Editor Howard Lederman, M.D. Ph.D. ISSUE 11 OCTOBER 2003 IDF Medical Advisory Committee Rebecca H. Buckley, M.D., Chairperson Duke University School of , Durham, NC

Douglas J. Barrett, M.D. University of Florida, Gainesville, FL

R. Michael Blaese, M.D. PreGentis, Inc., Newtown, PA Clinical Focus Mary Ellen Conley, M.D. St. Jude Children’s Research Hospital, Memphis, TN on Primary Immune Deficiencies Max Cooper, M.D. University of Alabama at Birmingham, Birmingham, AL

Charlotte Cunningham-Rundles, M.D., Ph.D. Mount Sinai Medical Center, New York, NY

Erwin W. Gelfand, M.D. National Jewish Center for and Respiratory Medicine, Denver, CO

Richard Hong, M.D. University of Vermont School of Medicine, Burlington, VT

Richard B. Johnston, Jr., M.D. University of Colorado School of Medicine, Denver, CO

Alexander Lawton, III, M.D. Vanderbilt University School of Medicine, Nashville, TN Primary Humoral Stephen E. Miles, M.D. All Seasons & Asthma, Woodlands, TX : Hans D. Ochs, M.D. University of Washington, School of Medicine, Seattle, WA Optimizing IgG Fred Rosen, M.D. The Center for Blood Research, Boston, MA William T. Shearer, M.D., Ph.D. Replacement Texas Children’s Hospital, Houston, TX

E. Richard Stiehm, M.D. UCLA School of Medicine, Los Angeles, CA

John L. Sullivan, M.D. University of Massachusetts Medical Center, Worchester, MA

Diane W. Wara, M.D. UCSF Medical Center, San Francisco, CA

Jerry Winkelstein, M.D. Johns Hopkins University School of Medicine, Baltimore, MD

Jonathan C. Goldsmith, M.D. IDF Vice President of Medical Affairs, Towson, MD Are all IGIVs the same? Creative by Euro RSCG Life Toronto Euro RSCG Life by Creative

IGIVs (Immune Globulin Intravenous (Human)) are all manufactured differently – but how does that impact a product’s efficacy or tolerability?

The medical community now expects solid evidence-based medicine through:

• controlled and comparative trial designs

• well-defined clinical endpoints

• appropriate trial size what’s in IGIV? At Bayer, we agree.

next Bayer is taking a New Perspective.

www.gamunex.com www.IGIVnext.com Primary Humoral Immunodeficiency: Optimizing IgG Replacement Therapy

Erwin W.Gelfand1, M.D., Table 1: Examples of Primary Jonathan Goldsmith2, M.D., and Immunodeficiency Diseases Howard M. Lederman3, M.D., Ph.D. That Impair

1Division of Cell Biology, Department of Defects that exclusively impair humoral immunity , National Jewish Medical and Research •X-linked agammaglobulinemia • Selective IgA deficiency Center, 1400 Jackson Street, Denver, CO 80206; •IgG subclass deficiency 2Immune Deficiency Foundation, 40 W.Chesapeake Avenue, Suite 308, Defects that predominantly impair humoral immunity Towson, MD 21204; and • Common variable immunodeficiency • X-linked hyper-IgM syndrome 3Eudowood Division of Pediatric Allergy and •Wiskott-Aldrich syndrome Immunology, Johns Hopkins Hospital, 600 N. Wolfe Street, CMSC 1102, Baltimore, MD 21287 Defects of both humoral and cell-mediated immunity • Severe combined immunodeficiency •DiGeorge Syndrome

Primary immune deficiency diseases (PIDD) are naturally occurring defects of the immune system X-linked Hyper-IgM syndrome). Patients may and comprise a diverse group of illnesses. In the last have defective humoral immunity with normal decade, incredible progress has been made in the cell-mediated immune function, or defects of both diagnosis and treatment of these diseases. Concerns arms of the immune system. remain about under diagnosis but important educational advances have certainly contributed to Increased susceptibility to is common to a dramatic increase in awareness and suspicion of all of the primary humoral , PIDD in the general medical community.Continuing with the possible exception of asymptomatic IgA efforts to ensure that patients are diagnosed and deficiency.With the rapid institution of antibiotics, treated as early as possible remain a priority. it is rare today to see osteomyelitis, meningitis or Importantly, rapid advances in defining the genetic consolidated pneumonia as the presenting feature. bases of the diseases, the potential for antenatal More commonly, recurrent upper respiratory tract diagnosis, and even prospects for successful gene , such as otitis media and sinusitis are therapy have all been accomplished.To date, 150-200 seen. Less commonly, patients develop mastoiditis, genetic defects have been defined (1). failure to thrive and chronic/recurrent . In some forms of deficiency, such as the Among the patients with PIDD are a group of hyper-IgM syndrome, autoimmune cytopenias, or disorders in which the ability to produce antibody infection with unusual pathogens such as is reduced or absent (Table 1). Such problems can Pneumocystis carinii or Cryptosporidium parvum be caused by defects intrinsic to the B lymphocyte infection, and chronic inflammatory disorders (e.g., X-linked agammaglobulinemia in which (e.g., sclerosing cholangitis) may be features of the B lymphocytes fail to mature) and by problems disease. intrinsic to the CD4 helper T lymphocyte (e.g.

