Mark R. Stein

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

Author(s): Wasserman, RL; Melamed, I; Stein, MR; Gupta, S; Puck, J; Engl, W; Leibl, H; McCoy, B; Empson, VG; Gelmont, D; Schiff, RI | Abstract: 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 5 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 subjectyear 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.

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

A laboratory evaluation of immune complexes in patients on inhalant immunotherapy

Patients with allergic rhinitis receiving maintenance inhalant immunotherapy and two control groups were studied for evidence of circulating immune complexes. The first control group contained patients with allergic rhinitis who had never received immunotherapy. The second control group contained normal volunteers. Patients in the treatment group had no proteinuria. When compared with the control group, the treatment group had no statistically significant differences in incidence of Clq binding immune complexes, cryoglobulinemia, rheumatoid factor, or complement depletion. This initial study suggests that maintenance immunotherapy does not result in an increase of circulating immune complexes.

Current treatment options with immunoglobulin G for the individualization of care in patients with primary immunodeficiency disease

Primary antibody deficiencies require lifelong replacement therapy with immunoglobulin (Ig)G to reduce the incidence and severity of infections. Both subcutaneous and intravenous routes of administering IgG can be effective and well tolerated. Treatment regimens can be individualized to provide optimal medical and quality‐of‐life outcomes in infants, children, adults and elderly people. Frequency, dose, route of administration, home or infusion‐centre administration, and the use of self‐ or health‐professional‐administered infusion can be tailored to suit individual patient needs and circumstances. Patient education is needed to understand the disease and the importance of continuous therapy. Both the subcutaneous and intravenous routes have advantages and disadvantages, which should be considered in selecting each patients treatment regimen. The subcutaneous route is attractive to many patients because of a reduced incidence of systemic adverse events, flexibility in scheduling and its comparative ease of administration, at home or in a clinic. Self‐infusion regimens, however, require independence and self‐reliance, good compliance on the part of the patient/parent and the confidence of the physician and the nurse. Intravenous administration in a clinic setting may be more appropriate in patients with reduced manual dexterity, reluctance to self‐administer or a lack of self‐reliance, and intravenous administration at home for those with good venous access who prefer less frequent treatments. Both therapy approaches have been demonstrated to provide protection from infections and improve health‐related quality of life. Data supporting current options in IgG replacement are presented, and considerations in choosing between the two routes of therapy are discussed.

Pharmacokinetics of a new 10% intravenous immunoglobulin in patients receiving replacement therapy for primary immunodeficiency.

Intravenous immunoglobulin (IVIg) is used in treating immunodeficiencies and autoimmune or inflammatory disorders. As manufacturing processes and storage can alter IgG molecules, pharmacokinetic assessments are important for new preparations. Thus, we studied pharmacokinetics of IgPro10, a new 10% liquid IVIg product stabilised with l-proline, in patients with common variable immunodeficiency (CVID) and X-linked agammaglobulinaemia (XLA). Patients received IgPro10 for >or=4 months (median dose of 444mg/kg, at 3- or 4-week intervals). Median total IgG serum concentrations increased from 10.2g/l pre-infusion to 23.2g/l at infusion end. Serum IgG concentrations decreased in a biphasic manner; median terminal half-life was 36.6 days. Median half-lives were 33.2 for IgG(1), 36.3 for IgG(2), 25.9 for IgG(3) and 36.4 days for IgG(4). Specific antibody concentrations (anti-CMV, anti-Hemophilus influenzae type B, anti-tetanus toxoid and anti-Streptococcus pneumoniae) decreased with median half-lives of 22.3-30.5 days. IgPro10 pharmacokinetics were similar in patients with CVID and XLA, although patients with CVID showed higher levels of anti-tetanus and anti-S. pneumoniae antibodies than patients with XLA, suggesting residual specific antibody production. IgPro10 pharmacokinetics fulfilled expectations for and were similar to intact IgG products. Administration of IgPro10 at 3- or 4-week intervals achieved sufficient plasma concentrations of total IgG, IgG subclasses and antibodies specific to important pathogens.

