CUTAQUIG Solution for infusion Ref.[10790] Active ingredients: Human normal immunoglobulin G

CUTAQUIG contains mainly IgG with a broad spectrum of antibodies against various infectious agents reflecting the IgG activity found in the donor population. CUTAQUIG which is prepared from pooled material from not less than 1000 donors, has an IgG subclass distribution similar to that of native human plasma. Adequate doses of Immune Globulin Subcutaneous (Human) (IGSC) can restore an abnormally low IgG level to the normal range. Standard pharmacodynamic studies were not performed.

A pharmacokinetic (PK) sub-study was conducted in 18 adult subjects who were enrolled in the 61-subject safety and efficacy study. Blood samples for PK study were collected prior to switching to CUTAQUIG (IGIV profile: PK_IV), after the 11^th infusion of CUTAQUIG (first SC profile: PK_SC1) and after the 28th infusion of CUTAQUIG (second SC profile: PK_SC2). The objective of the PK sub-study was to compare the AUCs following the IV and SC administration. At steady state, the geometric mean of the ratio (SC2:IV) was 1.02, (90% CI: 0.96, 1.08), indicating comparable exposure between IGSC and IGIV treatment (standardized to a 7-day period). Dose conversion factors from IGIV to IGSC of individual subjects ranged from 1.24 to 1.89 (mean: 1.40).

Serum IgG and IgG subclass trough levels were nearly constant during the IGSC phase of the study, with higher mean levels after SC treatment compared with those following IGIV. At the end of the IGIV period, trough levels ranged from 5.8 g/L to 13.9 g/L. Over the entire IGSC treatment period individual trough levels of total IgG ranged between 6.1 g/L to 24.0 g/L.

Table 6 summarizes the Key PK parameters for CUTAQUIG.

Table 6. Key Pharmacokinetic Parameters for CUTAQUIG and IGIV in Adults:

^# T_max is presented as Median (range)
^* standardized to a 7-day period
⁺ apparent clearance (CL/F) for CUTAQUIG (F = bioavailability)

No animal studies were conducted with CUTAQUIG to assess carcinogenesis, mutagenesis or impairment of fertility.

Safety of CUTAQUIG has been demonstrated in several standard nonclinical toxicology studies (local tolerance in rabbits, cardiovascular and respiratory effects in dogs, thrombogenic potential in rabbits).

The product given subcutaneously to CD1 mice inoculated with Streptococcus pneumoniae showed a dose related improvement in survival.

TNBP and Octoxynol may be found in CUTAQUIG in trace amounts. In animals and in vitro studies, these compounds were not genotoxic and did not have mutagenic properties. They did not show teratogenic effects when administered to pregnant rabbits and rats during organogenesis.

The study was a prospective, open-label, non-controlled, single-arm, multicenter study to evaluate the pharmacokinetics (PK), efficacy, tolerability and safety of subcutaneous human immunoglobulin (CUTAQUIG) in subjects with primary humoral immunodeficiency (PI).

The study was conducted in 61 subjects (38 adult and 23 pediatric subjects <16 years of age) who received weekly SC infusions with CUTAQUIG during a 12-week wash-in/wash-out period followed by a 12-month efficacy period during which efficacy, pharmacokinetics, safety, tolerability, and quality of life (QoL) parameters of CUTAQUIG were evaluated. At the time of data analysis, 47 subjects (35 adults; 12 pediatric subjects) had completed the study, 8 pediatric subjects were continuing in the study, and 6 subjects (3 adults; 3 pediatric subjects) had discontinued the study prematurely at the time of data analysis.

During the efficacy period the mean weekly dose was 175 mg/kg BW, with individual doses ranging from 60 to 390 mg/kg BW. The median duration of infusion per week was 1.5 hours.

All enrolled subjects (n=61) were included in the Safety Analysis Set and the Full Analysis Set (FAS). Four subjects were excluded from the Per-Protocol (PP) Set because they terminated early before the start of the primary treatment period.

Overall, 33 female subjects and 28 male subjects participated in this study. The youngest subject enrolled in the study was 2 years old and the oldest was 73 years old. The mean age in the adult group (16–75 yrs) was 46.6 years. Reported race was white for all but one subject, and all subjects were of not Hispanic/Latino ethnicity.

The main objective of the study was to assess the efficacy of CUTAQUIG in preventing serious bacterial infections (SBI defined as bacteraemia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia and visceral abscess). This endpoint was considered successful if the upper bound of the 99% confidence interval for the rate of SBIs was <1.0 per subject-year of follow up. This criterion was met, as no SBIs were reported at any time during the study.

Other endpoints of the study included, but were not limited to: the number of episodes of any other infections, along with type and severity of infection and time to resolution; number of days of use and annual rate of antibiotics; absence and number of days of absence from work/school/kindergarten/day care; and hospitalisations due to infections and number of days and annual rate of hospitalisation.

Efficacy results are summarized in Table 7.

Table 7. Summary of efficacy results (FAS set):

^*Defined as bacterial pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess.
^# Upper one-sided 99% confidence limit: 0.08.