A pilot study on the use of prednisolone‐encapsulated liposomes for the treatment of moderate‐to‐severe Graves’ orbitopathy with reduced systemic steroid exposure

Abstract

To demonstrate that long-circulating PEGylated liposomal prednisolone is a safe and effective therapy in patients with active moderate-to-severe Graves' orbitopathy.Methods: Open-label, proof-of-concept, multicentre pilot study. Ten patients with moderate-to-severe Graves's orbitopathy, who were euthyroid for at least three months. Long-circulating PEGylated liposomal prednisolone 150 mg was administered intravenously twice, with 2-week interval. Total follow-up was 12 months, with visits at baseline, week 2, 6, 13, 26 and 52. Physical, laboratory and ophthalmological examinations were performed. Response to treatment was defined as a reduction in Clinical Activity Score by ≥2 points; palpebral aperture by ≥3 mm; soft tissue signs by ≥2 grades; exophthalmos by ≥2 mm; and motility by >8 degrees or improvement in diplopia score. A response was sustained when equally observed at weeks 6 and 13.Results: One patient achieved a sustained response according to the predetermined definition. All patients showed a decrease in Clinical Activity Score after one infusion, with a mean decrease of two points. The Clinical Activity Score was ≤1 at week 52 for all patients. Improvement was also observed in the soft tissue signs. Most of the adverse events were mild and of a transient nature. Two patients required further treatment with intravenous methylprednisolone. Conclusion:This pilot study showed a positive effect of long-circulating PEGylated liposomal prednisolone on the Clinical Activity Score in patients with moderate-to-severe Graves's orbitopathy, resulting in fewer hospital visits and possibly less glucocorticoidrelated side-effects.

Thyroid stimulating immunoglobulin concentration is associated with disease activity and predicts response to treatment with intravenous methylprednisolone in patients with Graves’ orbitopathy

“…Furthermore, 24 patients with moderate-to-severe disease were treated with weekly infusions of IVMP, with a median cumulative dose of 4500mg (IQR = 0). Another four patients with moderate-to-severe disease from this cohort received treatment with prednisolone-encapsulated liposomes, with a cumulative dose of 300mg ( 50 ). Median time between obtaining the serum sample and the start of IVMP treatment was 11 days (IQR = 39.50).…”

“…For moderate-to-severe disease, the standard dosing regimen consisted of a cumulative dose of 4500mg of IVMP in 12 weekly infusions. As part of a recent study by our group, a small subset of patients with moderate-to-severe disease was treated with a regimen of prednisolone-encapsulated liposomes (two times 150mg intravenously with a 2-week interval), that is potentially associated with a more specific targeted delivery of the drug at the inflamed areas and requires fewer hospital visits while typical steroid-related adverse events are reduced ( 50 ). A beneficial response to IVMP treatment was defined as (1) achievement of a total CAS < 3 in both eyes, or (2) an improvement of ≥ 2 points in one eye without concomitant deterioration in the fellow eye.…”

A phase I first-in-man study to investigate the pharmacokinetics and safety of liposomal dexamethasone in patients with progressive multiple myeloma

“…The most advanced GC nanodrug is pegylated liposomal prednisolone, which was recently shown to improve efficacy over GC standard-of-care in a large cohort of patients with active rheumatoid arthritis [39]. The same product was also evaluated in patients with severe orbital inflammation due to Graves' disease and in patients on dialysis with arteriovenous fistula failure [40,41]. The use of the same liposome system encapsulating the 6.5-fold more potent dexamethasone, and thus theoretically requiring less liposomes for the same effect, seems a logical next step especially for indications in which dexamethasone is the clinically preferred GC.…”

Intravenous pegylated liposomal prednisolone outperforms intramuscular methylprednisolone in treating rheumatoid arthritis flares: A randomized controlled clinical trial

“…It was hypothesized that EPR-mediated targeted delivery GC into arthritic joints would result in a much higher tissue concentration, leading to stronger efficacy [5][6][7][8]. While this unique property of inflamed target site delivery of GC by LCL has been shown in several studies and in several manifestations of inflammatory disease, thus far these studies were mostly preclinical or performed in small patient populations [11,12,[16][17][18]. The current study is the first to show that this therapeutic approach can provide a clinical benefit in a large cohort of patients.…”

“…We previously performed a Phase 2a study in 22 RA patients showing that a single infusion of GC encapsulated in LCL (referred to as Nanocort) results in a temporary but strong suppressive effect on joint inflammation, with a clear dose-relationship and with a maximum benefit at 150 mg prednisolone phosphate [16]. While Nanocort has been evaluated in small clinical studies in other diseases [17][18][19], a larger clinical study with a head-to-head comparison to standard-of-care has never been done. We here present the results obtained in 150 patients with active RA, evaluating the efficacy and safety of Nanocort (i.v.…”