Biol Ther (2011) 1(1):003
`DOI 10.1007/s13554-011-0009-3
`
`REVIEW
`
`New Frontiers in Subcutaneous Immunoglobulin
`Treatment
`
`Stephen Jolles ∙ Mark R. Stein ∙ Hilary J. Longhurst ∙ Michael Borte ∙ Bruce Ritchie ∙ Matthias H. Sturzenegger ∙
`Melvin Berger
`
`To view enhanced content go to www.biologicstherapy-open.com
`Received: October 28, 2011 / Published online: 14 December, 2011
`© The Author(s) 2011. This article is published with open access at Springerlink.com
`
`ABSTRACT
`
`Subcutaneous immunoglobulin (SCIG) treatment
`provides stable serum immunoglobulin G (IgG)
`levels, is associated with fewer systemic adverse
`events than intravenous immunoglobulin
`(IVIG) treatment, and offers the convenience
`of home therapy. In clinical practice, IVIG
`is still used preferentially for initiation of
`treatment in newly diagnosed patients with
`primary immunodeficiency (PI) and for
`immunomodulatory therapy, such as treatment
`of peripheral neuropathies, when high doses are
`believed to be necessary. The authors discuss
`
`recent experience in using SCIG in place of IVIG
`in these settings. SCIG has been successfully used
`for initiation of therapy in previously untreated
`PI patients. Seventeen of 18 PI patients achieved
`serum IgG levels ≥5 g/L after the loading phase.
`Daily treatment was well tolerated and provided
`opportunities for patient/parent training in self-
`infusion. SCIG has been used for maintenance
`therapy in multifocal motor neuropathy (MMN)
`in three recent clinical trials, with good efficacy
`and tolerability results. Seven of eight MMN
`patients maintained serum IgG levels of 14-22 g/L
`with a mean dose of 272 mg/kg/week, had
`stable muscle strength, and felt comfortable
`
`Stephen Jolles (*
`University Hospital of Wales, Heath Park, Cardiff, CF14
`4XW, UK. Email: jollessr@cardiff.ac.uk
`
`Michael Borte
`Hospital “St. Georg” GmbH Leipzig, Academic Teaching
`Hospital of the University of Leipzig, Leipzig, Germany
`
`Mark R. Stein
`Allergy Associates of the Palm Beaches, North Palm
`Beach, FL, USA
`
`Bruce Ritchie
`Division of Hematology, Faculty of Medicine,
`University of Alberta, Edmonton, AB, Canada
`
`Hilary J. Longhurst
`Barts and London NHS Trust London, London, UK
`
`Matthias H. Sturzenegger
`Department of Neurology, University Hospital and
`University of Berne, Berne, Switzerland
`
`Melvin Berger
`CSL Behring LLC, King of Prussia, PA, USA, and Case
`Western Reserve University, Cleveland, OH, USA
`
`Enhanced content for this article is
`available on the journal web site:
`www.biologicstherapy-open.com
`
`CSL EXHIBIT 1024
`CSL v. Shire
`
`Page 1 of 15
`
`

