Regulatory Decision Summary for HIZENTRA

To date, several publications have reported the therapeutic efficacy of Immunoglobulin subcutaneous (IGSC) administration in patients with CIDP. IGSC replacement therapy is considered to be effective, safe, and also highly appreciated by patients and to have a low risk of systemic adverse reactions (ARs).

Some of the proposed advantages of IGSC over IGIV (intravenous) include:

1) an improved safety profile and improved tolerability;
2) an alternative for patients with poor venous access;
3) option for home treatment;
4) improved health-related quality of life (HRQOL);
5) ease of administration and flexibility of dosing; and
6) increased convenience and compliance.

The main disadvantages are:
1) the limited volume of fluid that can be delivered subcutaneously, and
2) the lower bioavailability (65%-69%) of the IGSC therapy. These limitations in turn require more frequent dosing typically to be weekly to several times a week and, in the case of large doses, administration at multiple sites to deliver the entire dose.

IGSC maintenance therapy in CIDP has been studied for 6 months and for a further 12 months in a follow-up study.

The overall objective was to determine the efficacy of 2 different doses of Hizentra (0.2 g/kg bw and 0.4 g/kg bw) in the maintenance treatment of CIDP in comparison to placebo.

In the 24-week randomized, placebo-controlled study, the absolute risk reduction for CIDP relapse when including subjects being withdrawn from the study as a relapse, was 25% for the 0.2 g/kg Hizentra dose and 30% for the 0.4 g/kg Hizentra dose, compared with placebo.

When only considering CIDP relapse and not subjects who withdrew, the 0.2 g/kg Hizentra dose prevented CIDP relapse in 67% of subjects and the 0.4 g/kg dose in 81% of subjects. The absolute risk reduction compared with placebo was 23% for the 0.2 g/kg Hizentra dose and 37% for the 0.4 g/kg dose. In contrast 44% of subjects on placebo remained relapse-free. Thus, both doses effectively prevent CIDP relapse and are recommended when switching subjects from IV to SC treatment with Hizentra.

The adverse events (AEs), laboratory parameters, and vital signs observed during the study are consistent with the known safety profile of Hizentra including other IGIV products. The most frequent AEs were local reactions, which occurred more often in Hizentra treated subjects than in placebo treated subjects. The frequencies of were generally highest at the earlier infusions in the SC Treatment Period, and declined thereafter. The frequency of causally related AEs was low; most AEs were mild or moderate. One serious adverse reaction, allergic dermatitis, was reported in the 0.2 g/kg body weight Hizentra group which started at SC Week 9 and lasted 15 days.

A Risk Management Plan was also submitted and reviewed, finding that the routine risk minimization measures are sufficient to manage the safety concerns for the indications already approved (Primary Immune Deficiency [PID] / Secondary Immune Deficiency [SID]) as well as for the proposed indication (CIDP) and thus no additional risk minimisation activities were deemed necessary.