A Multicentre Study on the Efficacy, Safety and Pharmacokinetics of IqYmune®, a Highly Purified 10% Liquid Intravenous Immunoglobulin, in Patients with Primary Immune Deficiency

A Multicentre Study on the Efficacy, Safety and Pharmacokinetics of IqYmune®, a Highly Purified... J Clin Immunol (2017) 37:539–547 DOI 10.1007/s10875-017-0416-4 ORIGINAL ARTICLE A Multicentre Study on the Efficacy, Safety and Pharmacokinetics of IqYmune®, a Highly Purified 10% Liquid Intravenous Immunoglobulin, in Patients with Primary Immune Deficiency 1 2 3 4 Gergely Krivan & Ludmila Chernyshova & Larysa Kostyuchenko & Andrzej Lange & 5 6 7 8 9 Zoltan Nyul & Beata Derfalvi & Jacek Musial & Anne Bellon & Martin Kappler & 8 10 Alain Sadoun & Ewa Bernatowska Received: 28 October 2016 /Accepted: 22 June 2017 /Published online: 15 July 2017 The Author(s) 2017. This article is an open access publication Abstract This multicentre, open-label, prospective, single- absence from work or school and of hospitalization due to arm study was designed to evaluate the efficacy, pharmacoki- infections were 1.01 and 0.89 days/patient, respectively. The netics, and safety of IqYmune®, a highly purified 10% poly- mean serum IgG trough level before the 6th infusion was valent immunoglobulin preparation for intravenous adminis- 7.73 g/L after a mean dose of IqYmune® of 0.57 g/kg. The tration in patients with primary immunodeficiency. pharmacokinetic profile of IqYmune® was consistent with IqYmune® was administered to 62 patients (aged 2–61 years) that of other intravenous immunoglobulins. Overall, 15.5% with X-linked agammaglobulinemia or common variable im- of infusions were associated with an adverse event occurring mune deficiency at a dose from 0.22 to 0.97 g/kg every 3 to within 72 h post infusion. Headache was the most common 4 weeks for 12 months with an infusion rate up to 8 mL/kg/h. adverse event. In conclusion, IqYmune® was shown to be A pharmacokinetic study was performed at steady state be- effective and well tolerated in patients with primary tween the 8th and the 9th infusion. A single case of serious immunodeficiency. bacterial infection was observed, leading to an annualized rate . . of serious bacterial infections/patient (primary endpoint) of Keywords IVIg Immunoglobulins Clinical trials 0.017 (98% CI: 0.000, 0.115). Overall, 228 infections were reported, most frequently bronchitis, chronic sinusitis, nasopharyngitis and upper respiratory tract infection. The Introduction mean annualized rate of infections was 3.79/patient. A lower risk of infections was associated with an IgG trough lev- Primary immunodeficiencies (PIDs) are a heterogeneous el > 8 g/L (p = 0.01). The mean annualized durations of group of inherited diseases predisposing individuals to * Alain Sadoun Children’s Department, University of Pécs, Pécs, Hungary sadoun@lfb.fr 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary Paediatric Haematology and Stem Cell Transplantation Department, Szent Laszlo Hospital, Budapest, Hungary Alergiczno Internistyczny All-Med Specjalistyczny Osrodek, 2 Krakow, Poland Department of Paediatric Infectious Diseases and Clinical Immunology, P.L. Shupyk National Medical Academy for Clinical Development Department, LFB Biotechnologies, BP 40305, Post-graduate Education, Kiev, Ukraine 3 avenue des Tropiques, Les Ulis 91958, Courtaboeuf Cedex, France West Ukrainian Specialized Children’s Medical Centre, Lviv, Ukraine 9 Statalpha, Baziège, France Lower Silesian Center for Cellular Transplantation/Institute of Immunology and Experimental Therapy, Polish Academy of Immunology Clinic Department, Children’s Memorial Health Sciences, Wroclaw, Poland Institute, Warsaw, Poland 540 J Clin Immunol (2017) 37:539–547 increased risk of infection. To date, more than 200 types of 2011 to March 2013. Approvals were obtained from the re- PIDs have been reported in the literature, but less than 10 of spective national and institutional ethics committees. Written them account for more than 60% of all PID cases [1]. Most informed consent and/or assent as appropriate were signed by types of PIDs are associated with a hypogammaglobulinemia all patients and/or their legal representatives/witnesses. due to impaired antibody production. Chronic or recurrent upper and lower respiratory tract infections, sinusitis, and oti- tis media are the most common infections, while severe bac- Study Patients terial infections (SBIs) such as sepsis, meningitis, septic ar- thritis, and osteomyelitis can also occur [2–4]. In the absence Patients aged from 2 to 65 years with XLA or CVID of early diagnosis and appropriate therapy, recurrent respira- diagnosed according to the European Society for tory infections eventually lead to the development of bronchi- Immunodeficiencies (ESID) criteria, either Ig-naïve or previ- ectases and other chronic pulmonary diseases [5, 6]. ously treated with Ig replacement therapy, were recruited. Immunoglobulin (Ig) replacement is the mainstay of ther- Previously treated patients were to be administered with a apy for PID patients with hypo- or agammaglobulinemia. Its stable dose of Ig and to have at least three IgG trough levels efficacy in preventing severe infections is widely demonstrat- ≥4 g/L within the last 6 months prior to study entry. ed [7, 8]. X-linked agammaglobulinemia (XLA) and common The main exclusion criteria were history of allergy or seri- variable immune deficiency (CVID) are the most common ous adverse reaction to Ig therapy, anti-IgA antibodies, glo- forms of PIDs requiring Ig replacement therapy [9, 10]. merular filtration rate (GFR) <80 mL/min/1.73 m according Treatment with intravenous immunoglobulin (IVIg) is gen- to MDRD formula in adults or creatinine clearance <60 mL/ erally well tolerated. Headache, chills, fever, and myalgia are min/1.73 m according to Schwartz formula in paediatric pa- the most common adverse reactions, usually mild in intensity tients, alanine aminotransferase (ALT), or aspartate amino- [11]. Severe complications are rare and include acute renal transferase (AST) >3 times upper limit of normal, total biliru- failure, mainly associated with sucrose when used as a stabi- bin >2 times upper limit of normal, protein-losing enteropathy lizer [12], haemolysis caused by the presence of red blood cell or nephrotic syndrome, history of thrombosis within the past IgG alloantibodies in Ig preparations [13], thromboembolic 12 months, pregnancy, and breastfeeding. events mainly due to the increased blood viscosity early after Ig administration and/or the presence of pro-coagulant con- taminants in Ig preparations [14], and severe allergic reac- Study Product tions, particularly in IgA-deficient patients [15]. IqYmune® is a highly purified 10% liquid preparation of IqYmune® is a ready-to-use liquid IVIg preparation contain- human normal immunoglobulin for intravenous administra- ing at least 95% of IgG. The IgA content is ≤28 μg/mL, and tion obtained from thousands of healthy donors. The the osmolality of 300 ± 30 mOsm/kg is in the physiological manufacturing process consists of cold ethanol and caprylic range. The sodium chloride concentration is <0.02 mmol/L, acid fractionation steps followed by purification steps includ- making the product appropriate for patients with sodium- ing an anion exchange chromatography for IgA and IgM restricted diet. No procoagulant activity is detected. clearance and an affinity chromatography ensuring a low IqYmune® is stabilized with glycine and polysorbate 80 at a anti-A and anti-B haemaglutinin content. The inactivation/ pH of 4.8 ± 0.2 and can be stored at room temperature (25 °C). removal process of potential blood-borne pathogens is mainly based on a solvent/detergent treatment followed by a 20-nm nanofiltration. Study Treatments The present study investigated the efficacy, pharmacokinet- ics, and safety of IqYmune® in paediatric and adult patients IqYmune® was to be administered intravenously every 3 or with XLA or CVID. 4 weeks (±3 days) for 12 months, at a stable dose between 0.2 and 0.8 g/kg/month. Dose adjustment was allowed in case of IgG trough level < 6 g/L and/or recurrent infections. Clinical Study Methods The initial infusion rate was 1 mL/kg/h for 30 min, to be increased up to 4 mL/kg/h for the first three administrations Study Design and 8 mL/kg/h for the subsequent infusions. No premedication was allowed, unless the patient experi- An open-label, prospective, single-arm study designed ac- enced an adverse reaction on two consecutive infusions that cording to the European Medical Agency (EMA) guidelines could be prevented by acetaminophen, antihistamines, [16] was