Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration, ATC code: J06BA02.
Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents.

Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1000 donors. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range and thus help against infections.
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 evaluated in 7 prospective, open-label, single-arm, multicenter studies performed in Europe (ITP, PID and CIDP studies) , Japan (PID and CIDP studies), and the US (PID and CIDP studies).
Additional safety data were collected in a Post-Authorization Safety Study (PASS), an observational multicentre trial in patients with various immunological conditions performed in the US.

PID
The PID pivotal study included a total of 80 patients aged between 3 and 69 years old. 19 children (3 to 11 years), 12 adolescents (12 to 16 years) and 49 adults were treated with Privigen over 12 months. 1038 infusions were administered, 272 (in 16 patients) in the 3-week schedule and 766 (in 64 patients) in the 4-week schedule. The median doses administered for the 3-week and 4-week treatment schedules were almost identical to each other (428.3 vs. 440.6 mg IgG/kg bw).The PID extension study included a total of 55 patients aged between 4 and 81 years old. 13 children (3 to 11 years), 8 adolescents (12 to 15 years) and 34 adults were treated with Privigen over 29 months.
771 infusions were administered and the median dose administered was 492.3 mg IgG/kg bw.

ITP
In the ITP pivotal study, in total 57 patients aged between 15 and 69 years old were treated with 2 infusions of Privigen for a total of 114 infusions. The scheduled dose of 1 g/kg bw per infusion was closely adhered to in all patients (median 2 g IgG/kg bw).

In the second ITP study, 57 patients with ITP (baseline platelet counts ≤ 30×109/l) aged between 18 and 65 years were treated with Privigen at 1 g/kg bw. On day 3 patients could receive a second dose of 1 g/kg bw, for patients with a platelet count of < 50×109/l on day 3 this second dose was mandatory.

Overall, 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. 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 after the first dose, 30% showed a platelet response of ≥ 50×109 /l after the mandatory second dose.

CIDP
In the first CIDP study, a prospective multicenter open label trial (Privigen impact on mobility and autonomy PRIMA study), 28 patients (13 subjects who have previously received IVIG and 15 subjects not) were treated with a Privigen loading dose of 2g/kg bw given over 2-5 days followed by 6 maintenance doses of 1g/kg bw over 1-2 days every three weeks. Previously treated patients were withdrawn from IVIG until confirmed deterioration before start of Privigen. On the adjusted 10 point INCAT (Inflammatory Neuropathy Cause and Treatment) scale a clinically meaningful improvement of at least 1-point from baseline to treatment week 25 was observed in 17 out of 28 patients. The INCAT responder rate was 60.7% (95% confidence interval [42.41, 76.4]). 9 patients responded after receiving the initial induction dose by week 4, 16 patients responded by week 10.

Muscle strength as measured by the MRC (Medical Research Council) Score improved in all patients by 6.9 points (95% confidence interval [4.11, 9.75], in previously treated patients by 6.1 points (95% confidence interval [2.72, 9.44]) and in untreated patients by 7.7 points (95% confidence interval [2.89, 12.44]). The MRC responder rate, an increase of at least 3 points, was 84.8% which was similar in previously treated (81.5% [58.95, 100.00]) and untreated (86.7% [69.46, 100.00]) patients.
In patients defined as INCAT non-responders, muscle strength improved by 5.5 points (95% confidence interval [0.6, 10.2]) as compared to INCAT responders (7.4 points (95% confidence interval [4.0, 11.7])).

In a second prospective, multicenter randomized, placebo-controlled clinical study (Polyneuropathy and Treatment with Hizentra, PATH trial), 207 subjects with CIDP were treated with Privigen in the prerandomization phase of the study. Subjects all with IVIg pretreatment of at least 8 weeks and with an IVIg-dependence confirmed by clinically evident deterioration during an IVIg withdrawal phase of up to 12 weeks, received a Privigen loading dose of 2 g/kg bw followed by up to 4 Privigen maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks.
Following clinical deterioration during IVIg withdrawal, clinical improvement of CIDP was primarily defined by a decrease of ≥ 1 point at the adjusted INCAT score. Additional measures of CIDP improvement were an increase in R-ODS (Rasch-built Overall Disability Scale) score of ≥ 4 points, a mean grip strength increase of ≥ 8 kPa, or an MRC sum score increase of ≥ 3 points.
Overall, 91 % of subjects (188 patients) showed improvement in at least one of the criteria above by week 13.
By adjusted INCAT score, the responder rate by week 13 was 72.9 % (151/207 patients), with 149 patients responding already by week 10. A total of 43 of the 207 patients achieved a better CIDP status as assessed by the adjusted INCAT score compared to their CIDP status at study entry.

The mean improvement at the end of the treatment period compared to reference visit was 1.4 points in the PRIMA (1.8 points in IVIg pretreated subjects) and 1.2 points in PATH study.

In PRIMA, the percentage of responders in the overall Medical Research Council (MRC) score (defined as an increase by ≥ 3 points) was 85% (87% in the IVIg-untreated and 82% in IVIg- pretreated) and 57 % in PATH. The overall median time to first MRC sum score response in PRIMA was 6 weeks (6 weeks in the IVIg-untreated and 3 weeks in the IVIg-pretreated) and 9.3 weeks in PATH. MRC sum score in PRIMA improved by 6.9 points (7.7 points for IVIg- untreated and 6.1 points for IVIg-pretreated) and by 3.6 points in PATH.
The grip strength of the dominant hand improved by 14.1 kPa (17.0 kPa in IVIg-untreated and 10.8 kPa in IVIg pretreated subjects) in the PRIMA study, while in PATH the grip strength of the dominant hand improved by 12.2 kPa. For the non dominant hand similar results were observed in both PRIMA and PATH trials.