`

`2
`
`Biol Ther (2011) 1(1):003
`
`with self-administration. Four patients with
`polymyositis or dermatomyositis achieved
`improvement in serum creatine kinase levels
`and muscle strength with SCIG therapy. Recent
`experience with SCIG suggests that traditional
`concepts of immunoglobulin therapy may be
`challenged to increase available therapy options.
`SCIG can be used to achieve high IgG levels
`within several days in untreated PI patients
`and to maintain high serum levels, as shown in
`patients with MMN.
`
`Keywords: immunoglobulin G; immunoglobulin
`therapy; multifocal motor neuropathy; primary
`immunodeficiencies; serum levels; subcutaneous
`administration
`
`INTRODUCTION
`
`Intravenous immunoglobulin (IVIG) has been the
`preferred route of therapy for primary immune
`deficiencies since the early 1980s. Subcutaneous
`immunoglobulin (SCIG) administration was
`first described by Bruton in 1952.1 Later,
`SCIG administration with small pumps was
`introduced in the United States (US) and became
`widely used in Sweden and Norway.2-4 Positive
`treatment experience increased the popularity
`of the subcutaneous route among physicians
`and patients elsewhere.5,6 SCIG therapy obviates
`the need for venous access, maintains stable
`serum IgG levels, offers fewer systemic adverse
`events (AEs) when compared to IVIG, and
`is amenable to self-infusion.7-9 Self-infusion
`and home administration allow flexibility in
`adapting to the patient’s own schedule and
`are associated with improved quality of life
`compared to hospital or office-based intravenous
`treatment.10-12
`Recent IVIG products are still given mostly
`at a clinic, doctor’s office, or infusion center.
`Recently developed SCIG preparations offer more
`
`rapid infusion in addition to good efficacy and
`tolerability. These technological advancements
`prompt reconsideration of the use of SCIG in
`different indications currently reserved for IVIG.
`In current practice, SCIG has mainly been
`used for maintenance replacement therapy in
`primary immunodeficiency (PI), while IVIG
`is used for initiation and maintenance of
`replacement therapy and for the high doses
`required in immunomodulatory therapy.
`However, SCIG has the potential to play a more
`important role in indications besides PI, such as
`neuropathies and myopathies. Here, the authors
`review emerging developments in the use
`of SCIG.
`
`METHODS
`
`Studies presented here were selected for their
`contribution to the development of SCIG
`therapy beyond the established clinical practice,
`based on the authors’ experience in the field.
`An initial PubMed search was performed using
`the terms immunoglobulin, immune globulin,
`subcutaneous, PI, chronic inflammatory
`demyelinating polyradiculoneuropathy
`(CIDP), multifocal motor neuropathy (MMN),
`myasthenia gravis, Kawasaki disease, immune
`thrombocytopenia, and Guillain-Barré
`syndrome, without restriction to publication
`date or publication language.
`
`SCIG IN INITIATION OF
`REPLACEMENT THERAPY
`
`Traditionally, maintenance replacement SCIG
`therapy is preceded by a switch from existing
`IVIG therapy. Different regimens for initiating
`SCIG have been tested, but usually the first
`subcutaneous infusion is given 1 week after the
`last intravenous infusion in order to maintain
`high serum IgG levels.13-15 Thereafter, the
`
`Page 2 of 15
`
`

`

`Biol Ther (2011) 1(1):oo3
`
`average daily IgG level achieved with IVIG
`
`Eighteen patients (aged 2-65 years) received
`
`can be maintained with regular subcutaneous
`
`an initial loading dose of 100 mg/kg body
`
`infusions (Figure 1). Alternatively, however, the
`
`weight/day for 5 consecutive days followed
`
`IgG loading can be achieved directly with SCIG.
`
`by maintenance therapy with 100-200 mg/kg
`
`Study of SCIG in Previously Untreated
`Patients with P1
`
`weekly (Figure 2A). Seventeen patients (94%)
`
`achieved the target serum IgG level of 25 g/L by
`
`day 12 (1 week after completion of the loading
`
`dose) and one patient achieved the target
`
`A recently completed open-label, single-arm,
`
`IgG level by day 26. Mean IgG levels increased
`
`phase 2 study of Vivaglobin® (CSL Behring
`
`more than twofold from screening to day 12
`
`GmbH, Marburg, Germany), a 16% SCIG, in
`
`(Figure 2B)16 and remained stable for the entire
`
`previously untreated patients with P1, showed
`
`6-month maintenance phase of the study.
`
`that initial IgG loading of patients can be easily
`
`The study design allowed dose adjustments
`
`achieved with daily SCIG administration.“
`
`in week 3; however, no patient required dose
`
`Figure l . Schematic presentation ofserum IgG levels
`achieved with intravenous and/or subcutaneous
`
`administration. Serum IgG levels are presented
`schematically to illustrate the different rate ofIgG increase
`with different administration routes and regimens. The
`curves labeled IVIG and SCIG refer to treatment with
`
`IVIG or SCIG alone, without loading. The shaded area
`marked “Higher risk zone between two IVIG infusions”
`denotes the waning period of treatment effect, resulting
`in increased rate of infections in P1 or deteriorating
`muscle strength in MMN. IgG=immunoglobulin G;
`IVIG=intravenous immunoglobulin; MMN=multifocal
`motor neuropathy; PI=primary immunodeficiency;
`SCIG=subcutaneous immunoglobulin.
`
`SerumIgGconcentration
`
`Week
`
`- -- Average daily IgG level with IVIG
`SCIG
`
`— IVIG loading + SCIG maintenance
`Loading with SCIG
`i Higher risk zone between two IVIG infusions
`
`Page 3 of 15
`
`adjustment. The doses chosen at study start
`
`were maintained throughout the study and
`
`were effective in all patients.
`
`Treatment was well tolerated, with 98% of
`
`ABS being mild or moderate. Similar tolerability
`
`has been reported in P1 patients switched
`
`from IVIG to Vivaglobin in another study:
`
`in 60 patients, of whom 16 were children,
`98% of local reactions and 86% of subcutaneous
`
`infusion-related systemic AEs were mild, with
`
`only one severe systemic AE (hypotension).14
`
`The results from this study showed that
`
`protective IgG levels are achieved by initiating
`
`SCIG treatment directly, without prior IVIG
`
`loading, creating new treatment possibilities for
`
`patients with P1.
`
`SCIG in Immunomodulation
`
`Immunoglobulin treatment
`
`is considered
`
`the first choice of therapy in a number of
`
`autoimmune or inflammatory diseases. A
`
`recent report of the United Kingdom (UK)
`
`National Immunoglobulin Database identified
`
`idiopathic/autoimmune thrombocytopenia as
`
`the major hematological indication in which
`
`immunoglobulin has been used in the UK
`
`between 2008-2009.” In neurological indications,
`
`Q Springer Healthcare
`
`
`
`Page 3 of 15
`
`

