CUVITRU Solution for injection Ref.[27466] Active ingredients: Human normal immunoglobulin G

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 has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma.

Adequate doses of CUVITRU may restore abnormally low immunoglobulin G levels to the normal range.

Pharmacokinetic (PK) parameters of subcutaneously administered CUVITRU were evaluated in 60 subjects with primary immunodeficiency (PI) during a clinical study in North America [See Clinical Studies (14)] Subjects were treated intravenously for 13 weeks with a comparator product [GAMMAGARD LIQUID, Immune Globulin (Human), 10%] and then switched to weekly subcutaneous CUVITRU infusions. Initially, subjects were treated for up to 12 to 16 weeks at a subcutaneous dose that was 145% of the intravenous dose. A comparison of the area under the curve (AUC) for subcutaneous versus intravenous infusions was performed on 15 subjects aged 12 years and older. Subsequently, all subjects were treated with this dose for 12 weeks after which the dose was individualized for all subjects using the trough IgG levels, as described below. After approximately 4 months treatment at this subcutaneous dose, a PK evaluation was conducted on all subjects.

At this dose adjustment, the geometric mean ratio of the AUC for subcutaneous CUVITRU versus intravenous administration immune globulin 10% was 109%. The peak IgG level occurred at a geometric mean of 79 hours after subcutaneous CUVITRU administration.

In part 4 of the study, pharmacokinetic parameters for CUVITRU were assessed for 60 subjects aged 2 years and older. The pharmacokinetic parameters of CUVITRU administered subcutaneously are shown in Table 8. The median peak IgG levels were lower (1809 mg/dL) during subcutaneous treatment with CUVITRU compared to IGIV 10% administration (2602 mg/dL for 3 week intervals and 2521 mg/dL for 4 week intervals), consistent with the lower weekly dose compared with the dose administered every 3 or 4 weeks intravenously. In contrast, the geometric mean trough levels were higher with CUVITRU (1474 mg/dL), compared with those when given intravenously (1158 mg/dL for 3 week intervals and 1019 mg/dL for 4 week intervals), a result of both higher monthly dose and more frequent dosing. Weekly subcutaneous administration resulted in relatively stable steady-state serum IgG levels compared with IGIV administered at 3 to 4 week intervals. Pharmacokinetic parameters for CUVITRU did not significantly differ between age groups. The pharmacokinetic parameters of CUVITRU for the different age groups are shown in Table 9.

Table 8. Pharmacokinetic Parameters:

Table 9. Pharmacokinetic Parameters by Age Group:

No animal studies were conducted to evaluate the carcinogenic or mutagenic effects of CUVITRU or its effects on fertility.

Animal studies were conducted to evaluate possible toxicity of CUVITRU.

In a local tolerance study in mini-pigs, 50 mL of CUVITRU were administered subcutaneously to anesthetized mini-pigs. Subcutaneous administration of CUVITRU was well tolerated in this study.

In local tolerance studies in rabbits, mild to moderate inflammatory reactions were observed locally after subcutaneous administration of 2.5 mL/kg of CUVITRU. These reactions are considered to be a consequence of the animals' immune response to the human IgG preparation and thus model specific and of minor relevance for the assessment of clinical local tolerability.

North America Study

A prospective, open-label, non-controlled, multi-center clinical study was conducted in North America to determine the efficacy, tolerability and PK of CUVITRU in 77 adult and pediatric subjects with PI. Efficacy was determined in 53 adults aged 16 years or older, 6 adolescents aged 12 to <16 years, and 15 children aged 2 to <12 years. CUVITRU was administered to 74 subjects with a mean dose of 222 mg/kg/week ± 71 mg/kg/week for a median treatment duration of 380.5 days (range: 30 – 629 days) and a mean (± SD) of 413.1 ± 116.5 days. The median duration of treatment did not vary significantly between age groups. The total exposure to CUVITRU was 83.70 subject-years and 4327 infusions.

Initially subjects received immune globulin 10% intravenously (IGIV) every 3 or 4 weeks at a monthly dose equivalent to that received prior to the study for 13 weeks. The objective of part 1 of the study was to determine AUC_IV of total IgG following IGIV administration. In part 2 of the study, subjects received CUVITRU subcutaneously at an adjusted dose of 145% of the IGIV dose. The objective of part 2 was to determine AUC_SC of total IgG following weekly CUVITRU administration and to calculate an adjusted dose to be used in part 3. The dose adjustment factor was assesed to be 145% of the IGIV 10% dose by comparing the AUC_SC with the AUC_IV,0-τ (standardized to 1 week) of part 1 for the first 15 subjects that completed part 2. Subjects who completed part 1 after this assessment was available, went directly into part 3. In part 3 of the study, subjects were treated weekly for 12 weeks at the adjusted dose. The ratio of serum IgG trough levels for part 1 and 3 were compared to the expected trough level determined in part 2 to establish the individually adapted dose for part 4 for each subject. In part 4 of the study, subjects were infused weekly with CUVITRU at the individually adapted dose for 40 weeks. During part 4, an additional pharmacokinetic assessment was performed. Follow-up with the subject either by diary system or by investigator occurred 3-5 days after every infusion in each study part to document adverse events. Adverse events were assessed using the subject’s eDiary – all subjects received eDiary tablet to continuously record home treatments, adverse events, and additional information as they occurred.

