Mikhail Rojavin

C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks – final results of the I.M.P.A.C.T.2 study

To cite this article: Craig TJ, Bewtra AK, Bahna SL, Hurewitz D, Schneider LC, Levy RJ, Moy JN, Offenberger J, Jacobson KW, Yang WH, Eidelman F, Janss G, Packer FR, Rojavin MA, Machnig T, Keinecke H‐O, Wasserman RL. C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks – final results of the I.M.P.A.C.T.2 study. Allergy 2011; 66: 1604–1611.

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

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

Pharmacokinetics of Subcutaneous IgPro20 in Patients with Primary Immunodeficiency

AbstractBackground and Objectives: Immunoglobulin replacement is a standard therapy for patients with primary immunodeficiencies. Subcutaneous administration of immunoglobulin offers more constant IgG levels than intravenous administration and simplifies administration for some patients. Use of L-proline as an excipient contributes to the stability of highly concentrated IgG preparations. The aims of the present study were to evaluate the pharmacokinetics of IgPro20 (Hizentra®), a new 20% subcutaneous IgG solution, and compare the area under the serum concentration-time curve (AUC) with that of a similar intravenous 10% IgG solution (IgPro10; Privigen®). At the request of the US FDA, an algorithm for determining IgG trough level ratios (TLRs) was developed in order to provide physicians with a practical tool for monitoring doses during steady-state IgPro20 therapy. Methods: This was a prospective, open-label, multicentre, single-arm, phase III clinical trial conducted in the US. The study was performed in a primary-care setting. Eligible patients were males or females aged 6–75 years with a primary immunodeficiency (common variable immunodeficiency or X-linked agamma-globulinaemia) who had received regular treatment with IgPro10 for at least 3 months prior to entering this study and had achieved serum trough concentration (Ctrough) values ≥5 g/L.IgPro20 was administered subcutaneously once weekly at initial doses equivalent to 130% of patients’ previous doses, based on the results obtained in a Vivaglobin® study and due to an FDA request. After run-in, each patient’s dose was adjusted to achieve an AUC comparable to that achieved with IgPro10 administered intravenously. Results: Eighteen patients completed the study. Mean IgPro20 : IgPro10 dose ratio (dose adjustment coefficient) was 1.53 (range 1.26–1.87). The resulting mean AUCs were 105.6g · day/L for IgPro20 versus 103.2g · day/L for IgPro10 (geometric mean ratio 1.002; lower one-sided 95% confidence limit [CL] 0.951). Thus, the primary endpoint of the study was met, as this result exceeded the pre-specified criterion of the lower one-sided 95% CL of ≥0.8 for non-inferiority. At these AUCs, which were considered equivalent, the mean IgPro20 : IgPro10 TLR, determined by the developed algorithm, was 1.29 (range 1.18–1.73). Titres of specific antibodies tested were well above respective product specifications, suggesting that protection against infection would be effective. Conclusion: Steady-state AUCs with subcutaneous IgPro20 and intravenous IgPro10 were equivalent. Mean dose adjustment coefficient and mean TLR can be used for initial dose conversion without risk of under-protection but vary too widely to be considered measures of equivalence.Trial registration number (clinicaltrials.gov): NCT00419341

Effect of time to treatment on response to C1 esterase inhibitor concentrate for hereditary angioedema attacks.

BACKGROUND C1 esterase inhibitor (C1-INH) concentrate is well established as effective therapy for hereditary angioedema (HAE). It is thought that treatment of an acute HAE attack with C1-INH as early as possible improves efficacy, but there are limited data from prospective studies supporting this recommendation. OBJECTIVE To assess the effect of time to treatment (<6 vs ≥6 hours after start of an attack) with 20 U/kg of C1-INH concentrate on efficacy. METHODS A post hoc analysis of time to treatment after start of an attack was performed for 2 studies with C1-INH concentrate: International Multicenter Prospective Angioedema C1-INH Trial (IMPACT) 1 (randomized, placebo-controlled) and IMPACT 2 (open-label, uncontrolled extension). Because of differences in study design, the data sets were analyzed separately. IMPACT 1 data were analyzed using Cox regression with hazard ratios (HRs). For IMPACT 2 data, linear regression was applied to evaluate whether earlier treatment leads to faster recovery. Descriptive statistics for treatment response were calculated for both studies. RESULTS In IMPACT 1, treatment with C1-INH within less than 6 hours after start of an attack resulted in considerably shorter times to onset of symptom relief (HR, 3.36) and complete resolution (HR, 4.30) vs placebo. The benefit of C1-INH compared with placebo was reduced when administered after 6 or more hours (HRs, 1.18 for times to onset of symptom relief and 1.61 for complete resolution). Analysis of IMPACT 2 data indicated slower complete resolution of symptoms with later start of treatment. CONCLUSION Early treatment with C1-INH (<6 hours) provides a better treatment response than late treatment (≥6 hours), supporting the international recommendation to treat HAE attacks as early as possible. TRIAL REGISTRATION ClinicalTrials.gov Identifiers: NCT00168103 and NCT00292981.

