Safety And Tolerability Study Of RN564 In Women With Osteopenia And Healthy Men.

Dose-limiting or intolerable treatment related AEs was defined as any of the following criteria occurred in 2 or more participants: Serious adverse events, Increased liver transaminases, Increased bilirubin (in absence of ALT/AST elevations, allergic / hypersensitivity reactions, vasculitis, Musculoskeletal pain, Increased serum creatinine, Diarrhea, enteritis or nausea, Prolongation of QTcF interval or any other criteria If considered appropriate by the Medical Monitor and Investigator. A dose level was also be considered intolerable if, in the judgment of the Investigator and Sponsor, the type, frequency, or severity of AEs becomes unacceptable.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity was graded as Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity was graded as Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. Relatedness to drug was assessed by investigator.

Criteria for abnormality: hematology: hemoglobin, hematocrit, red blood cell count: less than(<) 0.8*lower limit of normal (LLN); platelets: <0.5*LLN,>1.75*ULN, white blood cell count: <0.6*LLN, >1.5*ULN; lymphocytes, total neutrophils: <0.8*LLN, >1.2*ULN; eosinophils, basophils, monocytes: >1.2*ULN; coagulation: activated partial thromboplastin time, prothrombin, prothrombin international ratio: >1.1*ULN; liver function: bilirubin: >1.5*ULN; aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase: >3.0*ULN; protein, albumin: <0.8*LLN></0>1.2*ULN; renal function: blood urea nitrogen, creatinine: >1.3*ULN; uric acid: >1.2*ULN; electrolytes: sodium>1.05*ULN, potassium, chloride, calcium, bicarbonate: <0.9*LLN,>1.1*ULN; urinalysis: pH<4.5, >8; glucose, protein, blood, ketones, urobilinogen, bilirubin, nitrite; Other(glucose: <0.6*LLN,>1.5*ULN), urine casts, granular casts, hyaline casts>1 LPF; hormones: T4, T3, TSH<0.8*LLN.

Median change from baseline in platelets, WBC count, lymphocytes (absolute [Abs]), total neutrophils (Abs), basophils (Abs), eosinophils (Abs), and monocytes (Abs)

Includes median changes from baseline in total bilirubin, direct bilirubin, indirect bilirubin, blood urea nitrogen (BUN), creatinine, uric acid, calcium, magnesium, and glucose

Includes median changes in aspartate aminotransferase (AST), alanine aminotransferase (AST), gamma glutamyltransferase (GGT), and alkaline phosphatase

Participants with maximum changes from baseline (defined as increases or decreases of greater than or equal to [≥]20 mmHg or ≥30 mmHg) in either standing or supine systolic blood pressure (SBP) or diastolic blood pressure (DBP) measured in millimeters mercury (mmHg).

Participants with maximum changes from baseline (BSL) defined as: ≥25 to 50 percent (%) increase in maximum PR interval or QRS complex; increase from BSL of ≥30 milliseconds (msec) but <60 msec in corrected QT (QTc) interval or QTcF interval (QTc interval corrected using Fridericia's correction); or increase from BSL ≥60 msec in either QTc interval or QTcF interval.

Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state.

CL is a quantitative measure of the rate at which a drug substance is removed from the body.

Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half.

AUC (0 - inf)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf).

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. Based on internal clinical pharmacology guidance on the most appropriate parameter calculations for this study design, data for Vz/F was not collected instead Vss was reported.

Baseline calculated as average of Day -1 and Day 1 prior to infusion of PF-04840082

Baseline calculated as average of Day -1 and Day 1 prior to infusion of PF-04840082

Baseline calculated as average of Day -1 and Day 1 prior to infusion of PF-04840082

Baseline calculated as average of Day -1 and Day 1 prior to infusion of PF-04840082

Baseline calculated as average of Day -1 and Day 1 prior to infusion of PF-04840082

BMD was evaluated by dual energy X-ray absorptiometry (DXA).

BMD was evaluated by DXA. T-score was calculated based on actual measured bone density value and is the standardized scores that reflect the standard deviations (SDs) above/below the mean. A BMD T-score of -1.0 or more indicates normal bone density. T-score between -1.0 and -2.5 indicates low bone density known as osteopenia. A T-score of -2.5 or less is diagnostic of osteoporosis.

BMD was evaluated by DXA.

Data for this Outcome Measure are not reported here because the analysis population includes participants who were not enrolled in this study. ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the Participant Flow and Baseline Characteristics modules.