October 2003 Immune Deficiency Foundation: Clinical Focus 3 The most common offending organisms generally appeared that maintenance of trough levels are encapsulated bacteria, such as Hemophilus (4 weeks post-infusion) above 500 mg/dL resulted influenzae and Streptococcus pneumoniae. in a reduction of major and minor infections, and Patients with humoral immunodeficiency also the need for hospitalization.These studies also appear to be uniquely susceptible to systemic revealed individual variations in time to achieve a mycoplasma infection, especially Ureaplasma stable plateau at trough and in catabolic rates. urealyticum, M. hominis and other species (2-4). These findings highlight the need to tailor IGIV Indeed, some of the and osteomyelitis regimens to the requirements of the individual seen in these patients may be secondary to patient and that a single fixed dose regimen may mycoplasma infection (2, 5). Similarly, acute and not be applicable to all patients. chronic lung disease may also be due to these organisms (3, 4). Often, the mycoplasma infections Despite almost five decades of use and more than are insidious, evoking only a low grade febrile and two decades of IGIV therapy, there is little docu- leukocyte response.These organisms are very mentation, which specifically addresses the efficacy difficult to culture and do not respond to the of IGIV in the prevention of significant infections, usual antibiotics instituted for infections caused by especially pneumonia, and long-term and progressive encapsulated organisms.Tetracyclines or quinolones lung disease.There has been reasonable documen- are often required to eradicate these organisms (2, 5). tation of the overall effectiveness of IGIV in preventing acute respiratory infections, otitis, and The foundation for therapy of the humoral immun- sinusitis, but some patients still suffer from these odeficiency diseases is immunoglobulin (IgG) and gastrointestinal problems and other infections, replacement.This form of therapy has evolved despite institution of IGIV prophylaxis. Replacement significantly over the last 50 years. Bruton, in 1952, IgG therapy, at standard doses, may not interrupt first treated his patient with subcutaneous injec- the occurrence or progression of permanent lung tions of gammaglobulin. Intramuscular injections damage (9). Acute pulmonary infections may be prevailed for almost 30 years until Bayer significantly prevented, but not permanent lung Pharmaceuticals introduced the first ready-to-use damage (10). Patients who present with significant liquid preparation of modified gammaglobulin lung disease, such as bronchiectasis, prior to initiation suitable for intravenous infusion in North America of IGIV therapy, may continue to suffer from in the early 1980’s. Intramuscular gammaglobulin progressive lung disease. In turn, a subset of patients, was generally injected at 0.6 cc (100 mg)/kg body despite optimal IGIV dosing and maintenance of weight.These injections were painful and limited adequate trough levels, may also develop permanent the amounts injected. Nonetheless, even at these lung damage for reasons that are not currently doses, reports of benefit emerged with reduction understood. Chronic lung disease in patients with in febrile episodes and the incidence of infection. primary humoral immunodeficiency remains a With the introduction of intravenous gammaglobulin major factor affecting quality of life and longevity. replacement (IGIV), therapeutic strategies also changed.The ability to administer IgG intravenously At present, it is not known why “therapeutic failures” provided the possibility to administer larger continue to occur despite the many advances in amounts. Several studies demonstrated the benefit treatment. Surprisingly, in a recent survey carried of higher doses (400-600 mg/kg body weight) in out by the Immune Deficiency Foundation (IDF), infection prophylaxis and improvement in lung 40% of patients felt that their disease was not optimally function (6, 7). Furthermore, the higher doses were controlled and recurrent infections persisted. associated with elimination of mycoplasma (8). It Approximately 60% complained that the effects of

4 Immune Deficiency Foundation: Clinical Focus October 2003 IGIV were wearing off prior to their next scheduled Table 2: Guidelines for Managing infusion, even two weeks after an infusion.There Patients with Antibody are several possibilities to explain these incomplete Deficiency responses, suggesting the need to regularly re-evaluate our approach to these patients. • An immunologist should direct life-long care of the patient

Management Guidelines • Assess pulmonary status with high resolution Although the data may not be at hand, it makes computed tomography (CT) and spirometry at empirical sense that the earlier the diagnosis and baseline and every 12-24 months institution of appropriate therapy, the better the • IgG replacement therapy at doses of at least 400- likelihood of preventing permanent lung damage. mg/kg/month and higher doses in patients where It is unclear if there are significant numbers of infections persist, especially bronchiectasis primary humoral immunodeficiency patients who • Institute appropriate antibiotic therapy when are undiagnosed, who warrant therapy or whose indicated therapy has been delayed. It is not surprising that the diagnosis may be delayed given the usual find- ings today that these patients most often present Antibiotics with common infections, such as otitis media and A mainstay of therapy of antibody deficiency disorders sinusitis, and initially respond appropriately to is appropriate use of antibiotics.As discussed, routine antibiotics. Indeed, a common presenting patients with antibody deficiency disorders are symptom in adults may be fatigue with little in the susceptible to the common encapsulated bacteria way of significant infections. (H. influenzae, S. pneumoniae), but also are uniquely susceptible to mycoplasma.The former are easy to Once the diagnosis of (antibody) immunodeficiency culture, the latter are not and the specific antibiotics is made, it is important to establish, at baseline, the for each are quite different. Because of the difficulty extent of lung damage.The most effective way is to in isolating the mycoplasmas, empirical therapy perform a high-resolution computed tomography (e.g., doxycycline) may be indicated in patients (CT) scan of the chest (9). If lung damage, e.g., with chronic/recurrent infection, who fail to bronchiectasis, is detected at presentation, then respond to usual antibiotics. management may need to be modified. Follow-up CT lung scans should be considered every 12-24 IgG Replacement months, depending on the presenting features. IGIV is the current standard of therapy with few if Similarly, an initial CT scan of the paranasal sinuses any indications currently for intramuscular injections. may aid in the long-term management of these Most patients receive IgG replacement via the patients (Table 2). intravenous route although some patients receive subcutaneous infusions (11). Suboptimal clinical The recent IDF survey also identified that 71% of outcomes could reflect a number of possibilities. patients were followed by primary care Although there are no obvious differences in efficacy, and not by an immunologist. Primary humoral careful scrutiny must be exercised as route and immunodeficiency is a lifelong and chronic disease frequency of administration could potentially affect requiring close co-operation between the patient, outcome. For example, it is not clear whether more the primary care and the specialist. frequent infusions at lower doses are more or less effective than larger infusions every three to four weeks.After appropriate training and the absence

