FRI0135 INTRAVENOUS PEGYLATED LIPOSOMAL PREDNISOLONE SODIUM PHOSPHATE MORE EFFECTIVE THAN INTRAMUSCULAR INJECTION OF METHYLPREDNISOLONE ACETATE IN TREATING RA PATIENTS WHO ARE EXPERIENCING A FLARE: A PHASE III, RANDOMIZED, DOUBLE-BLIND, DOUBLE DUMMY, ACTIVE CONTROLLED, MULTI-CENTER STUDY
Authors: Johannes W.J. Bijlsma, Bart Metselaar, Leonie Middelink, Cees Wortel, Reinhard Bos, Jacob M. van Laar, Harald Vonkeman, Rene Westhovens, Siu Long Yao, Mudgal Kothekar, Atul Raut
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Intravenous pegylated liposomal prednisolone sodium phosphate is developed to deliver liposomal entrapped prednisolone in the bloodstream; the lipid vesicles allow selective accumulation of glucocorticoids in inflamed tissues by locally increased permeability of blood vessel walls, while limiting systemic exposure. <h3>Objectives:</h3> To assess efficacy and safety of liposomes with prednisolone in patients with active rheumatoid arthritis (RA) who are experiencing a flare in comparison to a standard of care medication (methylprednisolone injections). <h3>Methods:</h3> The study enrolled active RA patients (≥ 18 years) who were experiencing a flare of their disease, defined as a recent switch from a period with well documented remission or low disease activity to an active disease phase, as determined by a change in the Disease Activity Score in 28 Joints (DAS28 ≥ 3.2). Patients were randomized 1:1:1 into liposomal prednisolone 75 mg, liposomal prednisolone 150 mg and methylprednisolone 120 mg groups. Treatment was administered on Day 1 and Day 15. Patients treated with liposomal prednisone IV received IM placebo injections; patients treated with methylprednisolone IM received IV placebo infusions. Evaluations were performed weekly for the first 4 weeks, and every second week thereafter. The primary endpoint was EULAR response rate (good and moderate combined) at Day 8. The primary analysis involved two comparisons: 1) liposomal prednisone 150 mg vs. methylprednisolone 120 mg, 2) liposomal prednisone 75 mg vs. methylprednisolone 120 mg. Safety results (AEs, vital signs, physical examinations, laboratory, ECG) were also evaluated. A total of 172 patients were screened and 150 were randomized to liposomal prednisone 75 mg (N=49), liposomal prednisone 150 mg (N=52) and methylprednisolone 120 mg (N=49). 144 (96%) patients completed the study; mean study duration was 82.9 days; adverse events or intercurrent illness were primary reasons for discontinuation. <h3>Results:</h3> EULAR response rate at Week 1 (Day 8) was 90.0% for liposomal prednisone 150 mg and 85.7% for liposomal prednisone 75 mg vs. 66.7% for methylprednisolone 120 mg treated patients (p-values of 0.007 and 0.018, resp.). Other secondary endpoints supported the primary endpoint results showing significant or clinically meaningful improvements in other EULAR response evaluations, as well as DAS28, VAS, ACR20/50/70, SF-36, HAQ and FACIT-F assessments. Similar numbers of patients reported at least one adverse event (AE) in each treatment group; 42 (86 %), 46 (89 %) and 39 (80 %), resp., for the liposomal prednisone 75 mg, liposomal prednisone 150 mg and methylprednisolone 120 mg groups. Most commonly reported AEs were nausea in the liposomal prednisone groups and headache in all 3 treatment arms. Approximately 8% of patients in the liposomal prednisone groups reported AEs related to study drug administration, versus 6% in the methylprednisolone group. Serious adverse events (SAEs) were reported by 4 (8.2%), 1 (1.9%) and 2 patients (4.1%) resp for the liposomal prednisone 75 mg, liposomal prednisone 150 mg and methylprednisolone 120 mg groups. Five of the 7 SAEs were treatment related; these included 4 events of hypersensitivity in the liposomal prednisone arms and one event of viral upper respiratory tract infection in the methylprednisolone group. <h3>Conclusion:</h3> In this phase III trial, liposomal prednisone 75 mg and 150 mg were significantly more effective than 120 mg -methylprednisolone in treating patients with a flare of their RA. The overall incidence of AEs was similar across treatment groups, although hypersensitivity appeared to be more common with liposomal prednisone. <h3> Disclosure of Interests: </h3> Johannes WJ Bijlsma Grant/research support from: The department of the author who included patients (JWJB) in the U-Act-Early trial received reimbursements from Roche Nederland BV. JWJB reported grants and fees from Roche, AbbVie, Bristol-Myers Squibb, Merck Sharp &amp; Dohme, Pfizer, and UCB University Medical Center Utrecht, Utrecht University, Consultant for: SUN Pharma, Speakers bureau: Lilly, Roche, Bart Metselaar Shareholder of: Enceladus, Grant/research support from: SUN Pharma, Leonie Middelink Grant/research support from: SUN Pharma, Cees Wortel Shareholder of: Enceladus, Accelovance, Grant/research support from: SUN Pharma, Consultant for: SUN Pharma, Reinhard Bos Grant/research support from: SUN Pharma, Jacob M. van Laar Grant/research support from: Genentech, Consultant for: F. Hoffmann-La Roche, Harald Vonkeman: None declared, Rene Westhovens Grant/research support from: Bristol-Myers Squibb, Consultant for: Celltrion, Galapagos-Gilead, Siu Long Yao Shareholder of: SUN Pharma, Employee of: SUN Pharma, Mudgal Kothekar Shareholder of: SUN Pharma, Employee of: SUN Pharma, Atul Raut Shareholder of: SUN Pharma, Employee of: SUN Pharma