Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study

BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year. METHODS: Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676

Travelers' health problems and behavior : prospective study with post-travel follow-up

Background: The annual number of international tourist arrivals has recently exceeded one billion, yet surprisingly few studies have characterized travelers' behavior, illness, and risk factors in a prospective setting. Particularly scarce are surveys of data spanning travel, return, and follow-up of the same cohort. This study examines behavior and illness among travelers while abroad, after return home, and at follow-up. Patterns of behavior connected to type of travel and illness are characterized so as to identify risk factors and provide background data for pre-travel advice. Methods: Volunteers to this prospective cohort study were recruited at visits to a travel clinic prior to departure. Data on the subjects' health and behavior were collected by questionnaires before and after journeys and over a three-week follow-up. In addition, the subjects were asked to fill in health diaries while traveling. Results: The final study population consisted of 460 subjects, 79 % of whom reported illness during travel or on arrival: 69 % had travelers' diarrhea (TD), 17 % skin problems, 17 % fever, 12 % vomiting, 8 % respiratory tract infection, 4 % urinary tract infection, 2 % ear infection, 4 % gastrointestinal complaints other than TD or vomiting, and 4 % other symptoms. Of all subjects, 10 % consulted a doctor and 0.7 % were hospitalized; 18 % took antimicrobials, with TD as the most common indication (64 %). Ongoing symptoms were reported by 25 % of all travelers upon return home. During the three-week follow-up (return rate 51 %), 32 % of respondents developed new-onset symptoms, 20 % visited a doctor and 1.7 % were hospitalized. Factors predisposing to health problems were identified by multivariable analysis: certain regions (Southern Asia, South-Eastern Asia, and Eastern Africa), female gender, young age, and long travel duration. Conclusions: Despite proper preventive measures like vaccinations, malaria prophylaxis, and travel advice, the majority of our subjects fell ill during or after travel. As the symptoms mostly remained mild, health care services were seldom needed. Typical traveler profiles were identified, thereby providing a tool for pre-travel advice. The finding that one third reported new-onset illness during follow-up attests to the importance of advising clients on potential post-travel health problems already during pre-travel visits.Peer reviewe

Pharmacokinetics of Novel Plant Cell-Expressed Taliglucerase Alfa in Adult and Pediatric Patients with Gaucher Disease

<div><p>Taliglucerase alfa is a beta-glucocerebrosidase enzyme replacement therapy approved in the United States, Israel, and other countries for treatment of Type 1 Gaucher disease in adults, and is the first approved plant cell—expressed recombinant protein. In this report, taliglucerase alfa pharmacokinetics were assessed in adult and pediatric patients with Gaucher disease from separate multicenter trials of 30 Units/kg and 60 Units/kg doses infused every 2 weeks. Serial blood samples were obtained from adult patients following single-dose administration on day 1 (n = 26) and multiple doses at week 38 (n = 29), and from pediatric patients following administration of multiple doses of taliglucerase alfa for 10–27 months (n = 10). In both adult and pediatric patients, maximum plasma concentration (C_max), area under the plasma concentration-time curve from time zero to last measureable concentration (AUC_0-t), and from time zero to infinity (AUC_0-∞) were higher after 60 Units/kg dose than 30 Units/kg dose. No tendency for accumulation or change in taliglucerase alfa pharmacokinetic parameters over time from day 1 to week 38 was observed with repeated doses of 30 or 60 Units/kg in adults. After multiple doses, mean (range) dose-normalized pharmacokinetic parameters were similar for adult versus pediatric patients receiving 60 Units/kg: C_max expressed in ng/mL/mg was 42.4 (14.5–95.4) in adults and 46.6 (34.4–68.4) in pediatric patients, AUC_{0 t} expressed in ng•h/mL/mg was 63.4 (26.3–156) in adults and 63.9 (39.8–85.1) in pediatric patients, t_1/2 expressed in minutes was 34.8 (11.3–104) in adults and 31.5 (18.0–42.9) in pediatric patients and total body clearance expressed in L/h was 19.9 (6.25–37.9) in adults and 17.0 (11.7–24.9) in pediatric patients. These pharmacokinetic data extend the findings of taliglucerase alfa in adult and pediatric patients.</p><p>Trial Registration</p><p>ClinicalTrials.gov. <a href="http://clinicaltrials.gov/show/NCT00376168" target="_blank">NCT00376168</a> (in adults); <a href="http://clinicaltrials.gov/show/NCT01411228" target="_blank">NCT01411228</a> (in children)</p></div

