Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks.

BACKGROUND: Approved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy. METHODS: In this phase 3, double-blind, three-way crossover trial, we randomly assigned participants at least 12 years of age with type 1 or type 2 hereditary angioedema to take up to two oral doses of sebetralstat (300 mg or 600 mg) or placebo for an angioedema attack. The primary end point, assessed in a time-to-event analysis, was the beginning of symptom relief, defined as a rating of "a little better" on the Patient Global Impression of Change scale (ratings range from "much worse" to "much better") at two or more consecutive time points within 12 hours after the first administration of the trial agent. Key secondary end points, assessed in a time-to-event analysis, were a reduction in attack severity (an improved rating on the Patient Global Impression of Severity [PGI-S] scale, with ratings ranging from "none" to "very severe") at two or more consecutive time points within 12 hours and complete attack resolution (a rating of "none" on the PGI-S scale) within 24 hours. RESULTS: A total of 136 participants were assigned to one of six trial sequences, with 110 treating 264 attacks. The time to the beginning of symptom relief with the 300-mg dose and the 600-mg dose was faster than with placebo (P<0.001 and P = 0.001 for the two comparisons, respectively), with median times of 1.61 hours (interquartile range, 0.78 to 7.04), 1.79 hours (1.02 to 3.79), and 6.72 hours (1.34 to >12), respectively. The time to reduction in the attack severity with the 300-mg dose and the 600-mg dose was faster than with placebo (P = 0.004 and P = 0.003), with median times of 9.27 hours (interquartile range, 1.53 to >12), 7.75 hours (2.19 to >12), and more than 12 hours (6.23 to >12). The time to complete resolution was faster with the 300-mg and 600-mg doses than with placebo (P = 0.002 and P<0.001). The percentage of attacks with complete resolution within 24 hours was 42.5% with the 300-mg dose, 49.5% with the 600-mg dose, and 27.4% with placebo. Sebetralstat and placebo had similar safety profiles; no serious adverse events related to the trial agents were reported. CONCLUSIONS: Oral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo. (Funded by KalVista Pharmaceuticals; KONFIDENT ClinicalTrials.gov number, NCT05259917; EudraCT number, 2021-001226-21.).

BT595, a 10% Human Normal Immunoglobulin, for Replacement Therapy of Primary Immunodeficiency Disease: Results of a Subcohort Analysis in Children.

PURPOSE: To assess the efficacy, pharmacokinetics, and safety of a new, highly purified 10% IVIg (BT595, Yimmugo®) administered in children with PID. METHODS: This was an open-label, prospective, uncontrolled, multicenter Phase III pivotal trial. Among the 67 subjects in the trial were 18 pediatric patients aged 2 to 17 years with diagnosis of PID included in this analysis. They received doses between 0.2 and 0.8 g/kg body weight for approximately 12 months at intervals of either 3 or 4 weeks. Dosage and dosing interval were based on each patient's pre-trial infusion schedule. The rates of acute serious bacterial infections (SBI), secondary efficacy, safety, and pharmacokinetic outcomes were evaluated. RESULTS: No SBI occurred in the pediatric population. Two hundred sixty infusions were administered to the 18 pediatric patients. The mean (SD) IgG trough level was 8.55 (1.67) g/L at baseline and 8.84 (2.17) g/L at the follow-up visit after the last BT595 infusion. At the single infusions respectively, the average mean IgG trough levels ranged between 8.52 and 10.58 g/L. More than 85% of all infusions administered were not associated with any infusional AE (start during or within 72 h post-infusion). None of the severe or serious AEs were related to the investigational medicinal product (IMP). No premedication was used. Thirteen children reached a maximum infusion rate between > 2.0 and 8 mL/kg/h; no AE with an onset during the infusion occurred at these infusion rates. CONCLUSION: BT595 is effective, convenient, well tolerated, and safe for the treatment of children with PID. TRIAL REGISTRATION: EudraCT: 2015-003652-52; NCT02810444, registered June 23, 2016.

Subcutaneous Immunoglobulin 16.5% (Cutaquig®) in Primary Immunodeficiency Disease: Safety, Tolerability, Efficacy, and Patient Experience with Enhanced Infusion Regimens.

