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Keywords:

  • clinical trial;
  • Flebogamma® 5% DIF;
  • intravenous immunoglobin;
  • primary immunodeficiency disease

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. References

The development of effective, safe, liquid intravenous immunoglobulins (IVIG) preparations has represented a major therapeutic advancement in the treatment of patients with antibody deficiencies. Flebogamma® 5% was the first liquid IVIG licensed in Europe that has been widely used in the treatment of immunodeficiency diseases. It has been proven to have an excellent efficacy and safety profile. Flebogamma® 5% dual inactivation and filtration (DIF) is a newly developed IVIG preparation that shares formulation characteristics and identical biochemical and stability profiles with Flebogamma® 5%. In addition to pasteurization, already performed in Flebogamma® 5%, solvent-detergent treatment and sequential nanofiltration through filters with pore sizes of 35 nm followed by 20 nm have been added to further enhance the pathogen safety margin. The purpose of this study was to evaluate the efficacy, safety, and pharmacokinetics of Flebogamma® 5% DIF for immunoglobulin replacement therapy in patients with primary immunodeficiency diseases (PID). Flebogamma® 5% DIF was administered at seven clinical sites to 46 subjects with well-defined primary immunodeficiency diseases at a dose of 300–600 mg/kg every 21–28 days for 12 months. The serious bacterial infection rate was 0.021/subject/year. The incidence of adverse events considered potentially related to Flebogamma® 5% DIF during or within 72 h after completing an infusion was approximately 10%. The half-life in serum of the administered IgG was around 31 days. In summary, Flebogamma® 5% DIF is efficacious and safe, has good pharmacokinetic properties, is well-tolerated and maintains the profile of Flebogamma® 5% for the treatment of patients with primary humoral immune deficiency diseases.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. References

Gammaglobulins were first introduced as therapeutic modalities in 1952, using the intramuscular route to treat patients with hypogammaglobulinaemia. The first intravenous preparation of gammaglobulin was available for the clinical treatment of patients with primary immune deficiency disease (PID) in 1981 [1,2]. The first intravenous immunoglobulins (IVIG) were proteolytic enzyme-treated immunoglobulins that had the following advantages over the intramuscular gammaglobulin preparation; they: (i) could be administered in large volumes without painful intramuscular injections, (ii) rapidly achieve physiological concentrations of serum immunoglobulin (Ig)G and (iii) had similar pharmacokinetic features as native IgG [3,4]. Subsequently, newer, highly purified IVIGs became available for clinical use, but they were still lyophilized preparations which had issues of tolerability, and difficulty in reconstitution/preparation for administration. Until the mid-1990s, the principle viral safety approach for IVIGs was cold ethanol treatment. However, in 1984, there were more than 100 reported cases in the United States of acute hepatitis C in recipients of IVIG therapy, especially in patients with PID and those individuals receiving IVIG therapy as adjunct therapy following bone marrow transplantation[5–7]. This crisis prompted the Food and Drug Administration (FDA) and manufacturers to develop new anti-viral processes and screening techniques for donors to ensure greater safety from viral pathogens [8]. Besides rigorous donor screening and plasma testing by sensitive nucleic acid testing [polymerase chain reaction (PCR)], additional viral inactivation steps during the manufacturing processes for IVIG were implemented. During the latter part of the 1990s, two common processes were adopted, either solvent–detergent treatment or pasteurization, as viral removal steps which were effective in destroying lipid-enveloped viruses. In aggregate, these new anti-viral steps led to a potential removal of 10–20 (depending on the virus) log10 reduction of viral activity [4]. However, one potential pathogen that was still of concern was transmissible spongiform encephalopathy prions, which could lead to a fatal degenerative disease of the brain [9]. Although there are many tissue regulations that prevented the transmission of the sporadic type of Jakob–Creutzfeldt disease (CJD), there was concern about a new-variant CJD (vCJD) prion that was emerging as a potential pathogen in the United Kingdom and in some parts of Europe [10]. The IVIG manufacturers recognized that this vCJD potential pathogen was a problem and initiated steps during the manufacturing process to address this issue employing depth filtration and nanofiltration.