October 2003 Immune Deficiency Foundation: Clinical Focus 5 of a history of adverse reactions, infusion by either complex.Whether any of these or other activities route can be performed at home. If monitored of IGIV play a role in these patients beyond carefully,home infusion programs can be as effective antibody replacement is an interesting possibility. as monthly visits to a recognized center under physician supervision. Convenience, however, is not Are All IGIVs the Same? a substitute for good medical management and home When surveyed, patients express four major concerns infusion programs do not replace the requirement about IGIV: safety,supply,tolerability/adverse events, for regular patient follow-up with physicians. and outcome. For the patients, their physicians and other healthcare personnel, there has been an From the IDF survey, it appears that a significant assumption that all eight licensed products in the proportion of patients may be under-dosed. Many United States are equivalent in these and other of the product package inserts recommend monthly parameters.This assumption has in large part been doses of 100-200 mg/kg body weight, but numer- fostered by the absence of any significant comparison ous studies have convincingly shown how dose data. However, these products do differ in terms of and trough levels affect outcome. In a double donor pools, manufacturing and final formulation. blind, randomized study in PIDD patients, doubling It is possible that a number of these differences the dose of IGIV (from 300 to 600 mg/kg body can affect tolerability, risk of adverse events, weight in adults and 400 to 800 mg/kg body weight infusion rate and efficacy. in children) significantly reduced the number and duration of infections (12).Appropriate dosing is Differences in basic fractionation and the addition essential and should not be determined by costs, of various modifications for further purification, longer infusion times, or concerns about convenience. stabilization and virus inactivation/ removal have yielded products clearly different from one to the Mechanism of Action of other (Table 3).There are well-established differences IgG Replacement in chemical structure, antibody content, subclass It is interesting to speculate on how IgG replacement distribution and electrophoretic profile. Further, works in the antibody deficiency diseases. Is it the composition of the final product also differs simply replacement of missing or do widely. Some attempts at standardization, for other potentially important activities come into example by a WHO Expert Committee on Biologic play? For many organisms, the levels of specific Standardization (14), has mandated that the IgG antibodies are surprisingly low (e.g., against common be as unmodified as possible, maintain its biologic serotypes of S. pneumoniae) and are not standardized function (opsonic activity, complement fixation, from batch-to-batch or brand-to-brand (see below). Fc-receptor binding), contain certain levels of specific Interestingly,there are virtually no detectable anti- antibody and meet accepted safety standards. bodies to the mycoplasmas, yet IGIV appears to play a role in their elimination or containment. Despite meeting these standards, it is possible that the different preparations and the modifications IGIV has also been shown to have a number of used to enable safe intravenous administration can anti-inflammatory and immunomodulatory activities induce alterations in the biologic activity of the (13).These include inhibition of the production of IgG molecule (15, 16).Whereas most commercial pro-inflammatory cytokines, neutralization of preparations are screened for levels of antibodies bacterial exotoxins, modulation of Fcg receptors, to several viral and bacterial antigens to validate triggering of lymphocyte apoptosis and prevention purification procedures, there is little routine of deposition of the complement membrane attack evaluation of the relationship between antibody

6 Immune Deficiency Foundation: Clinical Focus October 2003 Table 3: Characteristics of IGIV Products Licensed for Use in the United States (October 2003)

BRAND Polygam S/D Panglobulin Gammar-P I.V. Gammagard S/D Iveegam EN Gamunex1 Venoglobulin-S Carimune NF NAME 5% 10% 5% 10% 5% 10%

Manufacturer American American Aventis Baxter Corporation/ Baxter Corporation/ Bayer Grifols ZLB or Distributor Red Cross Red Cross Behring, LLC BioScience Division BioScience Division HealthCare/ Bioplasma, Inc. Biologic Products Division

Method of Cohn-Oncley Kistler Cohn-Oncley Cohn-Oncley Cold ethanol Cohn-Oncley Cold alcohol Kistler Production fractionation, Nitschmann fractionation, fractionation, fractionation, fractionation, fractionation, Nitschmann (Including ultra-filtration, fractionation, ultra-filtration ultra-filtration, PEG, trypsin caprylate/ PEG/Bentonite fractionation, Viral ion-exchange pH 4.0, pasteurization ion-exchange treatment chromatography fractionation, pH 4.0, Inactivation) chromatography, trace pepsin, at 60° C chromatography, purification, ion-exchange trace pepsin, solvent nanofiltration for 10 hours solvent cloth and depth chromatography, nanofiltration detergent detergent filtration, solvent treatment treatment final container detergent low pH treatment incubation