Taliglucerase alfa plasma concentration in pediatric patients.

<p>Mean plasma concentration-versus-time curve of taliglucerase alfa in pediatric patients for approximately 100-minute infusions showing dose-dependent increase (linear plot). Abbreviation: U/kg, Units/kg. Error bars represent standard deviations.</p

Taliglucerase alfa plasma concentration in adult patients.

<p>Mean plasma concentration-versus-time curve of taliglucerase alfa in adult patients for 120-minute infusions showing dose-dependent increase (linear plot): a) on day 1; b) at week 38. Abbreviation: U/kg, Units/kg. Error bars represent standard deviations.</p

Summary of PK parameters of taliglucerase alfa in pediatric patients.

<p>AUC_0–t, area under the plasma concentration-time curve from time zero to the last sampling time; AUC_0–∞, area under the plasma concentration-time curve extrapolated from time zero to infinity; CL, total body clearance; C_max, maximum plasma concentration; PK, pharmacokinetics; SD, standard deviation; T_max, time of maximum plasma concentration; t_1/2, elimination half-life; U/kg, Units/kg; V_ss, volume of distribution during steady-state.</p><p>Summary of PK parameters of taliglucerase alfa in pediatric patients.</p

Data from: Immunogenicity of glycans on biotherapeutic drugs produced in plant expression systems - the taliglucerase alfa story

Plants are a promising alternative for the production of biotherapeutics. Manufacturing in-planta adds plant specific glycans. To understand immunogenic potential of these glycans, we developed a validated method to detect plant specific glycan antibodies in human serum. Using this assay, low prevalence of pre-existing anti-plant glycan antibodies was found in healthy humans (13.5%) and in glucocerebrosidase-deficient Gaucher disease (GD) patients (5%). A low incidence (9% in naïve patient and none in treatment experienced patients) of induced anti-plant glycan antibodies was observed in GD patients after up to 30 months replacement therapy treatment with taliglucerase alfa, a version of human glucocerebrosidase produced in plant cells. Detailed evaluation of clinical safety and efficacy endpoints indicated that anti-plant glycan antibodies did not affect the safety or efficacy of taliglucerase alfa in patients. This study shows the benefit of using large scale human trials to evaluate the immunogenicity risk of plant derived glycans, and indicates no apparent risk related to anti-plant glycan antibodies

Defensive Medicine among Obstetricians and Gynecologists in Tertiary Hospitals

<div><p>Objective</p><p>To describe the daily work practice under the threat of defensive medicine among obstetricians and gynecologists.</p> <p>Study Design</p><p>A prospective cross-sectional survey of obstetricians and gynecologists working at tertiary medical centers in Israel.</p> <p>Results</p><p>Among the 117 obstetricians and gynecologists who participated in the survey, representing 10% of the obstetricians and gynecologists registered by the Israel Medical Association, 113 (97%) felt that their daily work practice is influenced by concern about being sued for medical negligence and not only by genuine medical considerations. As a result, 102 (87%) physicians are more likely to offer the cesarean section option, even in the absence of a clear medical indication, 70 (60%) follow court rulings concerning medical practices, and 85 (73%) physicians mentioned that discussions about medical negligence court rulings are included in their departments' meetings.</p> <p>Conclusions</p><p>Defensive medicine is a well-embedded phenomenon affecting the medical decision process of obstetricians and gynecologists.</p> </div