Efficacy, safety and tolerability of rozanolixizumab in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a randomised, subject-blind, investigator-blind, placebo-controlled, phase 2a trial and open-label extension study.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a peripheral nerve disorder characterised by weakness and sensory loss. We assessed the neonatal Fc receptor inhibitor rozanolixizumab for CIDP management. METHODS: CIDP01 (NCT03861481) was a randomised, subject-blind, investigator-blind, placebo-controlled, phase 2a study. Adults with definite or probable CIDP receiving subcutaneous or intravenous immunoglobulin maintenance therapy were randomised 1:1 to 12 once-weekly subcutaneous infusions of rozanolixizumab 10 mg/kg or placebo, stratified according to previous immunoglobulin administration route. Investigators administering treatment and assessing efficacy, and patients, were blinded. The primary outcome was a change from baseline (CFB) to day 85 in inflammatory Rasch-built Overall Disability Scale (iRODS) score. Eligible patients who completed CIDP01 entered the open-label extension CIDP04 (NCT04051944). RESULTS: In CIDP01, between 26 March 2019 and 31 March 2021, 34 patients were randomised to rozanolixizumab or placebo (17 (50%) each). No significant difference in CFB to day 85 in iRODS centile score was observed between rozanolixizumab (least squares mean 2.0 (SE 3.2)) and placebo (3.4 (2.6); difference -1.5 (90% CI -7.5 to 4.5)). Overall, 14 (82%) patients receiving rozanolixizumab and 13 (76%) receiving placebo experienced a treatment-emergent adverse event during the treatment period. Across CIDP01 and CIDP04, rozanolixizumab was well tolerated over up to 614 days; no clinically meaningful efficacy results were seen. No deaths occurred. CONCLUSIONS: Rozanolixizumab did not show efficacy in patients with CIDP in this study, although this could be due to a relatively high placebo stability rate. Rozanolixizumab was well tolerated over medium-to-long-term weekly use, with an acceptable safety profile.

Antineonatal Fc Receptor Antibody Treatment Ameliorates MOG-IgG-Associated Experimental Autoimmune Encephalomyelitis.

BACKGROUND AND OBJECTIVES: Myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) is a rare, autoimmune demyelinating CNS disorder, distinct from multiple sclerosis and neuromyelitis optica spectrum disorder. Characterized by pathogenic immunoglobulin G (IgG) antibodies against MOG, a potential treatment strategy for MOGAD is to reduce circulating IgG levels, e.g., by interference with the IgG recycling pathway mediated by the neonatal Fc receptor (FcRn). Although the optic nerve is often detrimentally involved in MOGAD, the effect of FcRn blockade on the visual pathway has not been assessed. Our objective was to investigate effects of a monoclonal anti-FcRn antibody in murine MOG-IgG-associated experimental autoimmune encephalomyelitis (EAE). METHODS: We induced active MOG35-55 EAE in C57Bl/6 mice followed by the application of a monoclonal MOG-IgG (8-18C5) 10 days postimmunization (dpi). Animals were treated with either a specific monoclonal antibody against FcRn (α-FcRn, 4470) or an isotype-matched control IgG on 7, 10, and 13 dpi. Neurologic disability was scored daily on a 10-point scale. Visual acuity was assessed by optomotor reflex. Histopathologic hallmarks of disease were assessed in the spinal cord, optic nerve, and retina. Immune cell infiltration was visualized by immunohistochemistry, demyelination by Luxol fast blue staining and complement deposition and number of retinal ganglion cells by immunofluorescence. RESULTS: In MOG-IgG-augmented MOG35-55 EAE, anti-FcRn treatment significantly attenuated neurologic disability over the course of disease (mean area under the curve and 95% confidence intervals (CIs): α-FcRn [n = 27], 46.02 [37.89-54.15]; isotype IgG [n = 24], 66.75 [59.54-73.96], 3 independent experiments), correlating with reduced amounts of demyelination and macrophage infiltration into the spinal cord. T- and B-cell infiltration and complement deposition remained unchanged. Compared with isotype, anti-FcRn treatment prevented reduction of visual acuity over the course of disease (median cycles/degree and interquartile range: α-FcRn [n = 16], 0.50 [0.48-0.55] to 0.50 [0.48-0.58]; isotype IgG [n = 17], 0.50 [0.49-0.54] to 0.45 [0.39-0.51]). DISCUSSION: We show preserved optomotor response and ameliorated course of disease after anti-FcRn treatment in an experimental model using a monoclonal MOG-IgG to mimic MOGAD. Selectively targeting FcRn might represent a promising therapeutic approach in MOGAD.