conducted in 18 centres in five countries in Europe hydroxyzin, non-steroidal anti-inflammatory drugs, or anti- (France, Hungary, Poland, Serbia and Ukraine) from August emetic agents. Prophylactic antibiotics were forbidden. J Clin Immunol (2017) 37:539–547 541 Pharmacokinetics Diary Cards Serum IgG trough levels were assessed in all patients before The patients or parents/guardians had to record on diary cards each IqYmune® infusion throughout the study period. the following information: AEs, infectious episodes and relat- In addition, a subset of 28 adult patients (four on a 3-week ed events (school/work days missed, hospitalisations, and fe- and 24 on a 4-week dosing schedule) were enrolled in a formal ver), and concomitant medications. pharmacokinetic (PK) study. Blood samples were drawn shortly before and immediately at the end of the 8th infusion, Statistical Analysis then 30 min, 6 h, 12 h, 24 h, 3 days, 7 days, 14 days, 21 days and 28 days (if applicable) after the end of infusion. Serum The statistical analysis was performed on the total treated set IgG level were measured in a central laboratory using a neph- (TTS) which consisted of all patients who received at least one elometric method. IqYmune® administration. All efficacy and safety analyses PK parameters were estimated from a population PK model ® were performed using SAS Software version 9.1.3. using Phoenix NLME version 1.2. A supportive non- Sixty patients were planned to be enrolled in the study to compartmental analysis (NCA) was performed using ensure a power of at least 80% to reject a null hypothesis of ≥1 Phoenix WinNonlin version 6.3 (Pharsight, Cary, NC, SBI/patient/year, the threshold below which Ig replacement USA). The PK parameters assessed were the maximum serum therapy can be considered effective [16]. Assuming that the IgG concentration (C ), the time to reach the maximum max number of SBIs is following a Poisson distribution, an exact serum IgG concentration (T ), the half-life (t ), the elimi- max 1/2 one-sided one-sample Poisson test at a type I error of 0.01 was nation rate constant (K ), the clearance (Cl), the volume of el chosen. distribution (Vd), and the area under the concentration-time The rate of infusions with at least one TAAE was calculat- curve at infinite (AUC ). 0-∞ ed, and the upper one-sided 95% confidence interval (CI) limit was compared to the threshold of 0.40 specified in the FDA guidance [17]. Evaluation of Efficacy The primary efficacy endpoint was the rate of SBIs per patient per year. SBIs included bacterial pneumonia, bacteraemia or Study Results sepsis, osteomyelitis, septic arthritis, visceral abscess, and bacterial meningitis as defined in the Food and Drug Study Patients Administration (FDA) guidance [17]. The secondary efficacy endpoints were the annualized rate A total of 62 patients were enrolled in the study, 36 (58.1%) of all infections and number of days of infection-related pa- adults and 26 (41.9%) paediatric patients. Baseline character- rameters (absence from school/work, hospitalization, fever istics of the patients are presented in Table 1. Among them, 58 episode, and antibiotic therapy). (93.5%) patients were previously on Ig replacement therapy, while four (6.5%) patients were naïve to Ig therapy. Seven (11.3%) patients had a medical history of bronchiectasis. Evaluation of Safety Mean interval from diagnosis of PID to study entry was 7.4 years. Patients were monitored for adverse events (AEs) and serious Nine of the 62 (14.5%) patients, all adults, discontinued adverse events (SAEs). Treatment-emergent AEs (TEAEs) prematurely the study. Reasons for and times of discontinua- were defined as AEs occurring from the time of the first tions are summarized in Table 2. IqYmune® infusion to the date of the end-of-study/early ter- mination (EoS/ET) visit. Temporally associated adverse events (TAAEs) were defined as AEs occurring from the start Treatment of infusion up to 72 h after end of infusion. Vital signs were monitored during and 30 min after the end All enrolled patients were treated with IqYmune®: 57 patients of each infusion. Biochemistry (AST, ALT, GGT, alkaline were on a 4-week and five on a 3-week dosing schedule. phosphatase, total bilirubin, albumin, creatinine, and hapto- Patients received a mean number of 12.4 ± 3.2 infusions globin) and haematology (complete blood count with differ- (range 1–17) leading to a total of 766 infusions over a mean ential and platelet count) parameters were recorded at base- period of 44.5 ± 11.6 weeks (range 0.1–54.4) at a mean dose line, within 30 min after end of each infusion and at the EoS/ of 0.56 ± 0.17 g/kg (range 0.22–0.97, excluding one patient ET. Direct antiglobulin test (DAT) was analysed at the same who received 0.01 g/kg due to an infusion-related reaction time points except EoS/ET. leading to premature study drug discontinuation). 542 J Clin Immunol (2017) 37:539–547 Table 1 Patient baseline characteristics (TTS, N =62) infusion rate was ≤4 mL/kg/h and 1.70 ± 0.40 h when the maximum infusion rate was >4 mL/kg/h. Characteristics Paediatrics Adults Total (n =26) (n =36) (N =62) Age (years) Pharmacokinetics Mean 10.9 39.4 27.4 Range 2–17 18–61 2–61 The mean serum IgG trough level in the total population in- Gender (n,%) creased from 5.79 ± 2.03 g/L at baseline (range 0.45–9.99) to Male 23 (88.5) 20 (55.6) 43 (69.4) 7.73 ± 2.36 g/L before the 6th infusion and 7.96 ± 1.53 g/L Female 3 (11.5) 16 (44.4) 19 (30.6) before the 13th infusion visit (last infusion for patients on a 4- Weight (kg) week dosing schedule). In parallel, the mean dose of Mean 42.4 65.7 55.9 IqYmune® was 0.48 ± 0.15 g/kg at the 1st infusion, Range 12–88 46–95 12–95 0.57 ± 0.17 g/kg at the 5th infusion, and 0.60 ± 0.17 g/kg at Type of PID (n,%) the 12th infusion. The mean ratio of IgG trough levels over XLA 17 (65.4) 3 (8.3) 20 (32.3) dose by infusion was stable over time and was comparable to CVID 9 (34.6) 33 (91.7) 42 (67.7) that obtained at baseline with the IVIgs administered prior to Treatment (n,%) the first IqYmune® infusion. IVIg 23 (88.5) 34 (94.4) 57 (91.9) The primary PK parameters derived from the population PK model were 4.9 mL/h for clearance and 3.5 L for the SCIg 1 (3.8) 0 (0.0) 1 (1.6) volume of distribution in the central compartment. Derived Ig-naïve 2 (7.7) 2 (5.6) 4 (6.5) secondary PK parameter estimates were a half-life of 33.6 days SBI within the previous year (n, %) 5 (19.2) 3 (8.3) 8 (12.9) and an AUC of 383 day × g/L. The C , calculated using 0-∞ max TTS total treated set the NCA instead of NLME model to take into account a het- erogeneity in infusion durations, was 18.1 g/L. The median T wasapproximately2hafter theonset of infusion. max The mean maximum infusion rate per infusion was 4.88 ± 1.89 mL/kg/h, increasing with the visit number as shown in Fig. 1. The mean maximum infusion rate per patient Efficacy was 6.10 ± 2.03 mL/kg/h. The maximum infusion rate was ≤4 mL/kg/h for 439 (57.3%) infusions, >4 to 6 mL/kg/h for One SBI was reported during the total study period of 57.74 162 (21.1%) infusions, and >6 to 8 mL/kg/h for 165 (21.5%) patient-years, leading to a rate of 0.017 SBI per patient per infusions. A total of 27 (43.5%) patients had at least one in- year significantly lower than the predefined threshold of 1.0 fusion with a maximum flow rate equal to 8 mL/kg/h. Mean (p < 0.001, 98% CI [0.00, 0.115]) as required by the EMA infusion duration was 2.28 ± 0.64 h when the maximum guideline [16]. Table 2 Reasons for and times of Reason for discontinuation N (%) Time of discontinuation premature discontinuations (TTS, N =62) (after infusion number) Adverse event 4 (6.5) a,b c Infusion-related reaction 1 (1.6) 1 Recurrent neutropenia 1 (1.6) 4 Hodgkin’sdisease 1 (1.6) 5 Gastrointestinal disorders and ascites 1 (1.6) 5 Withdrawal of consent 2 (3.2) 7 and 8 Late identification of an exclusion criterion 1 (1.6) 2 Pregnancy 1 (1.6) 6 Omission of the last study visit 1 (1.6) 15 TTS total treated set Consisting of a transient episode of dyspnoea, oropharyngeal pain, and chest pain Drug-related Five minutes after the start of the infusion Not drug-related J Clin Immunol (2017) 37:539–547 543 Fig. 1 Mean (±SD) maximum infusion rate per infusion over time (TTS, N =62). SD standard deviation, TTS total treated set. Infusions beyond the 13th are not reported as only five to eight patients were concerned The only SBI observed was an acinetobacter bacteraemia B12 deficiency and one case of testicular torsion, and diagnosed in a 24-year-old male CVID patient just before the were not related to the study drug. 6th