ObjectivesThere is a need for effective and safe treatment during pregnancy in women with chronic inflammatory diseases. This study evaluated placental transfer of certolizumab pegol (CZP), an Fc-free anti-tumour necrosis factor drug, from CZP-treated pregnant women to their infants.MethodsCRIB was a pharmacokinetic (PK) study of women ≥30 weeks pregnant receiving commercial CZP for a locally approved indication (last dose ≤35 days prior to delivery). Blood samples were collected from mothers, umbilical cords and infants at delivery, and infants again at weeks 4 and 8 post-delivery. CZP plasma concentrations were measured with a highly sensitive and CZP-specific electrochemiluminescence immunoassay (lower limit of quantification 0.032 μg/mL).ResultsSixteen women entered and completed the study. Maternal CZP plasma levels at delivery were within the expected therapeutic range (median [range] 24.4 [5.0–49.4] μg/mL). Of the 16 infants, 2 were excluded from the per-protocol set: 1 due to missing data at birth and 1 due to implausible PK data. Of the remaining 14 infants, 13 had no quantifiable CZP levels at birth (<0.032 μg/mL), and 1 had a minimal CZP level of 0.042 μg/mL (infant/mother plasma ratio 0.0009); no infants had quantifiable CZP levels at weeks 4 and 8. Of 16 umbilical cord samples, 1 was excluded due to missing data; 3/15 had quantifiable CZP levels (maximum 0.048 μg/mL).ConclusionsThere was no to minimal placental transfer of CZP from mothers to infants, suggesting lack of in utero foetal exposure during the third trimester. These results support continuation of CZP treatment during pregnancy, when considered necessary.Trial registration numberNCT02019602; Results.

TZP-101 appears to be safe, well-tolerated, and effective at acutely addressing several gastroparesis symptoms.

BackgroundWomen with chronic inflammatory diseases face uncertainty regarding the safety of biologics during breast feeding. CRADLE was the first industry-sponsored study to evaluate certolizumab pegol (CZP) concentrations in human breast milk and estimate average daily infant dose (ADID) of maternal CZP.MethodsCRADLE (NCT02154425) was a pharmacokinetic study of lactating mothers receiving CZP. After ≥3 CZP doses, breast milk samples were collected across one dosing period (14 days for 200 mg every 2 weeks [Q2W]; 28 days for 400 mg every 4 weeks [Q4W]). Optimal analytical methods were developed to determine CZP and polyethylene glycol (PEG) levels in breast milk. ADID and relative infant dose (RID) were estimated. Safety events in mothers and infants were assessed.Results19 CZP-treated mothers were screened; 17 entered the sampling period: 16 on 200 mg Q2W, 1 on 400 mg Q4W. 77/137 (56%) breast milk samples had no measurable CZP. For 4/17 mothers, all samples were below the lower limit of quantification (LLOQ). Estimated ADID was 0–0.0104 mg/kg/day; median RID: 0.15%. PEG was undetectable in 134/137 samples (results could not be determined in three samples). Infants of CZP-exposed mothers had a safety profile consistent with that of unexposed similar-age infants.ConclusionWhen quantifiable, CZP concentrations were <3× LLOQ (<1% plasma concentration observed with therapeutic dose), indicating no/minimal CZP transfer from plasma to breast milk. RID was 0.15% of maternal dose; <10% is considered unlikely to be of clinical concern. No PEG transfer was observed. CZP absorption by infants via breast milk is unlikely due to its low oral bioavailability and Fc-­free molecular structure. These findings are reassuring and support continuation of CZP treatment during breast feeding.Trial registration numberNCT02154425; Results.

SUMMARYBackground TZP-101 is a synthetic, selective ghrelin agonist in development for gastroparesis.

Human cases of West Nile virus (WNV) disease have been reported in Italy since 2008. So far, most cases have been identified in north-eastern Italy, where, in 2012, the largest outbreak of WNV infection ever recorded in Italy occurred. Most cases of the 2012 outbreak were identified in the Veneto region, where a special surveillance plan for West Nile fever was in place. In this outbreak, 25 cases of West Nile neuroinvasive disease and 17 cases of fever were confirmed. In addition, 14 WNV RNA-positive blood donors were identified by screening of blood and organ donations and two cases of asymptomatic infection were diagnosed by active surveillance of subjects at risk of WNV exposure. Two cases of death due to WNND were reported. Molecular testing demonstrated the presence of WNV lineage 1 in all WNV RNA-positive patients and, in 15 cases, infection by the novel Livenza strain was ascertained. Surveillance in other Italian regions notified one case of neuroinvasive disease in the south of Italy and two cases in Sardinia. Integrated surveillance for WNV infection remains a public health priority in Italy and vector control activities have been strengthened in areas of WNV circulation.

