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Immunoglobulin Potency and Purity Considerations for Patients With Primary Immunodeficiency
This publication was sponsored by Grifols USA, LLC.

Immunoglobulin Potency and Purity Considerations for Patients With Primary Immunodeficiency

This publication was sponsored by Grifols USA, LLC.
INTRODUCTION AND BACKGROUND
Primary immunodeficiency (PID) diseases occur in about 1 in every 1200 individuals and are associated with recurrent infections and several comorbidities that contribute to its substantial morbidity and mortality, especially prior to diagnosis.1-5 Most PID diseases are chronic, and, thereby require continuous treatment.2,6 Herein, the epidemiology, clinical burden, and economic burden of PID will be summarized. Additionally, current treatment options for PID will be reviewed and a subcutaneous (SC) immunoglobulin G (IgG) therapy will be introduced.

Disease Overview
PID diseases are a group of chronic, noncontagious disorders that are characterized by a dysregulated immune system. PID is caused by genetic or hereditary defects and affects both children and adults. There are over 400 rare types of PID disorders that can affect 1 or more components of the immune system.7 They can be categorized based on whether they affect specific or adaptive immunity (eg, humoral or antibody deficiencies) or combined deficiencies affecting both humoral and cellular immune mechanisms.8 Approximately half of all patients with a diagnosis of PID have antibody deficiencies.3

Patients with PID have variable clinical presentations of the disease, although most have higher predisposition to infections.9 These infections are periodic or due to unusual organisms and can affect the skin, ears, brain, spinal cord, respiratory system, urinary tract, or gastrointestinal tract.2 The affected organ systems and pathogens involved vary based on the type of immune defect, although many immunodeficiencies have autoimmune disease and malignancy characteristics as a common phenotype.8

Diagnosis of PID typically does not occur until after a patient experiences recurrent or severe infections, highlighting the need for earlier detection.2 The average time to diagnosis of PID after onset of symptoms is 12.4 years, and in some patients it may take up to 20 years for a diagnosis.10,11 A delayed diagnosis of PID can result in permanent functional impairment, loss of function, and substantial morbidity. In a 2013 survey of 1394 patients with PID conducted by the Immune Deficiency Foundation (IDF), patients reported permanent impairment or losses in lung function (28%), hearing (15%), digestive function (14%), mobility (9%), neurological function (9%), vision (6%), kidney function (3%), and liver function (2%) prior to PID diagnosis.10 In separate analyses, a delayed diagnosis of PID was most commonly associated with recurrent sinusitis, recurrent pneumonia, and/or subsequent treatment with IgG.3,5 PID diagnosis may be suspected if there are recurrent or persistent infections, when mild childhood disease becomes life-threatening, or if there are high or low blood cell counts.2 PID is most often diagnosed by an immunologist and 17% of patients have a family history.11

Epidemiology
PID is estimated to occur in 83.3 per 100,000 individuals based on a 2007 survey sample of 10,000 households.1 This estimate corresponds to an estimated prevalence of 270,193 of 3.13 million in the United States, based on an estimation of the 2011 US population drawn from World Population Prospects, 2010 Revision.1,12 Results of several studies have demonstrated PID prevalence has increased over time in the United States.13,14 In 1 report, the prevalence of diagnosed PID increased by 30% and 41% from 2001 to 2007 and 2001 to 2005, respectively.13 The physician-reported prevalence of patients with PID increased by 57% from 2013 to 2018 (40,560 patients in 2013 and 63,684 patients in 2018).14 Campaigns to educate and raise awareness of PID among health care providers and the general public may have contributed to the rise in incidence and prevalence of PID over time.13

Clinical Burden of PID
PID is associated with substantial morbidity and mortality in a majority of patients, especially due to increased susceptibility to infections.4,13 Additional comorbidities in patients with PID include gastrointestinal diseases, liver diseases, autoimmune diseases, cytopenias, and cancer.3,15 To understand the burden of PID-associated morbidity, the number of hospital admissions and length of hospitalizations for patients with PID were identified using claims data from the Truven Health MarketScan of Commercial Claims and Encounters (from 2001-2007) and Multi-State Medicaid databases (from 2001-2005). Patients with PID were 2 times more likely to be hospitalized and have significantly longer hospital stays than patients without PID, which may partly be due to infections and other comorbidities.13 According to data from the National Center for Health Statistics from 1999 to 2014, the overall age-adjusted mortality rate in patients with PID was 0.43 per 1,000,000 population (95% CI, 0.40-0.46), with the highest mortality rates from the southern part of the United States (36% PID-related deaths).4 The contributing cause of mortality in the US PID population included extrapulmonary infections (35%), respiratory illnesses that were either infectious (eg, pneumonia) or noninfectious (eg, acute respiratory distress syndrome) pulmonary illnesses (17%), cardiovascular (11%), endocrine/metabolic (6%), and malignancy (5%).4 Some serious complications of primary antibody deficiency may be fatal. Patients with PID have a 10-year survival rate of 93.5% after diagnosis with PID.3,15,16