Flebogamma® 5% was the first liquid IVIG licensed in Europe, and licensed subsequently in the United States, that has been used widely in the treatment of patients with PID. Flebogamma® 5% dual inactivation and filtration (DIF) is a newly developed IVIG preparation [11] (manufactured by Instituto Grifols S.A., Barcelona, Spain) that shares formulation characteristics and identical biochemical and stability profiles with Flebogamma® 5%. In addition to pasteurization, solvent–detergent treatment and sequential nanofiltration through filters with pore sizes of 35 nm followed by 20 nm was added during the manufacturing process of the Flebogamma® DIF to enhance pathogen safety further.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. References

Product description

Flebogamma® 5% DIF is a liquid immunoglobulin containing 5 g of human IgG immunoglobulin in 100 ml. The IgG content is = 99%, with more than 99·9% being monomeric and dimeric forms. The Fc region is intact and functional. IgA is present in only trace amounts (< 50 µg/ml). Flebogamma® 5% DIF contains = 3 mg/ml polyethylene glycol and 50 mg/ml of D-sorbitol as a stabilizer. There are no preservatives. The pH is between 5 and 6. There is no added sucrose, maltose or sodium chloride. The osmolality is in the physiological range of 240–370 mOsm/l. Flebogamma® 5% DIF can be stored at room temperature (2 years between 2 and 25°C) [12].

Anti-viral data

Three specific viral elimination steps were validated: pasteurization (60°C for 10 h), solvent–detergent treatment and double sequential nanofiltration (planova-35 nm and 20 nm filters). Three additional anti-virals are also part of the manufacturing process: ethanol fractionation, polyethylene glycol (PEG) precipitation and pH4 treatment. Viruses of different physiochemical properties including human immune deficiency virus (HIV), herpesvirus, hepatitis C-like virus, hepatitis A and B19 virus models were studied in laboratory-scale experiments [13,14]. In addition, West Nile virus was investigated as an emerging virus. Each virus was spiked into the scaled model of the production process at each of the steps to determine viral removal activity at the end of the each step. As shown in Fig. 1, all viruses tested were inactivated effectively and/or removed. More than 4 log10 to more than 6 log10 of virus were eliminated in each step. The overall elimination ranged from 15·04 log10 to = 20 log10, depending on the type of virus. West Nile virus, as a model for a lipid-enveloped RNA virus, was removed effectively by these processes.

image

Figure 1. Viral safety reduction factors and overall reduction capacity (log10/ml). HIV: human immunodeficiency virus; WNV: West Nile virus. Model viruses: pseudorabies virus for hepatitis B virus (HBV) and herpesvirus (env. DNA); bovine viral diarrhoea virus for hepatitis C virus (env. RNA); encephalomyocarditis virus for hepatitis A virus (non-env. RNA); and porcine parvovirus for B19 virus (non-env. DNA virus). *Overall viral reduction capacity.

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Clinical study methods

Fifty subjects, age 15 years and older, with well-defined PID, e.g. common variable immunodeficiency disease, X-linked agammaglobulinaemia and autosomal forms of agammaglobulinaemia, and hyper-IgM syndrome patients, were enrolled from seven investigative sites in the United States [11]; 96% of the patients were Caucasian, 63% were male and 37% were female. The mean age was 38·9 years (range 15–75). The dosing interval was 3 weeks in 13 patients (28%) and 4 weeks in 33 patients (72%). The study time-line was for 12 months. All subjects had been receiving IVIG replacement therapy at a dose that had not changed by more than 50% of the mean dose before entrance into the study, and had maintained a trough level of at least 300 mg/dl above the serum IgG level recorded before initiation of any immunoglobulin treatment. Flebogamma® 5% DIF was administered at a dose of 300–600 mg/kg per infusion every 21 or 28 days matched to each subject's prestudy infusion schedule. A subset of 20 subjects was included in a pharmacokinetic (PK) analysis for total IgG, IgG subclasses and antibodies to tetanus and Streptococcus pneumoniae. The primary end-point was the number of serious bacterial infections (e.g. bacterial pneumonia, bacteraemia or sepsis, osteomyelitis or septic arthritis, visceral abscesses or bacterial meningitis) per patient in 12 months of observation on the IVIG replacement therapy. For safety analysis, the number and percentage of infusions with at least one adverse event considered at least possibly related to the infusion within 72 h was determined. For the patients in the PK study, the Cmax, Tmax, area under the curve (AUC 0–28 days), clearance and half-life (t1/2) were determined. The total IgG and IgG subclasses were measured and the results plotted in mg/dl on a log scale against time. Trough serum IgG levels were determined on blood drawn just before each infusion.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. References