Background Certolizumab pegol (CZP) is a PEGylated Fc-free anti-TNF approved in 45 countries for the treatment of rheumatoid arthritis (RA) and/or Crohn's disease (CD); it was recently approved by the EMA for psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). Analysis of pregnancy data from the UCB Pharma global safety database through 06 March 2012 has been published previously.1 Objectives To provide an updated analysis of pregnancy outcomes in rheumatic patients (pts) after CZP exposure, with a focus on RA, by including new reports and pregnancies that were still ongoing at the time of the last retrospective analysis. Methods The UCB Pharma global safety database, designed to house and report adverse events for UCB Pharma products, was searched for all medically confirmed cases of pregnancy through 28 March 2013. Reported pregnancies included women who became pregnant while participating in a clinical study and spontaneous post-marketing reports. The number of live births, spontaneous miscarriages and elective terminations for neonates exposed to CZP (maternal and paternal exposure) was examined. Congenital abnormalities, neonatal deaths and maternal demographics were also investigated. Results As of 28 March 2013, 309 CZP exposed pregnancies were reported: 285 were maternal exposure, 24 were paternal. For pregnancies with maternal exposure, although the major underlying condition was CD (190/285), RA was the underlying condition for 52 of the 285 women with the remaining 43/285 encompassing other indications, including axSpA and PsA. Pregnancy outcomes were available for 190 of these 285 pregnancies: 42 in women with RA, 124 in women with CD and 24 in women with other rheumatic indications. For the 42 pregnancies in women with RA with known outcomes, whether spontaneously reported or within a clinical trial context, 26 (61.9%) resulted in live birth, 9 (21.4%) in spontaneous miscarriage and 7 (16.7%) in elective termination. The Table presents characteristics for pregnancies in women with RA compared to those for all reported maternal exposure pregnancies. Five congenital anomalies were reported, in four neonates, among all live births with maternal CZP exposure (n=132): vesicoureteric reflux, congenital morbus hirschsprung disease and club foot, right aortic arch with aberrant left subclavian artery, and mild unilateral hydronephrosis on antenatal ultrasound (described as healthy upon birth). None of these events were considered related to CZP by the treating physicians. A single neonatal death was reported after maternal exposure in one of a set of twins delivered before 26 weeks of gestation. Conclusions Updated analysis of pregnancy outcomes after exposure to CZP supports previous reports suggesting no apparent impact of maternal CZP exposure on pregnancy outcomes. Additional prospective data are required to fully evaluate the safety and tolerability of CZP in pregnancy. References Clowse M. Arthritis Rheum 2012; 64(Suppl10):S702 Acknowledgements The authors acknowledge Co...

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ObjectiveAnti–tumor necrosis factor (anti‐TNF) medications are effective in controlling chronic inflammatory diseases, but information about their use and safety in pregnancy is limited. Consequently, anti‐TNF agents are often discontinued early in gestation. Certolizumab pegol (CZP), a PEGylated, Fc‐free anti‐TNF agent approved for the treatment of rheumatic diseases and/or Crohn's disease, has minimal to no active placental transfer. This analysis was undertaken to evaluate pregnancy outcomes in women receiving CZP, especially those exposed during early pregnancy.MethodsProspective and retrospective data on maternal CZP exposure were extracted from the UCB Pharma safety database through March 6, 2017. Analysis was limited to prospective reports to avoid potential bias associated with retrospective submissions. The numbers of live births, miscarriages, elective abortions, stillbirths, and major congenital malformations were ascertained.ResultsOf 1,137 prospectively reported pregnancies with maternal exposure to CZP, 528 (including 10 twin pregnancies) had 538 known outcomes: 459 live births (85.3%), 47 miscarriages (8.7%), 27 elective abortions (5.0%), and 5 stillbirths (0.9%). There were 8 major congenital malformations (1.7%) among the 459 infants. First trimester exposure occurred in 367 (81.2%) of 452 pregnancies resulting in 459 live births. Exposure during all 3 trimesters occurred in 201 (44.5%) of 452 pregnancies.ConclusionThis analysis represents the largest cohort of pregnant women exposed to an anti‐TNF agent for management of chronic inflammatory diseases. Analysis of pregnancy outcomes does not indicate a teratogenic effect of CZP, compared to the general population, nor an increased risk of fetal death. The data are reassuring for women of childbearing age considering treatment with CZP.