PURPOSE: To achieve reductions in infusion time, infusion sites, and frequency, a prospective, open-label, multicenter, Phase 3 study evaluated the safety, efficacy, and tolerability of subcutaneous immunoglobulin (SCIG) 16.5% (Cutaquig®, Octapharma) at enhanced infusion regimens. METHODS: Three separate cohorts received SCIG 16.5% evaluating volume, rate, and frequency: Cohort 1) volume assessment/site: up to a maximum 100 mL/site; Cohort 2) infusion flow rate/site: up to a maximum of 100 mL/hr/site or the maximum flow rate achievable by the tubing; Cohort 3) infusion frequency: every other week at twice the patient's weekly dose. RESULTS: For Cohort 1 (n = 15), the maximum realized volume per site was 108 mL/site, exceeding the currently labeled (US) maximum (up to 40 mL/site for adults). In Cohort 2 (n = 15), the maximum realized infusion flow rate was 67.5 mL/hr/site which is also higher than the labeled (US) maximum (up to 52 mL/hr/site). In Cohort 3 (n = 34), the mean total trough levels for every other week dosing demonstrated equivalency to weekly dosing (p value = 0.0017). All regimens were well tolerated. There were no serious bacterial infections (SBIs). Most patients had mild (23.4%) or moderate (56.3%) adverse events. The majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens and reported that switching to SCIG 16.5% was easy. CONCLUSIONS: SCIG 16.5% (Cutaquig®), infusions are efficacious, safe, and well tolerated with reduced infusion time, fewer infusion sites, and reduced frequency. Further, the majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens.

Long-term efficacy, safety, and tolerability of a subcutaneous immunoglobulin 16.5% (cutaquig®) in the treatment of patients with primary immunodeficiencies.

A prospective study and its long-term extension examined whether weekly treatment of patients with primary immunodeficiencies (PIDs) with a 16.5% subcutaneous immunoglobulin (SCIg; cutaquig®) confers acceptable efficacy, safety, and tolerability over a follow-up of up to 238 weeks (>4 years). Seventy-five patients received 4462 infusions during up to 70 weeks of follow-up in the main study and 27 patients received 2777 infusions during up to 168 weeks of follow-up in the extension. In the main study, there were no serious bacterial infections (SBIs), and the annual rate of other infections was 3.3 (95% CI 2.4, 4.5). One SBI was recorded in the extension, for an SBI rate of 0.02 (upper 99% CI 0.19). The annual rate of all infections over the duration of the extension study was 2.2 (95% CI 1.2, 3.9). Only 15.0% (1085) of 7239 infusions were associated with infusion site reactions (ISRs), leaving 85.0% (6153) of infusions without reactions. The majority of ISRs were mild and transient. ISR incidence decreased over time, from 36.9% to 16% during the main study and from 9% to 2.3% during the extension. The incidence of related systemic adverse events was 14.7% in the main study and 7.4% in the extension. In conclusion, this prospective, long-term study with cutaquig showed maintained efficacy and low rates of local and systemic adverse reactions in PID patients over up to 238 weeks of follow-up.

Evaluation of the Safety, Tolerability, and Pharmacokinetics of Gammaplex® 10% Versus Gammaplex® 5% in Subjects with Primary Immunodeficiency.

