Presenation Overview: IgG in PIDD: treatment goals IgG trough levels and personalizing dose IGIV vs IGSC: pros and cons today Enzyme-facilitated IgG administration Presentation by: Richard L. Wasserman, MD, PhD DallasAllergyImmunology Research Clinical Professor of Pediatrics University of Texas Southwestern Medical School Medical Director of Pediatric Allergy and Immunology Medical City Children’s Hospital Dallas, Texas

1. FRONTIERS IN IMMUNOGLOBULIN THERAPY
Richard L. Wasserman, MD, PhD
DallasAllergyImmunology Research
Clinical Professor of Pediatrics
University of Texas Southwestern Medical School
Medical Director of Pediatric Allergy and Immunology
Medical City Children’s Hospital
Dallas, Texas

2. Financial Disclosures
Faculty and Content Contributors
Consulting fees: ADMA, Baxter, Bioplasma Laboratories, Biotest,
Cangene, CSL Behring, Grifols, Kedrion.
Speakers Bureau: Baxter and CSL Behring
Research funding: ADMA, Baxter, CSL Behring and Green Cross
(South Korea), Kedrion.

3. PROGRAM OVERVIEW
• IgG in PIDD: treatment goals
• IgG trough levels and personalizing dose
• IGIV vs IGSC: pros and cons today
• Enzyme-facilitated IgG administration

4. TREATMENT GOALS

5. PIDD Prevalence
• ~ 250,000 individuals diagnosed with PIDD1
• NIH estimates at least 500,000 patients undiagnosed2
• Incidence of 1 in 2,000 live births3
• Mean diagnostic delay of 12.4 years5
– May lead to substantial morbidity and premature
mortality4
– 27% diagnosed by age 6; 51% diagnosed at ≥30 years5
1.Boyle J. J Clin Immunol. 2007;27:497-502.
2.Modell V. Immunol Res. 2007;38:43-47.
3.Bonilla FA et al. Ann Allergy Asthma Immunol. 2005;94(suppl 1):S1-S63.
4.Wasserman RL, Manning SC. Am J Otolaryngol. 2010;32:329-337.
5.IDF.
http://www.primaryimmune.org/publications/surveys/National_Patient_Survey_Report(2
007).pdf. Accessed September 2010.

6. Diagnosis – Who To Work Up For
Antibody Deficiency Disorders
• Patients whose infection history is more
prominent than typical
• Obligate evaluations
– Recurrent otitis media after age three
– Recurrent sinusitis after two surgical procedures
– Bronchiectasis (not cystic fibrosis or smoker)

7. IgG Purification
• IgG initially enriched from plasma by sequential
cold ethanol precipitation (Cohn)1
• Modern IgG products manufactured from
thousands of units of plasma
– Recovered plasma, donated blood
– Source plasma, harvested by plasmapheresis
• Purification technologies
– Ethanol precipitation, ion exchange chromatography,
caprylate precipitation, polyethylene glycol
precipitation
1. Berger M. Curr Allergy Asthma Rep. 2002.

8. IgG Production
• Anti-infective procedures
– Low pH, enzyme exposure, pasteurization,
nanofiltration, solvent/detergent treatment
• Stabilizers
– Carbohydrates - mono or disaccharides
– Amphiphilic amino acids
• Osmolality
• IgA concentration

9. Issues in IgG Product Selection
• Stability
– Lyophylized vs liquid products
• Storage
– Room temperature vs refrigerated
• Concentration
• Osmolality
• Stabilizer – carbohydrate vs amino acid
• IgA content

10. Goals of IgG Therapy
• Improved patient outcome usually measured
by infections per year
• IgG level
– Used for 30 years to monitor therapy
– Predicts infection frequency
– Does not reliably predict AUC
• Specific antibody concentrations may be more
useful than total IgG concentrations

11. PERSONALIZING DOSE

12. IgG Dose
• IgG dose has evolved from a dose of
100 mg/kg before 1982
• Laboratory monitoring of IgG therapy has
focused on trough IgG serum concentrations
• 30 years experience has supported the use of
higher IgG doses to achieve higher trough
serum levels
• There is no evidence that IgG peak impacts
efficacy – never studied???