`

`Biol Ther (2011) 1(1):oo3
`
`Figure 2. Initialization ofSCIG therapy in previously untreated primary immunodeficiency (PI) patients. (A) PI study
`design. Dose adjustments in patients not achieving serum IgG levels of 25 g/L by day 12 were planned for day 15 (an
`additional dose of 150 mg/kg bw) and day 19 (a dose increased to 150 mg/kg). Reproducedfi‘om BorteM et 41., 16_] Clin
`17717711010120] 1; Sep 20. [Epub ahead ofprint] (fig. 1), with kindpemziw’onfiom Springer Sa'encHBusiness Media BJJ
`(B) Increase in serum IgG levels after five consecutive daily doses of 100 mg/kg SCIG. Mean :t SD serum levels are shown.
`The arrow indicates the target for primary endpoint: IgG levels >5 g/L at day 12. bw=body weight; IgG=immunoglobulin
`G; s.c.=subcutaneous; SCIG=subcutaneous immunoglobulin.
`
`A .
`
`Study start
`Study end
`
`1 Training
`Self-administration
`
`l
`
`Week
`
`Day
`
`25
`5
`fl
`1
`“m WWWWWWWWWWWWWW
`1234512(15)l9
`
`Starting dose:
`100 mg/kg bw
`
`Maintenance dose:
`100—200 mg/kg bw
`
`Dose adjustment allowed
`if required (lgG level <5 g/I.)
`
`A Vivaglobin’ s.c.
`Primary endpoint: IgG trough levels ZSg/L on day 12.
`
`10
`
`.3).
`
`N
`
`0
`
`
`
`lgG(g/L),mean1SD
`
`Screening Day 1
`
`Day 5 Day 12 Day 19 Day 26
`Visits
`
`85% of immunoglobulin use has been reported in
`
`high peaks are necessary for treatment effect,
`
`CIDP, MMN, myasthenia gravis, or Guillain-Barré
`
`but in several conditions — particularly in
`
`syndrome.17 In the recently initiated Assessment
`
`neuromuscular diseases — patients experience
`
`of Immunoglobulins in a Long-Term Non-
`
`recurrent symptoms (muscle weakness) at
`
`Interventional Study (SIGNS), the use of IVIG and
`
`low trough levels when the next intravenous
`
`SCIG in immunodeficiencies and neurological
`autoimmune indications will be evaluated.18
`
`infusion is due.22 Studies involving several
`indications have been initiated to determine
`
`An updated summary of mechanisms of action
`
`whether equivalent-dose SCIG could be as
`
`and indications for use of immunoglobulin
`
`effective as IVIG; eliminating these low troughs
`
`therapy in immunomodulation have been
`
`published recently.19 It is not clear which of the
`
`and the attendant increase in symptoms.”29
`The use of SCIG instead of
`IVIG in
`
`many immunomodulatory mechanisms of IgG
`
`maintenance therapy in MMN, polymyositis, and
`
`are responsible for its effects in neuropathies or
`
`dermatomyositis has been reported recently.”34
`
`myopathies.”21 Effective immunomodulation
`
`is traditionally associated with high IgG doses,
`
`Crossover study of SCIG and IVIG in MN
`
`although these are not based on actual dose-
`
`finding studies. For most conditions, it has
`been assumed that the dose used in Kawasaki
`
`In a randomized, single-blinded, crossover
`
`study, nine MMN patients who showed a good
`
`syndrome and immune thrombocytopenia
`
`response to previous IVIG therapy were enrolled.
`
`(2 g/kg) is needed. It is unknown whether
`
`Responsiveness to IgG therapy was defined as a
`
`@ Springer Healthcare
`
`Page 4 of 15
`
`
`
`Page 4 of 15
`
`