The results of studies have reported that patients with PID experience lower health-related quality of life (HRQOL) than those without PID.17,18 In a 2016 observational study of 18 adult patients and 8 pediatric patients diagnosed with PID—specifically primary antibody deficiencies—HRQOL was assessed through self-administered questionnaires.17 Patients who were eligible were recently diagnosed with or suspected of having common variable immunodeficiency, X-linked agammaglobulinemia, or autosomal recessive agammaglobulinemia, or specific antibody deficiency. Patients who had a life expectancy of 1 year or less, dementia and/or mental incapacity, or comorbidities or other conditions that would interfere with interpretation of the data were excluded. The 36-question Short Form Health Survey, version 2 (SF-36v2) was used to assess HRQOL in adults; it measures 8 domains including limitations in physical activities because of health problems (physical function), limitations in usual role activities because of physical health problems (role physical), bodily pain, general health perceptions, mental component score, vitality (ie, energy and fatigue), limitations in social activities because of physical or emotional problems (social functioning), limitations in usual role activities because of emotional problems (role emotional), general mental health (ie, psychologic distress and well-being). The Pediatric Quality of Life Inventory was used in children, which evaluates physical, emotional, social, and school-related parameters. Comparative samples were age- and sex-matched using separate least squares multiple regression models for each QOL scale and summary measure with the available normative data for the SF-36v2. For the mental health domains of the SF-36v2, adult patients with PID experienced significantly diminished (P <.05) vitality (38.2 vs 49.4), social functioning (33.6 vs 49.8), and role emotional (41.0 vs 49.7), but not mental health, compared with the general US population. Compared with the general US population, adult patients with PID had lower HRQOL scores, with significantly lower scores on the physical domains assessed by the SF-36v2. (Table 1). In children, The Pediatric Quality of Life Inventory, which evaluates physical, emotional, social, and school-related parameters was used. Some pediatric patients reported an improvement after 12 months of treatment, however, others reported no change or worsening of their HRQOL; changes were not significant.17

In a separate survey-based 2-part study, 945 adult patients with common variable immune deficiency completed a 75-question survey (IDF survey), followed by a 12-question Short Form Health Survey (SF-12), to assess their HRQOL as a measure of disease burden. Results of the survey showed that the population with PID reported substantially diminished functional health and well-being compared with the general US population.18

Economic Burden of PID
Prior to diagnosis of PID, patients experience a substantially higher rate of acute infections (6.38 vs 1.78), severe infections (4.32 vs 0.59), and bacterial pneumonias (2.84 vs 0.62) compared with postdiagnosis (Table 2).19 As a result of this increased infection burden in patients with PID who have not yet been diagnosed, there is potential that greater healthcare resource utilization for infection management and productivity losses may drive the economic burden of this disease even before diagnosis. For example, this increased rate of infection can lead to more days in the hospital (70.88 vs 11.79) and a greater number of school or work days missed (33.90 vs 8.90) compared with patients who experience infections postdiagnosis.19 The estimated annual cost of PID per patient prior to diagnosis was $138,760.19 After diagnosis and IgG replacement therapy, including the cost of treatment, the estimated cost per patient was $60,297—an annual savings of $78,166 that is attributable to treatment of PID.17,19 A report conducted in 2018 found that the annual savings post diagnosis were $85,882 globally.14

In patients treated with IgG therapy, infections are common, with 2.16 infections per patient per year on average.20 A retrospective claims analysis investigated the cost of infection among patients with PID, including infection-related resource utilization and infection-related medical expenditures longitudinally across a 7-month period.21 A total of 1742 patients with a diagnosis of PID and healthcare claims for immunoglobulin intravenous (IGIV) therapy were identified from the Truven Health Analytics MarketScan Commercial Research Database (January 1, 2008, to September 30, 2010).21 Across the 7-month study period, 490 patients had claims for a resource that indicated they experienced 1 or more infections; of those patients, 89.8% had 1 or more infection-related office visits and 25.1% had infection-related inpatient hospitalizations.21 The mean total infection-related medical expenses were $11,925 per patient during the 7-month study period.21 Among the drivers of infection-related resource utilization, inpatient hospitalizations, outpatient visits, and emergency department visits were the highest cost contributors per patient ($38,574, $1460, and $899, respectively).21