IVIg administration. The patient had a serum IgG trough Thirty-three (53.2%) patients presented a total of 148 drug- level of 2.47 g/L at the time of the onset of the SBI due to a related TEAEs, most commonly headache (16.1% of pa- chronic protein-losing enteropathy gone unnoticed at study tients), chills (14.5%), neutropenia (11.3%), pyrexia (9.7%), entry. Resolution of the infection was complete after intrave- back pain (6.5%), and hypertension (6.5%). nous antibiotic therapy. Thirty-nine (62.9%) patients experienced a total of 170 Overall, a total of 228 infections were experienced by 51 of TAAEs. the 62 patients (82.3%). The mean annualized rate of infec- Out of the 766 infusions, 119 were associated with at least tions per patient was 3.79 ± 3.62 (range 0.0–14.9) in the total one TAAE, resulting in a proportion of 15.5% (95% CI: 13.0; population, 3.01 ± 3.24 (range 0.0–14.0) in adults, and 18.3). As shown in Fig. 2, the percentage of infusions with at 4.88 ± 3.88 (range 1.0–14.9) in paediatric patients. Most of least one TAAE was maximal after the first administration and infections involved the upper respiratory tract. Their distribu- decreased over time. Taking into account the maximum rate of tion is presented in Table 3. Infections were assessed to be each infusion, 77/439 (17.5%) infusions ≤4 mL/kg/h, 19/162 mild in severity in 192 cases (84.2%), moderate in 33 cases (11.7%) infusions from >4 to 6 mL/kg/h and 23/165 (13.9%) (14.5%), and severe in 3 cases (1.3%). The severe infections infusions >6 mL/kg/h were associated with at least one TAAE. were a gastrointestinal candidiasis and a gastroenteritis Four (6.5%) patients discontinued the study drug due to a cryptosporidial infection in one adult patient and an exacerba- TEAE, including two patients with drug-related TEAEs (see tion of a chronic sinusitis in one paediatric patient. In all cases, Table 2). One of them presented with a hypersensitivity reac- the infections resolved without sequelae. tion consisted of an acute infusion-related reaction of moder- The relationship between infections and IgG trough level ate intensity with transient dyspnea and oropharyngeal and (assessed just before the infusion preceding the infection) was chest pain. Temporary interruptions and/or flow rate decreases analysed. The rate of infusions associated with at least one or limitations of an infusion due to a TAAE occurred in 2% of infection was 26.3 and 18.6% in trough level categories of the total infusions, mostly at the first or second administration. ≤8 and >8 g/L, respectively (p =0.01). Twenty SAEs were reported in 15 (24.2%) patients includ- Other infection-related parameters results (absence from ing four drug-related SAEs consisting of asymptomatic tran- work or school, hospitalization, fever episode, and antibiotics sient and spontaneously reversible episodes of neutropenia. use) are summarized in Table 4. A total of 12 (21.1%) of 57 evaluable patients had positive DAT at baseline, whereas 25 (55.6%) of the 45 DAT negative patients converted to positivity during the study period. No Safety patients exhibited biological signs of IVIg-induced haemolysis defined as simultaneous reduction of Hb lev- Adverse events are summarized in Table 5. Fifty-one of el ≥ 1 g/dL within 10 days post-infusion and positive DAT the 62 (82.3%) patients experienced a total of 343 associated with low haptoglobin or increased bilirubin serum TEAEs of mild (79%), moderate (20%), or severe levels. Regardless of the other parameters associated with he- (1%) intensity. Severe TEAEs consisted of one case of molysis, no patients presented with a clinically significant low haptoglobin level throughout the study period. anaemia secondary to both inflammation and vitamin 544 J Clin Immunol (2017) 37:539–547 Table 3 Distribution of Infection Number of patients Number of infections infections (TTS, N =62) (% of total patients) (% of total infections) All infections 51 (82.3) 228 (100) Bronchitis 15 (24.2) 30 (13.2) Nasopharyngitis 14 (22.6) 26 (11.4) Upper respiratory tract infection 11 (17.7) 18 (7.9) Pharyngitis 10 (16.1) 13 (5.7) Chronic sinusitis 9 (14.5) 28 (12.3) Rhinitis 8 (12.9) 12 (5.3) Tracheitis 7 (11.3) 8 (3.5) Oral herpes 6 (9.7) 7 (3.1) Respiratory tract infection 5 (8.1) 5 (2.2) Conjunctivitis 4 (6.5) 7 (3.1) Cystitis 4 (6.5) 5 (2.2) Tracheobronchitis 4 (6.5) 5 (2.2) Other infections ≤3(4.8) each ≤4 (1.8) each TTS total treated set Seven (11.3%) patients were reported with a drug-related All episodes of hypertension occurred in adults were of neutropenia. Three (3) of them had individual factors potentially mild severity and did not require any medications. contributing to neutropenia, i.e., low neutrophil count at baseline, No thromboembolic events, renal failure, or anaphylactic medical history of bicytopenia, or diagnosis of Hodgkin’sdisease reactions were reported. Analysis of vital signs and laboratory during the study period. Return to normal or baseline values was parameters did not show any other safety signals. spontaneous at the next pre-infusion analysis in all patients. One neutropenia episode with a nadir <0.5 × 10 /L was reported in four of these seven patients. No infections occurred in two of Discussion them, while the other two patients presented with mild cystitis and common cold, respectively. The study met its primary efficacy endpoint with an annual- In the whole study population, the mean post-infusion neutro- ized SBI rate of 0.017 per patient significantly lower than the phil count was approximately 1 × 10 /L lower than the mean count EMA/FDA requirement of less than one SBI/patient/year [16, before the first IqYmune® administration with a greater relative 17] and in line with SBI rates published in similar studies decrease in those patients who had a higher baseline value (data ranging from 0.0 to 0.12/patient/year [18, 19]. The only SBI not shown). The ratio of the number of infections over the number occurred in a context of a very low IgG trough level due to an of periods with neutrophil count in each categories (<0.5 × 10 /L, aggravation of a chronic enteropathy with protein loss. The 9 9 9 0.5to1.0 ×10 /L, 1.0 to 1.5 × 10 /L, and ≥1.5 × 10 /L) was annual rate of all infections of 3.79 per patient and their types similar, ranging between 19.1 and 29.7%. All three severe infec- were in line with those reported for other IVIg products tions reported in the study were associated with a neutrophil count [18–20]. The study treatment duration of 1 year for a single ≥1.5 × 10 /L. patient was scheduled in order to prevent a seasonal bias due Table 4 Infection-related Infection-related endpoints Number of Number of patients Annualized number of days with endpoints (TTS, N =62) events (%) events Mean (SD) [95% CI] All infections 228 51 (82.3) 51.8 (64.6) [35.4, 68.2] Hospitalization 6 5 (8.1) 0.9 (3.3) [0.1, 1.7] Fever episode 33 19 (30.6) 1.6 (3.7) [0.6, 2.5] Antibiotics use 131 38 (61.3) 19.5 (26.8) [12.7, 26.3] Absence from work or 15 8 (12.9) 1.0 (3.6) [0.1, 1.9] school CI confidence interval, SD standard deviation, TTS total treated set J Clin Immunol (2017) 37:539–547 545 Table 5 Summary of adverse Patients (n %) Infusions (n %) AEs Total events (TTS, N =62) (N =62) (N =766) (per infusion) TEAEs 51 (82.3) 205 (26.8) 343 (0.45) Drug-related TEAEs 33 (53.2) 105 (13.7) 148 (0.19) TAAEs 39 (62.9) 119 (15.5) 170 (0.22) ≤4 mL/kg/h (439 infusions) 31 (50.0) 77 (17.5) 116 (0.26) >4 to ≤6 mL/kg/h (162 infusions) 14 (22.6) 19 (11.7) 24 (0.15) >6 mL/kg/h (165 infusions) 12 (19.4) 23 (13.9) 30 (0.18) SAEs 15 (24.2) 19 (2.5) 20 (0.03) Drug-related SAEs 4 (6.5) 4 (0.005) 4 (0.005) Discontinuation of study drug due to AE 4 (6.5) 4 (0.005) 5 (0.007) Interruption of study drug due to AE 4 (6.5) 5 (0.007) 7 (0.009) Flow rate decrease or no increase due to AE 8 (12.9) 10 (0.03) 11 (0.01) AE adverse event, SAE serious adverse event, TAAE temporally associated adverse event, TEAE treatment- emergent adverse event, TTS total treated set to a greater rate of infections in the winter months. The higher increases in IgG trough levels. A satisfactory mean IgG trough rate of infections in paediatric patients as compared to adults level of 7.73 ± 2.36 g/L was achieved before the 6th infusion. was expected, due to the exposure to not previously encoun- As reported in other studies, fewer infections were observed tered pathogens (mainly viruses) easily transmissible in the when trough IgG levels were >8 g/L [7, 9, 21, 22]. The mean childhood environment (child care centres and kindergarten), IgG half-life of 33.6 days was within the range of those re- as well as anatomical ENT characteristics and hypotrophy of ported with other IVIgs [18, 23–25]. mucosal lymphoid tissues. IqYmune® was well tolerated. The observed types, The number of days of work/school missed due to infec- severity, and frequency of TEAEs did not differ from tions (1.0 day/patient/year) and with curative antibiotic thera- those commonly reported with other IVIg preparations py (19.5 days/patient/year) compared favourably with the [11, 26]. Approximately 99% of the TEAEs were ranges of 2.28 to 13 days and 32.1 to 55.7 days/patient/year, assessed as mild or moderate in severity and the three respectively, reported in the literature while the rate of days of severe TEAEs were judged as not related to the study hospitalization (0.9 day/patient/year) was within the range of drug. As reported in recent studies, both in adults and 0.21 to 2.31 days/patient/year reported with other IVIg prod- children, the most frequent TEAE was headache [26, ucts [18–20]. 