`

`Biol Ther (2011) 1(1):003
`
`5
`
`decrease of ≥10% in combined dynamometric
`strength of one or more muscle groups in a
`prestudy, treatment-free period of a maximum
`10 weeks.32 Prior to entering the main study,
`muscle strength was restored by administering
`two IVIG doses as a “wash-out” treatment prior
`to the main study. In the main study, patients
`were randomized to receive SCIG (Subcuvia®,
`Baxter International Inc., Deerfield, IL, USA)
`or IVIG (Endobulin®, Baxter International Inc.)
`for a period equivalent to three IVIG treatment
`intervals (18-56 days) and then switched to
`the other treatment. SCIG was administered
`two to three times weekly, while IVIG was
`given at individually adjusted intervals. The
`two treatments were equally effective and
`the combined dynamometric strength was
`maintained in eight of nine patients during each
`intervention period; one patient was poorly
`compliant. Thus, SCIG was as effective as IVIG
`in short-term treatment. Transient injection site
`reactions during SCIG treatment were reported
`by six patients, but only one patient experienced
`sustained erythema and edema at the injection
`site that necessitated temporary reduction of
`the injected volume. Three patients on IVIG
`reported AEs: rash, phlebitis, and venous
`catheter infection.32
`
`Dose-Finding Study of SCIG in MMN
`
`In a single-center, open-label study, 10 patients
`with MMN were treated one to two times a
`week for 6 months with SCIG (GammaQuin®,
`Sanquin, Amsterdam, The Netherlands) at
`monthly doses equivalent to either 50% or
`100% of the previous IVIG dose (five patients
`in each group).31 In case of worsening of disease
`symptoms, the low dose could be doubled.
`The primary endpoint was muscle strength in
`10 predefined bilateral muscle groups, evaluated
`using the Medical Research Council Scale.
`
`In the low-dose group, one patient discontinued
`the study due to injection site reactions (local
`swelling and pain) and the remaining four
`patients experienced deteriorating muscle
`strength and had to be reloaded with IVIG,
`which resulted in improvement. Four of
`five patients in the equivalent-dose group
`maintained muscle strength throughout the
`study. The fifth patient was administered an
`IVIG loading dose and, because of the patient’s
`preference for an SCIG treatment, maintained
`on a higher SCIG dose (166% of the previous
`IVIG dose) with which muscle strength
`remained stable. The treatment was tolerated
`well, with no serious AEs and decreasing
`incidence of local reactions during therapy.
`
`Smooth Transition Protocol Study of SCIG
`in MMN
`
`A recently completed prospective, open-label,
`multicenter, phase 2 study in patients with
`MMN showed that IgG concentrations can be
`maintained over 6 months with weekly SCIG
`(Vivaglobin) administration using a protocol in
`which the dose of SCIG was increased weekly
`to maintain the serum IgG levels achieved
`with prior IVIG therapy (smooth transition
`protocol).34 After an initial run-in period,
`eight patients aged 42-66 years on stable
`IVIG treatment received weekly subcutaneous
`Vivaglobin infusions for 24 weeks (Figure 3A)34
`at doses equivalent to the calculated weekly
`IVIG dose from previous therapy. The dose
`was adjusted stepwise during the first month
`to achieve a smooth transition of the total
`administered IgG dose from monthly IVIG
`treatment to weekly SCIG infusions. With a
`mean dose of 272 mg/kg/week (corresponding
`to 1087 mg/kg/month), seven of eight patients
`maintained serum IgG levels (14-22 g/L)
`similar to those at study start and had stable or
`
`Page 5 of 15
`
`

