title: Safety, tolerability, pharmacokinetics, and efficacy of AMG 403, a human anti-nerve growth factor monoclonal antibody, in two phase I studies with healthy volunteers and knee osteoarthritis subjects.
abstract: BACKGROUND
  Nerve growth factor plays a key role in the pathology of osteoarthritis (OA) related chronic pain. The aim of these studies was to evaluate the safety, tolerability, pharmacokinetics, and clinical response of AMG 403, a human anti-nerve growth factor monoclonal antibody, in healthy volunteers and subjects with knee OA.
  
  
  METHODS
  Two phase I, randomized, placebo-controlled, double-blind studies were conducted. The single-ascending dose study randomized healthy volunteers (n = 48) 3:1 to receive AMG 403 (1, 3, 10, or 30 mg intravenously; or 10 or 30 mg subcutaneously; n = 8 per group) or placebo. The multiple-ascending dose study randomized knee OA subjects (n = 18) 3:1 to receive AMG 403 (3, 10, or 20 mg subcutaneously once monthly for four doses) or placebo. Safety, tolerability, and pharmacokinetics (PK) were assessed for both studies. Patient's and physician's disease assessments and total WOMAC score were determined in knee OA subjects.
  
  
  RESULTS
  AMG 403 appeared to be well-tolerated after single and multiple doses, except for subject-reported hyperesthesia, pain, and paresthesia (mild to moderate severity). These treatment-emergent neurosensory events showed evidence of reversibility and a possible dose-dependence. Three serious adverse events were reported in AMG 403 treated subjects, but were not considered treatment related. AMG 403 PK was linear with an estimated half-life of 19.6 to 25.8 days. After multiple doses, AMG 403 PK showed modest accumulation (≤2.4-fold increase) in systemic exposure. Knee OA diagnosis, body weight, and anti-drug antibody development did not appear to affect AMG 403 PK. Patient's and physician's disease assessments and total WOMAC score showed improvement in AMG 403 treated knee OA subjects compared with placebo.
  
  
  CONCLUSIONS
  AMG 403 was generally safe and well-tolerated in both healthy volunteers and knee OA patients, and exhibited linear pharmacokinetics. Preliminary clinical efficacy was observed in knee OA subjects.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT02348879 . Registered 23 December 2014. Clintrials.gov NCT02318407 . Registered 2 December 2014.
authors.affiliation: Amgen, Inc, 1201 Amgen Court West, Seattle, WA, 98119, USA. jasonmg8@yahoo.com.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Gow
authors.affiliation: Amgen, Inc, 1201 Amgen Court West, Seattle, WA, 98119, USA. tsujiw@amgen.com.
authors.forename: Wayne H
authors.initials: WH
authors.lastname: Tsuji
authors.affiliation: Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA, 91320, USA. gary.j.williams@questdiagnostics.com.|Quest Diagnostics, Inc, 1311 Calle Batido, San Clemente, CA, 92673, USA. gary.j.williams@questdiagnostics.com.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Williams
authors.affiliation: Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA, 91320, USA. dmytych@amgen.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mytych
authors.affiliation: Amgen Limited, 240 Cambridge Science Park, Milton Road, Cambridge, CB4 0WD, UK. david.sciberras@ucb.com.
authors.forename: David
authors.initials: D
authors.lastname: Sciberras
authors.affiliation: PRA Health Sciences, 3838 South 700 East, Salt Lake City, UT, 84106, USA. searleshawn@prahs.com.
authors.forename: Shawn L
authors.initials: SL
authors.lastname: Searle
authors.affiliation: Quintiles Drug Research Unit at Guy's Hospital, 6 Newcomen Street, London, SE1 1YR, UK. tim.mant@quintiles.com.
authors.forename: Tim
authors.initials: T
authors.lastname: Mant
authors.affiliation: Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA, 91320, USA. gibbsj@amgen.com.
authors.forename: John P
authors.initials: JP
authors.lastname: Gibbs
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors*; D020370:Osteoarthritis, Knee / Q000188:drug therapy*
chemical_list: C000609797:AMG 403; D000911:Antibodies, Monoclonal; C502240:NGF protein, human; D020932:Nerve Growth Factor