Safety and efficacy of Home-Based Subcutaneous Immunoglobulin G in Elderly Patients with Primary Immunodeficiency Diseases

Abstract Background: Subcutaneous immunoglobulin (SCIG) is as effective as intravenous immunoglobulin (IVIG) in minimizing infections in patients with primary immunodeficiency diseases (PIDD) and is associated with fewer systemic adverse events (AEs). Self-infusion/home-based infusion of SCIG improves quality of life and may lower treatment costs compared with hospital or office-based IVIG therapy, but its suitability has not been assessed in elderly patients (≤ 65 years). Methods: We conducted a retrospective chart review of 47 elderly patients with PIDD in a single clinical practice in the United States to evaluate the practicality, safety, and efficacy of home-based SCIG infusions in elderly patients with PIDD over a 13-month period. Measurements included baseline disease characteristics, previous and current immunoglobulin G (IgG) replacement regimens, self-administered versus assisted SCIG infusions, SCIG infusion parameters, serum IgG levels, infections, and AEs. Results: Forty-seven of 111 elderly patients (42%) treated with IgG in this practice elected to receive SCIG. All 47 patients received SCIG infusions at home; 39 (83.0%) self-infused the medication. Most patients (n = 46; 98%) received weekly infusions, requiring a mean duration of 65.3 minutes. The mean SCIG dose of 103 mg/kg/week resulted in a mean steady-state serum IgG concentration of 1074 mg/dL. Two patients experienced serious infections on SCIG: an exacerbation of chronic obstructive pulmonary disease/bronchitis, and an abscess. There were no serious systemic AEs. Local injection site reactions, including swelling, redness, burning, or itching, were considered mild or moderate by the patients and resolved within 24 hours. No bruising, bleeding, or skin breakdown occurred, despite concomitant anticoagulant or platelet inhibitor treatment in 45% of patients. Two patients discontinued home-based SCIG, but did not continue any IgG treatment. No patient switched from SCIG to another route of IgG treatment. Conclusions: Home-based SCIG is safe and effective in elderly patients with PIDD, most of whom can self-infuse. Infection rates were low, and no AEs or difficulties in administering SCIG occurred that resulted in treatment discontinuation.

Efficacy and safety of a new immunoglobulin G product, Gammaplex(®), in primary immunodeficiency diseases.

This open‐label multi‐centre study evaluated a new intravenous immunoglobulin, Gammaplex®, in the treatment of 50 patients with primary immunodeficiency and significant hypogammglobulinaemia. Patients treated previously with other intravenous immunoglobulins received Gammaplex® on their same infusion schedule for 1 year; 22 were on a 21‐day and 28 on a 28‐day regimen (300–800 mg/kg/infusion). There were no serious, acute bacterial infections, whereas six subjects (12·0%) had at least one such infection in the 6 months before enrolment. Forty subjects (80·0%) had at least one non‐serious infection; the median number of infective episodes per subject per year was 3·07. Antibiotics were taken by 38 subjects therapeutically and prophylactically by 16 at some time. Fewer than half (46·0%) missed any time off work or school because of infection or other illness. Trough immunoglobulin (Ig)G levels were above 6·00 g/l in all subjects at all assessments after 15 weeks with two exceptions. Overall, 21·2% of infusions were associated with an adverse event up to 72 h after infusion. The frequency of adverse events increased with infusion rate. Headache was the most common product‐related adverse event (7·5% of 703 infusions). In conclusion, Gammaplex® is effective in primary immunodeficiency and is well tolerated.

New Frontiers in Subcutaneous Immunoglobulin Treatment

Subcutaneous immunoglobulin (SCIG) treatment provides stable serum immunoglobulin G (IgG) levels, is associated with fewer systemic adverse events than intravenous immunoglobulin (IVIG) treatment, and offers the convenience of home therapy. In clinical practice, IVIG is still used preferentially for initiation of treatment in newly diagnosed patients with primary immunodeficiency (PI) and for immunomodulatory therapy, such as treatment of peripheral neuropathies, when high doses are believed to be necessary. The authors discuss recent experience in using SCIG in place of IVIG in these settings. SCIG has been successfully used for initiation of therapy in previously untreated PI patients. Seventeen of 18 PI patients achieved serum IgG levels ≥5 g/L after the loading phase. Daily treatment was well tolerated and provided opportunities for patient/parent training in self-infusion. SCIG has been used for maintenance therapy in multifocal motor neuropathy (MMN) in three recent clinical trials, with good efficacy and tolerability results. Seven of eight MMN patients maintained serum IgG levels of 14–22 g/L with a mean dose of 272 mg/kg/week, had stable muscle strength, and felt comfortable with self-administration. Four patients with polymyositis or dermatomyositis achieved improvement in serum creatine kinase levels and muscle strength with SCIG therapy. Recent experience with SCIG suggests that traditional concepts of immunoglobulin therapy may be challenged to increase available therapy options. SCIG can be used to achieve high IgG levels within several days in untreated PI patients and to maintain high serum levels, as shown in patients with MMN.

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.

Erratum to: 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 21or 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.