Systematic central monitoring of clinical trial data can identify problems at the same trials and sites identified during FDA site inspections. Central data monitoring in conjunction with an overall monitoring process that adapts to identify risks as a trial progresses has the potential to reduce the frequency of site visits while increasing data integrity and decreasing trial costs compared to processes that are dependent primarily on source documentation.

Objective. To evaluate the efficacy and safety of PF-06651600 (ritlecitinib), an irreversible inhibitor of JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family, in comparison with placebo in patients with rheumatoid arthritis (RA). Methods. An 8-week, phase II, double-blind, parallel-group study was conducted. Seventy patients who were seropositive for anti-citrullinated protein antibodies and/or rheumatoid factor were randomized 3:2 to receive oral PF-06651600 (200 mg once daily) or placebo for 8 weeks. Eligible patients had an inadequate response to methotrexate, and the study design allowed up to 50% of patients to have previously received 1 tumor necrosis factor inhibitor that was inadequately effective and/or not tolerated. The primary end point was change from baseline in the Simplified Disease Activity Index (SDAI) score at week 8, assessed by Bayesian analysis using an informative prior distribution for placebo response. Results. Mean change from baseline in the SDAI score at week 8 was greater in the PF-06651600 group (−26.1 [95% credible interval −29.7, −22.4]) than in the placebo group (−16.8 [95% credible interval −20.9, −12.7]; P < 0.001). Most adverse events (AEs) were mild in severity, and no treatment-related serious AEs, severe AEs, or deaths were reported. The most common classes of AE were infections and infestations as well as skin and subcutaneous tissue disorders; there was 1 mild case of herpes simplex in the PF-06651600 group that was considered to be treatment related, which resolved within 3 days without study treatment discontinuation or antiviral therapy. Conclusion. Treatment with the oral JAK3/TEC inhibitor PF-06651600 (200 mg once daily) was associated with significant improvements in RA disease activity and was generally well-tolerated in this small 8-week study. ClinicalTrials.gov identifier: NCT02969044.

Domagrozumab, a monoclonal antibody that binds to myostatin, is being developed for Duchenne muscular dystrophy (DMD) boys following a first-in-human study in healthy adults. Literature reporting pharmacokinetic parameters of monoclonal antibodies suggested that body-weight- and body-surface-area-adjusted clearance and volume of distribution estimates between adults and children are similar for subjects older than 6 years. Population modeling identified a Michaelis-Menten binding kinetics model to optimally characterize the target mediated drug disposition profile of domagrozumab and identified body mass index on the volume of distribution as the only significant covariate. Model parameters were predicted with high-precision pharmacokinetics (clearance 1.01 × 10 L/[h·kg]; central volume of distribution 457 × 10 L/kg; maximum elimination rate 17.5 × 10 nmol/[h·kg], Km 10.6 nmol/L) and pharmacodynamics (myostatin turnover rate 457 × 10 h ; complex removal rate 90 × 10 h ; half-saturation constant 4.32 nmol/L) and were used to predict target coverage for dosage selection in the DMD population. Additionally, allometric approaches (estimated scaling exponents (standard error) for clearance and volume were 0.81 [0.01] and 0.98 [0.02], respectively) in conjunction with a separate analysis to obtain the population mean weight and standard deviation suggested that if dosed per body weight, an only 11% difference in clearance is expected between the heaviest and lightest patient, thus preventing the need for dose adjustment. In summary, quantitative approaches were instrumental in bridging and derisking the fast-track development of domagrozumab in DMD.

BackgroundPF-06650833 is a potent, selective inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). Two randomized, double-blind, sponsor-open phase 1 studies evaluated the safety, pharmacokinetics, and pharmacodynamics of single (SAD) and multiple ascending doses (MAD) of PF-06650833 immediate-release (IR) and modified-release (MR) oral formulations in healthy adult subjects.MethodsStudy 1 (NCT02224651) was a 96-day, placebo-substitution, SAD study of once-daily (QD) oral PF-06650833 IR 1 to 6000 mg and MR 30 to 300 mg in fasted and fed states. Study 2 (NCT02485769) was a 14-day, placebo-controlled, MAD study of PF-06650833 IR 25 to 750 mg twice daily, IR 1000 mg four times per day, IR 330 mg three times per day, and MR 300 mg QD.ResultsPF-06650833 was generally well tolerated, with no dose-limiting treatment-emergent adverse events (TEAEs) identified in either study. TEAEs were generally mild in severity, with headache, gastrointestinal disorders, and acne most commonly reported. No serious AEs or deaths were reported. A maximum tolerated dose was not established in either study. In the SAD study, food intake delayed absorption of IR 30 mg and increased total exposure by 33%. Delayed absorption was achieved with the MR formulation (Tmax of 1 h versus 8 h for IR 100 mg and MR 100 mg formulations, respectively). Food had no effect on total exposure for MR 30 mg, but reduced half-life 1.8-fold and increased Cmax by 62%. In the MAD study, accumulation ranged from 0.9-fold to 1.4-fold for AUCtau and 0.9-fold to 1.3-fold for Cmax. Less than 1% of the dose was recovered unchanged in urine for all dose groups, with renal clearance ranging from 14 to 23 mL/min for IR < 750 mg and MR 300 mg. There was a sustained decrease in serum high-sensitivity C-reactive protein for IR ≥ 250 mg and MR 300 mg. Based on the cholesterol/hydroxycholesterol ratio, no apparent CYP3A induction or inhibition was observed.ConclusionsPF-06650833, the first IRAK4 inhibitor to enter clinical development, has a favorable safety and pharmacokinetic profile and has shown evidence of pharmacological effect. The data support continued evaluation in human clinical trials for the treatment of rheumatic and autoimmune diseases.Trial registrationClinicaltrials.gov, NCT02224651, registered 25 August 2014; NCT02485769, registered 30 June 2015

Objective-Examine relations of blood pressure (BP) to single photon emission computed tomography (SPECT)-derived estimates of cerebral blood flow in older men and women.Methods-Seventy-four stroke and dementia-free, community-dwelling older adults (ages 54-83; 68% men; 91% White) free of major medical, neurological, or psychiatric disease, engaged in a) clinical assessment of resting systolic and diastolic BP; b) magnetic resonance imaging (MRI) rated for brain atrophy; and c) brain SPECT studies with computerized coding of cortical and select subcortical regions of interest (ROIs).Results-Given significant interactions of BP and sex with respect to multiple SPECT outcomes, sex-stratified multiple regression models were computed. Models were adjusted for age, fasting glucose levels, antihypertensive medication, body mass index, and MRI ratings of brain atrophy. In men (n= 50), higher levels of systolic and/or diastolic BP were associated significantly with lower estimates of cerebral perfusion in the right and left frontal, temporal, parietal, and occipital cortex, thalamus, head of caudate and cingulate cortex accounting for up to 28% of the variance in these measures (p's < .05). In women (n= 24), higher diastolic BP related marginally to higher levels of perfusion in the right temporal cortex (p = .05).Conclusions-Higher resting systolic or diastolic BP was associated with lower levels of cerebral perfusion in otherwise healthy older men, but not women, in the present sample. Reduced cerebral blood flow may play a pathogenic role in increasing risk for stroke, dementia, and or cognitive decline particularly among older men with high blood pressure.