One acute serious bacterial infection (ASBI) of pneumonia was reported in a 78-year old subject who had specific antibody deficiency and allergic bronchopulmonary aspergillosis while receiving CUVITRU. The point estimate of the annualized rate of ASBIs was 0.012 (upper limit of 99% CI: 0.024) during CUVITRU treatment. This annual rate of ASBIs was lower than 1.0 ASBIs /year (p<0.0001), the threshold specified as providing substantial evidence of efficacy.

The summary of infections and associated events for subjects during subcutaneous treatment with CUVITRU is summarized in Table 10.

Table 10. Summary of Infections and Associated Events:

In the clinical study, across all age groups, the median maximum infusion rate was 60 mL/hr/site. This infusion rate was achieved in 57.3% (2480/4327) of completed CUVITRU infusions. CUVITRU infusion rate of 60 mL/h/site was achieved in 28.6% (6/21) of pediatric subjects (2 years to <16 years of age), in 88.7% (47/53) of adults (16 years of age and older) and in 71.6% (53/74) of all subject. For more than half of CUVITRU infusions (2393/4327), a volume of 30 to 39 mL (1096/4327 infusions) or 40 to 49 mL (1297/4327 infusions) was infused per site. For 320/4327of CUVITRU infusions, a volume of 60 mL/site or more was infused. Infusion paramenters resulted in a median of 2 infusion sites (range: 1 to 4) per CUVITRU administration. During CUVITRU treatment, 84.9% (3662/4314) of infusions were administered using 1 infusion site (18.5%; 798/4314) or 2 infusion sites (66.4%; 2864/4314) across all ages. The median duration of infusions was less than 1 hour (0.95 h; range: 0.2-6.4 hours). During all treatment periods, 99.8% of infusions were completed without a reduction, interruption, or discontinuation for tolerability reasons. Infusion characteristics did not significantly differ between adult and pediatric subjects.

Throughout the study, health-related quality of life was assessed using the Pediatric Quality of Life Inventory (PEDS-QL) questionnaire¹⁴ (pediatric subjects) or the self-administered SF-36 survey¹⁵ (adult subjects). Quality of life was analyzed separately for the age groups 2 to 4 and 5 to 7 years (PEDS-QL, observer: parent), 8 to 12 and 13 years (PEDS-QL, observer: subject) and 14 years and older (SF-36, observer: subject). Treatment satisfaction was measured using the Life Quality Index questionnaire (LQI)^16,17 and the Treatment Satisfaction Questionnaire for Medication (TSQM-9)¹⁸. The LQI was assessed for the age group 2 years to 12 years (observer: parent) and the age group 13 years and older (observer: subject) in three domains: Treatment Interference, Therapy-related Problems and Therapy Settings. The TSQM-9 was assessed in subjects aged 2 to 12 years (observer: parent) and 13 years and older (observer: subject) in 3 domains: Effectiveness, Convenience and Global Satisfaction. Differences between scores during the intravenous study part and subcutaneous 20% study part were calculated for selected domains of the instruments, see Table 11.

Table 11. Selected Patient Reported Outcomes: Differences Between the Intravenous and Subcutaneous Treatment:

European Study

A prospective, open-label, non-controlled, multi-center study conducted in 16 sites in Europe to evaluate the efficacy, safety, tolerability, and PK parameters of CUVITRU in subjects with PI aged 2 years and older at time of screening. The study consisted of 2 parts. In study part 1, subjects were treated with IGSC 16% for 12 weeks or with IGIV 10% for 13 weeks. Administration, dosage frequency, and dose were dependent on the pre-study treatment. However, the dose range had to be within 0.3-1.0 g/kg BW/4 weeks.

During study part 2, subjects received weekly CUVITRU infusions for 51 weeks at the dose used during study part 1, adjusted to a weekly equivalent dose if necessary. PK assessments were performed before the end of study part 1 and after approximately 5 months in study part 2 in subjects aged ≥12 years. For younger subjects (aged 2 to <12 years) only IgG trough levels were assessed to avoid multiple blood draws. The geometric mean of CUVITRU trough levels was 827 mg/dL [95% CI: 748-913]. Human and population PK parameters for CUVITRU were calculated from levels of Immunoglobulin G (IgG) measured during each part of the study.

CUVITRU was administered at the same weekly-equivalent dose as with the previously used IG product (mean (± SD) dose: 0.125 ± 0.042 g/kg/week). CUVITRU administered at this dose was shown to be effective in PI subjects aged ≥2 years.

One acute serious bacterial infection (ASBI) of pneumonia was reported in a 12-year old subject with a more severe form of hypogammaglobulinemia (XLA) while receiving CUVITRU. The point estimate of the annualized rate of ASBIs was 0.022 (upper limit of 99% CI: 0.049) during CUVITRU treatment. This annual rate of ASBIs was lower than 1.0 ASBIs /year, (p<0.0001), the threshold specified as providing substantial evidence of efficacy.

The summary of infections and associated events for subjects in the EU study during subcutaneous treatment with CUVITRU are summarized in Table 12.

Table 12. Summary of Infections and Associated Events:

^* Rate = number of infections divided by the total number of subject-years under treatment