Efficacy and Safety of Rozanolixizumab in Moderate to Severe Generalized Myasthenia Gravis: A Phase 2 Randomized Control Trial.

OBJECTIVE: To explore the clinical efficacy and safety of subcutaneous (SC) rozanolixizumab, an anti-neonatal Fc receptor humanized monoclonal antibody, in patients with generalized myasthenia gravis (gMG). METHODS: In this phase 2a, randomized, double-blind, placebo-controlled, 2-period, multicenter trial (NCT03052751), patients were randomized (1:1) in period 1 (days 1-29) to 3 once-weekly (Q1W) SC infusions of rozanolixizumab 7 mg/kg or placebo. In period 2 (days 29-43), patients were re-randomized to either rozanolixizumab 7 mg/kg or 4 mg/kg (3 Q1W SC infusions), followed by an observation period (days 44-99). Primary endpoint was change from baseline to day 29 in Quantitative Myasthenia Gravis (QMG) score. Secondary endpoints were change from baseline to day 29 in MG-Activities of Daily Living (MG-ADL) and MG-Composite (MGC) scores and safety. RESULTS: Forty-three patients were randomized (rozanolixizumab 21, placebo 22 [period 1]). Least squares (LS) mean change from baseline to day 29 for rozanolixizumab vs placebo was as follows: QMG (LS mean -1.8 vs -1.2, difference -0.7, 95% upper confidence limit [UCL] 0.8; p = 0.221; not statistically significant), MG-ADL (LS mean -1.8 vs -0.4, difference -1.4, 95% UCL -0.4), and MGC (LS mean -3.1 vs -1.2, difference -1.8, 95% UCL 0.4) scores. Efficacy measures continued to improve with rozanolixizumab 7 mg/kg in period 2. The most common adverse event in period 1 was headache (rozanolixizumab 57%, placebo 14%). CONCLUSION: Whereas change from baseline in QMG was not statistically significant, the data overall suggest rozanolixizumab may provide clinical benefit in patients with gMG and was generally well tolerated. Phase 3 evaluation is ongoing (NCT03971422). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with gMG, rozanolixizumab is well-tolerated, but did not significantly improve QMG score.

Targeting FcRn for immunomodulation: Benefits, risks, and practical considerations.

The neonatal fragment crystallizable (Fc) receptor (FcRn) functions as a recycling mechanism to prevent degradation and extend the half-life of IgG and albumin in the circulation. Several FcRn inhibitors selectively targeting IgG recycling are now moving rapidly toward clinical practice in neurology and hematology. These molecules accelerate the destruction of IgG, reducing pathogenic IgG and IgG immune complexes, with no anticipated effects on IgA, IgM, IgE, complement, plasma cells, B cells, or other cells of the innate or adaptive immune systems. FcRn inhibitors have potential for future use in a much wider variety of antibody-mediated autoimmune diseases. Given the imminent clinical use, potential for broader utility, and novel mechanism of action of FcRn inhibitors, here we review data from 4 main sources: (a) currently available activity, safety, and mechanism-of-action data from clinical trials of FcRn inhibitors; (b) other procedures and treatments that also remove IgG (plasma donation, plasma exchange, immunoadsorption); (c) diseases resulting in loss of IgG; and (d) primary immunodeficiencies with potential mechanistic similarities to those induced by FcRn inhibitors. These data have been evaluated to provide practical considerations for the assessment, monitoring, and reduction of any potential infection risk associated with FcRn inhibition, in addition to highlighting areas for future research.

Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is a predominantly immunoglobulin G (IgG)-autoantibody-mediated disease characterized by isolated thrombocytopenia. Rozanolixizumab, a subcutaneously infused humanized monoclonal anti-neonatal Fc receptor (FcRn) antibody, reduced serum IgG in healthy volunteers. In this phase 2, multicenter, open-label study, patients with persistent/chronic primary ITP received 1 to 5 once-weekly subcutaneous infusions of rozanolixizumab (cumulative doses, 15-21 mg/kg). Primary objectives were safety and tolerability, and secondary objectives were clinical efficacy (change in platelet count) and pharmacodynamic effect (change in IgG). In all, 51 (77.3%) of 66 patients reported 1 or more adverse events (AEs), all mild-to-moderate, most commonly headaches (26 [39.4%] of 66), of which 15 were treatment related. Four patients had serious AEs, but none were treatment related. No AEs resulted in discontinuation of the study drug. No serious infections occurred. Platelet counts of ≥50 × 109/L were achieved at least once at any time after multiple infusions (5 × 4, 3 × 7, or 2 × 10 mg/kg: 35.7%, 35.7%, and 45.5% of patients, respectively) or single infusions (15 or 20 mg/kg: 66.7% and 54.5% patients, respectively). Minimum mean IgG levels and maximum mean platelet counts both occurred by day 8 in the higher (15 and 20 mg/kg) single-dose cohorts and maximum platelet count occurred by day 11 onward in the multiple-dose cohorts. No clinically meaningful changes occurred in IgA, IgM, IgE, or albumin levels. In patients with persistent/chronic primary ITP, rozanolixizumab demonstrated a favorable safety profile and rapid, substantial platelet increases concordant with substantial IgG reductions, especially with single doses. By day 8, in the 15 and 20 mg/kg single-dose cohorts, >50% patients achieved clinically relevant platelet responses (≥50 × 109/L), coinciding with the lowest mean IgG levels. These data support phase 3 development of rozanolixizumab in persistent/chronic primary ITP. This trial was registered at www.clinicaltrials.gov as #NCT02718716.

The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study.

Pathogenic immunoglobulin G (IgG) autoantibodies characterize some human autoimmune diseases; their high concentration and long half-life are dependent on recycling by the neonatal Fc receptor (FcRn). Inhibition of FcRn is an attractive new treatment concept for IgG-mediated autoimmune diseases. Rozanolixizumab (UCB7665; CA170_01519.g57 IgG4P) is an anti-human FcRn monoclonal antibody. In cynomolgus monkeys, rozanolixizumab reduced IgG (maximum 75 to 90% by about day 10), was well tolerated, and did not increase risk of infection. We also report a first-in-human, randomized, double-blind, placebo-controlled, dose-escalating study of intravenous (IV) or subcutaneous (SC) rozanolixizumab in healthy subjects (NCT02220153). The primary objective was to evaluate safety and tolerability. Secondary objectives were assessment of rozanolixizumab pharmacokinetics and pharmacodynamics, including effects on circulating IgG concentrations. Forty-nine subjects were randomized to receive rozanolixizumab (n = 36) or placebo (n = 13) across six cohorts. The first three cohorts received IV doses, and the subsequent three cohorts received SC doses, of rozanolixizumab 1, 4, or 7 mg/kg (n = 6 for each cohort; plus n = 7 or 6 for placebo, respectively). The most frequent treatment-emergent adverse event [TEAE; headache, 14 of 36 (38.9%) subjects] was dose-dependent and more prominent after IV administration. Severe TEAEs occurred in four subjects, all in the highest-dose IV group [headache (n = 3) and back pain (n = 1)]. Rozanolixizumab pharmacokinetics demonstrated nonlinear increases with dose. There were sustained dose-dependent reductions in serum IgG concentrations (IV and SC rozanolixizumab). These data provide clinical evidence for the therapeutic potential of rozanolixizumab.