Form Lyophilized Lyophilized Lyophilized Lyophilized Lyophilized Liquid Liquid Lyophilized

Shelf-Life 24 24 24 24 24 36 24 24 Months Months Months Months Months Months Months Months

Reconstitution <5 minutes at room Several <20 minutes <5 minutes at room ≤10 minutes None None Several Time temperature minutes temperature at room (Liquid Solution) (Liquid Solution) minutes >20 minutes >20 minutes temperature if cold if cold

Available 5% 10% 3 to 12% 5% 5% 10% 5% 10% 5% 10% 3 to 12% Concentrations

Maximum 4 mL/ 8 mL/ >2.5 mL/kg/hour 3.6 mL/kg/hour 4 mL/ 8 mL/ 1.8 mL/kg/hour 4.8 mL/kg/hour 4.8 mL/ 3.0 mL/ >2.5 mL/kg/hour Recommended kg/hour kg/hour kg/hour kg/hour kg/hour kg/hour Infusion Rate

Time to Infuse 2.5 0.6 <3.3 hours 2.8 hours 2.5 0.6 5.6 hours 1.0 hours 2.1 1.7 <3.3 hours 35 gms2 hours hours (6% solution) hours hours hours hours (6% Solution)

Sugar Content 20 mg/mL 40 mg/mL 1.67 gm sucrose per 50 mg/mL sucrose 20 mg/mL 40 mg/mL 50 mg/mL glucose None 50 mg/mL 1.67 gm sucrose per glucose glucose gram of protein glucose glucose D-Sorbitol gram of protein

Sodium Content 8.5 mg/mL 17 mg/mL <20 mg sodium 5 mg/mL 8.5 mg/mL 17 mg/mL 3 mg/mL Trace <1 <20 mg sodium sodium sodium chloride per sodium chloride sodium sodium sodium chloride Amounts mEq/L chloride per chloride chloride gram of protein chloride chloride gram of protein

Osmolarity/ 636 1250 192 - 1074 309 636 1250 ≥240 mOsm/L 258 mOsm/kg 300 330 192 - 1074 Osmolality mOsm/L mOsm/L mOsm/kg mOsm/L mOsm/L mOsm/L mOsm/L mOsm/L mOsm/kg

PH 6.4 - 7.2 6.4 - 6.8 6.4 - 7.2 6.4 - 7.2 6.4 - 7.2 4.0 - 4.5 5.2 - 5.8 6.4 - 6.8

IgA Content < 2.2 µg/mL 720 µg/mL <25 µg/mL < 2.2 µg/mL <10 µg/mL 46 µg/mL 15.1 20 - 50 720 µg/mL in a 5% solution in a 5% solution µg/mL µg/mL

1 Gamunex will replace Gamimune N, 10% during the first half of 2004. 2 0.5 gm/kg for a 70 kg adult = 35 gms; 5% Concentrations: 1g = 20 mL; 10% Concentrations: 1g = 10 mL The time to infuse is based on the maximal infusion rate.

October 2003 Immune Deficiency Foundation: Clinical Focus 7 titer and antibody function. Evaluation by determi- Production of IGIV nations of antibody avidity or affinity, opsonic IGIVs are prepared from plasma pooled from activity or viral neutralization that may be affected thousands of donors. Most production processes by the purification steps, is rarely carried out. begin with sequential precipitation and fractionation with ethanol to isolate IgG from other plasma proteins. Comparative studies have shown differences and The material is subjected to freeze-drying to remove lack of consistency (product-to-product/batch-to- the ethanol and produce stable intermediates. batch) that affect (reduce) opsonic activity (17-19). Freeze drying in the presence of ethanol promotes These and other differences related to enzyme formation of insoluble IgG aggregates.The IgG treatment, chemical modification and fractionation, concentrates from initial fractionation are then underscore the need for concerns about biologic subjected to additional processing to produce efficacy and not simply meeting the standards material suitable for intravenous administration. established for protein electrophoretic profile and This is where major differences exist among subclass determinations.These differences have also products and where biologic function is most been extended to the protective effects of IGIV in susceptible to alteration.Treatment with proteolytic patients with antibody deficiency (20).Although enzymes generally gave way to chemical modification the commercial preparations are different with in an attempt to preserve the integrity of the IgG varying biologic activities, no systematic evaluation molecule, reduce aggregate formation and eliminate of the clinical implication of this fact has been anti-complementary activity. Further modifications reported, making it difficult for the clinician to led to improved products, higher purity, improved select the best preparation for a specific indication. stability and normal IgG subclass distribution.

