of adverse events typically associated with corticosteroid use (e.g. hypertension, hyperglycemia, headache, weight gain, edema) [48]. In particular, bone turnover markers were stable, suggesting minimal further impact of Acthar Gel on bone metabolism in patients already receiving corticosteroids [48].…”

“…Taken together, the combined engagement profile of Acthar Gel at MC1R, MC3R, MC4R, and MC5R suggests a distinct direct immune cell effect beyond the indirect antiinflammatory effect from MC2R-dependent production of corticosteroids. Despite less sustained cortisol induction, Acthar Gel remains efficacious [48,49], suggesting direct interaction with immune cells to treat disease [24][25][26]. The mechanism of action of Acthar Gel is unique from that of pACTH 1-39 , ACTH 1-24 , N25D-ACTH 1-39 , and other MCR agonists, suggesting that its complex mixture of peptides interacts with MCRs differently than any single MCR agonist does.…”

Repository corticotropin injection attenuates collagen-induced arthritic joint structural damage and has enhanced effects in combination with etanercept

“…Micro-CT analysis supported positive effects of RCI on bone remodeling; significant improvement in the cortical bone volume difference and a trend for treatment-related improvement of mean bone density were observed. The beneficial effects of RCI have also been observed in patients with persistently active RA despite the use of corticosteroid/ DMARD therapy, where bone turnover markers remained stable with RCI treatment, suggesting a minimal impact on bone metabolism [52].…”