PURPOSE: This phase 3, multicenter, open-label, randomized, two-period, crossover bioequivalence trial evaluated the safety, tolerability, and pharmacokinetics of intravenous immunoglobulins (IVIGs) Gammaplex 5% and Gammaplex 10% in 33 adults and 15 children with primary immunodeficiency diseases (PIDs). METHODS: Eligible adults received five Gammaplex 5% infusions followed by five Gammaplex 10% infusions, or vice versa, stratified by a 21- or 28-day dosing regimen. Pediatric subjects received five Gammaplex 10% infusions only. RESULTS: The primary objective, to demonstrate the bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval, was met based on the Gammaplex 10%/Gammaplex 5% ratio of area under the concentration versus time curve (AUC0-28) values. Throughout the study, total immunoglobulin G trough levels were well maintained, with total values generally ≥600 mg/dL (minimum level for study inclusion). At the dosing schedules and infusion rates used in this study, safety and tolerability were comparable and acceptable in adult and pediatric PID subjects treated with Gammaplex 10% and 5%. CONCLUSIONS: In this study, the first direct comparison of 5% IVIG and 10% IVIG products in PID subjects, the pharmacokinetic analysis demonstrated bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval. The Gammaplex 10% formulation was safe and well tolerated in pediatric and adult PID subjects. Based on the results from this bridging study in PID subjects, Gammaplex 10% could be expected to have a therapeutic effect similar to the licensed Gammaplex 5%, which has demonstrated efficacy and tolerability in patients with PID and idiopathic thrombocytopenic purpura.

Efficacy and Safety of Human Intravenous Immunoglobulin 10% (Panzyga®) in Patients with Primary Immunodeficiency Diseases: a Two-Stage, Multicenter, Prospective, Open-Label Study.

PURPOSE: To assess the efficacy and safety of panzyga® (intravenous immunoglobulin 10%) in preventing serious bacterial infections (SBIs) in patients with primary immunodeficiency diseases (PIDs), a prospective, open-label, multicenter, phase 3 study and an open-label extension study were undertaken. METHODS: Initially, the study drug (infusion rate ≤0.08 mL/kg/min) was administered at intervals of 3 or 4 weeks for 12 months, followed by 3 months of panzyga® at infusion rates increasing from 0.08 to 0.14 mL/kg/min. The primary endpoint in the main study was the rate of SBIs per patient-year on treatment. Secondary outcomes included non-serious infections, work/school absence, episodes of fever, quality of life, and adverse events (AEs). RESULTS: The main study enrolled 51 patients (35% female, mean age 26.8 years), with 21 participating in the extension study. The rate of SBIs per patient-year was 0.08 in the total population; there were four SBIs in the 4-weekly treatment group (2/30 patients) and none in the 3-weekly group (n = 21). Compared with 4-weekly treatment, 3-weekly treatment was associated with a higher rate of upper respiratory tract infections (RTIs), ear infections, and work/school absences, but a lower rate of lower RTIs and fever. Treatment was generally well tolerated; no AE led to treatment withdrawal or death. CONCLUSIONS: Overall, the use of panzyga® in patients with antibody-deficient PID was associated with a low rate of AEs and was effective in preventing SBIs, exceeding US FDA and European Medicines Agency recommendations for efficacy.

Pharmacokinetics, Safety, and Tolerability of Subcutaneous Immune Globulin Injection (Human), 10 % Caprylate/Chromatography Purified (GAMUNEX®-C) in Pediatric Patients with Primary Immunodeficiency Disease.

PURPOSE: This phase 4, multicenter, open-labeled, single-sequence, crossover study in pediatric patients (ages 2 to 16) with primary immunodeficiency disease (PID) evaluated the pharmacokinetics, safety, and tolerability for subcutaneously (SC) administered 10 % caprylate/chromatography purified human immune globulin injection (IGIV-C, GAMUNEX®) compared with intravenously (IV) administered IGIV-C. METHODS: This study included a screening phase, run-in phase (where required), IV treatment phase, SC treatment phase, and end of study/early termination visit. Eligible patients receiving a stable dose of IGIV-C entered into the IV phase to receive two IV infusions of IGIV-C (200-600 mg/kg per infusion) every 3-4 weeks. The weekly SC dose of IGIV-C was calculated using a conversion factor of 1.37 times the prior IV dose. RESULTS: Twelve subjects between the ages of 2 and 16 years participated in the clinical study with the median age being 11 years old. The adjusted weekly mean AUC0-τ,IV was 216,873.7 h*mg/dL for the IV phase versus a mean AUC0-τ,SC of 230,830.0 h*mg/dL for the SC phase. The mean (range) C trough was 997.2 (784-1320) mg/dL in the IV phase and 1325.0 (1077-1690) mg/dL in the SC phase. During the SC phase, 100.0 % of the patients (n = 11) experienced treatment-emergent adverse events (TEAEs) that were local infusion reactions and 9 patients (81.8 %) had TEAEs that were non-infusion site reactions. The majority of TEAEs were mild or moderate in severity. CONCLUSION: In pediatric patients with PID, SC-administered IGIV-C provides comparable overall serum exposure to total IgG to that produced by IV-administered IGIV-C. We have concluded that weekly SC administration of 10 % IGIV-C based on a dose conversion factor of 1.37 is safe and well-tolerated in pediatric patients with PID. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01465958. https://clinicaltrials.gov/ct2/show/NCT01465958?term=NCT01465958.&rank=1.