27]. The rate of infusions with TAAEs of 15.5% was At baseline, the majority of patients (36/62) had IgG trough significantly below the safety threshold of 40% required levels <6 g/L which can be explained by lower Ig doses used by the FDA [17] and compares favourably with the in some countries and the inclusion of four Ig-naïve patients. range of 20.1 to 27.7% recently reported with other Therefore, doses were increased during the study in order to IVIg products [18]. Due to the initiation of the IVIg reach an IgG trough level ≥ 6 g/L and to prevent recurrent treatment or the switch to a new IVIg preparation, the infections. Dose increases were associated with proportional first infusion was associated with more TAAEs than the Fig. 2 Proportion of infusions with TAAEs over time (TTS, 35 N =62). TTS total treated set. Infusions beyond the 13th are not reported as only five to eight patients were concerned 1234567 89 10 11 12 13 62 61 60 60 59 59 56 55 54 54 54 54 54 Infusion number Number of paents Percentage of infusions with TAAEs 546 J Clin Immunol (2017) 37:539–547 LFB Biotechnologies employees: Nehza Chambron (medical writing) subsequent ones [11, 28]. The rate of infusions with at and Rosanna Rende-Fournier (clinical project management). least one TAAE then decreased even though a rebound was observed at the time of the 4th infusion, when Compliance with Ethical Standards maximal infusion rate up to 8 mL/kg/h was first allowed. For the whole study period, the maximum in- Conflicts of Interest A. Bellon and A. Sadoun are LFB fusion rate was not correlated with the risk of TAAEs Biotechnologies employees. M. Kappler is the consultant for LFB (17.5, 11.7, and 13.9% of the infusions with a maxi- Biotechnologies. All other co-authors were the study investigators and mum flow rate of ≤4, 4–6, and >6 mL/kg/h, respective- received investigator honoraria or funds for research from LFB Biotechnologies. ly), showing a good adaptation of the patients to high infusion rates. Open Access This article is distributed under the terms of the Creative Nonspecific positive DAT after IVIg infusions have been Commons Attribution 4.0 International License (http:// reported with an incidence ranging from 8.5 to 47% [18]. This creativecommons.org/licenses/by/4.0/), which permits unrestricted use, finding is likely to be favoured by the immediate post-infusion distribution, and reproduction in any medium, provided you give appro- priate credit to the original author(s) and the source, provide a link to the sampling and is deemed to be related to the nonspecific bind- Creative Commons license, and indicate if changes were made. ing of IgG to red blood cells [29, 30]. A decrease in neutrophil count is frequently observed with IVIgs. This decrease is of short duration, with a nadir occurring usually within 4 days and a return to References baselinewithin1to2weeks [31, 32]. Neutrophil count after IVIg depends on the sampling time and blood 1. Gathmann B, Grimbacher B, Beauté J, et al. The European internet- sampling shortly after the end of each infusion in this based patient and research database for primary immunodefi- study may have favoured the report of neutropenia. ciencies: results 2006–2008. Clin Exp Immunol. 2009;157:3–11. Asymptomatic, transient, and spontaneously reversible 2. Cooper MD, Lanier LL, Conley ME, Puck JM. Immunodeficiency neutropenia has been reported after IVIg administration disorders. Hematology Am Soc Hematol Educ Program. 2003: 314–30. in up to 58% of patients, including in patients with PID 3. Wood P. Primary antibody deficiency syndromes. Ann Clin without an increased risk of infection [32–35]. The Biochem. 2009;46(Pt 2):99–108. pathophysiology of the neutropenia is unclear and sev- 4. Bonilla FA, Geha RS. Primary immunodeficiency diseases. J eral mechanisms have been hypothesised including ag- Allergy Clin Immunol. 2003;111(2 Suppl):S571–81. gregation of neutrophils [36], adhesion on endothelial 5. Plebani A, Soresina A, Rondelli R, et al. Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked cells with rapid migration to tissues [33, 37], and pres- agammaglobulinemia: an Italian multicenter study. Clin Immunol. ence of alloantibodies to neutrophil membrane compo- 2002;104(3):221–30. nents in the IVIg preparation [38]. IqYmune® tested 6. Kainulainen L, Varpula M, Liippo K, et al. Pulmonary abnormali- negative for anti-human neutrophil antigen antibodies. ties in patients with primary hypogammaglobulinemia. J Allergy Clin Immunol. 1999;104:1031–6. No IgG aggregate or polymer levels were detected that 7. Quartier P, Debré M, De Blic J, et al. Early and prolonged intrave- could have activated neutrophils or increase their adhe- nous immunoglobulin replacement therapy in childhood agamma- sion to endothelial cells. In addition, no signal of neu- globulinemia: a retrospective survey of 31 patients. J Pediatr. trophil activation or degranulation was observed when 1999;134(5):589–96. both the expression of CD11b and lactoferrin were mea- 8. Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intrave- nous immunoglobulin in the prevention of pneumonia in patients suredexvivoinawhole blood assay.The absenceof with common variable immunodeficiency. J Allergy Clin Immunol. severe infections in patients with neutrophil count 2002;109(6):1001–4. <0.5 × 10 /L is consistent with the assumption that a 9. Cunningham-Rundles C. Key aspects for successful immunoglob- pool of functionally active blood neutrophils can be ulin therapy of primary immunodeficiencies. Clin Exp Immunol. mobilized to combat infections. 2011;164(Suppl 2):16–9. 10. Hernandez-Trujillo HS, Chapel H, et al. Comparison of American In summary, IqYmune® is effective in preventing and European practices in the management of patients with primary infections and well tolerated as replacement therapy in immunodeficiencies. Clin Exp Immunol. 2012;169(1):57–69. patients with PID, including at high infusion rates. 11. Stiehm ER. Adverse effects of human immunoglobulin therapy. Transfus Med Rev. 2013;27(3):171–8. 12. Dantal J. Intravenous immunoglobulins: in-depth review of excip- ients and acute kidney injury risk. Am J Nephrol. 2013;38:275–84. Acknowledgements Study investigators: Margit Zeher (Debrecen) and 13. Quinti I, Pulvirenti F, Milito C, et al. Hemolysis in patients with Gábor Sütö (Pécs) in Hungary; Bożena Mikołuć (Białystok) in Poland; antibody deficiencies on immunoglobulin replacement treatment. Goran Marjanovic (Nis) in Serbia; and Jean-François Viallard (Pessac), Transfusion. 2015;55(5):1067–74. Jean-Louis Pasquali (Strasbourg), Marianne Debré (Paris), Yves Perel (Bordeaux), Caroline Thomas (Nantes), and Dr. Cyrille Hoarau (Tours) 14. Funk MB, Gross N, Gross S, et al. Thromboembolic events associated with immunoglobulin treatment. Vox Sang. 2013;105(1):54–64. in France. J Clin Immunol (2017) 37:539–547 547 15. Anani W, Triulzi D, Yazer MH, Qu L. Relative IgA-deficient recip- 28. Ameratunga R, Sinclair J, Kolbe J. Increased risk of adverse events when changing intravenous immunoglobulin preparations. Clin ients have an increased risk of severe allergic transfusion reactions. Vox Sang. 2014;107(4):389–92. Exp Immunol. 2004;136(1):111–3. 29. Heddle NM, Kelton JG, Turchyn KL, Ali MA. 16. Guideline on the clinical investigation of human normal immuno- Hypergammaglobulinemia can be associated with a positive direct globulin for intravenous administration (IVIg). European antiglobulin test, a nonreactive eluate, and no evidence of hemo- Medicines Agency: EMA/CHMP/BPWP/94033/2007 rev.2. lysis. Transfusion. 1988;28(1):29–33. 