Forty-six patients (94·1%) completed the study, and four patients (5·9%) withdrew from the study; none due to an adverse event related to the study drug. The mean number of days in the study was 383 (range: 181–484); the mean dose per infusion was 449 mg/kg. All analyses were performed on the intent-to-treat population defined as patients enrolled in the study who received at least one infusion of Flebogamma® 5% DIF.

One subject experienced one serious bacterial infection, an episode of bacterial pneumonia. There were no other subjects who had any other serious bacterial infection for inclusion in the primary end-point. A calculated rate of serious bacterial infection (SBI) per patient per year was 0·021. Secondary end-points are shown in Figs 2 and 3. Although 71·7% of patients had other infectious episodes, all non-serious bacterial infections, the mean number of these infectious episodes per subject per year was low: 1·96. This correlates well with the very low number of days per subject per year of therapeutic parenteral antibiotic use. Therefore, most of these other infectious episodes were of a minor degree, which necessitated only oral antibiotic use. Corresponding with these data is the low number of days in the hospital and unscheduled visits to a physician or emergency room. The number of days of normal activities missed and days of work or school missed compares favourably with the statistics for the typical normal US worker.

image

Figure 2. Secondary efficacy end-points.

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image

Figure 3. Secondary efficacy end-points – infections and antibiotic use. White bars: mean number of events, days or visits per subject per year. Dark bars: % of subjects.

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The PK analysis of the total serum IgG levels, IgG subclass levels and the IgG antibody levels to specific antigens did not appear to give evidence of excessive catabolism in the study subjects. For patients on the 21-day infusion schedule, the mean estimated serum t1/2 for all four IgG subclasses ranged between 26 and 33 days. For patients on the 28-day infusion schedule, the mean estimated serum t1/2 for the four IgG subclasses ranged between 29 and 40 days.

Adverse events

A total of 709 infusions were administered. Most adverse events were graded from mild to moderate in intensity. The most common infusion-related adverse events were headache, fever, injection site reactions, diarrhoea and rigors. None of these adverse events resulted in any sequelae. Only one infusion-related adverse event was considered severe, in a patient developing urticaria after the seventh infusion.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. References

Flebogamma® 5% DIF represents an advance in IVIG products with its additional viral safely steps. These extra safety steps did not reduce the tolerability of the product in the PID patients in this study. The pharmacokinetic parameters of this study are similar to those seen with other IVIG products [15–17]. Safety from the transmission of a potential pathogen, particularly viruses, is the primary question that clinical immunologists are asked from their patients with PID. Although one can never make guarantees in medicine, it is desirable to include as many safety steps as possible to increase the margin of safety from the potential transmission of a viral pathogen. In 1994 clinical immunologists observed the unfortunate circumstance of a totally unanticipated transmission of hepatitis C by an IVIG product [6]. Donor selection, donor processing, manufacturing processes and the inclusion of viral inactivation and removal steps have been major advances with IVIG products since the mid-1990s [4]. Thus, demonstrating the efficacy and safety in PID patients in this clinical trial of Flebogamma® 5% DIF is a major advance in the treatment of these patients. Most of the previous preparations of IVIG products utilized several steps during the manufacturing process to ensure viral safety. Flebogamma® 5% DIF has additional improvements in the manufacturing process with the addition of more viral inactivation and viral removal steps [13]. These steps include pasteurization, solvent–detergent treatment and two sequential nanofiltrations through 35 and 20 nm pore size nanofilters. By utilizing the smallest pore size filter (20 nm), this filtering process has been shown to be effective in removing more than 4 log10 virus of a small size (porcine parvovirus) and potentially prion particles [14].