Metabolic engineering in strawberry fruit uncovers a dormant biosynthetic pathway.

Wild strawberry (Fragaria vesca) fruit contains several important phenylpropene aroma compounds such as eugenol, but cultivated varieties are mostly devoid of them. We have redirected the carbon flux in cultivated strawberry (Fragaria×ananassa) fruit from anthocyanin pigment biosynthesis to the production of acetates of hydroxycinnamyl alcohols, which serve as the precursors of the phenylpropenes, by downregulating the strawberry chalcone synthase (CHS) via RNAi-mediated gene silencing and, alternatively, by an antisense CHS construct. Simultaneous heterologous overexpression of a eugenol (EGS) and isoeugenol synthase (IGS) gene in the same cultivated strawberry fruits boosted the formation of eugenol, isoeugenol, and the related phenylpropenes chavicol and anol to concentrations orders of magnitude greater than their odor thresholds. The results show that Fragaria×ananassa still bears a phenylpropene biosynthetic pathway but the carbon flux is primarily directed to the formation of pigments. Thus, partial restoration of wild strawberry flavor in cultivated varieties is feasible by diverting the flavonoid pathway to phenylpropene synthesis through metabolic engineering.

Pharmacokinetics of subcutaneous immunoglobulin and their use in dosing of replacement therapy in patients with primary immunodeficiencies.

Bioavailability and pharmacokinetics of subcutaneous IgG (SCIG) and intravenous IgG (IVIG) differ. It is not clear if and/or how the dose should be adjusted when switching from IVIG to SCIG. Area under the curve (AUC) of serum IgG versus time and trough level ratios (TLRs) on SCIG/IVIG were evaluated as guides for adjusting the dose. The mean dose adjustments required for non-inferior AUCs with 2 different SCIG preparations were 137% (± 12%) and 153% (± 16%). However, there were wide variations between adjustments required by different subjects, and in the resulting TLRs. In contrast, combined data from multiple studies allow estimation of the ratio of IgG levels with different dose adjustments, and of the steady state serum levels with different SCIG doses. When switching a patient from IVIG to SCIG, individualizing the dosage based on measured serum IgG levels and the clinical response is preferable to using mean pharmacokinetic parameters.

Hereditary angioedema: Validation of the end point time to onset of relief by correlation with symptom intensity.

Time to onset of symptom relief in hereditary angioedema (HAE) is a common primary end point in clinical studies but it has never been validated by correlation with the course of HAE symptoms. This study was designed as a retrospective validation of the primary end point for a placebo-controlled phase II/III study in patients with HAE. Ninety-eight abdominal attacks were treated with 10 or 20 U/kg of a highly purified C1 esterase inhibitor (C1-INH) concentrate or placebo. The primary end point was the time to onset of symptom relief, as determined by the patients. Patients assessed the intensity of the symptoms of pain, nausea, vomiting, cramps, and diarrhea over time. By Spearman rank correlation, the primary end point was compared with the time to first reduction of (1) any symptom intensity, (2) the sum of symptom intensity scores, and (3) the intensity of the last symptom present at baseline. The C1-INH, 20 U/kg, and placebo groups were compared by one-sided two-sample Wilcoxon tests. The time to first reduction in intensity of the last symptom present at baseline had the highest correlation with the primary end point (r = 0.77). The time to onset of symptom relief and the time to the first reduction in intensity of the last symptom were significantly shorter for the C1-INH, 20 U/kg, group compared with placebo (p = 0.009 and p = 0.0036, respectively). The association with the intensity of single symptoms confirmed that the time to onset of symptom relief is an appropriate end point for assessing the efficacy of C1-INH therapy.

Prospective study of C1 esterase inhibitor in the treatment of successive acute abdominal and facial hereditary angioedema attacks.

