title: Tofacitinib (CP-690,550), a Janus kinase inhibitor for dry eye disease: results from a phase 1/2 trial.
abstract: OBJECTIVE
  To evaluate safety and efficacy of topical ophthalmic tofacitinib (CP-690,550), a novel Janus kinase inhibitor, in treating dry eye disease (DED).
  
  
  METHODS
  A phase 1/2 prospective, randomized, double-masked, multicenter, vehicle- and comparator-controlled trial (NCT00784719).
  
  
  METHODS
  Patients (n = 327) 18 years of age and older with a DED diagnosis for 6 months or more.
  
  
  METHODS
  Tofacitinib (0.0003% twice daily, n = 46; 0.001% in both eyes twice daily, n = 47; 0.003% twice daily, n = 48; 0.005% twice daily, n = 48; 0.005% once daily, n = 44) results were compared with those of groups receiving active treatment cyclosporine ophthalmic emulsion 0.05% twice daily (n = 47) and vehicle twice daily (n = 47). Safety and efficacy evaluations were performed at baseline and throughout the 8-week study.
  
  
  METHODS
  Schirmer wetting, corneal staining, tear film break-up time, conjunctival staining, Ocular Comfort Index (OCI), and Ocular Surface Disease Index (OSDI).
  
  
  RESULTS
  All tofacitinib doses were well tolerated, exhibiting better patient-reported ocular tolerability than cyclosporine. For the proportion of patients achieving 10 mm or more Schirmer wetting (without anesthesia) at week 8 (primary end point), greater response rates were observed in the tofacitinib 0.001% twice daily (27.3%), 0.005% twice daily (25.5%), and 0.005% once daily (26.1%) groups versus vehicle (20.0%); however, the differences were not statistically significant. Mean increase in Schirmer wetting (without anesthesia) from baseline was statistically significant (P<0.2, 2-sided) for all tofacitinib doses (1.7-3.1 mm), cyclosporine (3.9 mm), and vehicle (1.4 mm). For corneal staining (total score), significant improvement (reduction) from baseline was observed for all tofacitinib doses (-0.9 to -1.9) and vehicle (-2.0), but not for cyclosporine. The proportion of patients with complete corneal clearing (CCC; 100%) at week 8 was greatest with tofacitinib 0.005% once daily (15.9%) versus vehicle (6.7%). Symptom scores (OCI, OSDI) at week 8 showed significant improvements from baseline for all tofacitinib groups, and tofacitinib demonstrated greater improvements than cyclosporine. The tofacitinib 0.005% once daily group showed significant improvements in both a sign (Schirmer wetting without anesthesia) and symptom (OSDI environmental triggers subscale) versus vehicle and also demonstrated the highest response rate for CCC (16.7%) at week 8.
  
  
  CONCLUSIONS
  This phase 1/2 study of tofacitinib demonstrated a trend for improving both signs and symptoms of dry eye. All doses of tofacitinib exhibited a reasonable safety profile and were well tolerated by patients with DED.
authors.affiliation: Pfizer, Inc, Collegeville, Pennsylvania, USA.
authors.forename: Shiao Hui Melissa
authors.initials: SH
authors.lastname: Liew
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Nichols
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Klamerus
authors.forename: Jim Z
authors.initials: JZ
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Gary N
authors.initials: GN
authors.lastname: Foulks
mesh_terms: D016572:Cyclosporine / Q000008:administration & dosage; D004311:Double-Blind Method; D015352:Dry Eye Syndromes / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D009883:Ophthalmic Solutions; D010880:Piperidines; D011446:Prospective Studies; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects; D011795:Surveys and Questionnaires; D013666:Tears / Q000737:chemistry / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D009883:Ophthalmic Solutions; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D016572:Cyclosporine; C479163:tofacitinib; D053616:Janus Kinase 3