Another concern that emerged during the late 1990s was the potential transmission of vCJD producing transmissible spongiform encephalopathy (TSE) [9]. Unlike classic CJD, which is located in the central nervous system, vCJD can be found in lymphatic systems and non-neural tissues, although at lower concentrations [10]. Although there has never been a documented case of transmission of CJD with plasma products or IVIG, manufacturers became extremely interested in introducing new processes to ensure the removal of any possible vCJD contaminant. The manufacturers studied the ability of the production process to remove experimental TSE agents [14]. In a laboratory model, hamster scrapie strain prion was spiked into an intermediate process IVIG material to determine if this prion could be removed by the purification process; namely, PEG and nanofiltration. Of interest, PEG precipitation removed > 4·08–5·14 log10 /ml, and the nanofiltration process removed > 3·3 log10/ml. No residual agent was detected after these removal steps. The overall clearance of prion from the entire process was = 18·4 log10/ml. Employing a laboratory model of TSE prion infectants and the additional viral removal steps indicates that low levels of vCJD agent, if present in the plasma, would be eliminated in the final Flebogamma® 5% DIF product by the purification and viral removal steps [14].

Only one subject enrolled in the study experienced one serious infection, which resulted in an overall serious infection rate of 0·021 infections/subject/year. This compares very favourably with other recent IVIG studies of other products [15–17]. Similarly, the observed types, frequency and severity of adverse events that were potentially related to Flebogamma® 5% DIF indicated good tolerability. In addition, secondary efficacy end-point data also showed that Flebogamma® 5% DIF was very well tolerated and indicated efficacy comparable to the original Flebogamma® 5%, as well as other IVIG products [11].

In summary, this study shows that Flebogamma® 5% DIF administered to patients with PID has an excellent profile of efficacy, safety and pharmacokinetics.

Conflicts of interest

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. References

M. Ballow is the site investigator of a phase III clinical trial.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. References
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    Barandun S, Isliker H. Development of immunoglobulin preparations for intravenous use. Vox Sang 1986; 51:15760.
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    Buckley RH, Schiff RI. The use of intravenous immune globulin in immunodeficiency diseases. N Engl J Med 1991; 325:1107.
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    Ballow M, ed. IVIG therapy today. Totowa, NJ: Humana Press, 1992.
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    Ballow M. Intravenous immunoglobulins: clinical experience and viral safety. J Am Pharm Assoc 2002; 42:44959.
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    Anonymous. Outbreak of hepatitis C associated with intravenous immunoglobulin administration – United States, October 1993–June 1994. MMWR 1994; 43:5059.
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    Bjoro K, Froland SS, Yun Z, Samdal HH, Haaland T. Hepatitis C infection in patients with primary hypogammaglobulinemia after treatment with contaminated immune globulin. N Engl J Med 1994; 331:160711.
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    Ballow M. Safety of IVIG therapy and infusion-related adverse events. Immunol Res 2007; 38:12232.
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    Johnson RT, Gibbs CJ Jr. Creutzfeldt–Jakob disease and related transmissible spongiform encephalopathies. N Engl J Med 1998; 339:19942004.
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    Berger M. A multicenter, prospective, open label, historically controlled clinical trial to evaluate efficacy and safety in primary immunodeficiency diseases (PID) patients of Flebogamma® 5% DIF, the next generation of Flebogamma®. J Clin Immunol 2007; 27:62833.
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    Lopez M, Ristol P, Jorquera J. Characterisation of a new intravenous immunoglobulin. J Allergy Clin Immunol 2007; 119:S2623.
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    Díez J, Biescas H, Caballero S, Gajardo R, Jorquera J. Capacity of human intravenous immunoglobulin (IVIG31) production process to eliminate an experimental TSE-model agent. J Allergy Clin Immunol 2007; 119:S263.
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    Berger M, Cunningham-Rundles C, Bonilla FA et al. Carimune NF liquid is a safe and effective immunoglobulin replacement therapy in patients with primary immunodeficiency diseases. J Clin Immunol 2007; 27:5039.
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    Church JS, Leibl H, Stein MR et al. Efficacy, safety and tolerability of a new 10% liquid intravenous immune globulin [(IVIG 10%] in patients with primary immunodeficiency. J Clin Immunol 2006; 26:38895.
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    Ochs HD, Pinciaro PJ. Octagam®5%, an intravenous IgG product, is efficacious and well tolerated in subjects with primary immunodeficiency diseases. J Clin Immunol 2004; 24:30914.