title: Sustained efficacy of a single intra-articular dose of FX006 in a rat model of repeated localized knee arthritis.
abstract: OBJECTIVE
  To evaluate the efficacy of a single intra-articular (IA) dose of FX006, an extended-release formulation of triamcinolone acetonide (TCA) in poly(lactic-co-glycolic acid) (PLGA) microspheres, on the sequelae of repeated episodes of synovitis.
  
  
  METHODS
  Three flares of localized synovitis in the right knee of rats were induced over 4 weeks following a single IA injection of various doses of FX006, Kenalog(®) (TCA immediate release or TCA IR), or vehicle. Gait scores were employed to assess analgesic effect, and the joints were evaluated by histology at the end of the study. TCA plasma concentrations and corticosterone levels were monitored through the study.
  
  
  RESULTS
  A single IA dose of 0.28 mg FX006 significantly improved gait scores through all three reactivations. TCA IR at 0.06 mg (providing comparable plasma TCA exposure, 10-fold higher Cmax) demonstrated comparable benefit through the first reactivation only and reduced-to-no efficacy thereafter. Significantly improved histological joint scores were observed with effective doses of FX006 but not with TCA IR. Corticosterone levels were initially decreased following both TCA IR and FX006 treatment, but recovered by Day 14.
  
  
  CONCLUSIONS
  In localized, repeated synovitis in rats, sustained release of TCA following a single IA injection of FX006 significantly prolonged analgesia relative to TCA IR and significantly improved histological scores with no adverse effect on the HPA axis. Since synovitis can contribute to the pathophysiology of multiple joint diseases such as osteoarthritis (OA), RA and gout, FX006 may be an important treatment option for these conditions.
authors.affiliation: Flexion Therapeutics, Inc., Burlington, MA, USA. Electronic address: akumar@flexiontherapeutics.com.
authors.forename: A
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Bolder BioPATH, Inc., Boulder, CO, USA. Electronic address: alison@bolderbiopath.com.
authors.forename: A M
authors.initials: AM
authors.lastname: Bendele
authors.affiliation: Ardelyx, Fremont, CA, USA(a). Electronic address: rblanks@ardelyx.com.
authors.forename: R C
authors.initials: RC
authors.lastname: Blanks
authors.affiliation: Flexion Therapeutics, Inc., Burlington, MA, USA. Electronic address: nbodick@flexiontherapeutics.com.
authors.forename: N
authors.initials: N
authors.lastname: Bodick
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D005938:Glucocorticoids / Q000008:administration & dosage*; D007270:Injections, Intra-Articular; D007719:Knee Joint; D019344:Lactic Acid / Q000008:administration & dosage*; D008297:Male; D008863:Microspheres; D011100:Polyglycolic Acid / Q000008:administration & dosage*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D011917:Rats, Inbred Lew; D013585:Synovitis / Q000188:drug therapy*; D014222:Triamcinolone Acetonide / Q000008:administration & dosage*
chemical_list: D005938:Glucocorticoids; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D014222:Triamcinolone Acetonide
keywords: Animal model; Corticosteroids; Intra-articular; Joint protection; Sustained-release; Synovitis