`

`Biol Ther (2011) 1(1):oo3
`
`Figure 3. Maintenance therapy with SCIG in MMN patients. (A) MMN study design. Dose increases of 25% in patients
`with deteriorating muscle strength were planned for week 8 or 16. Reproducedfiom Witwah S etaL,”]Peripher Nerv Syst
`2011;16:92-97(Ft;g. I), with kindpermissionfiom john they 6’? Sons Ltd. (B) Maintenance of muscle strength. Muscle
`strength scores at baseline and week 24 are shown. The strengths of40 standardized muscles or muscle groups of the upper
`and lower limbs (20 on each side) were assessed according to the MRC Scale. The full scale ranges from 0-200 points, with
`200 meaning normal muscle power. Patient 2 (red cross) discontinued at week 12 due to progressive worsening despite
`dose increase. (C) Clinical scores as function ofIgG trough levels in one patient who discontinued due to treatment
`failure. Worsening in muscle strength, disability score and motor function score, in the MMN patient who discontinued
`due to treatment failure is shown together with serum IgG concentrations (IgG and motor function data available only for
`baseline and week 8 due to discontinuation after week 12). Muscle strength score was determined as described for Figure 33.
`Disability was assessed using a modified Guy’s Neurological Disability scale. The scale ranges from 0-10 points, with
`10 meaning inability to use arms and legs. Motor function score was based on 4 individually defined tasks. The scale ranges
`from 0-16 points, with 16 meaning inability to perform any task. IVIG=intravenous immunoglobulin; MMN=mutifocular
`motor neuropathy; MRC=Medical Research Council; s.c.=subcutaneous; SCIG=subcutaneous irnmunoglobulin.
`
`A.
`
`Study start
`i Training
`
`B.
`
`Study end
`Self-administration
`l
`
`Muscle strength
`maintained
`200
`
`I
`
`X
`
`I
`
`./
`
`I
`
`./
`
`./
`
`/
`
`Week
`
`1
`W
`
`2
`W
`
`3 4
`5
`8/ 16
`24
`W W W W W W W W W
`
`Week 2:
`Week 1:
`25% ofmtal 50% oftotal
`SCIG dose SCIG dose
`
`Weeks 3.24.
`100% oftoral
`SCIG dose
`
`plus last dose
`“MG
`
`Dose increase
`by25%allowed
`if required (worsening
`ofmuscle function)
`
`A Vivaglobin's.c.
`Primary endpoint: muscle strength at Week 24 with
`SCIG comparable to that with previous IVIG.
`
`-‘= A l 0
`‘5» g
`5
`E 3 100
`i: “2‘
`E v 50
`
`0
`
`C.
`
`20
`
`1
`
`2
`
`3
`
`4
`
`s
`
`6
`
`7
`
`8
`
`Patient No.
`
`- Baseline
`- week 24
`
`— 160
`
`+ IgG (gm
`+ Disability score
`'_ 150
`— 140 E -0- Motor function score
`8
`-I- Muscle stren th
`_
`m
`8
`130 U
`(MRC score)
`— 120 =4
`E,
`— 110 .1:
`w
`3°
`a
`.3
`
`— 100
`
`— 9o
`
`
`
`18
`16
`
`2
`g
`a
`e
`E g 14
`3 8 12
`.. E”
`8 =1
`10
`o a
`E "'9
`:1 ‘3‘
`:9
`
`8
`
`6
`
`go
`
`2
`
`0
`
`4 /_—‘ — 80
`
`-— 70
`
`E;
`
`0
`
`I
`4
`
`l
`8
`
`|
`12
`
`60
`
`16
`
`Week
`
`@ Springer Healthcare
`
`Page 6 of 15
`
`
`
`Page 6 of 15
`
`

`

`Biol Ther (2011) 1(1):003
`
`7
`
`somewhat improved muscle strength (Figure 3B).
`One patient’s muscle strength and disability
`worsened despite dose increase, resulting in
`withdrawal from the study (Figure 3C). This
`patient had a body mass index indicative of
`cachexia (<17.5 kg/m²), suggesting that IgG
`absorption from the subcutaneous sites may have
`been suboptimal. Patients felt comfortable with
`self-infusion and tolerated SCIG administration
`well. Four patients did not experience any AEs.
`No severe AEs were reported and 89% of all
`AEs were mild. Only one patient experienced
`injection site reactions (edema, pruritus, and
`skin reaction). The results of this study suggest
`that rapidly raising peak IgG concentrations, as
`achieved with intravenous administration, may
`not be required for ongoing clinical efficacy
`in MMN. Due to the small number of patients
`in the study, the results need to be verified
`and expanded to other diseases requiring
`immunomodulatory therapy.
`
`SCIG Therapy in Other Neuropathies
`
`Two case reports of the use of SCIG in the
`maintenance of CIDP demonstrated stabilization
`of patients with monthly doses equivalent to
`previous IVIG treatment.33 The weekly dose was
`administered either once per week or on three
`consecutive days per week. Tolerability was
`good, with only local reactions observed.
`Initiation of immunomodulation therapy
`with SCIG in patients with polymyositis or
`dermatomyositis was reported recently.30
`Although six of the seven patients had been
`treated with IVIG at some point, four were not
`receiving IVIG at the start of the study. In these
`patients, SCIG therapy was initiated by once
`weekly administration of 0.2 g/kg/week, resulting
`in improved serum creatine kinase levels and
`muscle strength.30 Apart from mild local reactions
`in two patients, no major AEs were observed.
`
`DISCUSSION
`
`The Importance of Stable Trough IgG Levels
`
`Despite the small patient populations in the
`studies described above, it appears that both
`intravenous and subcutaneous regimens can be
`used in the initiation of replacement therapy in
`PI and maintenance of patients with MMN.
`It has been suggested that a minimal IgG
`concentration (5 g/L) is required for protection
`from infections in immunodeficiencies35-37
`and that higher serum IgG levels result in
`better protection.38-40 Thus, achievement of an
`optimal serum IgG level has become a primary
`target of therapy.41 Patient databases, such as
`the European Society for Immunodeficiencies
`(ESID) online registry, clearly suggest improved
`efficacy at higher serum IgG levels. For
`example, in patients with common variable
`immunodeficiency, infection rate and number
`of days spent in hospital decrease substantially
`as IgG levels increase from <5 g/L to >7 g/L.41
`In two recent studies of IgPro20 (Hizentra®,
`CSL Behring, Berne, Switzerland) in PI, using
`median IgG doses of 113.9 and 213.2 mg/kg,42,43
`mean IgG trough levels of 8.10 and 12.53 g/L,
`respectively, were achieved. There were no
`serious infections and the corresponding rates
`of non-serious infections were 5.18 versus
`2.76 infections/patient/year, respectively.
`The correlation between IgG levels and
`clinical outcomes in MMN is illustrated
`with data for one patient from the smooth
`transition protocol study, whose IgG levels
`failed to increase, probably due to the low
`body fat, with associated worsening of disease
`symptoms (see Figure 3C).34 It remains to be
`established whether stable IgG trough levels are
`as effective in autoimmune-mediated disorders
`as they are in PI. After the pioneering work of
`Imbach et al. in immune thrombocytopenia,44
`
`Page 7 of 15
`
`