13. IgG Trough Levels vs. % CVID/XLA Patients with <4.5, <2.5, vs 0 Infections/yr
Lucas M et al. J Allergy Clin Immunol. 2010..

14. IgG Levels By Decade
Lucas M et al. J Allergy Clin Immunol. 2010.
Blue - 1980 -89
Red - 1990-99
Yellow - 2000-07
A – Trough
B – Dose
C - No. of Infections

15. Relation of IgG Dose to Trough Level
Trough IgG increases 121 mg/dL for every 100mg/kg dose increase
Orange et al. Clin Immunol. 2010. .

16. Relation of IgG trough level to pneumonia
incidence
Every 100mg/dL trough level increase
decreases pneumonia incidence by 27%
Orange, et. al. Clin. Immunol. May 2010, 137:21-30

17. Biologic Trough IgG
Biologic IgG Level in Primary Immunodeficiency
Disease: The IgG Level That Protects
Against Recurrent Infection
Bonagura VR et al. J Allergy Clin Immunol. 2008.

18. IgG Ideal Dosing
The appropriate dose of IgG is the
dose that keeps the patient well!

19. IgG Administration Options
• IGIM – intramuscular
• IGSC – subcutaneous
• IGIV – intravenous
• IGHy* - enzyme facilitated subcutaneous
*Investigational agent. FDA approval pending as of May 1, 2013

20. IGIV vs IGSC: Pros and Cons Today

21. IGIM
• Routine from 1950s to 1982 in the US and
most of the world
• Dose 100 mg/kg every 3 weeks
• Significant pain associated with injections
• Reduced invasive infections
• No impact on the development of
bronchiectasis

22. IGIV
• Introduced in US in 1982
• In 1982 the dose was 100-200 mg/kg/mo
• Standard of therapy in the US from 1980s to
2010s
• “Rate-related” side effects
– Headache, fever, sinus tenderness, cough,
myalgias, malaise, etc.
• Serious side effects
– Renal failure, aseptic meningitis, thrombosis

23. Technical Aspects of IGIV Therapy
• Intravenous access is required and usually
requires trained medical personnel
• Dose – limited only by fluid tolerance
• Infusion interval may be as long as 4 weeks,
reported intervals as short as 10 days
• Infusion location of care may be the
office/clinic, infusion center, or home
• Rate-related side effects affect a significant
minority of patients

24. IgG Pharmacokinetics - IV
• Endogenous IgG is contained 50% intravascular and
50% in the interstitial space
• IV administration
– Initial high peak concentration
– Redistribution phase
– Catabolism (1st order kinetics – concentration dependent)
• The US FDA applied the concept of area under the
time/concentration curve (AUC) bioequivalence as a
surrogate for adequate treatment based on
observations of small molecule efficacy (e.g.,
antibiotics) to IgG therapy in the 2000s.

25. IGIV Area Under the Curve

26. IGSC
• First used by Bruton in 1953
• “Rediscovered” in the early 1980s – Berger
• Variable adoption – IMIG product used
– High in Scandinavia, variable in the rest of Europe
– Low in the US
• Increased interest in the US in late 1990s
• IGSC-specific products introduced into the US
– Increased adoption in the US and Europe
Berger M. Clin Immunol. 2004.