Is there an “ideal”IGIV? The concept of ideal may Because of the different modifications used, it is vary significantly depending on the constituency not surprising that the different products vary queried – manufacturers require product integrity, when the amounts of IgG monomer, dimer and the clinician is primarily interested in efficacy, polymers are assessed, fragment levels are examined while the patient may identify safety as the critical and the levels of excipient proteins are quantified feature. For pharmacists, often in a central decision- (e.g., albumin).While they can vary from lot to lot making position, the acquisition cost of a product within a product, the manufacturer’s specifications may be the major determining factor in product must be met. It is not unreasonable to assume that selection. However, selection based on acquisition longer process times, more suspension/precipitation cost alone may be more costly in the long run if steps, and harshness of the treatment procedures biologic function or efficacy is compromised or contribute to some loss of the integrity of the IgG adverse events are higher and need to be managed. molecules and biologic function as well as create Given the paucity of comparative trials or data, what the potential for differences in efficacy, incidence factors or criteria may be used to help the clinician of adverse events and batch-to-batch variability. choose among the many products available? The factors include manufacturing process, safety, A major goal in improving the available products composition of the final product, tolerability and would be to increase yield (to help overcome efficacy.As a consequence, many of the defined supply issues), reduce processing time, minimize functions may also differ, as may a large number the harshness of the modification procedures, and of the unknowns that contribute to efficacy in ensure purity while maintaining batch-to-batch the wide-ranging number of diseases now being consistency. treated with IGIV.

8 Immune Deficiency Foundation: Clinical Focus October 2003 Product Characteristics enzyme treatment including pepsin or trypsin, Liquid vs. Lyophilized pasteurization, caprylate, acidification, PEG The manufacturing process also impacts other Bentonite, nanofiltration and depth filtration. important features.The first is whether the final Traditional calculation of overall process reduction product is in liquid form or not. Liquid preparations of viruses has been based on the sum of reductions have been accepted as more convenient, easier to determined for individual production steps (21). use and may be associated with fewer adverse An important aspect is the selection of comple- events. In ready-to-use form, the liquid preparations mentary safety steps for incorporation into the shorten preparation time and delays for patients. manufacturing process. If these steps act through When there is concern for wastage for example, if independent mechanisms in the inactivation/removal the patient does not show up for an appointment, of viruses, they can be considered additive, thereby liquid products can be returned to inventory and increasing overall safety and providing the widest used later. Concerns about wastage often mean possible safety margin against known and unknown that preparation of lyophilized products does not viruses. Further validation of the robustness of these begin until the patient arrives. viral reduction steps, under conditions outside standard operating conditions adds to the safety Product Concentration margin. The second consequence of the manufacturing process is product concentration. Products that Recently, a new IGIV product has been licensed: can be given at higher concentrations decrease Gamunex, Immune Globulin Intravenous (Human), volume load, an important aspect in certain patient 10% Caprylate/Chromatography Purified.The populations. For example, a 40 kg patient receiving production process for Gamunex includes viral 0.5 gm IGIV/kg body weight would receive 200 mL inactivation with the use of caprylate (caprylic of a 10% solution compared to 400 mL of a 5% acid), a naturally occurring octanoic fatty acid. solution. Simply concentrating certain products by Caprylate has been shown to be an effective virus reconstitution in a smaller volume will increase the inactivator with rapid kinetics and robustness osmolality of the final solution and may contribute when evaluated at different pH, temperature and to significant adverse events such as renal compli- protein concentrations (22).The kinetics of virus cations or thromboembolic episodes (see below). inactivation are much faster than seen with solvent detergent under many conditions.As time in the Viral Inactivation manufacturing process is a critical variable for quality Minimizing the risk of transmission of an infectious of the end product, introduction of caprylate may disease is now required during the manufacturing not only be less harsh to the IgG molecule than of IGIV.Safety standards have been implemented solvent detergent or pasteurization, but could with respect to viral pathogens, including markedly shorten processing time.This shorter documentation of the capacity of the manufacturing processing time could impact the quality of the process to remove or inactivate viruses. Plasma end product. testing, both of individual donations using serologi- cal tests and manufacturing pools using poly- Advances have also been made in effective merase chain reaction tests, is the initial step in screening for prion contamination on an providing source material that is free of high levels experimental basis. Once fully evaluated, these of clinically significant viruses.Accepted viral methods may permit direct testing of the inactivation or removal steps include treatment inactivation steps for reduction or elimination of with solvent detergent, polyethylene glycol (PEG), the potential for prion contamination.

October 2003 Immune Deficiency Foundation: Clinical Focus 9 failure or insufficiency.Although rare, the CDC Table 4: Differences Among IGIV reported that 90% of the IGIV-associated renal Preparations adverse events in the United States occurred with sucrose-containing IGIV preparations (24). • Final preparation in liquid or lyophilized form