Efficacy, Safety, and Pharmacokinetics of a Novel Human Immune Globulin Subcutaneous, 20 % in Patients with Primary Immunodeficiency Diseases in North America.

Patients with primary immunodeficiency disease (PIDD) typically require life-long intravenous (IV) or subcutaneous (SC) immunoglobulin (Ig) replacement therapy to prevent recurrent infections. The efficacy, safety, and pharmacokinetics of a highly concentrated (20 %) Ig preparation for SC administration (IGSC 20 %) were evaluated in a prospective trial in patients with PIDD. A total of 74 patients (aged 3-83 years) received 4327 IGSC 20 % infusions over a median of 380.5 days. The rate of validated serious bacterial infections was 0.012 event/patient-year (p < 0.0001 compared with the historical control), and the annualized rate of infection was 2.41 events/patient. Median IgG trough levels were >14.5 g/l. The median maximum infusion rate was 60 ml/h/site (range 4.4-180), resulting in a median infusion duration of 0.95 h. A volume ≥30 ml was infused per site in 74.8 % of IGSC 20 % infusions. Most (84.9 %) infusions were administered using ≤2 infusion sites; for 99.8 % of infusions, there was no need to interrupt/stop administration or reduce the infusion rate. No related serious adverse event (AE) occurred during IGSC 20 % treatment; related non-serious AEs occurred at a rate of 0.036 event/infusion. The incidence of related local AEs was 0.015 event/infusion and of related systemic AEs was 0.021 event/infusion; most were mild in severity, none severe. Increased infusion rates or volumes were not associated with higher AE rates. The investigated IGSC 20 % treatment was shown to be effective and safe, enabling higher infusion rates and volumes per site compared to conventional SC treatments, resulting in fewer infusion sites and shorter infusion durations.

Efficacy, Safety, and Pharmacokinetics of a New 10 % Liquid Intravenous Immunoglobulin Containing High Titer Neutralizing Antibody to RSV and Other Respiratory Viruses in Subjects with Primary Immunodeficiency Disease.

PURPOSE: Immune globulins for IgG supplementation have been produced for over 35 years with essentially no differentiating features regarding their specific antibody composition. Furthermore, the compositions of plasma donor pools used for IG manufacturing are not standardized. While all immune globulin products meet the specifications set by the US FDA for antibodies to pathogens like measles and polio, they have variable levels of antibodies to other important viruses and infectious pathogens, particularly respiratory syncytial virus (RSV). METHODS: An IVIG was developed that satisfies the requirements for treating patients with primary immune deficiency disease (PIDD) and also has standardized elevated levels of RSV neutralizing antibodies (RI-002). Plasma donors who have naturally occurring high circulating levels of neutralizing anti-RSV antibody were selected as the source for manufacturing IVIG to treat patients with PIDD to prevent serious bacterial infections. While the introduction of the monoclonal antibody Palivizumab has had a dramatic impact in diminishing the burden of RSV disease in the pediatric population, it does not meet the standards for replacing the deficient immune compartments of patients with PIDD. RESULTS: Fifty-nine patients with PIDD at 9 different sites across the US were enrolled in this study and received regular infusions of RI-002 over the course of 1 year. CONCLUSIONS: There were zero serious bacterial infections, thus meeting the primary endpoint for this trial. The secondary endpoints including days missed from work due to infection, unscheduled visits to the physician, and days of hospitalization due to infection compared favorably to published reports of other IVIG products.

