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Versus Prednisone Or Placebo in Rheumatoid Arthritis: a Randomised, Double-Blind, Multicentre, Phase Iib Study

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Versus Prednisone Or Placebo in Rheumatoid Arthritis: a Randomised, Double-Blind, Multicentre, Phase Iib Study Rheumatoid arthritis RMD Open: first published as 10.1136/rmdopen-2018-000889 on 16 April 2019. Downloaded from ORIGINAL ARTICLE Fosdagrocorat (PF-04171327) versus prednisone or placebo in rheumatoid arthritis: a randomised, double-blind, multicentre, phase IIb study Frank Buttgereit, 1 Vibeke Strand,2 Eun Bong Lee,3 Abraham Simon-Campos,4 Dorothy McCabe,5 Astrid Genet,6 Brinda Tammara,7 Ricardo Rojo,8 Judith Hey-Hadavi5 To cite: Buttgereit F, Strand V, ABSTRACT Lee EB, et al. Fosdagrocorat (PF- Objectives Glucocorticoids have anti-inflammatory, Key messages 04171327) versus prednisone transrepression-mediated effects, although adverse events or placebo in rheumatoid (AEs; transactivation-mediated effects) limit long-term use What is already known about this subject? arthritis: a randomised, in patients with rheumatoid arthritis (RA). We evaluated ► Glucocorticoids (GCs) are widely used to treat double-blind, multicentre, patients with rheumatoid arthritis (RA). phase IIb study. RMD Open the efficacy and safety of fosdagrocorat (PF-04171327), a dissociated agonist of the glucocorticoid receptor, versus ► However, they are associated with adverse effects, 2019;5:e000889. doi:10.1136/ and efforts to improve efficacy and reduce adverse rmdopen-2018-000889 prednisone or placebo. Methods In this 12-week, phase II, randomised controlled consequences of GCs include the development of trial, 323 patients with moderate to severe RA were dissociated agonists of the GC receptors (DAGRs). Prepublication history and ► randomised 1:1:1:1:1:1:1 to fosdagrocorat (1 mg, 5 mg, ► Phase I studies of the DAGR, fosdagrocorat additional material for this 10 mg or 15 mg), prednisone (5 mg or 10 mg) or placebo, (10–25 mg), showed equivalent anti-inflammatory paper are available online. To effects and bone formation biomarker reductions view these files, please visit the once daily. The primary endpoints (week 8) were American to prednisone (5–20 mg); and in a short phase IIa journal (http:// dx. doi. org/10. College of Rheumatology 20% improvement criteria (ACR20) 1136/ rmdopen- 2018- 000889). responses, and percentage changes from baseline in study in patients with RA on stable background biomarkers of bone formation (procollagen type 1 N-terminal methotrexate (MTX), fosdagrocorat (10 and 25 mg) http://rmdopen.bmj.com/ Received 21 December 2018 peptide [P1NP]) and resorption (urinary N-telopeptide to improved the symptoms of active disease compared Revised 27 February 2019 urinary creatinine ratio [uNTx:uCr]). Safety was assessed. with prednisone (5 mg once daily). Accepted 21 March 2019 Results ACR20 responses with fosdagrocorat 10 mg What does this study add? and 15 mg were superior to placebo, and fosdagrocorat ► In patients with RA receiving background MTX, we 15 mg was non-inferior to prednisone 10 mg (week 8 have demonstrated the similar efficacy of fosdagro- model-predicted ACR20 responses: 47%, 61%, 69% and corat (10 mg and 15 mg) to prednisone (10 mg), and 73% vs 51%, 71% and 37% with fosdagrocorat 1 mg, the similar safety profile of these doses of fosdagro- 5 mg, 10 mg and 15 mg vs prednisone 5 mg, 10 mg and corat to prednisone (5 mg). placebo, respectively). Percentage changes from baseline on October 1, 2021 by guest. Protected copyright. in P1NP with fosdagrocorat 1 mg, 5 mg and 10 mg met How might this impact on clinical practice? non-inferiority criteria to prednisone 5 mg. Corresponding ► Larger-scale, and longer-term, evaluations of fos- changes in uNTx:uCr varied considerably. All fosdagrocorat dagrocorat in patient populations with active RA who doses reduced glycosylated haemoglobin levels. AEs were are naïve to GC will help clarify the bone and glucose similar between groups; 63 (19.5%) patients reported metabolism effects of fosdagrocorat and assist in treatment-related AEs; 9 (2.8%) patients reported serious determining its future role in the treatment of RA. AEs. No patients had adrenal insufficiency, treatment-related significant infections or laboratory abnormalities. No deaths were reported. © Author(s) (or their during treatment to reduce signs and symp- employer(s)) 2019. Re-use Conclusion In patients with RA, fosdagrocorat 10 mg and toms of active disease and inhibit progression 15 mg demonstrated efficacy similar to prednisone 10 mg permitted under CC BY-NC. No of joint structural damage.1–3 Unfortunately, commercial re-use. See rights and safety similar to prednisone 5 mg. and permissions. Published Trial registration number NCT01393639 GCs are associated with adverse effects, espe- by BMJ. cially at doses >7.5 mg/day and over longer For numbered affiliations see treatment