• IgG concentration Sodium Content In the commercially available preparations, sodium •Viral inactivation process content varies widely from trace amounts to 0.85% • Sugar content concentrations (Table 3). Caution must be exercised • Sodium content when lyophilized preparations are reconstituted to higher concentrations in an attempt to reduce • Osmolality volume load. In some instances, concentrating a •pH lyophilized product from 5% to 10% can create a nearly 2% saline solution. Concerns about increased • IgA content salt concentrations and association with significant adverse events and thromboembolic complications have been raised. Product Composition As discussed in a NIH consensus conference on Osmolality IGIV (23), the variety of manufacturing processes, In IGIV solutions, the major contributors to as well as starting materials, leads to differences osmolality include sodium, sugars, and other among preparations that may be clinically important. excipient proteins. Physiologic osmolality is 280- Choosing the preparation of IGIV must take into 296 mOsm/kg of water. Solutions of IGIV range account specific differences that can significantly from physiologic osmolality to solutions that far impact the outcome in recipients (Table 4). exceed these levels, greater than 1,000 mOsm. Some sugar-stabilized products have higher Fluid Volumes osmolalities than sugar-free preparations. In Issues related to fluid load were discussed above reconstituting lyophilized preparations, careful and are linked to the final concentration of the attention to osmolality is required as significant solution.The ability to deliver higher amounts of adverse events may occur with solutions exceeding IgG in lower volumes has a major impact on the physiologic range.With some lyophilized recipients who may be intolerant of large fluid preparations, reconstitution to higher concentrated volumes, such as infants or patients with congestive solutions results in hyperosmolar solutions. heart failure or renal insufficiency.In addition, larger fluid volumes require longer infusion times, a pH factor that patients may like to minimize. The pH optimum for IGIV to prevent aggregation is 4.0-4.5.As a consequence, for preparations at Sugar Content higher pH, agents are added to maintain stability Various sugars (Table 3), sorbitol, glucose and and prevent aggregation.There are scattered reports sucrose have been added to some preparations as that low pH may be associated with phlebitis. a stabilizer, preventing aggregate formation. Some products contain no sugar.The major problem IgA Content associated with sugar content is the incidence of Patients with selective IgA deficiency and the significant adverse events, particularly acute renal ability to produce antibodies may be at risk for

10 Immune Deficiency Foundation: Clinical Focus October 2003 developing IgE or IgG anti-IgA antibodies resulting Tolerability in reactions.Although anaphylaxis is a theoretical Tolerability, the ability to receive IGIV without risk, it is indeed very rare; so rare that the NIH incident and at rates that reduce the need for consensus conference did not recommend burdensome and long infusion times, varies screening for anti-IgA antibodies in IGIV recipients markedly among preparations. In patients with (23).The content of IgA in a given preparation, primary immune deficiency diseases, the incidence except in the rarest of circumstances, is not usually of adverse events ranges from <5-16%, whereas an important factor. the incidence of adverse events is higher among patients with immune-mediated diseases, such as Isohemagglutinin Titers immune thrombocytopenia.This may be related to Preparations of IGIV do contain low-titered anti-A, differences in IGIV dose that is generally 0.5 gm/kg anti-B, and anti-Rh blood group antibodies and for immunodeficiency, but 1-2 gm/kg for immune- they may be detectable, transiently,in post-treatment mediated diseases.The reactions most commonly direct and indirect antiglobulin tests (25).There seen include headache, fever, myalgia, chills, nausea are no known reports of these antibodies in and vomiting.The cause(s) of these reactions is not (non-hyperimmune) IGIV preparations being known but may be the result of aggregate formation. associated with hemolysis.The European Union Many patients and clinicians notice differences Pharmacopea mandates that anti-A and anti-B titers among products in tolerability related to headache, be less than 1:64 in IGIV preparations. fever, chills and shortness of breath.Transient elevations of serum ALT and AST without clinical Antibody Titers correlation have been seen in some patients There are marked differences in the levels of some following infusions of different preparations of antibodies among different preparations. Levels of IGIV (28,29). Issues related to tolerability were certain antibodies, e.g., to tetanus or to ubiquitous significant enough to trigger a switch to another organisms, such as H. influenzae type b, may not product in 24% of patients, while another 18% differ significantly. However, realization of such either refused a product or delayed the infusion differences has prompted screening of certain in the recent IDF survey. preparations for higher titers to treat specific diseases, as for example, chronic ECHO virus An important issue in the administration of IGIV is meningitis in antibody-deficient patients (26). the rate of infusion as this relates directly to patient Differences in antibody titers can influence clinical acceptability.The incidence of adverse events, outcomes as was shown in clinical trials of low including thromboembolic events, has been tied to birth weight neonates treated with IGIV – here the rate of infusion (30, 31). Current recommended antibody levels against S. epidermidis were an rates fall within the range of 0.03-0.13 mL/kg/min, important factor in determining success or failure depending on the preparation.There are in fact (27).As antibody levels may also play a role in the relatively few studies examining the tolerability of mechanism of action of IGIV in PIDD or different rapid infusion of IGIV.The concentration of the autoimmune and allergic diseases (e.g., anti-idio- solution and the rate will dictate the length of time type, anti-exotoxin/superantigen, anti-cytokine an infusion will take (Table 3).With a 10% solution levels, etc.), these differences in antibody content at a rate of 0.08 mL/kg/min (8 mg/kg/min, 480 between preparations could significantly determine mg/kg/hr), an infusion of 0.5 gm/kg would require efficacy of intervention with IGIV. about one hour to complete compared to a 5% solution, which would require two hours. Some IGIV preparations have slower recommended rates of infusion.