`

`8
`
`Biol Ther (2011) 1(1):003
`
`clinicians have used similar high doses of IVIG,
`without dose ranging or alternative treatment
`schedule studies, for the successful treatment
`of other disorders with autoimmune and/or
`inflammatory pathogenesis.
`
`Active Choice for Patients
`
`With increasingly widespread use of SCIG,
`patients have the opportunity to choose a
`treatment schedule to fit a lifestyle, family
`activities, and personal preference. Physicians
`should take into account both clinical and
`lifestyle factors when selecting the route of
`administration (Table 1). Important clinical
`factors are venous access and the tolerability
`of the IgG product used.45 Particular emphasis
`should be placed on the timely and thorough
`patient characterization to ensure that risk
`factors for AEs are identified before treatment
`with IVIG or SCIG is chosen. Underlying
`conditions predisposing to acute renal
`insufficiency after IVIG administration have
`been adequately described and may include
`renal insufficiency, diabetes mellitus, volume
`depletion, sepsis, paraproteinemia, high titer
`of rheumatoid factor, and advanced age.46 High
`serum viscosity may lead to vascular events such
`as thromboembolism and a history of migraine
`has been associated with an increased risk of
`aseptic meningitis after IVIG.46-48
`Patients’ attitudes to IVIG and SCIG are based
`on both preferences and concerns. Patients who
`live at a distance from doctor’s office or infusion
`center, as well as those who are employed or
`travel frequently usually prefer to infuse at
`home. Patients making this choice are willing to
`complete the training and take responsibility for
`the treatment. A preference for clinic or infusion
`center IVIG therapy is observed among the
`elderly, the unemployed, those with aversion to
`needles, and those with fear of facing potential
`
`AEs at home.11,12,49,50 Some patients prefer home
`therapy regardless of the administration route11
`and in that case SCIG therapy may often be
`more appropriate. The safety and security of
`the patient’s home environment, the patient’s
`schedule and availability during business hours,
`and the level of support the patient receives
`from family and physician are crucial factors in
`decision making. In addition, selecting one route
`of administration over the other must take into
`consideration the different AE profiles of IVIG
`and SCIG products: IVIG is more frequently
`associated with systemic AEs, such as headache,
`nausea, and fatigue;51 SCIG administration is
`largely free of these AEs, but may cause infusion
`site reactions, such as swelling and redness.36
`The treatment options available in clinical
`practice are extremely diverse. The same IgG
`dose can be administered in several different
`ways depending on the patient’s preference. Slow
`overnight administration, fast infusion with two
`pumps (less than 1 hour), and frequent, rapid
`manual (push) infusions all are viable options.
`With the frequent push method, a volume of
`3-20 mL of Vivaglobin can be easily administered
`daily or on alternate days without the cost or
`complications of a mechanical pump.21,22
`
`New Products Allow Faster Subcutaneous
`Infusions
`
`Preparations for intramuscular immunoglobulin
`(IMIG) administration were the first products
`to be infused subcutaneously.8,9,52 Infusions
`were initially very slow (10-20 mL over several
`hours), but as the improved tolerability of
`SCIG was recognized, infusion rates were
`increased. 3,11,53 Currently available 16%
`products are infused at 10-20 mL (1.6-3.2 g) per
`hour (Table 2).14,15 The recent introduction of a
`20% product (Hizentra), specifically formulated
`for subcutaneous use, allowed even higher
`
`Page 8 of 15
`
`