Long-Term Tolerability, Safety, and Efficacy of Recombinant Human Hyaluronidase-Facilitated Subcutaneous Infusion of Human Immunoglobulin for Primary Immunodeficiency.

PURPOSE: Treatment of primary immunodeficiency diseases (PIDD) with subcutaneous (SC) infusions of IgG preceded by injection of recombinant human hyaluronidase (rHuPH20) (IGHy) to increase SC tissue permeability was evaluated in two consecutive, prospective, non-controlled, multi-center studies. METHODS: Subjects >4 years of age received SC IgG replacement at a weekly dose equivalent of 108 % of their previous intravenous (IV) dose, facilitated by prior injection of 75 U/g IgG of rHuPH20. Starting with weekly SC infusions, the interval was increased (ramped-up) to a 3- or 4-week schedule. RESULTS: Eighty-three subjects (24 < 18 years; 59 ≥ 18 years) received 2729 infusions (excluding ramp-up) at a mean dose of 0.155 g/kg/week in the pivotal and 0.156 g/kg/week in the extension study. IGHy exposure exceeded 30 months in 48 subjects. During 187.7 subject-years of IGHy exposure, 2005 adverse events (AEs) (10.68 per subject-year) occurred. The rate of related systemic AEs during consecutive 1-year periods remained low; the rate of related local AEs decreased from 3.68/subject-year in months 1-12 to approximately 1.50/subject-year after 30 months of treatment. Fifteen subjects transiently developed anti-rHuPH20 binding antibody. There was no difference in AE rates in these subjects before and after the first titer increase to ≥1:160. The rate of infections during IGHy exposure was 2.99 per subject-year and did not increase during the studies. Annual infection rates were 3.02 in subjects <18 years and 2.98 in subjects ≥18 years. CONCLUSIONS: Long-term replacement therapy with IGHy was safe and effective in 83 pediatric and adult subjects with PIDD.

IVIG response in pediatric acute-onset neuropsychiatric syndrome correlates with reduction in pro-inflammatory monocytes and neuropsychiatric measures.

Introduction: Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) is characterized by abrupt onset of obsessive-compulsive disorder or eating restriction along with the abrupt onset of other co-occurring symptoms (tics, behavioral and cognitive regression, etc.). PANS is thought to be a post-infectious immunopsychiatric disorder, although as with most post-infectious disorders, it is challenging to establish a causal relationship with proposed infectious triggers. Intravenous immunoglobulin (IVIG) can modulate inflammation and support the elimination of infection and has been used for treatment of many post-infectious inflammatory disorders and autoimmune conditions. The aim of the study is to explore the pro-inflammatory state in PANS before and after administration of IVIG. Methods: Children with moderate-to-severe PANS received six infusions of IVIG (Octagam 5%, Octapharma) every 3 weeks with post treatment follow-up. Blood samples and psychiatric measures were obtained at Visits 1 (pre-treatment), 7 and 8 (4 and 11 weeks after last infusion, respectively). Myeloid cell activation was assessed via flow cytometry. Results: All ten patients included in the study were male, White, with mean age 12.4 years (range 6-16). Statistically significant improvements following IVIG treatment were demonstrated in all psychometric assessments and parent questionnaires including CY-BOCS (obsessive compulsive scale), YGTSS (tic scale) and a parent PANS rating scale (for all scales p<0.001). The fraction of pro-inflammatory monocytes and dendritic cells decreased from pre-IVIG treatment levels. The proportional reductions were not compensated by increases in total white blood cells; pro-inflammatory monocytes post-IVIG were decreased as a proportion of CD14+ myeloid cells and in absolute number. Conclusions: The results of this study suggest that active PANS is associated with a pro-inflammatory state. This pro-inflammatory profile and psychometric scores improved following IVIG treatment. Future work will aim to further elucidate the roles of innate and adaptive immune responses in PANS and the regulatory mechanism(s) of IVIG in PANS treatment.

Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency.