October 2003 Immune Deficiency Foundation: Clinical Focus 11 Efficacy Conclusions and Recommendations Ultimately, efficacy is a key and primary concern 1. Early diagnosis and institution of appropriate dictating selection of a particular product.There antibiotic and IGIV therapy are necessary to have been few, if any, comprehensive comparisons minimize long-term sequelae in PIDD patients of efficacy made in a controlled, clinical trial setting. with antibody deficiency. Recently, a direct comparison between products was made. In PIDD patients, infusion of Gamimune N 2. Education of primary care physicians, pediatricians, 10% at equivalent doses and frequency of infusions internists, and otolaryngologists is necessary to was compared to infusion of a new product, minimize delays in diagnosis. Gamunex 10%.This multi-center clinical trial was unprecedented in many ways. More than 170 patients 3. An integrated team approach, including the primary were enrolled compared to many previous licensure- physician, specialist, infusionist, pharmacist, and relevant trials that enrolled 15-50 patients.This trial the patient is necessary to optimize care. had clearly defined and clinically relevant end-points. The new product was manufactured by an entirely 4. Management can be optimized by establishing new process, which deliberately avoided harsh the level of baseline lung and sinus disease with detergents; shortened production time (by 70%); CT scans and lung function tests and establishing a and increased the efficiency of the entire process. plan for regular follow-up to prevent lung disease Caprylate was used for rapid virus inactivation and progression. as an additional purification step.The trial was powered to demonstrate non-inferiority showing 5. Prompt institution of appropriate antibiotic that Gamunex was at least as effective as therapy, especially in patients with chronic or Gamimune N 10%.Yet,Gamunex showed in virtually recurrent disease is an important part of treatment. all end-points, including incidence of validated infections, surprising differences in efficacy that 6.The importance of appropriate dosing regimens challenge current perceptions that all products are specific to the needs of the individual patient expected to provide similar clinical outcomes. In should be recognized. particular, the incidence of validated infections was reduced to a level not previously reported in antibody- 7. Differences among IGIV products (tolerability, deficient PIDD patients (32). Controlled trials such risk of adverse effects, recommended rates of as this one suggest that some differences in infusion and potentially efficacy) must be coupled preparation and formulation might affect clinical with the needs of the patient to optimize outcome. outcomes. Confirming studies are needed to learn more about this intriguing possibility. 8. Physicians should make an effort to learn more How these differences potentially affect functional about the products that have been carefully and activity of the IgG molecule, IgG circulating half-life stringently tested. or other biologic functions remains to be determined.

