Status: marketed in U.S. and EU

Cross ref.: See Immune Globulin Products (entry #743).

Organizations involved:

CSL Behring AG – Manuf.; R&D; Tech.; Intl. mark.; Parent

CSL Behring LLC – U.S. mark.

CSL Ltd. – Parent

Description: Hizentra is an aqueous formulation of highly purified polyvalent immunoglobulin G (IgG) obtained from fractionated pooled human Plasma for subcutaneous infusion for subcutaneous administration. Hizentra is manufactured from large pools of human plasma by a combination of cold alcohol fractionation, octanoic acid fractionation, and anion exchange chromatography. The IgG proteins are not subjected to heating or to chemical or enzymatic modification. The Fc and Fab functions of the IgG molecule are retained. manufacture includes 3 viral inactivation/reduction processes. Two of these are dedicated virus clearance steps: pH 4 (acidic) incubation to inactivate enveloped viruses; and virus filtration to remove, by size exclusion, both enveloped and non-enveloped viruses as small as approximately 20 nanometers. In addition, a depth filtration step contributes to the virus reduction capacity. Fab functions tested for release include antigen binding capacities, and Fc functions tested include complement activation and Fc-receptor-mediated leukocyte activation (determined with complexed IgG).

Hizentra has a purity of ≥98% IgG and a pH of 4.6 to 5.2. Hizentra contains approximately 250 (range: 210 to 290 mmol/L) L-proline (a nonessential amino acid) as a stabilizer, 10 to 30 mg/L polysorbate 80 (Tween 80), and trace amounts of sodium. Hizentra contains ≤50 mcg/mL IgA. Hizentra contains no carbohydrate stabilizers (e.g., sucrose, maltose) and no preservative. Hizentra is essentially sodium free.

Hizentra is a 20% (200 mg/mL) protein solution in single-use, tamper-evident vials (5 mL, 10 mL and 20 mL sizes in the U.S.; also a 15 mL size in Europe) containing 0.2 grams of protein per mL (1, 2 and 5 grams, respectively) of preservative-free liquid. Each vial label contains a peel-off strip with the vial size and product lot number for use in recording doses in a patient treatment record. The dating period is 24 months (18 upon approval; 20 months shelf life in EU) from the date of manufacture when stored at 2-25˚C, with date of manufacture defined as the date of final sterile filtration of the formulated drug product in accordance with 21 CFR 610.50. Following the final sterile filtration, no reprocessing/reworking is allowed without prior approval from FDA. Hizentra is subject to CBER lot release inspection requirements.

Hizentra is the first 20% subcutaneous immunoglobulin (SCIg) approved in the U.S. This high-concentration product is stabilized with L-proline, a naturally-occurring amino acid. L-proline allows Hizentra to be stored at room temperature (up to 25°C [77°F]). Because no refrigeration is necessary, Hizentra is ready to use, offering patients and physicians convenience and portability. Hizentra can be safely self-administered by PI patients under a physician's care. Hizentra’s ready-to-use attribute will allow patients to infuse the product where and when it suits them. Nomenclature: Immune globulin (SCIG) 20% [BIO]; Hizentra [TR]; Immune Globulin Subcutaneous (Human), 20% Liquid [FDA]; NDC 44206-451-01; NDC 44206-451-02; NDC 44206-451-04 [NDC]

Companies: Hizentra was developed and is manufactured and marketed by CSL. Upon approval, Hizentra was manufactured at a CSL plant in Bern, Switzerland, running a full capacity. By now, approval has (or will) likely be granted for Hizentra production at another plant nearby, allowing it to quadruple capacity.

FDA class: Biologic BLA

Approvals: Date = 20100304; full BLA (BL 125350/0)

Date = 20100217; supplemental BLA; Indication = include revised labeling to fulfill the required pediatric assessments

Date = 20100304; supplemental BLA; Indication = addition of results from European Study ZLB06_001CR to product insert/labeling

Indications: [Full text of the "INDICATIONS AND USAGE" section of the product insert/labeling]:
Hizentra is an Immune Globulin Subcutaneous (Human) (IGSC), 20% Liquid indicated as replacement therapy for primary humoral immunodeficiency (PI). This includes, but is not limited to, the humoral immune defect in congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

Status: In Nov. 2010, Hizentra received EU approval.

EU-approved indications are:
Replacement therapy in adults and children in primary immunodeficiency syndromes such as:
congenital agammaglobulinaemia and hypogammaglobulinaemia
common variable immunodeficiency
severe combined immunodeficiency
IgG subclass deficiencies with recurrent infections
Replacement therapy in myeloma or chronic lymphocytic leukaemia with severe secondary
hypogammaglobulinaemia and recurrent infections.

Trials: FDA approval of Hizentra was based on results from a prospective, open-label, multicenter, single-arm, clinical study (NCT 00542997) conducted in the U.S. This evaluated the efficacy, tolerability, and safety of Hizentra in adult and pediatric subjects with primary immunodeficiency (PI). Subjects previously receiving IVIg treatments every three or four weeks were switched to weekly subcutaneous administration of Hizentra for 15 months (a three-month wash-in/wash-out period followed by a 12-month efficacy period). The efficacy of Hizentra was analyzed in 38 subjects who received at least one infusion after the wash-in/wash-out period.

Market: CSL is trying to attract patients away from physician-office infusions, such as Baxter's Gammagard, with Hizentra, which patients can inject themselves. Hizentra has an advantage over other potential home-infused competitors, because it is highly concentrated, so an infusion takes less time. Many patients are expected to be shifted to Hizentra. But product supplies will be limited, until new manufacturing facilities come online.