RESUMEN
Osteoarthritis (OA) pain management options are currently limited. Fasinumab, an anti-nerve growth factor monoclonal antibody, has been investigated in healthy volunteers and patients with OA-related pain, among other conditions. Data from 12 Phase I-III clinical trials of 92 healthy volunteers and 7430 patients with OA were used to develop a population pharmacokinetic model to characterize fasinumab concentration-time profiles and assess the covariates' effect on fasinumab pharmacokinetic parameters. Participants received single or repeated fasinumab doses intravenously (IV)/subcutaneously (SC), based on body weight (0.03-1 mg/kg IV or 0.1-0.3 mg/kg SC)/fixed dose (9-12 mg IV or 1-12 mg SC). Fasinumab concentration-time data following IV and SC administration in healthy volunteers and patients with OA-related pain were adequately described by a 2-compartment model. Bioavailability increased with higher doses; estimated at 55.1% with 1 mg SC dose, increasing in a greater-than-proportional manner above this. Body weight had the largest predicted impact on fasinumab steady-state exposures, participants at the 5th and 95th percentiles had a 43%-45% higher/22%-23% lower exposure versus reference, respectively. Other covariates had small but clinically irrelevant impacts.
RESUMEN
PURPOSE: Enoticumab (REGN421) is a fully human IgG1 monoclonal antibody that binds human Dll4 and disrupts Notch-mediated signaling. The main objectives of this trial were to determine the safety, dose-limiting toxicities (DLT), pharmacokinetics (PK), and recommended phase II dose (RP2D) of enoticumab. EXPERIMENTAL DESIGN: Enoticumab was administered intravenously, with dose escalations from 0.25 to 4 mg/kg every 3 weeks (Q3W) and 0.75 to 3 mg/kg every 2 weeks (Q2W). RESULTS: Of 53 enrolled patients, 31 patients were treated Q3W and 22 patients were treated Q2W. Two DLTs occurred: grade 3 nausea (0.5 mg/kg Q3W) and grade 3 abdominal pain (1 mg/kg Q2W). An MTD was not reached on either schedule. The most frequent adverse events (AE) were fatigue, nausea, vomiting, hypertension, headache, and anorexia. Six treatment-related serious AEs were reported in 4 patients: brain natriuretic peptide (BNP) increase (0.25 mg/kg Q3W, Gr1), troponin I increase (4 mg/kg Q3W, Gr3), right ventricular dysfunction and pulmonary hypertension (1.5 mg/kg Q2W, both Gr3), and left ventricular dysfunction and pulmonary hypertension (3 mg/kg Q2W, both Gr3). Enoticumab was characterized by nonlinear, target-mediated PK, and had a terminal half-life of 8 to 9 days. With multiple Q2W or Q3W dosing, accumulation was not observed. Antitumor activity included two partial responses (non-small cell lung cancer bronchoalveolar-type with a ß-catenin mutation, and ovarian cancer) and 16 patients with stable disease (3> 6 months). CONCLUSIONS: Enoticumab was tolerated, with RP2D of 4 mg/kg Q3W and 3 mg/kg Q2W based on PK profile and clinical activity. Responses and SD were noted in ovarian cancer and other solid tumors. Clin Cancer Res; 21(12); 2695-703. ©2015 AACR.