`

`Biol Ther (2011) 1(1):003
`
`Table 1. Key features of intravenous immunoglobin (IVIG) and subcutaneous immunoglobin (SCIG).
`
`[VIC
`
`SCIG
`
`Efficacy
`
`Stable serum IgG levels
`
`Peak serum IgG
`
`Protection from infections
`
`Tolerability
`
`Treatment-associated systemic adverse events
`
`Treatment-related local reactions
`
`Administration specifics
`
`Need for venous access
`
`Duration ofinfusion
`
`No
`
`Yes
`
`Yes
`
`Yes
`
`None or very rare
`
`Yes
`
`Several hours
`
`Yes
`
`No
`
`Yes
`
`None or very rare
`
`Yes
`
`No
`
`Typically 1 hour or less
`
`Frequency ofinfusions
`
`Once every 2-4 weeks
`
`Typically once a week (ranges from
`
`once a day to once every 2 weeks)
`
`Convenience
`
`Self-infusion
`
`Home administration
`
`Yes (but more technically
`
`Yes (preferred by most patients,
`
`demanding)
`
`especially children)
`
`Yes (but now less frequently chosen)
`
`Yes (preferred by most patients)
`
`Training for home therapy
`
`Yes (longer and more technically
`
`Yes (typically achieved during first
`
`demanding, need for good veins)
`
`3-4 training sessions
`
`Flexibility for the patients
`
`Yes (2-4 weekly administrations are
`
`Yes (once daily, 2-4 times per week,
`
`necessary)
`
`once weekly, once every 2 weeks;
`
`Suitable for active life style (employment, school,
`
`Yes (chosen by some patients
`
`sports, frequent travel, etc)
`
`because ofthe longer gap between
`
`treatments)
`
`Indications
`
`Immunodeficiencies ('replacement-dose'
`
`indications)
`
`Autoimmune or inflammatory conditions
`
`(‘high-dose' indications)
`
`Initiation ofimrnunoglobulin therapy
`
`Maintenance immunoglobulin therapy
`
`IgG=immunoglobulin G.
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`pump or push infusion)
`Yes
`
`Yes
`
`Yes, increasingly used in
`
`neurological indications
`
`Yes, evaluated in primary
`immunodeficiencies
`
`Yes
`
`Page 9 of 15
`
`Q Springer Healthcare
`
`
`
`Page 9 of 15
`
`

`

`10
`
`Biol Ther (2011) 1(1);oo3
`
`
`
`.2534whawafifiao
`
`955.50
`
`.annnm
`
`338m
`
`“too—«F
`
`3260.505
`
`.3«>3033%
`
`338m
`
`28.diguana
`
`u_m=a_.F£93805
`
`b82033
`28.5£3.58
`
`OomN“a£2.882£0??me
`
`21£532.3
`
`mo3285VN“Eu
`
`BanBauamacqfi
`
`ofiurm2E0mm
`
`£28.:mm
`
`OomOoNa
`
`0.3a222:m£03?me
`
`3£2.65wm
`
`Dom-UoN
`
`3.5
`
`.053»258m
`
`
`
`mo3:305“00.93
`
`Sun-avg
`
`9.3ax33_aéagg
`
`$3
`
`21:08va
`
`Dow-UoNHa
`
`55:6”65ng
`
`
`
`.555».0332“.
`
`:23.338.»
`
`we83351..
`
`
`
`avioqu5:28
`
`.28£523qu
`
`3%:
`
`2
`
`3%:
`
`2
`
`2%:
`
`2
`
`A<mD.02can
`
`05.0235
`
`“5:08wm
`
`o.w.u.~a
`
`Ewlha
`
`2%:
`
`2
`
`02.82“.
`
`Sivan659:0
`
`Samoan659:0
`
`5:82.?wEWm8
`
`33,358.8
`
`A}3:3Q£3328.29.8M3:5
`
`comm—«£235cu
`3:335883.3333v5
`
`a:
`
`28559.0.5
`
`Animaommgm
`
`EKESE8
`
`
`
`
`
`
`
`.8358523.5“gunmanE323:98£8333;.2335.E..o:«EE«0.9553:.mD2w5388:982:342&«8850v50.55580.2335.
`
`
`
`
`
`
`
`
`
`
`
`
`
`.05—sno_mo§EE_u0mH“Emma?zvonnan
`
`“Soumov5as»:23umoBmE«.553:4:33838on33v5:3=E<5mb2.1Evascucoflv$3.omokamv5m32%Evow—nu:arc—wocafifim3858333*3«EEO—mg;
`
`638m2“5vows—2:no:a:geckos“
`
`
`
`
`
`.ESfiEEaU
`
`.2835
`
`.25:35.5
`
`.coauad
`
`
`
`@5335.258
`
`«5.3%qu
`
`mafiado
`
`uuuauamfiadz
`
`95353
`
`3%:
`
`m9
`
`3:5
`
`on
`
`8503.5538Ow—
`
`5.8m
`
`93a585_abiuav
`
`93a3
`
`E5
`
`$5
`
`21:06mm
`UomNud31:05om
`
`“Ea—Em
`
`
`
`£33”6231?
`
`
`
`pan—«>393.38
`
`45you
`
`.on8333—0...
`
`is8.2
`
`WeEa2L85.9.5389
`
`55:98
`
`2:232:.RN
`
`85331.,“
`
`2855293
`gamma95$
`
`A3»?mucous—:6?%5Se8v
`
`Ame:38:31.5:%é£4503a:
`
`“sagas8
`
`535235m”
`
`1%55532
`
`88comma—a
`
`838332
`
`@ Spnnger Healthcare
`
`Page 10 of 15
`
`
`
`
`
`.Coflubmmcmflafiagoon—3393‘;ho..—Quzgum:m—aan—mogF—Em0—342»,memumummkouuauafio.Nu—Aah.
`
`
`
`
`
`
`
`
`
`Page 10 of 15
`
`