BACKGROUND: Subcutaneous immunoglobulin (IGSC) replacement therapy for primary immunodeficiency (PI) is equally efficacious to intravenous immunoglobulin (IGIV), induces fewer systemic reactions, and may be self-infused. Limited SC infusion volumes and reduced bioavailability, however, necessitate multiple infusion sites, more frequent treatment, and dose adjustment to achieve pharmacokinetic equivalence. Recombinant human hyaluronidase (rHuPH20) increases SC tissue permeability and facilitates dispersion and absorption, enabling administration of monthly doses in one site. OBJECTIVE: This study investigated the efficacy and tolerability of rHuPH20-facilitated IGSC (IGHy) in patients with PI. METHODS: In this open-label, multicenter phase III study, 87 patients with PI aged ≥2 years received 10% IGIV for 3 months, then IGHy (n = 83) for approximately 14 to 18 months at 108% of the IGIV dose. IGHy infusions began weekly, increasing to 3- or 4-week intervals. RESULTS: The majority (94.0%) of IGHy infusions were administered every 3 or 4 weeks, using one site (median, 1.09/month), with a mean volume of 292.2 mL. The bioavailability of IGHy measured by area under the concentration versus time curve was 93.3% of IGIV, which is pharmacokinetically equivalent. Systemic reactions were less frequent with IGHy than with IGIV (8.3% vs 25.0% of infusions). Local reactions to IGHy were generally mild to moderate, with a rate of 0.203 per infusion. The acute serious bacterial infection rate per subject-year for IGHy was low (0.025; upper 99% CI limit, 0.046). Overall infection rates per subject-year were 2.97 for IGHy and 4.51 for IGIV. CONCLUSION: IGHy was effective, safe, and pharmacokinetically equivalent to IGIV at the same administration intervals, but it caused fewer systemic reactions. Tolerability was good despite high infusion volumes and rates.

Safety, efficacy and pharmacokinetics of a new 10% liquid intravenous immunoglobulin (IVIG) in patients with primary immunodeficiency.

INTRODUCTION: An investigational 10% liquid intravenous immunoglobulin (IVIG) was studied in 63 patients with primary immunodeficiency (PID) at 15 study sites. METHODS: Patients were treated every 3 or 4 weeks with 254-1029 mg/kg/infusion of IVIG. RESULTS: Overall, Biotest-IVIG infusions were well tolerated. The proportion of infusions that were associated with adverse events during infusion, and up to 72 h after infusion, including those unrelated to study product, was 27.7% with an upper 95% confidence limit ≤30.6%. Two serious bacterial infections (SBIs) were observed resulting in a serious bacterial infection rate of 0.035 per person per year and an upper one-sided 99% confidence limit of ≤0.136 SBI/patient/year. The number of days of work or school missed due to infection were relatively low at 2.28 days/patient/year. Two patients were hospitalized for infection producing a rate of 0.21 hospitalization days/patient/year. The IgG half-life was approximately 30 days with variation among individuals. CONCLUSIONS: Pharmacokinetic parameters of specific antibody activities were essentially the same as those of total IgG. Biotest-IVIG is safe and effective in the treatment of PID.

Corrigendum: Clinical efficacy, safety and tolerability of a new subcutaneous immunoglobulin 16.5% (Octanorm [Cutaquig®]) in the treatment of patients with primary immunodeficiencies.

[This corrects the article DOI: 10.3389/fimmu.2019.00040.].

Efficacy, safety, and pharmacokinetics of a 10% liquid immune globulin preparation (GAMMAGARD LIQUID, 10%) administered subcutaneously in subjects with primary immunodeficiency disease.

A multi-center, prospective, open-label study was conducted in primary immunodeficiency disease patients to determine the tolerability and pharmacokinetics of a 10% liquid IgG preparation administered subcutaneously. Forty-nine subjects (3-77 years old) were enrolled. Pharmacokinetic equivalence of subcutaneous treatment was achieved at a median dose of 137% of the intravenous dose, with a mean trough IgG level of 1,202 mg/dL at the end of the assessment period. The overall infection rate during subcutaneous treatment was 4.1 per subject-year. Three acute serious bacterial infections were reported, resulting in a rate of 0.067 per subject-year. A low overall rate of temporally associated adverse events (8%), and a very low rate of infusion site adverse events (2.8%), was seen at volumes up to 30 mL/site and rates ≤ 30 mL/h/site. Thus, subcutaneous replacement therapy with a 10% IgG preparation proved effective, safe and well-tolerated in our study population of subjects with primary immunodeficiency disease.