17. FDA Guidance for Industry on safety, efficacy and PK studies to 30. Huh YO, Liu FJ, Rogge K, et al. Positive direct antiglobulin test and support marketing of human IVGg as replacement therapy for pri- high serum immunoglobulin G values. Am J Clin Pathol. mary humoral immunodeficiency 2008. 1988;90(2):197–200. 18. Schröder HW, Dougherty CJ. Review of intravenous immunoglob- 31. Koffman BM, Dalakas MC. Effect of high-dose intravenous immuno- ulin replacement therapy trials for primary humoral immunodefi- globulin on serum chemistry, hematology, and lymphocyte subpopula- ciency patients. Infection. 2012;40(6):601–11. tions: assessments based on controlled treatment trials in patients with 19. Kreuz W, Erdös M, Rossi P, et al. A multi-centre study of efficacy neurological diseases. Muscle Nerve. 1997;20:1102–7. and safety of Intratect®, a novel intravenous immunoglobulin prep- 32. Matsuda M, Hosoda W, Sekijima Y, et al. Neutropenia as a compli- aration. Clin Exp Immunol. 2010;161(3):512–7. cation of high-dose intravenous immunoglobulin therapy in adult 20. Björkander J, Nikoskelainen J, et al. Prospective open-label study patients with neuroimmunologic disorders. Clin Neuropharmacol. of pharmacokinetics, efficacy and safety of a new 10% liquid intra- 2003;26(6):306–11. venous immunoglobulin in patients with hypo- or agammaglobu- 33. Lemos S, Jacob CMA, Pastorino AC, Castro APBM, Fomin ABF, linemia. Vox Sang. 2006;90(4):286–93. Carneiro-Sampaio MMS, et al. Neutropenia in antibody-deficient 21. Orange JS, Grossman WJ, Navickis RJ, Wilkes MM. Impact of patients under IVIG replacement therapy. Paed Allergy Immunol. trough IgG on pneumonia incidence in primary immunodeficiency: 2009;20:97–101. a meta-analysis of clinical studies. Clin Immunol. 2010;137:21–30. 34. Chae MH, Park SW, Jeon IS. An analysis of neutropenia after the 22. Eijkhout HW, Van der Meer JWM, Kallenberg CGM, et al. The administration of high-dose intravenous immunoglobulin or anti-D im- effect of two different dosages of intravenous immunoglobulin on munoglobulin on acute immune thrombocytopenic purpura children: the incidence of recurrent infections in patients with primary age based analysis. Clin Pediatr Hematol Oncol. 2013;20:22–8. hypogammaglobulinemia. Ann Intern Med. 2001;135:165–74. 35. Niebanck AE, Kwiatkowski JL, Raffini LJ. Neutropenia following 23. Koleba T, Ensom MH. Pharmacokinetics of intravenous immunoglob- IVIG therapy in pediatric patients with immune-mediated thrombo- ulin: a systematic review. Pharmacotherapy. 2006;26(6):813–27. cytopenia. J Pediatr Hematol Oncol. 2005;27:145–7. 24. Wasserman RL, Church JA, Peter HH, et al. IgPro10 in PID study 36. Zeltser D, Fusman R, Chapman J, et al. Increased leukocyte aggre- group pharmacokinetics of a new 10% intravenous immunoglobu- gation induced by gamma-globulin: a clue to the presence of lin in patients receiving replacement therapy for primary immuno- pseudoleukopenia. Am J Med Sci. 2000;320(3):177–82. deficiency. Eur J Pharm Sci. 2009;37(3–4):272–8. 37. Casulli S, Topçu S, Fattoum L, et al. A differential concentration- 25. Ballow M, Notarangelo L, Grimbacher B, et al. Immunodeficiencies. dependent effect of IVIg on neutrophil functions: relevance for anti- Clin Exp Immunol. 2009;158(Suppl 1):14–22. microbial and anti-inflammatory mechanisms. PLoS One. 26. Caress J, Kennedy B, Eickman K. Safety of intravenous immuno- 2011;6(10):e26469. globulin treatment. Expert Opin Drug Saf. 2010;9(6):971–9. 38. Baxley A, Akhtari M. Hematologic toxicities associated with intra- 27. Berger M. Adverse effects of IgG therapy. J Allergy Clin Immunol venous immunoglobulin therapy. Int Immunopharmacol. 2011;11: Pract. 2013;1:558–66. 1663–7. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Immunology Springer Journals

A Multicentre Study on the Efficacy, Safety and Pharmacokinetics of IqYmune®, a Highly Purified 10% Liquid Intravenous Immunoglobulin, in Patients with Primary Immune Deficiency

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Biomedicine; Immunology; Infectious Diseases; Internal Medicine; Medical Microbiology
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J Clin Immunol (2017) 37:539–547 DOI 10.1007/s10875-017-0416-4 ORIGINAL ARTICLE A Multicentre Study on the Efficacy, Safety and Pharmacokinetics of IqYmune®, a Highly Purified 10% Liquid Intravenous Immunoglobulin, in Patients with Primary Immune Deficiency 1 2 3 4 Gergely Krivan & Ludmila Chernyshova & Larysa Kostyuchenko & Andrzej Lange & 5 6 7 8 9 Zoltan Nyul & Beata Derfalvi & Jacek Musial & Anne Bellon & Martin Kappler & 8 10 Alain Sadoun & Ewa Bernatowska Received: 28 October 2016 /Accepted: 22 June 2017 /Published online: 15 July 2017 The Author(s) 2017. This article is an open access publication Abstract This multicentre, open-label, prospective, single- absence from work or school and of hospitalization due to arm study was designed to evaluate the efficacy, pharmacoki- infections were 1.01 and 0.89 days/patient, respectively. The netics, and safety of IqYmune®, a highly purified 10% poly- mean serum IgG trough level before the 6th infusion was valent immunoglobulin preparation for intravenous adminis- 7.73 g/L after a mean dose of IqYmune® of 0.57 g/kg. The tration in patients with primary immunodeficiency. pharmacokinetic profile of IqYmune® was consistent with IqYmune® was administered to 62 patients (aged 2–61 years) that of other intravenous immunoglobulins. Overall, 15.5% with X-linked agammaglobulinemia or common variable im- of infusions were associated with an adverse event occurring mune deficiency at a dose from 0.22 to 0.97 g/kg every 3 to within 72 h post infusion. Headache was the most common 4 weeks for 12 months with an infusion rate up to 8 mL/kg/h. adverse event. In conclusion, IqYmune® was shown to be A pharmacokinetic study was performed at steady state be- effective and well tolerated in patients with primary tween the 8th and the 9th infusion. A single case of serious immunodeficiency. bacterial infection was observed, leading to an annualized rate . . of serious bacterial infections/patient (primary endpoint) of Keywords IVIg Immunoglobulins Clinical trials 0.017 (98% CI: 0.000, 0.115). Overall, 228 infections were reported, most frequently bronchitis, chronic sinusitis, nasopharyngitis and upper respiratory tract infection. The Introduction mean annualized rate of infections was 3.79/patient. A lower risk of infections was associated with an IgG trough lev- Primary immunodeficiencies (PIDs) are a heterogeneous el > 8 g/L (p = 0.01). The mean annualized durations of group of inherited diseases predisposing individuals to * Alain Sadoun Children’s Department, University of Pécs, Pécs, Hungary sadoun@lfb.fr 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary Paediatric Haematology and Stem Cell Transplantation Department, Szent Laszlo Hospital, Budapest, Hungary Alergiczno Internistyczny All-Med Specjalistyczny Osrodek, 2 Krakow, Poland Department of Paediatric Infectious Diseases and Clinical Immunology, P.L. Shupyk National Medical Academy for Clinical Development Department, LFB Biotechnologies, BP 40305, Post-graduate Education, Kiev, Ukraine 3 avenue des Tropiques, Les Ulis 91958, Courtaboeuf Cedex, France West Ukrainian Specialized Children’s Medical Centre, Lviv, Ukraine 9 Statalpha, Baziège, France Lower Silesian Center for Cellular Transplantation/Institute of Immunology and Experimental Therapy, Polish Academy of Immunology Clinic Department, Children’s Memorial Health Sciences, Wroclaw, Poland Institute, Warsaw, Poland 540 J Clin Immunol (2017) 37:539–547 increased risk of infection. To date, more than 200 types of 2011 to March 2013. Approvals were obtained from the re- PIDs have been reported in the literature, but less than 10 of spective national and institutional ethics committees. Written them account for more than 60% of all PID cases [1]. Most informed consent and/or assent as appropriate were signed by types of PIDs are associated with a hypogammaglobulinemia all patients and/or their legal representatives/witnesses. due to impaired antibody production. Chronic or recurrent upper and lower respiratory tract infections, sinusitis, and oti- tis media are the most common infections, while severe bac- Study Patients terial infections (SBIs) such as sepsis, meningitis, septic ar- thritis, and osteomyelitis can also occur [2–4]. In the absence Patients aged from 2 to 65 years with XLA or CVID of early diagnosis and appropriate therapy, recurrent respira- diagnosed according to the European Society for tory infections eventually lead to the development of bronchi- Immunodeficiencies (ESID) criteria, either