title: IκB kinase inhibition as a potential treatment of osteoarthritis - results of a clinical proof-of-concept study.
abstract: This publication summarizes the clinical development of the compound SAR113945, an IκB kinase inhibitor injected intra-articularly in a slow-release formulation to treat patients with symptomatic osteoarthritis (OA) of the knee.
  
  
  
  In vitro experiments demonstrated a specific inhibition of the IκB kinase complex. Profiling of SAR113945 on kinases, enzymes and ion channels supported the initiation of a clinical development. Cellular assay systems also revealed an inhibition in the synthesis of interleukin 1β, tumor necrosis factor α (TNFα) and the prostaglandin E2 (PGE2). In vivo studies demonstrated positive effects of SAR113945 on thermal and mechanical hyperalgesia and even showed superiority in comparison with triamcinolone. Pharmacokinetic measurements showed a sustained release of dissolved SAR113945 locally supporting a comparably high exposure in the knee joint combined with a low systemic exposure. Three phase 1 studies with a dose-escalating design confirmed safety and tolerability of SAR113945. In those studies SAR113945 showed a positive trend on the WOMAC scores. The proof-of-concept or phase 2a study failed to show any effect in the overall group of recruited study participants for the primary endpoint, the WOMAC pain subscore at day 56, but showed a statistically significant difference in a subgroup of patients who had presented with effusion at baseline.
  
  
  
  Inhibiting the NFκB signaling pathway is an attractive method to treat patients with signs and symptoms of OA. The preclinical work and the results of the phase 1 studies appeared promising for a full clinical development, however, the proof-of-concept study failed to show efficacy in a larger patient sample size.
authors: Sanofi, Department of Chronic Inflammatory Diseases, Frankfurt, Germany. Electronic address: Kirsten.Grothe@sanofi.com.
authors: K
authors: K
authors: Grothe
authors: Sanofi, Department of Chronic Inflammatory Diseases, Frankfurt, Germany. Electronic address: Klaus.Flechsenhar@sanofi.com.
authors: K
authors: K
authors: Flechsenhar
authors: Sanofi, Research and Development, DSAR, Drug Disposition, Frankfurt, Germany. Electronic address: Tobias.Paehler@sanofi.com.
authors: T
authors: T
authors: Paehler
authors: Sanofi, Research and Development, Science & Innovation - Strategy, Science Policy & External Innovation, Frankfurt, Germany. Electronic address: Olaf.Ritzeler@sanofi.com.
authors: O
authors: O
authors: Ritzeler
authors: Sanofi, Research and Development, Biotherapeutics, BioInnovation, Frankfurt, Germany. Electronic address: Jochen.Beninga@sanofi.com.
authors: J
authors: J
authors: Beninga
authors: Sanofi, Department of Chronic Inflammatory Diseases, Frankfurt, Germany. Electronic address: Joachim.Saas@sanofi.com.
authors: J
authors: J
authors: Saas
authors: Sanofi, Department of Chronic Inflammatory Diseases, Frankfurt, Germany. Electronic address: Matthias.Herrmann@sanofi.com.
authors: M
authors: M
authors: Herrmann
authors: Sanofi, Department of Chronic Inflammatory Diseases, Frankfurt, Germany. Electronic address: Karl.Rudolphi@sanofi.com.
authors: K
authors: K
authors: Rudolphi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D007270:Injections, Intra-Articular; D007719:Knee Joint; D008297:Male; D020370:Osteoarthritis, Knee / Q000188:drug therapy*; D000075082:Proof of Concept Study; D051381:Rats; D020318:Rats, Long-Evans; D014221:Triamcinolone / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D003692:Delayed-Action Preparations; D014221:Triamcinolone; D051550:I-kappa B Kinase
keywords: Clinical findings; Intra-articular injection; IκB kinase inhibitor; Slow-release formulation; Treatment of knee osteoarthritis