Safety of C1-Esterase Inhibitor in Acute and Prophylactic Therapy of Hereditary Angioedema: Findings from the Ongoing International Berinert Patient Registry

BACKGROUND The plasma-derived, pasteurized C1-inhibitor (C1-INH) concentrate, Berinert has a 4-decade history of use in hereditary angioedema (HAE), with a substantial literature base that demonstrates safety and efficacy. Thromboembolic events have rarely been reported with C1-INH products, typically with off-label use or at supratherapeutic doses. OBJECTIVES Active surveillance of safety and clinical usage patterns of pasteurized C1-inhibitor concentrate and the more recent pasteurized, nanofiltered C1-INH, with a particular interest in thromboembolic events. METHODS A registry was initiated in April 2010 at 27 US and 4 EU sites to obtain both prospective and retrospective safety and usage data on subjects who were administered C1-INH (Berinert). RESULTS As of May 10, 2013, data were available for 135 subjects and 3196 infusions. By subject, 67.4% were using C1-INH as on-demand therapy and 23.0% as both on-demand therapy and prophylactic administration. Approximately half of the infusions (49.5%) were administered for prophylaxis and >90% were given by the patient or a caregiver in the home setting. A total of 299 adverse events were reported, for an overall rate of 0.09 events per infusion with only 6 considered related to C1-INH. Two thromboembolic events were reported, both in patients with prothrombotic risk factors. CONCLUSION This large pool of real-world clinical usage data in HAE further supports the extensive safety profile of 2 Berinert formulations when used on demand and/or for prophylaxis in both home and health care settings. No evidence was found to suggest that Berinert is an independent, causative risk factor for thromboembolic events.

Treatment response after repeated administration of C1 esterase inhibitor for successive acute hereditary angioedema attacks.

Placebo-controlled studies established the efficacy of replacement therapy with C1 esterase inhibitor (C1-INH) concentrate for treating single acute hereditary angioedema (HAE) attacks, but only limited data from prospective studies are available on repeated treatment of successive HAE attacks. This study evaluates the association between repeated treatments with 20 U/kg of C1-INH concentrate (Berinert; CSL Behring, Marburg, Germany) for HAE attacks at any body location and treatment response. In a post hoc analysis of an open-label extension study (International Multicenter Prospective Angioedema C1-INH Trial [I.M.P.A.C.T.2]), the association between repeated treatment with C1-INH and times to onset of symptom relief and complete resolution of HAE symptoms was assessed in patients who were treated for at least 15 attacks by linear regression on the ordinal attack number. Eighteen patients received C1-INH concentrate for at least 15 HAE attacks over a mean duration of 34 months. Demographic and baseline characteristics of these patients were similar to those of all patients in the study. The distribution of body locations and the intensity of HAE attacks were similar for each of the first 15 attacks and subsequent attacks. The extent of previous use of C1-INH concentrate had no effect on the time to onset of symptom relief, the time to complete resolution of HAE symptoms, or the time between attacks treated with C1-INH concentrate; the median of individual linear regression coefficients was not statistically significantly different from 0. Treatment with 20 U/kg of C1-INH concentrate provided consistent treatment response in patients treated for multiple successive HAE attacks at any body location. (Clinicaltrials.gov identifier: NCT00292981).