Recombinant Human C1 Esterase Inhibitor for the Management of Adverse Events Related to Intravenous Immunoglobulin Infusion in Patients With Common Variable Immunodeficiency or Polyneuropathy: A Pilot Open-Label Study.

It has been hypothesized that low levels of C1 esterase inhibitor (C1-INH), a key inhibitor of the complement pathway, may play a role in the occurrence of adverse events (AEs) associated with intravenous immunoglobulin (IVIG) therapy. This open-label pilot study evaluated C1-INH replacement, with recombinant human C1-INH (rhC1-INH), as a potential therapy for adults requiring IVIG and experiencing AEs. Patients received two rounds of IVIG infusion [pre-treatment phase (no rhC1-INH), 4-8 weeks] and then three rounds of one dose of intravenous rhC1-INH 50 U/kg (maximum, 4,200 U) with subsequent IVIG infusion (treatment phase, 6-12 weeks). Nineteen adults completed the study; all had an autoimmune condition linked to common variable immunodeficiency (CVID) or polyneuropathy, and 57.9% had low baseline C1-INH levels. Mean ± SD total scores improved significantly with the Headache Impact Test (from 62.8 ± 6.2 at pre-treatment to 57.7 ± 9.1 after treatment; mean Δ, -5.0; p = 0.02) and Modified Fatigue Impact Scale (from 59.3 ± 13.1 to 51.2 ± 15.4; mean Δ, -8.1; p = 0.006). Significant improvements in the Migraine Disability Assessment were observed for three of five items (p ≤ 0.002). Mean ± SD C1-INH level increased from 26.8 ± 5.9 mg/dl after the second round of IVIG (pre-treatment) to 32.1 ± 7.8 mg/dl after the third rhC1-INH treatment; functional C1-INH levels increased from 115.8 ± 34.7% to 158.3 ± 46.8%. Future research is warranted to explore the benefit of C1-INH therapy for reduction of IVIG-related AEs, as well as the role of C1-INH in patients with CVID and autoimmune disease. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03576469.

Evaluation of Intravenous Immunoglobulin in Pediatric Acute-Onset Neuropsychiatric Syndrome.

Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) is a clinical diagnosis in children who have an acute manifestation of varied neuropsychiatric symptoms, including obsessive compulsive disorder, eating disorders, tics, anxiety, irritability, and problems with attention/concentration. PANS may develop as a result of a postinfectious syndrome and may represent a new form of postinfectious autoimmunity. To test the hypothesis that multiple, consecutive infusions of intravenous immunoglobulin (IVIG) for PANS can be efficacious, a multisite, open-label study was designed. Methods: The primary endpoint was evaluation of the efficacy of IVIG [Octagam 5%] in PANS over a period of 6 months (six infusions) based on mean changes in psychological evaluation scores using 6 different assessments, including the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), Clinical Global Impression of Severity, and the Parent-Rated Pediatric Acute Neuropsychiatric Symptom Scale (PANS Scale). Results: The final cohort consisted of 21 subjects (7 per site) with moderate to severe PANS. The mean age was 10.86 years (range: 4-16 years). Results demonstrated statistically significant reductions in symptoms from baseline to end of treatment in all six assessments measured. CY-BOCS results demonstrated statistically significant reductions in obsessive compulsive symptoms (p < 0.0001), resulting in >50% improvement sustained for at least 8 weeks after the final infusion and up to 46 weeks in a subset of subjects. Conclusions: In PANS, which may be associated with an underlying immune dysregulation, sequential infusions of IVIG [Octagam 5%] successfully ameliorated psychological symptoms and dysfunction, with sustained benefits for at least 8 weeks, and up to 46 weeks in a subset of subjects. In addition, baseline immune and autoimmune profiles demonstrated significant elevations in a majority of subjects, which requires further evaluation, characterization, and study to clarify the potential immune dysfunction by which PANS manifests and progresses.