Ig-naïve or previ- ectases and other chronic pulmonary diseases [5, 6]. ously treated with Ig replacement therapy, were recruited. Immunoglobulin (Ig) replacement is the mainstay of ther- Previously treated patients were to be administered with a apy for PID patients with hypo- or agammaglobulinemia. Its stable dose of Ig and to have at least three IgG trough levels efficacy in preventing severe infections is widely demonstrat- ≥4 g/L within the last 6 months prior to study entry. ed [7, 8]. X-linked agammaglobulinemia (XLA) and common The main exclusion criteria were history of allergy or seri- variable immune deficiency (CVID) are the most common ous adverse reaction to Ig therapy, anti-IgA antibodies, glo- forms of PIDs requiring Ig replacement therapy [9, 10]. merular filtration rate (GFR) <80 mL/min/1.73 m according Treatment with intravenous immunoglobulin (IVIg) is gen- to MDRD formula in adults or creatinine clearance <60 mL/ erally well tolerated. Headache, chills, fever, and myalgia are min/1.73 m according to Schwartz formula in paediatric pa- the most common adverse reactions, usually mild in intensity tients, alanine aminotransferase (ALT), or aspartate amino- [11]. Severe complications are rare and include acute renal transferase (AST) >3 times upper limit of normal, total biliru- failure, mainly associated with sucrose when used as a stabi- bin >2 times upper limit of normal, protein-losing enteropathy lizer [12], haemolysis caused by the presence of red blood cell or nephrotic syndrome, history of thrombosis within the past IgG alloantibodies in Ig preparations [13], thromboembolic 12 months, pregnancy, and breastfeeding. events mainly due to the increased blood viscosity early after Ig administration and/or the presence of pro-coagulant con- taminants in Ig preparations [14], and severe allergic reac- Study Product tions, particularly in IgA-deficient patients [15]. IqYmune® is a highly purified 10% liquid preparation of IqYmune® is a ready-to-use liquid IVIg preparation contain- human normal immunoglobulin for intravenous administra- ing at least 95% of IgG. The IgA content is ≤28 μg/mL, and tion obtained from thousands of healthy donors. The the osmolality of 300 ± 30 mOsm/kg is in the physiological manufacturing process consists of cold ethanol and caprylic range. The sodium chloride concentration is <0.02 mmol/L, acid fractionation steps followed by purification steps includ- making the product appropriate for patients with sodium- ing an anion exchange chromatography for IgA and IgM restricted diet. No procoagulant activity is detected. clearance and an affinity chromatography ensuring a low IqYmune® is stabilized with glycine and polysorbate 80 at a anti-A and anti-B haemaglutinin content. The inactivation/ pH of 4.8 ± 0.2 and can be stored at room temperature (25 °C). removal process of potential blood-borne pathogens is mainly based on a solvent/detergent treatment followed by a 20-nm nanofiltration. Study Treatments The present study investigated the efficacy, pharmacokinet- ics, and safety of IqYmune® in paediatric and adult patients IqYmune® was to be administered intravenously every 3 or with XLA or CVID. 4 weeks (±3 days) for 12 months, at a stable dose between 0.2 and 0.8 g/kg/month. Dose adjustment was allowed in case of IgG trough level < 6 g/L and/or recurrent infections. Clinical Study Methods The initial infusion rate was 1 mL/kg/h for 30 min, to be increased up to 4 mL/kg/h for the first three administrations Study Design and 8 mL/kg/h for the subsequent infusions. No premedication was allowed, unless the patient experi- An open-label, prospective, single-arm study designed ac- enced an adverse reaction on two consecutive infusions that cording to the European Medical Agency (EMA) guidelines could be prevented by acetaminophen, antihistamines, [16] was conducted in 18 centres in five countries in Europe hydroxyzin, non-steroidal anti-inflammatory drugs, or anti- (France, Hungary, Poland, Serbia and Ukraine) from August emetic agents. Prophylactic antibiotics were forbidden. J Clin Immunol (2017) 37:539–547 541 Pharmacokinetics Diary Cards Serum IgG trough levels were assessed in all patients before The patients or parents/guardians had to record on diary cards each IqYmune® infusion throughout the study period. the following information: AEs, infectious episodes and relat- In addition, a subset of 28 adult patients (four on a 3-week ed events (school/work days missed, hospitalisations, and fe- and 24 on a 4-week dosing schedule) were enrolled in a formal ver), and concomitant medications. pharmacokinetic (PK) study. Blood samples were drawn shortly before and immediately at the end of the 8th infusion, Statistical Analysis then 30 min, 6 h, 12 h, 24 h, 3 days, 7 days, 14 days, 21 days and 28 days (if applicable) after the end of infusion. Serum The statistical analysis was performed on the total treated set IgG level were measured in a central laboratory using a neph- (TTS) which consisted of all patients who received at least one elometric method. IqYmune® administration. All efficacy and safety analyses PK parameters were estimated from a population PK model ® were performed using SAS Software version 9.1.3. using Phoenix NLME version 1.2. A supportive non- Sixty patients were planned to be enrolled in the study to compartmental analysis (NCA) was performed using ensure a power of at least 80% to reject a null hypothesis of ≥1 Phoenix WinNonlin version 6.3 (Pharsight, Cary, NC, SBI/patient/year, the threshold below which Ig replacement USA). The PK parameters assessed were the maximum serum therapy can be considered effective [16]. Assuming that the IgG concentration (C ), the time to reach the maximum max number of SBIs is following a Poisson distribution, an exact serum IgG concentration (T ), the half-life (t ), the elimi- max 1/2 one-sided one-sample Poisson test at a type I error of 0.01 was nation rate constant (K ), the clearance (Cl), the volume of el chosen. distribution (Vd), and the area under the concentration-time The rate of infusions with at least one TAAE was calculat- curve at infinite (AUC ). 0-∞ ed, and the upper one-sided 95% confidence interval (CI) limit was compared to the threshold of 0.40 specified in the FDA guidance [17]. Evaluation of Efficacy The primary efficacy endpoint was the rate of SBIs per patient per year. SBIs included bacterial pneumonia, bacteraemia or Study Results sepsis, osteomyelitis, septic arthritis, visceral abscess, and bacterial meningitis as defined in the Food and Drug Study Patients Administration (FDA) guidance [17]. The secondary efficacy endpoints were the annualized rate A total of 62 patients were enrolled in the study, 36 (58.1%) of all infections and number of days of infection-related pa- adults and 26 (41.9%) paediatric patients. Baseline character- rameters (absence from school/work, hospitalization, fever istics of the patients are presented in Table 1. Among them, 58 episode, and antibiotic therapy). (93.5%) patients were previously on Ig replacement therapy, while four (6.5%) patients were naïve to Ig therapy. Seven (11.3%) patients had a medical history of bronchiectasis. Evaluation of Safety Mean interval from diagnosis of PID to study entry was 7.4 years. Patients were monitored for adverse events (AEs) and serious Nine of the 62 (14.5%) patients, all adults, discontinued adverse events (SAEs). Treatment-emergent AEs (TEAEs) prematurely the study. Reasons for and times of discontinua- were defined as AEs occurring from the time of the first tions are summarized in Table 2. IqYmune® infusion to the date of the end-of-study/early ter- mination (EoS/ET) visit. Temporally associated adverse events (TAAEs) were defined as AEs occurring from the start Treatment of infusion up to 72 h after end of infusion. Vital signs were monitored during and 30 min after the end All enrolled patients were treated with IqYmune®: 57 patients of each infusion. Biochemistry (AST, ALT, GGT, alkaline were on a 4-week and five on a 3-week dosing schedule. phosphatase, total bilirubin, albumin, creatinine, and hapto- Patients received a mean number of 12.4 ± 3.2 infusions globin) and haematology (complete blood count with differ- (range 1–17) leading to a total of 766 infusions over a mean ential and platelet count) parameters were recorded at base- period of 44.5 ± 11.6 weeks (range 0.1–54.4) at a mean dose line, within 30 min after end of each infusion and at the EoS/ of 0.56 ± 0.17 g/kg (range 0.22–0.97, excluding one patient ET. Direct antiglobulin test (DAT) was analysed at the same who received 0.01 g/kg due to an infusion-related reaction time points except EoS/ET. leading to premature study drug discontinuation). 