CURRENT TREATMENT OPTIONS AND UNMET NEEDS
IgG, the Main Treatment Modality for PID
Treatment of PID antibody deficiency using IgG replacement therapy is common for most patients (administered through IV or SC).2 Patients with selective immunoglobulin A (IgA) deficiency and transient hypogammaglobulinemia of infancy are typically not treated with IgG replacement therapy.2 IgG replacement therapy contains purified pooled plasma with a broad spectrum of antibodies from multiple individuals (10,000-50,000).6 It is a lifelong therapy that requires repeat doses of IgG at regular intervals because the body produces IgG from its own immune cells and IgG must be replenished periodically.6 The typical half-life of IgG antibodies is about 19 to 21 days.2 IGIV is administered every 3 or 4 weeks, whereas IGSC may be administered daily, weekly, or every 3 to 4 weeks depending on the specific IGSC product administered.6 The dominant route of administration for IgG therapy has historically been IV22; however, more recent data show SC infusion to be an acceptable form of therapy for patients with PID.23 The use of IGSC has increased from 23.0% in 2008 to 45.2% in 2013 based on IDF surveys conducted during that time.10,24 Additionally, of 509 patients who switched from IGIV to IGSC, 55% of those patients reported they made the decision due to the convenience of IGSC therapy.10

IgG replacement therapy has resulted in improved in HRQOL in patients with PID administered through IV and SC.17 A 12-month observational study assessed the burden of disease of PID along with impact of IgG treatment on HRQOL as measured by the SF-36v2.17 Patients with PID experienced significant improvements in SF-36v2 domain score including physical role (34.7 vs 43.5; P = .01), general health (31.2 vs 40.3; P = .02), and social functioning (36.1 vs 44.9; P = .02) from baseline to 12 months of IgG treatment, respectively.17

Unmet Needs and Considerations in IgG Treatment
SC administration of IgG preparations provides another option for patients with poor venous access and a history of adverse events (AEs) to IGIV, and offers patient convenience due to at-home administration and lower infusion volume requirements.25 In a 2008 survey conducted among patients with PID (N = 68), 8% reported discontinuation of IgG therapy due to safety issues or AEs.24 AEs that occurred in 10% or more of the population treated with IGIV-10% included headaches, muscle aches, abdominal pain, fever/chills, an increase or decrease in blood pressure, anxiety, redness or swelling at infusion site, and wheezing (Table 3).24 In contrast, fewer systemic AEs are associated with IGSC and the majority are infusion site reactions.6 The results of another study found that more IGIV-treated patients reported experiencing fatigue and with greater frequency than IGSC-treated patients (46.0% vs 28.5%, respectively).18 Among the IGIV products available, there are numerous differences in product-specific formulations and features, including clinical tolerability, volume load, osmolality, sodium content, sugar content, pH, and IgA content.24,25 Formulas with a higher IgG concentration require lower volume and shorter infusion time. A greater incidence of thromboembolic complications is associated with formulations with higher sodium, whereas renal failure or insufficiency is associated with higher sugar content.26

An additional consideration with IGIV treatment is the wear-off effect that can occur toward the end of the dosing cycle. Three phase 3 studies were included in a pooled analysis of patients treated with IGIV for 3 or 4 weeks. The probability of acquiring an infection significantly increased during the final cycle week—by 1.26 and 1.55 for patients on 3- and 4-week dosing schedules, respectively—compared with week 1, suggesting a wear-off effect of the drug.27 Further, IgG replacement therapy only replaces circulating IgG levels and not external secretions of IgG, a factor that must be considered because infections that involve mucosal surfaces can be an issue.2

IGSC administration occurs at home, either via self-infusion or with the help of a caregiver, resulting in improvements in HRQOL and patient satisfaction versus administration of IGIV at a physician’s office or a hospital.23,28 Patients who received home infusions had higher HRQOL scores compared with patients who received treatment at an infusion suite.18 Additionally, adults and children with PID who switched from IGIV to IGSC had improved perceptions of general health after 12 months of treatment.29 Rider et al compared HRQOL in number of patients by route of IgG administration. In patients who perceived their PID to be less than adequately controlled, their mental component score of the SF-12 was higher when treated with IGSC compared with IGIV.18