BACKGROUND: hereditary angioedema (HAE) is a rare disorder characterized by a quantitative or functional deficiency of C1 esterase inhibitor (C1-INH), resulting in periodic attacks of acute edema at various body locations. The symptoms of these painful attacks can be treated effectively with C1-INH concentrate. OBJECTIVE: to document the efficacy and safety of a weight-based dose of C1-INH concentrate in the treatment of successive HAE attacks at abdominal and facial locations. METHODS: acute facial and abdominal attacks were each treated with C1-INH concentrate using a single intravenous dose of 20 U/kg body weight. Efficacy end points included patient-reported time to onset of symptom relief and time to complete resolution of all symptoms. Safety was assessed by monitoring adverse events and assaying for markers of viral infection. RESULTS: we treated 663 abdominal attacks in 50 patients and 43 facial attacks in 16 patients (a total of 706 attacks in 53 patients). The median time to onset of relief for all attacks was 19.8 minutes, with a median time to complete resolution of 11.0 hours. The median time to onset of relief was 19.8 minutes for abdominal attacks and 28.2 minutes for facial attacks, indicating efficacy for both types of attack. No treatment-related serious adverse events occurred, and C1-INH concentrate was well tolerated. No human immunodeficiency virus, hepatitis virus, or parvovirus B19 infections arose during the study. CONCLUSION: the C1-INH concentrate dose of 20 U/kg provides rapid, effective, and safe treatment for successive HAE attacks at abdominal and facial locations.

Population pharmacokinetics of plasma-derived C1 esterase inhibitor concentrate used to treat acute hereditary angioedema attacks.

BACKGROUND: C1 esterase inhibitor (C1-INH) replacement is recommended as a first-line therapy for acute edema attacks in hereditary angioedema (HAE). Only limited pharmacokinetic analyses of the administered C1-INH in plasma are available. OBJECTIVE: To investigate retrospectively the population pharmacokinetics of a plasma-derived C1-INH (pC1-INH) concentrate used to treat acute HAE attacks in a randomized, placebo-controlled phase 2/3 study in patients with HAE. METHODS: Acute abdominal and facial attacks were treated with either a pC1-INH concentrate (Berinert) at single intravenous doses of 10 or 20 U/kg body weight or placebo. Plasma sampling was conducted 0, 1, and 4 hours after dosing. A nonlinear retrospective population pharmacokinetic model was obtained using the assumption of a 1-compartment model. RESULTS: The final population pharmacokinetic model was based on data from 97 patients treated with 10 or 20 U/kg of pC1-INH concentrate. The estimated mean half-life was 32.7 hours (90% confidence interval, 16.6-48.8 hours), and the estimated mean clearance was 0.92 mL/kg/h (90% confidence interval, 0.50-1.33 mL/kg/h). CONCLUSIONS: The half-life of the same pC1-INH concentrate reported in a previous study was confirmed by this retrospective population pharmacokinetic analysis in patients treated for acute HAE attacks. In contrast to other treatment options with shorter half-lives, the long half-life of pC1-INH concentrate may provide an extended period of protection, even after the symptoms of an attack have subsided.

Prospective study of rapid relief provided by C1 esterase inhibitor in emergency treatment of acute laryngeal attacks in hereditary angioedema.

INTRODUCTION: Hereditary angioedema (HAE) is a rare disorder characterized by C1 esterase inhibitor (C1-INH) deficiency, resulting in periodic attacks of acute edema that can be life-threatening if they occur in the laryngeal region. We assessed the efficacy of C1-INH concentrate in the emergency treatment of rarely occurring acute laryngeal HAE attacks in a prospective, open-label clinical study. METHODS: Acute laryngeal attacks were each treated with C1-INH concentrate (Berinert) at a single dose of 20 U/kg body weight. Efficacy endpoints included time to onset of symptom relief and time to complete resolution of all symptoms, each based on the patient's assessment. RESULTS: All 39 laryngeal attacks in 16 patients were treated successfully. The median time to onset of symptom relief was 15 min. The median time to complete resolution of all symptoms was 8.25 h. No treatment-related serious adverse events occurred, and the treatment was well tolerated. The administration of C1-INH concentrate was not associated with any viral infections. CONCLUSION: C1-INH concentrate is an effective and safe emergency treatment for providing reliable and rapid relief from the potentially life-threatening symptoms of laryngeal HAE attacks.