542 J Clin Immunol (2017) 37:539–547 Table 1 Patient baseline characteristics (TTS, N =62) infusion rate was ≤4 mL/kg/h and 1.70 ± 0.40 h when the maximum infusion rate was >4 mL/kg/h. Characteristics Paediatrics Adults Total (n =26) (n =36) (N =62) Age (years) Pharmacokinetics Mean 10.9 39.4 27.4 Range 2–17 18–61 2–61 The mean serum IgG trough level in the total population in- Gender (n,%) creased from 5.79 ± 2.03 g/L at baseline (range 0.45–9.99) to Male 23 (88.5) 20 (55.6) 43 (69.4) 7.73 ± 2.36 g/L before the 6th infusion and 7.96 ± 1.53 g/L Female 3 (11.5) 16 (44.4) 19 (30.6) before the 13th infusion visit (last infusion for patients on a 4- Weight (kg) week dosing schedule). In parallel, the mean dose of Mean 42.4 65.7 55.9 IqYmune® was 0.48 ± 0.15 g/kg at the 1st infusion, Range 12–88 46–95 12–95 0.57 ± 0.17 g/kg at the 5th infusion, and 0.60 ± 0.17 g/kg at Type of PID (n,%) the 12th infusion. The mean ratio of IgG trough levels over XLA 17 (65.4) 3 (8.3) 20 (32.3) dose by infusion was stable over time and was comparable to CVID 9 (34.6) 33 (91.7) 42 (67.7) that obtained at baseline with the IVIgs administered prior to Treatment (n,%) the first IqYmune® infusion. IVIg 23 (88.5) 34 (94.4) 57 (91.9) The primary PK parameters derived from the population PK model were 4.9 mL/h for clearance and 3.5 L for the SCIg 1 (3.8) 0 (0.0) 1 (1.6) volume of distribution in the central compartment. Derived Ig-naïve 2 (7.7) 2 (5.6) 4 (6.5) secondary PK parameter estimates were a half-life of 33.6 days SBI within the previous year (n, %) 5 (19.2) 3 (8.3) 8 (12.9) and an AUC of 383 day × g/L. The C , calculated using 0-∞ max TTS total treated set the NCA instead of NLME model to take into account a het- erogeneity in infusion durations, was 18.1 g/L. The median T wasapproximately2hafter theonset of infusion. max The mean maximum infusion rate per infusion was 4.88 ± 1.89 mL/kg/h, increasing with the visit number as shown in Fig. 1. The mean maximum infusion rate per patient Efficacy was 6.10 ± 2.03 mL/kg/h. The maximum infusion rate was ≤4 mL/kg/h for 439 (57.3%) infusions, >4 to 6 mL/kg/h for One SBI was reported during the total study period of 57.74 162 (21.1%) infusions, and >6 to 8 mL/kg/h for 165 (21.5%) patient-years, leading to a rate of 0.017 SBI per patient per infusions. A total of 27 (43.5%) patients had at least one in- year significantly lower than the predefined threshold of 1.0 fusion with a maximum flow rate equal to 8 mL/kg/h. Mean (p < 0.001, 98% CI [0.00, 0.115]) as required by the EMA infusion duration was 2.28 ± 0.64 h when the maximum guideline [16]. Table 2 Reasons for and times of Reason for discontinuation N (%) Time of discontinuation premature discontinuations (TTS, N =62) (after infusion number) Adverse event 4 (6.5) a,b c Infusion-related reaction 1 (1.6) 1 Recurrent neutropenia 1 (1.6) 4 Hodgkin’sdisease 1 (1.6) 5 Gastrointestinal disorders and ascites 1 (1.6) 5 Withdrawal of consent 2 (3.2) 7 and 8 Late identification of an exclusion criterion 1 (1.6) 2 Pregnancy 1 (1.6) 6 Omission of the last study visit 1 (1.6) 15 TTS total treated set Consisting of a transient episode of dyspnoea, oropharyngeal pain, and chest pain Drug-related Five minutes after the start of the infusion Not drug-related J Clin Immunol (2017) 37:539–547 543 Fig. 1 Mean (±SD) maximum infusion rate per infusion over time (TTS, N =62). SD standard deviation, TTS total treated set. Infusions beyond the 13th are not reported as only five to eight patients were concerned The only SBI observed was an acinetobacter bacteraemia B12 deficiency and one case of testicular torsion, and diagnosed in a 24-year-old male CVID patient just before the were not related to the study drug. 6th IVIg administration. The patient had a serum IgG trough Thirty-three (53.2%) patients presented a total of 148 drug- level of 2.47 g/L at the time of the onset of the SBI due to a related TEAEs, most commonly headache (16.1% of pa- chronic protein-losing enteropathy gone unnoticed at study tients), chills (14.5%), neutropenia (11.3%), pyrexia (9.7%), entry. Resolution of the infection was complete after intrave- back pain (6.5%), and hypertension (6.5%). nous antibiotic therapy. Thirty-nine (62.9%) patients experienced a total of 170 Overall, a total of 228 infections were experienced by 51 of TAAEs. the 62 patients (82.3%). The mean annualized rate of infec- Out of the 766 infusions, 119 were associated with at least tions per patient was 3.79 ± 3.62 (range 0.0–14.9) in the total one TAAE, resulting in a proportion of 15.5% (95% CI: 13.0; population, 3.01 ± 3.24 (range 0.0–14.0) in adults, and 18.3). As shown in Fig. 2, the percentage of infusions with at 4.88 ± 3.88 (range 1.0–14.9) in paediatric patients. Most of least one TAAE was maximal after the first administration and infections involved the upper respiratory tract. Their distribu- decreased over time. Taking into account the maximum rate of tion is presented in Table 3. Infections were assessed to be each infusion, 77/439 (17.5%) infusions ≤4 mL/kg/h, 19/162 mild in severity in 192 cases (84.2%), moderate in 33 cases (11.7%) infusions from >4 to 6 mL/kg/h and 23/165 (13.9%) (14.5%), and severe in 3 cases (1.3%). The severe infections infusions >6 mL/kg/h were associated with at least one TAAE. were a gastrointestinal candidiasis and a gastroenteritis Four (6.5%) patients discontinued the study drug due to a cryptosporidial infection in one adult patient and an exacerba- TEAE, including two patients with drug-related TEAEs (see tion of a chronic sinusitis in one paediatric patient. In all cases, Table 2). One of them presented with a hypersensitivity reac- the infections resolved without sequelae. tion consisted of an acute infusion-related reaction of moder- The relationship between infections and IgG trough level ate intensity with transient dyspnea and oropharyngeal and (assessed just before the infusion preceding the infection) was chest pain. Temporary interruptions and/or flow rate decreases analysed. The rate of infusions associated with at least one or limitations of an infusion due to a TAAE occurred in 2% of infection was 26.3 and 18.6% in trough level categories of the total infusions, mostly at the first or second administration. ≤8 and >8 g/L, respectively (p =0.01). Twenty SAEs were reported in 15 (24.2%) patients includ- Other infection-related parameters results (absence from ing four drug-related SAEs consisting of asymptomatic tran- work or school, hospitalization, fever episode, and antibiotics sient and spontaneously reversible episodes of neutropenia. use) are summarized in Table 4. A total of 12 (21.1%) of 57 evaluable patients had positive DAT at baseline, whereas 25 (55.6%) of the 45 DAT negative patients converted to positivity during the study period. No Safety patients exhibited biological signs of IVIg-induced haemolysis defined as simultaneous reduction of Hb lev- Adverse events are summarized in Table 5. Fifty-one of el ≥ 1 g/dL within 10 days post-infusion and positive DAT the 62 (82.3%) patients experienced a total of 343 associated with low haptoglobin or increased bilirubin serum TEAEs of mild (79%), moderate (20%), or severe levels. Regardless of the other parameters associated with he- (1%) intensity. Severe TEAEs consisted of one case of molysis, no patients presented with a clinically significant low haptoglobin level throughout the study period. anaemia secondary to both inflammation and vitamin 544 J Clin Immunol (2017) 37:539–547 Table 3 Distribution of Infection Number of patients Number of infections infections (TTS, N =62) (% of total patients) (% of total infections) All infections 51 (82.3) 228 (100) Bronchitis 15 (24.2) 30 (13.2) Nasopharyngitis 14 (22.6) 26 (11.4) Upper respiratory tract infection 11 (17.7) 18 (7.9) Pharyngitis 10 (16.1) 13 (5.7) Chronic sinusitis 9 (14.5) 28 (12.3) Rhinitis 8 (12.9) 12 (5.3) Tracheitis 7 (11.3) 8 (3.5) Oral herpes 6 (9.7) 7 (3.1) Respiratory tract infection 5 (8.1) 5 (2.2) Conjunctivitis 4 (6.5) 7 (3.1) Cystitis 4 (6.5) 5 (2.2) Tracheobronchitis 4 (6.5) 5 (2.2) Other infections ≤3(4.8) each ≤4 (1.8) each TTS total treated set Seven (11.3%) patients were reported with a drug-related All episodes of hypertension occurred in adults were of neutropenia. Three (3) of them had individual factors potentially mild severity and did not require any medications. contributing to neutropenia, i.e., low neutrophil count at baseline, No thromboembolic events, renal failure, or anaphylactic medical history