Long-term efficacy, safety, and tolerability of Hizentra ® for treatment of primary immunodeficiency disease☆

Hizentra(®) (20% subcutaneous immunoglobulin [SCIG]) was administered to subjects with primary immunodeficiency disease in two extension studies in the EU and US to assess long-term efficacy and tolerability. Subjects (aged 4-69 years) were treated for 148 weeks in the EU (N = 40; 5405 infusions) and 87 weeks in the US (N = 21; 1735 infusions). Weekly doses were 116.0 mg/kg (EU) and 193.2 mg/kg (US); IgG levels were 7.97 g/L (EU) and 11.98 g/L (US). Annualized rates of serious bacterial infections were 0.05 infections/subject/year (EU) and 0.06 infections/subject/year (US). Rates of any infection were 3.33 infections/subject/year (EU) and 2.38 infections/subject/year (US). The rate of bronchopulmonary infections was higher in the EU study. No treatment-related serious AEs occurred; no subject discontinued because of treatment-related AEs. Self-administered Hizentra afforded sustained effective protection from infections and favorable tolerability during an extended treatment period of up to 3 years.

Patients with primary immunodeficiency receiving subcutaneous immune globulin Hizentra maintain health‐related quality of life and treatment satisfaction in a multicentre extension study of efficacy, tolerability and safety

Objective  The purpose of the study was to evaluate the maintenance and sustainability of health‐related quality of life (HRQoL) in patients being treated long‐term for primary immunodeficiency (PID) with subcutaneous infusions of Hizentra, a new human immunoglobulin G containing proline.

Tolerability of a New 10% Liquid Immunoglobulin for Intravenous Use, Privigen®, at Different Infusion Rates

PurposeThe tolerability of L-proline-stabilized Privigen®, a new 10% liquid immunoglobulin for intravenous administration, was assessed at high infusion rates in a Phase III, open-label, single-arm, multicenter study in 45 patients with primary immune deficiencies.Patients and MethodsMaximum infusion rates were not assigned prospectively. For analysis, patients were grouped according to maximum infusion rate in a low infusion rate group (8 mg/kg/min) and high infusion rate group (12 mg/kg/min).ResultsTwenty-three patients, selected at the investigators’ discretion for the high infusion rate group based on their good tolerability, tolerated Privigen® at 12 mg/kg/min with no increase in temporally associated adverse events (AEs) above the level they had experienced at 8 mg/kg/min. The proportion of infusions with temporally associated AEs in these patients was 0.079 [97.5% confidence interval (CI) 0.114] compared to 0.211 (97.5% CI 0.267) in the low infusion rate group. The most frequent AE was headache. Thus, selected patients tolerate Privigen® at high infusion rates.

Efficacy and Safety of an Intravenous C1-Inhibitor Concentrate for Long-Term Prophylaxis in Hereditary angioedema

Background The plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH) is approved in the United States as an intravenous (IV) on-demand treatment for hereditary angioedema (HAE) attacks, and, in Europe, as on demand and short-term prophylaxis. Objective This analysis evaluated Berinert Patient Registry data regarding IV pnfC1-INH used as long-term prophylaxis (LTP). Methods The international registry (2010–2014) collected prospective and retrospective usage, dosing, and safety data on individuals who used pnfC1-INH for any reason. Results The registry included data on 47 subjects (80.9% female subjects; mean age, 44.8 years), which reflected 4082 infusions categorized as LTP and a total of 430.2 months of LTP administration. The median absolute dose of pnfC1-INH given for LTP was 1000 IU (range, 500–3000 IU), with a median time interval between infusion and a subsequent pnfC1-INH–treated attack of 72.0 hours (range, 0.0–166.4 hours). Fifteen subjects (31.9%) had no pnfC1-INH–treated HAE attacks within 7 days after pnfC1-INH infusion for LTP; 32 subjects (68.1%) experienced 246 attacks, with rates of 0.06 attacks per infusion and 0.57 attacks per month. A total of 81 adverse events were reported in 16 subjects (34.0%) (0.02 events per infusion; 0.19 events per month); only 3 adverse events were considered related to pnfC1-INH (noncardiac chest pain, postinfusion headache, deep vein thrombosis in a subject with an IV port). Conclusion In this international registry, IV pnf-C1-INH given as LTP for HAE was safe and efficacious, with a low rate of attacks that required pnfC1-INH treatment, particularly within the first several days after LTP administration.