Immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration. ATC Code:
Pharmacology: Pharmacodynamics: Mechanism of Action:
The manufacturing process for Privigen includes the following steps: ethanol precipitation of the IgG plasma fraction, followed by octanoic acid fractionation and incubation at pH 4. Subsequent purification steps comprise depth filtration, chromatography, and a filtration step that can remove particles to a size of 20 nm.
Privigen contains mainly immunoglobulin G (IgG) with a broad spectrum of functionally intact antibodies to infectious agents. Both the Fc and the Fab functions of the IgG molecules are preserved. The ability of the Fab parts to bind antigens was demonstrated with biochemical and biological methods. The Fc function was tested with complement activation and with Fc receptor-mediated leukocyte activation. The inhibition of immune complex-induced complement activation ("scavenging", an anti-inflammatory function of IVIgs) is preserved in Privigen. Privigen does not lead to non-specific activation of the complement system or of prekallikrein.
Privigen contains the immunoglobulin G antibodies present in the normal population. It is prepared from plasma from not fewer than 1,000 donors. The IgG subclass distribution corresponds roughly to that of native human plasma. Adequate doses of Privigen may restore low IgG levels to the normal range.
The mechanism of action in indications other than replacement therapy is not fully elucidated, but includes immunomodulatory effects.
The safety and efficacy of Privigen was investigated in 5 prospective, open, single-arm, multicentre studies carried out in Europe (ITP, PID and CIDP studies) and in the USA (PID study). Further data on safety and efficacy were collected in a prospective, open, single-arm, multicentre extension study with PID patients performed in the USA.
In the pivotal study, 80 patients between 3 and 69 years of age with PID were given a Privigen infusion at a median dose of 200-888 mg/kg bw every 3 to 4 weeks for at most 1 year. With this treatment, constant IgG trough levels were achieved over the whole of the treatment period, the mean concentrations being 8.84 g/l to 10.27 g/l. The incidence of acute, severe bacterial infections (aSBI) was 0.08 per patient per year (the upper 97.5% confidence limit was 0.182).
As in the pivotal study, Privigen dosages were administered in the PID extension study to a total of 55 patients (of which 45 had already been treated in the pivotal study and 10 were newly recruited patients). The results of the pivotal study were confirmed for the average IgG trough levels (9.31 g/l to 11.15 g/l) and the rate of aSBI (0.018 per patient per year with an upper 97.5 % confidence interval of 0.098).
57 patients aged between 15 and 69 years with chronic ITP took part in the ITP study. Their platelet count at the start was 20 x 109
/l. After administration of Privigen at a dose 1 g/kg bw on two consecutive days, the platelet count rose to at least 50 x 109
/l within 7 days of the first infusion in 80.7% of the patients. In 43% of the patients, this increase occurred after just one day, before the second infusion. The mean time until this platelet count was reached was 2.5 days. In patients who responded to the treatment, the platelet count remained ≥50 x 109
/l for a mean period of 15.4 days.
In the second ITP study on patients aged between 18 and 65 years, in 42 subjects (74%) the platelet count increased at least once to ≥50 ×109
/l within 6 days after the first infusion, which was well within the expected range and similar to response rates were reported for other IVIGs in this indication (70%). A second dose in subjects with platelet counts ≥50×109
/l after the first dose provided a relevant additional benefit in terms of higher and longer-lasting increases in platelet counts compared to a single dose. In subjects with platelet counts <50 × 109
/l on day 3 receiving a mandatory second infusion, the lowest median platelet count (8.0×109
/l) was observed already at the baseline. In this group, only 30% of subjects were observed with platelet response after the mandatory second dose. Consequently, it was more difficult to increase platelet counts with one infusion in these subjects.
In the CIDP study, a multicentre open label trial PRIMA (Privigen impact on mobility and autonomy study), patients with CIDP (with or without IVIg pre-treatment) were treated with a starting dose of 2 g/kg bw given over 2-5 days followed by 6 maintenance doses of 1 g/kg bw given over 1-2 days every 3 weeks. Previously treated patients were withdrawn from IVIg before treatment with Privigen until the deterioration of clinical symptoms was confirmed on the basis of the INCAT scale (Inflammatory Neuropathy Cause and Treatment). On the adjusted 10 point INCAT scale an improvement of at least 1-point from baseline to treatment week 25 was observed in 17 / 28 patients (60.7%, 95% confidence interval 42.41, 76.4). Nine patients responded already after receiving the initial induction dose to the treatment and 16 by week 10.
Paediatric population: No differences were seen in the pharmacodynamic properties between adult and paediatric study patients.
Privigen is immediately and completely bioavailable in the recipient's circulation after intravenous administration. It is distributed relatively quickly between plasma and extravascular fluid. Equilibrium between the intravascular and extravascular compartments is reached after approximately 3 to 5 days.
The pharmacokinetic parameters for Privigen were determined in both clinical studies in patients with primary immunodeficiency syndrome (see previously mentioned text). 25 patients (aged 13 to 69 years) in the pivotal study and 13 patients (aged 9 to 59 years) in an extension of this study participated in the pharmacokinetic (PK) assessment (see Table 1 as follows).
Click on icon to see table/diagram/image
In the pivotal study the median half-life of Privigen in primary immunodeficiency patients was 36.6 days and 31.1 days in the extension of this study. The half-life may vary from patient to patient.
IgG and IgG complexes are broken down in the cells of the reticuloendothelial system.
No differences were seen in the pharmacokinetic parameters between adult and paediatric study patients with PID. There are no data on pharmacokinetic properties in paediatric patients with CIDP.
Toxicology: Preclinical data:
The safety of Privigen has been investigated in several preclinical studies with particular reference to the excipient L-proline. L-proline is a physiological, non-essential amino acid. Studies in rats given daily L-proline doses of 1450 mg/kg bw did not show any evidence of teratogenicity or embryotoxicity. Genotoxicity studies of L-proline did not show any pathological findings.
Some published studies pertaining to hyperprolinaemia have shown that long-term, high doses of L-proline have effects on brain development in very young rats. However, in studies where the dosing was designed to reflect the clinical indications for Privigen, no effects on brain development were observed. Further safety-pharmacology studies of L-proline in adult and juvenile rats did not reveal behavioural disorders.
Immunoglobulins are natural components of the human body. Data from animal testing of acute and chronic toxicity and embryofoetal toxicity of immunoglobulins are inconclusive on account of interactions between immunoglobulins from heterogeneous species and the induction of antibodies to heterologous proteins. In local tolerability studies in rabbits in which Privigen was administered intravenously, paravenously, intra-arterially, and subcutaneously, the product was well tolerated.