of bicytopenia, or diagnosis of Hodgkin’sdisease reactions were reported. Analysis of vital signs and laboratory during the study period. Return to normal or baseline values was parameters did not show any other safety signals. spontaneous at the next pre-infusion analysis in all patients. One neutropenia episode with a nadir <0.5 × 10 /L was reported in four of these seven patients. No infections occurred in two of Discussion them, while the other two patients presented with mild cystitis and common cold, respectively. The study met its primary efficacy endpoint with an annual- In the whole study population, the mean post-infusion neutro- ized SBI rate of 0.017 per patient significantly lower than the phil count was approximately 1 × 10 /L lower than the mean count EMA/FDA requirement of less than one SBI/patient/year [16, before the first IqYmune® administration with a greater relative 17] and in line with SBI rates published in similar studies decrease in those patients who had a higher baseline value (data ranging from 0.0 to 0.12/patient/year [18, 19]. The only SBI not shown). The ratio of the number of infections over the number occurred in a context of a very low IgG trough level due to an of periods with neutrophil count in each categories (<0.5 × 10 /L, aggravation of a chronic enteropathy with protein loss. The 9 9 9 0.5to1.0 ×10 /L, 1.0 to 1.5 × 10 /L, and ≥1.5 × 10 /L) was annual rate of all infections of 3.79 per patient and their types similar, ranging between 19.1 and 29.7%. All three severe infec- were in line with those reported for other IVIg products tions reported in the study were associated with a neutrophil count [18–20]. The study treatment duration of 1 year for a single ≥1.5 × 10 /L. patient was scheduled in order to prevent a seasonal bias due Table 4 Infection-related Infection-related endpoints Number of Number of patients Annualized number of days with endpoints (TTS, N =62) events (%) events Mean (SD) [95% CI] All infections 228 51 (82.3) 51.8 (64.6) [35.4, 68.2] Hospitalization 6 5 (8.1) 0.9 (3.3) [0.1, 1.7] Fever episode 33 19 (30.6) 1.6 (3.7) [0.6, 2.5] Antibiotics use 131 38 (61.3) 19.5 (26.8) [12.7, 26.3] Absence from work or 15 8 (12.9) 1.0 (3.6) [0.1, 1.9] school CI confidence interval, SD standard deviation, TTS total treated set J Clin Immunol (2017) 37:539–547 545 Table 5 Summary of adverse Patients (n %) Infusions (n %) AEs Total events (TTS, N =62) (N =62) (N =766) (per infusion) TEAEs 51 (82.3) 205 (26.8) 343 (0.45) Drug-related TEAEs 33 (53.2) 105 (13.7) 148 (0.19) TAAEs 39 (62.9) 119 (15.5) 170 (0.22) ≤4 mL/kg/h (439 infusions) 31 (50.0) 77 (17.5) 116 (0.26) >4 to ≤6 mL/kg/h (162 infusions) 14 (22.6) 19 (11.7) 24 (0.15) >6 mL/kg/h (165 infusions) 12 (19.4) 23 (13.9) 30 (0.18) SAEs 15 (24.2) 19 (2.5) 20 (0.03) Drug-related SAEs 4 (6.5) 4 (0.005) 4 (0.005) Discontinuation of study drug due to AE 4 (6.5) 4 (0.005) 5 (0.007) Interruption of study drug due to AE 4 (6.5) 5 (0.007) 7 (0.009) Flow rate decrease or no increase due to AE 8 (12.9) 10 (0.03) 11 (0.01) AE adverse event, SAE serious adverse event, TAAE temporally associated adverse event, TEAE treatment- emergent adverse event, TTS total treated set to a greater rate of infections in the winter months. The higher increases in IgG trough levels. A satisfactory mean IgG trough rate of infections in paediatric patients as compared to adults level of 7.73 ± 2.36 g/L was achieved before the 6th infusion. was expected, due to the exposure to not previously encoun- As reported in other studies, fewer infections were observed tered pathogens (mainly viruses) easily transmissible in the when trough IgG levels were >8 g/L [7, 9, 21, 22]. The mean childhood environment (child care centres and kindergarten), IgG half-life of 33.6 days was within the range of those re- as well as anatomical ENT characteristics and hypotrophy of ported with other IVIgs [18, 23–25]. mucosal lymphoid tissues. IqYmune® was well tolerated. The observed types, The number of days of work/school missed due to infec- severity, and frequency of TEAEs did not differ from tions (1.0 day/patient/year) and with curative antibiotic thera- those commonly reported with other IVIg preparations py (19.5 days/patient/year) compared favourably with the [11, 26]. Approximately 99% of the TEAEs were ranges of 2.28 to 13 days and 32.1 to 55.7 days/patient/year, assessed as mild or moderate in severity and the three respectively, reported in the literature while the rate of days of severe TEAEs were judged as not related to the study hospitalization (0.9 day/patient/year) was within the range of drug. As reported in recent studies, both in adults and 0.21 to 2.31 days/patient/year reported with other IVIg prod- children, the most frequent TEAE was headache [26, ucts [18–20]. 27]. The rate of infusions with TAAEs of 15.5% was At baseline, the majority of patients (36/62) had IgG trough significantly below the safety threshold of 40% required levels <6 g/L which can be explained by lower Ig doses used by the FDA [17] and compares favourably with the in some countries and the inclusion of four Ig-naïve patients. range of 20.1 to 27.7% recently reported with other Therefore, doses were increased during the study in order to IVIg products [18]. Due to the initiation of the IVIg reach an IgG trough level ≥ 6 g/L and to prevent recurrent treatment or the switch to a new IVIg preparation, the infections. Dose increases were associated with proportional first infusion was associated with more TAAEs than the Fig. 2 Proportion of infusions with TAAEs over time (TTS, 35 N =62). TTS total treated set. Infusions beyond the 13th are not reported as only five to eight patients were concerned 1234567 89 10 11 12 13 62 61 60 60 59 59 56 55 54 54 54 54 54 Infusion number Number of paents Percentage of infusions with TAAEs 546 J Clin Immunol (2017) 37:539–547 LFB Biotechnologies employees: Nehza Chambron (medical writing) subsequent ones [11, 28]. The rate of infusions with at and Rosanna Rende-Fournier (clinical project management). least one TAAE then decreased even though a rebound was observed at the time of the 4th infusion, when Compliance with Ethical Standards maximal infusion rate up to 8 mL/kg/h was first allowed. For the whole study period, the maximum in- Conflicts of Interest A. Bellon and A. Sadoun are LFB fusion rate was not correlated with the risk of TAAEs Biotechnologies employees. M. Kappler is the consultant for LFB (17.5, 11.7, and 13.9% of the infusions with a maxi- Biotechnologies. All other co-authors were the study investigators and mum flow rate of ≤4, 4–6, and >6 mL/kg/h, respective- received investigator honoraria or funds for research from LFB Biotechnologies. ly), showing a good adaptation of the patients to high infusion rates. Open Access This article is distributed under the terms of the Creative Nonspecific positive DAT after IVIg infusions have been Commons Attribution 4.0 International License (http:// reported with an incidence ranging from 8.5 to 47% [18]. This creativecommons.org/licenses/by/4.0/), which permits unrestricted use, finding is likely to be favoured by the immediate post-infusion distribution, and reproduction in any medium, provided you give appro- priate credit to the original author(s) and the source, provide a link to the sampling and is deemed to be related to the nonspecific bind- Creative Commons license, and indicate if changes were made. ing of IgG to red blood cells [29, 30]. A decrease in neutrophil count is frequently observed with IVIgs. This decrease is of short duration, with a nadir occurring usually within 4 days and a return to References baselinewithin1to2weeks [31, 32]. Neutrophil count after IVIg depends on the sampling time and blood 1. Gathmann B, Grimbacher B, Beauté J, et al. The European internet- sampling shortly after the end of each infusion in this based patient and research database for primary immunodefi- study may have favoured the report of neutropenia. ciencies: results 2006–2008. Clin Exp Immunol. 2009;157:3–11. Asymptomatic, transient, and spontaneously reversible 2. Cooper MD, Lanier LL, Conley ME, Puck JM. Immunodeficiency neutropenia has been reported after IVIg administration disorders. Hematology Am Soc Hematol Educ Program. 2003: 314–30. in up to 58% of patients, including in patients with PID 3. Wood P. Primary antibody deficiency syndromes. Ann Clin without an increased risk of infection [32–35]. 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Journal of Clinical ImmunologySpringer Journals

Published: Jul 15, 2017

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