The efficacy and safety profile in the PRIMA and the PATH study in CIDP patients were overall comparable.

Post-Authorisation Safety Study (PASS)
In an observational hospital-based cohort Post-Authorisation Safety Study (PASS), the risk of haemolytic anaemia following Privigen therapy was evaluated in patients with various immunological conditions from 1 January 2008 to 30 April 2019. The risk of haemolytic anaemia was assessed prior (baseline) and after the implementation of a risk minimisation measure, the introduction of the Immunoaffinity Chromatography (IAC) step in the Privigen manufacturing process. Probable cases of haemolytic anaemia were defined by an ICD-9 or ICD-10 hospital discharge code specific for haemolytic anaemia. (Possible cases of haemolytic anaemia consisted of an unspecified transfusion reaction identified via ICD-9 or ICD-10 discharge codes or via review of hospital charge descriptions in temporal association with a haptoglobin, a direct antiglobulin test or indirect antiglobulin performed in the workup of haemolytic anaemia).

A statistically significant rate reduction of 89% of haemolytic anaemia (based on an incidence rate ratio of 0.11; adjusted for in-/outpatient setting, age, sex, Privigen dose and indication for Privigen use; one-sided p-value <0.01) was observed after implementation of the IAC step compared to baseline:

Baseline                         IAC

Periodɸ                                                          1. January 2008-                1. October 2016- 
31. December 2012                 30. April 2019

Median anti-A titers£                                                    1:32                           1:8 
Median anti-B titers£                                                    1:16                           1:4 
Probable haemolytic anaemiaα cases                                        47                             4 
Patient number (n)                                                     n=9439                         n=7759 
Crude incidence rate of probable haemolytic                              0.74                           0.08 anaemia α per 10.000 patient-days at risk
95% CI&: 0.54-0.98               95% CI: 0.02-0.20

Incidence rate reduction of probable                                       -                           89% haemolytic anaemia α versus baseline

Adjustedꝣ incidence rate ratio for haemolytic                              -                            0.11 anaemia versus baseline
95% CI: 0.04-0.31,
 one-sided p-value: <0.01

ɸ The exclusion of human blood plasma donors with high anti-A titres performed between 1. October 2013 and 31. December 
2015 as the initial risk minimisation measure for haemolytic anaemia indicated a 38% reduction in probable haemolytic anaemia incidence versus baseline and was subsequently replaced by the IAC step in the Privigen manufacturing process, as provided above.
£   Median isoagglutinin titers measured by direct testing method according to Ph.Eur α Probable haemolytic anaemia case: defined by an ICD-9 or ICD-10 hospital discharge code specific for haemolytic anaemia and the occurrence during the time interval from the first infusion up to 30 days after the last infusion, if >1 Privigen infusions were administered
& Confidence    interval
ꝣ   Adjusted for: in-/outpatient setting, age, sex, Privigen dose and indication for Privigen use The reduction in probable haemolytic anaemia incidence rate after IAC implementation versus baseline was especially pronounced in patients treated with Privigen doses ≥0.75 g/kg bw.

Additionally, 28 paediatric patients with CIDP <18 years of age were identified throughout the entire study period from 1 January 2008 to 30 April 2019. No paediatric patients with CIDP given a total of 486 Privigen administrations experienced haemolytic anaemia, AMS, acute renal failure, severe anaphylactic reaction or a thromboembolic event. Two patients experienced a moderate anaphylactic reaction, equating to 0.4% of all Privigen administrations.

Paediatric population
No differences were observed in the pharmacodynamic properties and safety profile between adult and paediatric study patients.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
Human normal immunoglobulin is immediately and completely bioavailable in the recipient’s circulation after intravenous administration.

Distribution
It is distributed relatively rapidly between plasma and extravascular fluid, after approximately 3- 5 days equilibrium is reached between the intra- and extravascular compartments.

Elimination
IgG and IgG complexes are broken down in the cells of the reticuloendothelial system. The half- life may vary from patient to patient. The pharmacokinetic parameters for Privigen were determined in a clinical study in PID patients (see section 5.1). 25 patients (aged 13 - 69 years) participated in the pharmacokinetic (PK) assessment. In this study, the median half-life of Privigen in PID patients was 36.6 days. In an extension of this study, 13 PID patients (aged 3-65 years) participated in a PK sub-study. The results of this study show the median half-life of Privigen to be 31.1 days (see table below).

Pharmacokinetic parameters of Privigen in PID patients

Parameter                       Pivotal study (N=25)         Extension study (N=13) ZLB03_002CR                   ZLB05_006CR
Median (range)                Median (range)

Cmax (peak , g/l)                   23.4 (10.4-34.6)             26.3 (20.9-32.9) Cmin (trough , g/l)                  10.2 (5.8-14.7)          12.3 (10.4-18.8) (3-week schedule)

9.4 (7.3-13.2) (4-week schedule) t½ (days)                           36.6 (20.6-96.6)             31.1 (14.6-43.6) Cmax , maximum serum concentration; Cmin , trough (minimum level) serum concentration; t½ , elimination half-life


Paediatric population
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.