FX006 prolongs the residency of triamcinolone acetonide in the synovial tissues of patients with knee osteoarthritis

Abstract

reading method. Responders (patients with no relevant progression) were defined as those with a JSW loss between baseline and End, lower than 0.1 mm (JSN >-0.1 mm), or 0.2 mm (JSN >-0.2 mm) or 0.3 mm (JSN>-0.3 mm). Patients who withdrew from the study were counted as non-responder patients. SrRan 1g and SrRan 2g treatment groups were compared to placebo in the FAS using a chi 2 test. Results: The ITT set included 1371 (82%) patients. Age was 63AE7 years, BMI was 30AE5 kg/m2, JSW was 3.5AE0.8 mm. 61% were KL II. 69% were female. A statistically significant greater proportion of patients in both SrRan 1 g and SrRan 2 g groups were considered as responders (i.e. preserved from a radiological progression) as compared to placebo, when defined by a JSN >-0.3 mm threshold (40.5% and 44.1% vs. 32.8% of responders respectively, p¼0.006 and p¼0.003). In other words, the proportion of responders compared to placebo increased by 24% and 34% in the SrRan 1g and 2g groups respectively, using a JSN >-0.3 mm for responding definition, with a number of patients needed to be treated (NNT) of 13 and 9 respectively. Similar differences between groups were observed for responders at additional JSN cutoffs (i.e. JSN >-0.1 mm or JSN >-0.2 mm):

Local controlled release of corticosteroids extends surgically induced joint instability by inhibiting tissue healing

“…Even the 80 mg of bolus TAA administered in arthritic knees in several clinical studies did not result in adverse effects (C. E. Chavez‐Chiang et al, ; N. R. Chavez‐Chiang et al, ; Kumar, Dhir, Sharma, Sharma, & Singh, ; Popma et al, ). Moreover, the IA release of a dose of 60‐mg TAA from a PLGA MS platform, equivalent to the lowest dosage used in the current study, was shown to be safe in knee OA patients (Bodick et al, ). Also in a different, collagenase‐induced, rat model of OA, the extended release of TAA by PEA MSs did not show any effects on cartilage integrity nor induced tissue calcification (Rudnik‐Jansen et al, ).…”

An Intra-Articular, Extended-Release Formulation of Triamcinolone Acetonide Prolongs and Amplifies Analgesic Effect in Patients with Osteoarthritis of the Knee

“…In a previous clinical study, the 40-mg dose of FX006 demonstrated maintenance of synovial concentrations of triamcinolone acetonide consistent with pharmacologic activity for a period of at least six weeks, when levels of triamcinolone acetonide produced by an equivalent dose of immediate-release triamcinolone acetonide were below the limits of quantitation 19 . Not only did FX006 prolong the maximal effect of immediaterelease triamcinolone acetonide (which in the present study occurred at four weeks), but also, between two and eleven weeks, the analgesic effect of 40-mg FX006 exceeded the maximal effect of immediate-release triamcinolone acetonide at four weeks and was significantly superior to immediate-release triamcinolone acetonide from five weeks to ten weeks (p < 0.05 at each time point), with a mean pain reduction relative to immediate-release triamcinolone acetonide of 20.9 on the 11-point Numeric Rating Scale.…”

“…Loss of Efficacy at Six Weeks with the 60-Mg Dose I n a companion pharmacokinetic study, measurement of synovial triamcinolone acetonide concentrations at six weeks in patients revealed markedly lower levels at the 60-mg dose (with a geometric mean of 17,546 pg/mL) than the 40-mg dose (78,757 pg/mL) 19 . The loss of efficacy of the 60-mg FX006 dose may be associated with premature release of triamcinolone acetonide from the PLGA matrix at one through six weeks.…”

“…FX006 is an extended-release formulation of triamcinolone acetonide in poly(lactic-co-glycolic acid) (PLGA) microspheres that is designed to maintain therapeutic concentrations of triamcinolone acetonide in the joint over a period of months. In a previous pharmacokinetic study of FX006 in patients with knee osteoarthritis, both prolonged residency of triamcinolone acetonide in the joint and reduced plasma concentrations relative to an equivalent dose of immediate-release triamcinolone acetonide were demonstrated 19 . The primary objective of the present study was to determine if FX006 provides pain relief superior to that provided by immediaterelease triamcinolone acetonide.…”

Progress in intra-articular therapy

“…Overall, particle-based delivery systems have the potential to increase drug residence times greatly, with 10–30-fold increases reported in pre-clinical models. A clinical study reported in 2013 of a PGLA-encapsulated corticosteroid, triamcinolone acetonide (FX006, Flexion Therapeutics), demonstrated residence in the joint space at therapeutic concentrations at 6 weeks after injection, 137 providing some evidence of even longer periods of sustained release for microcapsules. Nevertheless, no particle-based or liposome drug-delivery system has yet advanced past clinical trials for intra-articular drug delivery in the USA, possibly because of the need to establish cost-effective manufacturing processes and dosing strategies.…”