duration,4–7 which cause consid- end of article. erable morbidity.8 Although guidelines and Correspondence to INTRODUCTION recommendations exist for managing patients 9–12 Professor Frank Buttgereit; Two-thirds of patients with rheumatoid receiving GC therapy, GC use presents a frank. buttgereit@ charite. de arthritis (RA) receive glucocorticoids (GCs) clinical challenge in balancing benefits and Buttgereit F, et al. RMD Open 2019;5:e000889. doi:10.1136/rmdopen-2018-000889 1 RMD Open RMD Open: first published as 10.1136/rmdopen-2018-000889 on 16 April 2019. Downloaded from risks. Developments to improve the efficacy and/or reduce response system, patients with stable background MTX adverse consequences include evaluation of selective GC were randomised 1:1:1:1:1:1:1 to receive fosdagrocorat 1 receptor agonists (SEGRAs), dissociated agonists of the GC mg, 5 mg, 10 mg or 15 mg, prednisone 5 mg or 10 mg, or receptor (DAGRs) and liposomal GCs. Here, we report the matched placebo for 8 weeks, followed by 4-week blinded findings of a phase II trial of fosdagrocorat (PF-04171327), taper and 1-week washout (online supplementary figure a first-in-class, oral, selective, high-affinity DAGR under S2). The randomisation procedure used blocks of 14, and investigation for the treatment of RA. there were four strata based on geographical randomisa- GCs are estimated to regulate transcription of ~1% of tion. All study treatments were administered once daily. the genome, including suppression of proinflammatory During taper, patients received the study drug (fosdagro- genes (transrepression) and upregulated protein synthesis corat 1 mg, prednisone 5 mg or placebo, according to (transactivation). It is considered that transrepression randomisation) and placebo on alternate days over weeks predominantly produces anti-inflammatory effects, while 9 and 10, every 3 days over weeks 11 and 12, and no study transactivation (affecting glucose metabolism) or a combi- medication during week 13 (online supplementary figure nation of both (affecting bone metabolism) are responsible S2). 13 14 for their adverse effects. An agent that shifts the transre- Patients (aged >18 years) with active RA defined as ≥6 pression/transactivation ratio towards transrepression may tender and ≥6 swollen joints (of 28-joint count) plus C provide an improved GC benefit to risk ratio. reactive protein (CRP) ≥7 mg/L at screening had received Fosdagrocorat demonstrated similar anti-inflammatory MTX for ≥3 months, with a stable dose (≤25 mg per week) activity to standard GC receptor agonists while avoiding for ≥8 weeks. Key exclusion criteria included GC use within some associated adverse events (AEs) in preclinical studies. 6 weeks of screening, active or latent tuberculosis, and clin- Phase I studies show single oral doses of fosdagrocorat ically significant infection within 6 months of screening 10–25 mg were associated with equivalent anti-inflam- (online supplementary section S1). matory effects and similar reductions in bone formation Patients were recruited at 73 centres globally (online 15 16 biomarkers to single doses of prednisone 5–20 mg. supplementary section S2; table S1). In a 2-week, phase IIa study in patients with active RA on stable background methotrexate (MTX), fosdagrocorat 10 Outcomes and procedures mg and 25 mg once daily were well tolerated and demon- The primary objectives were to compare the efficacy and strated rapid and robust onset of improved signs and symp- safety of fosdagrocorat 1 mg, 5 mg, 10 mg and 15 mg with toms of active disease versus placebo and prednisone 5 mg 17 prednisone 5 mg and 10 mg, and placebo, and to identify once daily. fosdagrocorat dose(s) with American College of Rheu- Fosdagrocorat is believed to bind to the cytosolic GC matology 20% improvement criteria (ACR20) respon- receptor with the resulting fosdagrocorat–GC receptor se(s) similar to prednisone 10 mg and bone biomarker complex conformation enabling transrepression while http://rmdopen.bmj.com/ changes similar to prednisone 5 mg. The primary effi- prohibiting, or reducing, transactivation activities.18 19 cacy endpoint was ACR20/50/70 responses at week 8; The transcription factor binding site may function like coprimary bone biomarker endpoints were percentage GC–GC receptor complexes, enabling suppression of changes from baseline at week 8 in serum procollagen proinflammatory gene expression, but the DNA-binding type 1 N-terminal propeptide (P1NP; bone formation) site is thought to be non-functional or dysfunctional, and urinary N-telopeptide to urinary creatinine ratio thereby reducing or preventing unwanted transactiva- (uNTx:uCr; bone resorption). tion activities (online supplementary figure S1). Preclin- ical studies of other SEGRA/DAGR agents support this on October 1, 2021 by guest. Protected copyright. theory of a shift in the transrepression/transactivation Efficacy assessments
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