`

`Biol Ther (2011) 1(1):003
`
`11
`
`flow rates: up to 50 mL (10 g) per hour42 or
`70 mL (14 g) per hour43 without compromising
`local tolerability in two phase 3 trials.
`Other tools for optimization are based on
`techniques previously used in the infusion of
`other subcutaneous medications. Hyaluronidase
`of animal origin has been used to increase tissue
`permeability by partial degradation of the
`extracellular matrix, which is a significant barrier
`to subcutaneous delivery. The development of
`recombinant human hyaluronidase (rHuPH20)
`has also opened new possibilities for IgG
`administration.21,54,55 Implanted subcutaneous
`infusion ports may help the infused fluid
`to distribute more evenly into the tissue;
`thus, potentially allowing increased volumes
`and shortened infusion times. However,
`with any implanted device in the setting of
`immunodeficiency, the risk of infection would
`need to be considered.
`
`Subcutaneous Administration and
`Home Therapy Reduce the Cost of
`Immunoglobulin Treatment
`
`Several studies have compared the costs of IgG
`treatment with subcutaneous versus intravenous
`and home versus hospital/office administration.
`The total yearly cost of home therapy was
`found to be 50% of the cost of hospital-based
`therapy in Sweden, Denmark, and Norway,
`and the out-of-pocket costs of patients were
`reduced by 85%.53 However, the reduction in
`costs was partially due to the substantially lower
`price of the IMIG used for the subcutaneous
`route. In Germany, SCIG treatment was found
`to be less expensive than IVIG treatment by
`approximately 50% due to the substantially
`reduced costs for treatment and diagnostic
`procedures, as well as the time for sick leave
`of caregivers of pediatric patients.56 A therapy-
`related cost reduction of 50% was reported in
`
`two case studies of patients with CIDP who
`switched from IVIG to SCIG receiving equivalent
`doses.33 A study performed by the Canadian
`Government Agency for Drugs and Technologies
`in Health (CADTH) provided data showing that
`home administration of IVIG or SCIG in patients
`with PI in Canada would be more cost-effective
`than hospital/office administration: the overall
`costs for self-administered IVIG (100%) and self-
`administered SCIG (103.6%) were lower than
`the costs for conventional hospital-administered
`IVIG therapy (113.5%).57 Thus, there remain
`potential savings that are independent of route,
`home administration, and drug costs.
`More pharmacoeconomic studies in Europe
`and the USA will be needed to evaluate the
`costs of immunoglobulin treatment, including
`products, healthcare personnel, hospital and
`facility charges, and infusion equipment, which
`add to the overall costs of treatment.58 These
`studies should take into consideration the value
`to the patient and family of costs now required
`for travel to the office or clinic, and time spent
`waiting for IVIG administration. The current
`clinical practice gives the general perception
`that home therapy and/or self-infusion are
`cost-neutral in most countries, but offer the
`added benefit of improvements to patients’
`quality of life.12,59 Additional potential sources
`of cost reduction with optimal immunoglobulin
`replacement therapy are the improved treatment
`efficacy and good tolerability of the currently
`used products, resulting in lower costs for
`the treatment of disease-specific symptoms
`(eg, recurrent infections in patients with PI),
`maintenance of the ability to ambulate and
`conduct activities of daily living (in neuropathies/
`myopathies), and alleviation or treatment of AEs.
`A potential source of increased cost for SCIG
`therapy in the US would be the current Food and
`Drug Administration (FDA) recommendation to
`use higher doses