How the green alga Chlamydomonas reinhardtii keeps time.

The unicellular green alga Chlamydomonas reinhardtii has two flagella and a primitive visual system, the eyespot apparatus, which allows the cell to phototax. About 40 years ago, it was shown that the circadian clock controls its phototactic movement. Since then, several circadian rhythms such as chemotaxis, cell division, UV sensitivity, adherence to glass, or starch metabolism have been characterized. The availability of its entire genome sequence along with homology studies and the analysis of several sub-proteomes render C. reinhardtii as an excellent eukaryotic model organism to study its circadian clock at different levels of organization. Previous studies point to several potential photoreceptors that may be involved in forwarding light information to entrain its clock. However, experimental data are still missing toward this end. In the past years, several components have been functionally characterized that are likely to be part of the oscillatory machinery of C. reinhardtii since alterations in their expression levels or insertional mutagenesis of the genes resulted in defects in phase, period, or amplitude of at least two independent measured rhythms. These include several RHYTHM OF CHLOROPLAST (ROC) proteins, a CONSTANS protein (CrCO) that is involved in parallel in photoperiodic control, as well as the two subunits of the circadian RNA-binding protein CHLAMY1. The latter is also tightly connected to circadian output processes. Several candidates including a significant number of ROCs, CrCO, and CASEIN KINASE1 whose alterations of expression affect the circadian clock have in parallel severe effects on the release of daughter cells, flagellar formation, and/or movement, indicating that these processes are interconnected in C. reinhardtii. The challenging task for the future will be to get insights into the clock network and to find out how the clock-related factors are functionally connected. In this respect, system biology approaches will certainly contribute in the future to improve our understanding of the C. reinhardtii clock machinery.

Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks.

BACKGROUND: Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare disorder. OBJECTIVE: To compare the efficacy of pasteurized C1 esterase inhibitor concentrate (Berinert, CSL Behring) at intravenous doses of 10 or 20 U/kg body weight with placebo in the treatment of single, acute abdominal or facial attacks in patients with hereditary angioedema. METHODS: This was a randomized, double-blind, placebo-controlled study in 125 patients with type I or II hereditary angioedema. The primary outcome was time from start of treatment to onset of symptom relief. Secondary outcomes were time to complete resolution, proportion of patients with worsened intensity of angioedema symptoms between 2 and 4hours after treatment, and number of vomiting episodes within 4 hours. RESULTS: Median time to onset of relief was significantly shorter with C1 esterase inhibitor concentrate at a dose of 20 U/kg than with placebo (0.5 vs 1.5 hours; P = .0025), whereas with 10 U/kg, the time to onset of relief was only slightly shorter than with placebo (1.2 vs 1.5 hours; P = .2731). Compared with placebo, the reduction in time to onset of relief was greatest for severe attacks (0.5 vs 13.5 hours). The secondary outcomes consistently supported the efficacy of the 20 U/kg dose. C1 esterase inhibitor concentrate was safe and well tolerated. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus. CONCLUSION: C1 esterase inhibitor concentrate given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial attacks in patients with hereditary angioedema, with a rapid onset of relief.

Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases.

