Subcutaneous Immunoglobulin Replacement Therapy with Hizentra, the First 20% SCIG Preparation: a Practical Approach

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1 SUMMARY SLIDE Subcutaneous Immunoglobulin Replacement Therapy with Hizentra, the First 20% SCIG Preparation: a Practical Approach Benefits of SCIG administration compared with IVIG include: avoidance of serum IgG peaks and troughs; more attractive to patients with poor venous access; ease of administration. Hizentra is the first, ready-to-use, 20% liquid preparation of human IgG specifically formulated for SCIG, which: effectively protects PI patients from serious and nonserious bacterial infections; labeled for secondary immunodeficiencies outside the US; has a good safety profile; is easily stored for up to 30 months at up to 25ºC, whilst retaining predefined values; is easily infused using conventional pumps; is well tolerated in children; has generally mild-to-moderate local AEs.

2 Subcutaneous Immunoglobulin Replacement Therapy with Hizentra, the First 20% SCIG Preparation: a Practical Approach

3 Abbreviations AE = adverse event CVID = common variable immunodeficiency FDA = US Food and Drug Administration HRQL = health-related quality of life IgA = immunoglobulin A IgG = immunoglobulin G IVIG = intravenous administration of IgG SCIG = subcutaneous administration of IgG PI = primary immunodeficiency XLA =X-linked agammaglobulinemia

4 Benefits of SCIG over IVIG IVIG is not suitable for those with poor venous access. Fewer related systemic AEs. Ease of administration i ti gives patients t a sense of independence and responsibility. Administration performed at a location convenient for the patient, avoiding unnecessary travel and potential nosocomial infections. SCIG administered into the extravascular compartment (see figure), resulting in more sustained serum IgG levels, avoiding the peaks and troughs associated with IVIG.

5 Hizentra efficacy advantages Hizentra achieved clinical efficacy in patients with PI with stable and physiologically relevant serum IgG levels and no serious bacterial infections. Clinical trials with Hizentra resulted in mean trough levels found in healthy individuals, and was also well tolerated in children. HRQL markedly improved upon switching from IVIG to Hizentra; with a significant improvement observed in the convenience domain. SCIG typically administered once a week due to high infusion rates (Hizentra infusion rates between ml/hr). 20% concentration benefits children as the required dose can be delivered in a small volume.

6 Benefits of Hizentra formulation and stability Hizentra has a high purity ( 98% IgG; trace amounts of IgA) and no preservatives. Screened for hepatitis B and C, HIV, and B19 virus. Overall prion reduction and viral reduction, ranging from >10 7 to >10 24, depending on viral model. Stabilized with a nonessential, natural amino acid, L-Proline (250 mmol/l). Hizentra storage at 25ºC for up to 30 months shows values within predefined specifications (content of aggregates, monomers/dimers, Fc function). Simplifies product storage at pharmacies and for patients at home.

7 Safety benefits of Hizentra administration Hizentra indicated for treatment of PIs, including congenital agammaglobulinemia, CVID, XLA, and Wiskott-Aldrich syndrome. Labeled for secondary immunodeficiencies outside the US. Good safety profile, effectively protecting PI patients from serious and nonserious bacterial infections. In clinical trials, systemic AEs such as headache, fatigue, and nausea were relatively rare, whilst no serious AEs were considered to be related to Hizentra. Local AEs were generally mild-to-moderate moderate and transient, decreasing in frequency over time.

8 SCIG administration advantages No need for hospital visits; can be administered at a location convenient for the patient. Self-administration with Hizentra was shown to be easy to learn. Supervision i of initial iti administrations i ti by a nurse or healthcare professional, followed by a home visit. Infusion can be administered using a conventional pump or a Push technique : between one and seven injections a week using a syringe and a gauge butterfly needle. Training sessions detail needle gauge and length, selection of infusion sites, aseptic infusion, and management of AEs. Requires no pump or tubing and is time and cost effective; hence, an attractive option to patients and insurance companies.

9 SCIG conventional pumps Hizentra preparations can also be administered with conventional pumps. FREEDOM60 Syringe Infusion system (top); most widely used in the US: simple, reliable, and not dependent on batteries or electrical outlets. Multiple Crono pumps are available and used, such as the Crono Super-PID (bottom) and Cane Crono PCA-50 pump. The Crono Super-PID is standard for patients commencing SCIG in Cardiff, UK, and are specified with home care packages provided.

10 Clinical trials and reviews Publication Maeder W, et al Borte M, et al Hagan JB, et al Results Storage of Hizentra at up to 25ºC for 24 months showed values within defined specifications. After 24 months, contents of aggregates in Hizentra increased from approximately <0.1% to 0.5%. Content of monomers/dimers changed from approximately 98% to around 95%. Content of fragments was 4%, below the specified limits of 10%. Long-term storage did not significantly affect antigen-specific antibody titers. Fc function changed from approximately 100% to between 79% and 101%. 21 pediatric patients, including 16 children (2-11 years) and five adolescents (12-15 years). Initiation of immunoglobulin replacement treatment with SCIG therapy was well tolerated. Successfully achieved sufficiently high IgG trough levels ( 5 g/l). Mean trough levels of children originally treated with IVIG (66%) increased by 13.3% (from 6.94 g/l to 7.86 g/l). Low rate of local infection and lower rate of AEs in children and adolescents (0.040 and events/infusion, respectively) US, 60-week, open-label, multicenter, single-arm trial evaluated efficacy and safety of Hizentra in patients with PI. 49 patients originally on IVIG underwent a 48-week efficacy period, with dose adjustment of Self administration was shown to be easy to learn, and no discontinuations resulted from technical difficulties. Short duration of weekly infusions, with median values ranging from 1.6 to 2 hours. Rate of infection was 2.76 events/patients/year. Jolles S, et al European 40-wk, open-label, l multicenter, t single arm trial evaluated efficacy and safety of Hizentra in PI patients. t 28 week efficacy period completed by 43 patients, including 16 below 12 years. HRQL statistically significantly improved for convenience. 17% increase in serum IgG in patients changing from IVIG to SCIG. Hizentra infused at a median infusion rate of 25.3 ml/hr, with 34% patients receiving 35.0 ml/hr. Rate of infection was 5.18 events/patients/year. HRQL found to be improved in patients switching from IVIG to Hizentra. 1. Maeder W, Lieby P, Sebald A, et al. Biologicals. 2011; 39:43-49.; 2. Borte M, Pac M, Serban M, et al. J Clin Immunol. 2011; 31: ; 3. Hagan JB, Fasano MB, Spector S, et al. J Clin Immunol. 2010; 30: ; 4. Jolles S, Bernatowska E, de Gracia J, et al. Clin Immunol. 2011; 141:

11 Summary SCIG administrations improve on IVIG infusions by: having more stable serum IgG levels avoidance of peaks and troughs; allowing administration in patients with poor venous access; giving patients the option to administer SCIG themselves - more convenient. Benefits of 20% Hizentra include: efficacious against serious and nonserious bacterial infections; reduced d duration of administration; i ti good safety profile, including administration in children; easily stored and administered using traditional pumps; easy to learn following initial training; generally mild-to-moderate local AEs; most local reactions are mild and decrease in frequency over time.

12 Acknowledgments Critical review of the manuscript by Jeff Baggish and Andrea Sebald is gratefully appreciated. Editorial assistance for the manuscript was provided by Phocus Services Ltd, supported by CSL Behring. Editorial assistance for the slide deck was provided by Springer Healthcare Ltd.