The measurement of serum trough IgG levels to ensure adequate protection against infection is important when administering IgG therapy.6 A meta-analysis of pneumonia rates and trough IgG levels showed that with every 100 mg/dL increment in trough IgG the rate of pneumonia incidence declined by 27%.30 A clinical study measured serum trough IgG levels in patients (n = 51) during IGSC treatment and compared them with levels that were previously recorded while the patients had IGIV therapy. Mean serum trough IgG levels with IGSC were 25% to 34% higher than the recorded levels for each subject during IGIV treatment.29 Therefore, serum trough IgG levels should be checked more often when a patient first starts IgG replacement therapy and then once per year after commencing therapy to determine if there are differences in the metabolism of blood levels of IgG.2

IGSC-C 20% FOR PID
Product Description 
The FDA approved Xembify® (immune globulin subcutaneous, human—klhw) a 20% immune globulin solution for SC infusion (referred to as IGSC-C 20%) in July 2019.28,31 It is indicated as a weekly SC dose for the treatment of primary humoral immunodeficiency in patients at least 2 years old. If desired, the dose may be divided into 2 to 7 infusions per week. It provides a wide spectrum of opsonizing and neutralizing IgG antibodies that fight bacterial, viral, parasitic, and mycoplasma agents and their toxins as well as antibodies able to interact and alter immune cell activity.28 The product is an appropriate option for patients with risk factors, including pediatric and elderly patients, and patients with diabetes, renal dysfunction, thromboembolic risk, and/or cardiac impairment.26 It has trace amounts of sodium, is sugar-free, and is close to physiologic osmolality.25,26 This is achieved through a unique manufacturing process using caprylate/chromatography. Caprylate is a safe, naturally occurring fatty acid of plant origin that is used in both the purification and virus-inactivation capacity steps of the manufacturing process. This process provides at least 98% IgG protein for maximum potency and maximum purity. Caprylate/chromatography yields maximum amounts of IgG protein, maintains IgG in liquid phase, and minimizes the denaturing of the IgG protein. The final result is a ready-to-use, sterile SC infusion that can be administered at home.28

IGSC-C 20% is manufactured by Grifols, similar to IGIV-C 10%, through a combination of cold ethanol fractionation, caprylate precipitation and filtration, and anion-exchange chromatography of plasma pooled from healthy human donors.25,32 Although the plasma fractionation and caprylate purification steps are the same for IGIV-C 10% and IGSC-C 20%, there are additional steps required to refine the formulation into an IGSC-C 20%, resulting in an approximately 55% increase in manhours and production equipment time compared with that of IGIV-C 10%. The IGSC-C 20% production involves a second purification and sterilization. IGSC-C 20% was found to have a similar composition, antibody potency, and purity as IGIV-C 10%, but it utilizes a smaller volume for administration than IGIV-C 10%, which results in shorter infusion times.25,26 The antibody potencies of IGSC-C 20% and IGIV-C 10% were tested for diphtheria, measles, polio, hepatitis A, hepatitis B, and parvovirus and were found to be comparable and above the US minimum requirements. In 2018, the FDA lowered the specification for measles (from 0.48 × reference to 0.36 × reference), but IGSC-C 20% still maintains the higher specification previously required.25
 
INDICATION
XEMBIFY® (immune globulin subcutaneous human–klhw) is a 20% immune globulin indicated for treatment of primary humoral immunodeficiency disease (PIDD) in patients 2 years of age and older. XEMBIFY is for subcutaneous administration only.

IMPORTANT SAFETY INFORMATION
WARNING: THROMBOSIS
  • Thrombosis may occur with immune globulin products, including XEMBIFY. Risk factors may include: advanced age, prolonged immobilization, estrogens, indwelling vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.
  • For patients at risk of thrombosis, administer XEMBIFY at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk of hyperviscosity
Contraindications
XEMBIFY is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. It is contraindicated in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity.

Warnings and Precautions
Hypersensitivity.
 Severe hypersensitivity reactions may occur with immune globulin products, including XEMBIFY. In case of hypersensitivity, discontinue infusion immediately and institute appropriate treatment. XEMBIFY contains IgA. Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions.

Please see full Prescribing Information for XEMBIFY® (immune globulin subcutaneous human-klhw) 20%.



 
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