Intravenous immunoglobulin (IVIg) infusions at 3-4 week intervals are currently standard therapy in the United States for patients with primary immune deficiency diseases (PIDD). To evaluate alternative modes of immunoglobulin administration we have designed an open-label study to investigate the efficacy and safety of a subcutaneously administered immunoglobulin preparation (16% IgG) in patients with PIDD. After their final IVIg infusion, 65 patients entered a 3-month, wash-in/wash-out phase, designed to bring patients to steady-state with subcutaneously administered immunoglobulin. This was followed by 12 months of weekly SCIg infusions, at a dose determined in a pharmacokinetic substudy to provide noninferior intravascular exposure. This resulted in a mean weekly dose of 158 mg/kg, calculated to equal 137% of the previous intravenous dose. Two patients (4%) each reported 1 serious bacterial infection (pneumonia), an annual rate of 0.04 per patient-year. There were 4.43 infections of any type per patient-year. Mean trough serum IgG levels increased from 786 to 1040 mg/dL during the study, a mean increase of 39%. The most frequent treatment-related adverse event was infusion-site reaction, reported by 91% of patients; this was predominantly mild or moderate, and the incidence decreased over time. No treatment-related serious adverse events were reported. We conclude that subcutaneous administration of 16% SCIg is a safe and effective alternative to IVIg for replacement therapy of PIDD.

Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies--a prospective, multi-national study.

Sixty patients (16 children, 44 adults) participated in the study aiming at evaluating: (i) IgG levels when switching patients from intravenous IgG (IVIG) infusions in hospital to subcutaneous (SCIG) self-infusions at home using the same cumulative monthly dose, (ii) protections against infections, and (iii) safety of a new, ready-to-use 16% IgG preparation. All children and 33 adults had received IVIG therapy for >6 months at enrolment. Ten adults who had been on SCIG therapy for many years served as controls. Mean serum IgG trough levels increased in the pre-IVIG children from 7.8 to 9.2 g/L (non-inferiority: p < 0.001) and in the adults from 8.6 to 8.9 g/L (non-inferiority: p < 0.001). Totally 114 respiratory tract infections occurred, 90% of them mild. One serious bacterial infection (pneumonia) was reported for one adult. The annualized rate of serious infections was 0.04 episodes/patient. In total 2297 infusions were given and 28 (1%) systemic adverse reactions occurred, none of them severe. Local tissue reactions declined over time, this being particularly distinct after 8 to 10 weeks. In conclusion, the SCIG administration route was safe. High IgG levels were easily maintained resulting in a very good protection against infections.

Health-related quality of life and treatment satisfaction in North American patients with primary immunedeficiency diseases receiving subcutaneous IgG self-infusions at home.

The lifelong IgG replacement therapy for patients with primary immunedeficiencies (PIDD) may be provided by intravenous (IVIG) or by subcutaneous IgG (SCIG) infusions. We investigated the impact of weekly SCIG self-infusions at home on the health-related quality of life, treatment satisfaction, and preferences in patients treated with IVIG at the hospital/doctor's office (Group A) or at home (Group B) before the study started. Forty-four adult North American PIDD patients were included in the study, 28 patients in Group A and 16 in Group B. Patients in Group A reported significantly less limitations with their work/daily activities, a significantly improved vitality, and better general health. Treatment satisfaction was significantly improved in Group A. The preference for the subcutaneous route and for home therapy was respectively 81% and 90% in Group A. In Group B, 69% preferred the subcutaneous route and 92% home therapy.

Phase I comparability of recombinant human albumin and human serum albumin.

Recombinant human albumin (rHA) is a highly purified animal-, virus-, and prion-free product developed as an alternative to human serum albumin (HSA), to which it is structurally equivalent. The present investigation compared the safety, tolerability, and pharmacokinetics/pharmacodynamics of rHA with HSA. Two double-blind, randomized trials were performed in healthy volunteers using intramuscular (IM) and intravenous (IV) administration. The IM trial included 500 volunteers, each receiving 5 repeat doses of 5 mg (100 subjects), 15 mg (100 subjects), or 65 mg (300 subjects) of rHA or HSA. Thirty volunteers participated in the IV trial, each receiving ascending doses (10 g, 20 g, and 50 g) of either rHA or HSA. In both trials, all adverse events were recorded and conventionally classified; potential allergic responses were also monitored. Blood samples were taken in both studies to test for IgG or IgE antibodies against test products and potential impurities. For the IV study, pharmacokinetic/pharmacodynamic assessments were performed, including measurement of serum albumin, colloid osmotic pressure, and hematocrit pre- and postinfusion. Nine subjects in the IM study (4 recipients of rHA and 5 of HSA) reported drug-related, potentially allergic events; all but 2 of these were skin related. No serious or potentially allergic events were reported with either product in the IV study. There was no immunological response to either product, and dose level did not influence the study outcomes. Serum albumin, colloid osmotic pressure changes, and hematocrit ratio were as expected, with no differences between rHA and HSA. rHA and HSA exhibited similar safety, tolerability, and pharmacokinetic/pharmacodynamic profiles, with no evidence of any immunological response.