12 Immune Deficiency Foundation: Clinical Focus October 2003 October 2003 Immune Deficiency Foundation: Clinical Focus 13 14 Immune Deficiency Foundation: Clinical Focus October 2003 References 1. Fischer A. diseases:An experimental 17. van Furth R, Leijh, PC, and Klein F. Correlation between model for molecular medicine. Lancet 357:1863-1869, 2001. opsonic activity for various microorganisms and composition of 2. Stuckey M, Quinn PA and Gelfand EW. Identification of gammaglobulin preparations for intravenous use. J. Infect. Dis. ureaplasma urealyticum (T-stain mycoplasma) in a patient with 149:511-517, 1984. polyarthritis. Lancet 2:917-920, 1978. 18. van Furth R, Braat AG, Leijh PC, and Gardi A. Opsonic activity and 3. Roifman CM, Rao CP,Lederman HM, Lavi S, Quinn P and Gelfand EW. physiochemical characteristics of intravenous immunoglobulin Increased susceptibility to mycoplasma infection in patients with preparations. Vox. Sang. 53:70-75, 1987. . Amer J Med 80:590-594, 1986. 19. Givner, LB. Human immunoglobulins for intravenous use: 4. Gelfand EW. Intravenous gammaglobulin therapy in Comparison of available preparations for group B streptococcal immunocompromised patients. In: Intravenous Gammaglobulin antibody levels, opsonic activity and efficacy in animal models. Therapy,RJ Garner and RA Sacher, eds. American Assoc,Blood Pediatrics 86:955-962, 1990. Banks (Arlington,VA) pp.31-46, 1988. 20. Steele RW,Augustine RA,Tannenbaum,AS, and Charlton RK. 5. Mohiuddin AA,Corren J, Harbeck RJ,Teague JL,Volz M and A comparison of native and modified intravenous immunoglobulin Gelfand EW. Ureaplasma urealyticum chronic osteomyelitis in a for the management of hypogammaglobulinemia. Amer. J. Med. patient with hypogammaglobulinemia. J Allergy Clin Immunol Sci. 293:69-74, 1987. 87:104-107, 1991. 21. Darling AJ. Considerations in performing virus spiking experiments 6. Roifman CM, Levison H and Gelfand EW. High-dose versus low- and process validation studies. Dev.Biol. Stand. 81:211-229, 1993. dose intravenous immunoglobulin in hypogammaglobulinaemia 22. Korneyeva M, Hotta J, Lebing W,Rosenthal RS, Franks L, and and chronic lung disease. Lancet I:1075-1077, 1987. Petteway SR, Jr. Enveloped virus inactivation by caprylate: 7. Quartier P,Debre M, De Blic J, et al. Early and prolonged A robust alternative to solvent-detergent treatment. intravenous immunoglobulin replacement therapy in childhood Biologicals 30:153-162, 2002. agammaglobulinemia:A retrospective survey of 31 patients. 23. National Institutes of Health Consensus Development Conference. J. Ped. 134:589-596, 1999. Intravenous immune globulin: Prevention and treatment of disease. 8. Gelfand EW,Reid B and Roifman CM. Intravenous immune serum Consensus statement, May 21-23, 1990.Vol. 8, No. 5. Bethesda MD: globulin replacement in hypogammaglobulinemia: A comparison Department of Health and Human Services, 1990. of high versus low dose therapy. In: Monographs in Allergy, 24. Renal insufficiency and failure associated with immune globulin Vol. 23, pp. 177-186, 1988. intravenous therapy. MMWR 48:1985-1998, 1999. 9. Kainulainen L,Varpula M, Liippo K, Svedstrom E, Nikoskelainen J, 25. Gaines AR. Acute onset hemoglobulinemia and/or hemoglobinuria and Ruuskanen O. Pulmonary abnormalities in patients with and sequelae following Rho(D) immune globulin intravenous primary hypogammaglobulinemia. J.Allergy Clin. Immunol. administration in immune thrombocytopenic purpura patients. 104:1031-1036, 1999. Blood 95:2523-2529, 2000. 10. Busse PJ, Razvi S, and Cunningham-Rundles C. Efficacy of 26. Abzug MJ, Keyserling HL, Lee ML, Levin MJ, and Rotbart HA. intravenous immunoglobulin in the prevention of pneumonia in Neonatal enterovirus infection:Virology,serology,and effects of patients with common variable immunodeficiency.J.Allergy Clin. intravenous immune globulin. Clin. Infect. Dis. 20:1201-1206, 1995. Immunol. 109:1001-1004, 2002. 27. Fischer GW,Hemming VG, Hunter KW Jr., et al. Intravenous 11. Waniewski J, Gardulf A,and Hammarstrom L. Bioavailability of immunoglobulin in the treatment of neonatal sepsis:Therapeutic g-globulin after subcutaneous infusions in patients with common strategies and laboratory studies. Ped. Infect. Dis. J. 5:171-175, 1986. variable immunodeficiency. J. Clin. Immunol. 14:90-97, 1994. 28. Stangel M, Kiefer R, Pette M, Smolka MN, Marx P,Gold R. Side effects 12. Eijkhout HW,van der Meer JWM, Kallenberg CGM,Weening RS, of intravenous immunoglobulins in neurological autoimmune van Dissel JT,Sanders LAM, Strengers RFW,Nienhuis H, and disorders.A prospective study.J Neurol, 250(7): 818-21, 2003. Schellekens PTA. The effect of two different dosages of 29. van der Meche FGA, Schmitz PIM.A randomized trial comparing intravenous immunoglobulin on the incidence of recurrent intravenous immune globulin and plasma exchange in Guillain- infections in patients with primary hypogammaglobulinemia. Barre syndrome. Dutch Guillain-Barre Study Group. N Engl J Med. Ann. Intern. Med. 135:165-174, 2001. 326(17): 1123-9, 1992. 13. Kazatchkine MD, and Kaveri SV. Advances in immunology: 30. Schiff RI, Sedlack D, and Buckley RH. Rapid infusion of Immunomodulation of autoimmune and inflammatory diseases with Sandoglobulin in patients with primary humoral immunodeficiency. intravenous immune globulin. New Eng. J. Med. 345:747-755, 2001. J.Allergy Clin. Immunol. 88:61-67, 1991. 14. World Health Organization. Appropriate use of human 31. Grillo JA, Gorson KC, Ropper AH,Lewis J, and Weinstein R. immunoglobulin in clinical practice: Memorandum from an Rapid infusion of intravenous immune globulin in patients with IUIS/WHO meeting. Bull WHO 60:43-47,1982. neuromuscular disorders. 57:1699-1701, 2001. 15. Hetherington SV,and Giebink GS. Opsonic activity of 32. Roifman CM, Schroeder H, Berger M, Sorensen R, Ballow M, immunoglobulin prepared for intravenous use. J. Lab. Clin. Med. Buckley RH, Gewurz A,Korenblat P,Sussman G, Lemm G, and the 104:977-986, 1984. IGIV-C in PIDD Study Group. Comparison of the efficacy of 16. Schroeder DD,Tankersley DL, and Lundblad JL. A new preparation IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as of modified immune serum globulin (human) suitable for intravenous replacement therapy in primary immune deficiency. A randomized administration. II. Functional characterization. Vox. Sang. double-blind trial. Intl. Immunopharm. 3:1325-1333, 2003. 40:383-394, 1981.

15 Immune Deficiency Foundation: Clinical Focus October 2003 Are all IGIVs well tolerated? Creative by Euro RSCG Life Toronto Euro RSCG Life by Creative

A review of medical literature reveals a wide range of IGIV (Immune Globulin Intravenous (Human)) related side reactions.

IGIVs are as unique as the patients whose lives depend on them.

At Bayer we believe in the discovery of new options that what’s in IGIV? address the needs of patients. next Tolerability can affect Quality of Life.

www.gamunex.com October 2003 www.IGIVnext.com Immune Deficiency Foundation: Clinical Focus 16 How much time should IGIV therapy take from patients’ lives? Creative by Euro RSCG Life Toronto Euro RSCG Life by Creative

Because all IGIVs (Immune Globulin Intravenous (Human)) are different, products can vary in terms of concentration and infusion time. Historically, patients had to choose between:

• speed of delivery or • tolerability

At Bayer we don’t think patients should have to make this what’s in IGIV? trade-off. next Bayer believes in finding Better Solutions.

17www.gamunex.com Immune Deficiency Foundation: Clinical Focus October 2003 www.IGIVnext.com The Immune Deficiency Foundation (IDF) is the national non-profit health organization dedicated to improving the diagnosis and treatment of primary immune deficiency diseases through research, education and advocacy. IDF was established more than two decades ago by concerned families of patients and their physicians. Since its inception, IDF has expanded to offer , fellowship and research opportunities and publications. IDF sponsors a biennial National Conference for patients, their families and healthcare professionals.

More information about primary immune deficiency diseases and IDF can be found at www.primaryimmune.org or by calling 1-800-296-4433.

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