Children and adults with primary antibody deficiencies gain quality of life by subcutaneous IgG self-infusions at home.

BACKGROUND: A large number of children and adults with primary antibody deficiencies need lifelong IgG replacement therapy. It is mostly unknown what effect the choice of replacement therapy has on the patients' health-related quality of life (HRQOL) and treatment satisfaction (TS). OBJECTIVE: To investigate whether a switch from hospital-based intravenous IgG (IVIG) to home-based subcutaneous IgG (SCIG) therapy would improve the HRQOL and TS. METHODS: Fifteen children (<14 years; hospital-based IVIG therapy at enrollment) and 32 adults (> or =14 years; 22 on hospital-based IVIG and 10 on home-based SCIG therapy at enrollment) were included. Questionnaires were completed at baseline and at 6 and 10 months: the Child Health Questionnaire-Parental Form 50 (children) or Short Form 36 (adults), the Life Quality Index, and questions regarding therapy preferences. RESULTS: The SCIG home therapy was reported to give better health (P=.001) and improved school/social functioning (P=.02) for the children, reduced emotional distress (P=.02) and limitations on personal time for the parents (P=.004), and fewer limitations on family activities (P=.002). Adults switching therapy reported improved vitality (P=.04), mental health ( P=.05), and social functioning ( P=.01). Adults already on SCIG home therapy at enrollment retained high HRQOL and TS scores. The SCIG home therapy improved TS because it led to greater independence and better therapy convenience ( P <.05). The patients preferred the SCIG administration route and having the treatment at home. CONCLUSIONS: Home-based SCIG therapy improves several important aspects of HRQOL and provides the patients with primary antibody deficiencies and their families with greater independence and better control of the therapy situation and daily life. SCIG home therapy is an appreciated therapeutic alternative for adults and children in need of lifelong IgG replacement therapy.

Interaction of myosin subfragment 1 with forms of monomeric actin.

The ability of myosin subfragment 1 to interact with monomeric actin complexed to sequestering proteins was tested by a number of different techniques such as affinity absorption, chemical cross-linking, fluorescence titration, and competition procedures. For affinity absorption, actin was attached to agarose immobilized DNase I. Both chymotryptic subfragment 1 isoforms (S1A1 and S1A2) were retained by this affinity matrix. Fluorescence titration employing pyrenyl-actin in complex with deoxyribonuclease I (DNase I) or thymosin beta4 demonstrated S1 binding to these actin complexes. A K(D) of 5 x 10(-8) M for S1A1 binding to the actin-DNase I complex was determined. Fluorescence titration did not indicate binding of S1 to actin in complex with gelsolin segment 1 (G1) or vitamin D-binding protein (DBP). However, fluorescence competition experiments and analysis of tryptic cleavage patterns of S1 indicated its interaction with actin in complex with DBP or G1. Formation of the ternary DNase I-acto-S1 complex was directly demonstrated by sucrose density sedimentation. S1 binding to G-actin was found to be sensitive to ATP and an increase in ionic strength. Actin fixed in its monomeric state by DNase I was unable to significantly stimulate the Mg2+-dependent S1-ATPase activity. Both wild-type and a mutant of Dictyostelium discoideum myosin II subfragment 1 containing 12 additional lysine residues within an insertion of 20 residues into loop 2 (K12/20-Q532E) were found to also interact with actin-DNase I complex. Binding of the K12/20-Q532E mutant to the actin-DNase I complex occurred with higher affinity than wild-type S1 and was less sensitive to mono- and divalent cations.