27. Technical Aspects of IGSC Therapy
• Standard “in-label” procedures are often modified by
experienced immunologists to minimize side effects
and optimize the patient experience
• Initiation of therapy – transition from IV vs initial
therapeutic approach
• Infusion sites – no. and selection/volume per site
• Needles, pumps
• Infusion rates
• Infusion interval – daily, weekly, biweekly
• Infusion site reactions
• Systemic reactions

28. Commonly Used IGSC Sites

29. IgG Pharmacokinetics - IGSC
• Absorption from the infusion site – 2-3 days
• No peak as one sees with IGIV
• When dosed every 7 days there is minimal
variation in IgG level
• To achieve AUC bioequivalence IGSC must be
dosed higher than IGIV
– 10% and 16% products – 137% of IV dose
– 20% product – 153% of IV dose
• There are no data supporting the value of AUC
bioequivalence in judging IgG dose adequacy
• In Europe IGSC is dosed at 100% of the IGIV dose

30. IgG Levels: IV vs SC
Berger M. Clin Immunol. 2004.

31. Correlation of Annualized Rate of Infections Other Than aSBI from
SCIG Efficacy Studies
Berger M. J Clin Immunol. 2011.
Correlation of annualized
rate of infections other than
aSBI
with steady-state serum IgG
level studies listed in Table I.
Y-axis is the
annual rate of infections
other than aSBI,
episodes/subject/year. X-axis
is mean serum IgG level at
steady state, mg/dl

32. Common Concerns About IGSC
• Patients
• Fear of needles
• Fear of pumps
• Fear of responsibility
• Practitioners
• Dose conversion factors
• Frequency
• Pumps

33. Choices in IgG Therapy:
Flexibility and Patient Satisfaction
• Dosing
• Schedule
• Number and location of sites
• Method of delivery
• Needles
• Pumps

34. IgG Replacement: IGIV vs IGSC

35. ENZYME-FACILITATED IgG
ADMINISTRATION

36. IGHy
• Enzyme-facilitated IGSC
• Hyaluronidase
– Digests hyaluronan, the major constituent of the
subcutaneous space
– Enhances bulk fluid flow
• Enables rapid infusion of high dose IgG into
the subcutaneous space

37. Overcoming SQ Barriers Components of the SQ Space
Subcutaneous Administration Barriers:
• Rate and volume of SQ administration
is limited by the flow restrictions
caused by the interstitial matrix
• The 3-D interstitial matrix comprises a
structural network that contains:
1. Collagen – structural
2. Elastin – structural
3. Hyaluronan (hyaluronic acid) –
fills the space
Day TD. J Physiol. 1952. CONFIDENTIAL

38. Hyaluronan
1. Forms large, random coil structures
2. Binds large quantities of water
3. Restricts flow through the interstitial matrix
1. Degraded by naturally secreted protein:
hyaluronidase
2. Turnover is approximately every 5 days
(unlike other stable structural components)
• Hypothesis: Can we take advantage of this
natural turnover process to temporarily increase
the permeability of the interstitial matrix using
recombinant hyaluronidase?
CONFIDENTIAL
• What it does:
• How it’s regulated:
Day TD. J Physiol. 1952.
Laurent TC, Fraser JR. FASEB J. 1992.
Tammi MI et al. J Biol Chem. 2002.
Stern R. Glycobiology. 2003.
Laurent UB et al. Exp Physiol. 1991.

39. Mechanism of Action of Hyaluronidase
· Focal depolymerization of hyaluronan increases hydraulic conductivity in the
interstitium increasing rates of infusion/injection
· Increased dispersion decreases residence time in the interstitium
· More rapid uptake leads to better pharmacokinetics resulting in increased
bioavailability
· Because of the of short enzyme half-life and rapid endogenous substrate
turnover in the skin, the change is rapidly reversed

40. IGHy – IgG + Human Hyaluronidase*
• Enzyme facilitated subcutaneous IgG infusion
– Human recombinant hyaluronidase is infused
subcutaneously
– The subcutaneous needle hub is then connected to an IgG
reservoir
– IgG is infused
• Rate up to 300 mL/hr
• Volume up to 600 mL/site
*At this time, the US FDA is evaluating a Biologicals Licensing Application for hyaluronidase-facilitated
subcutaneous infusion of IgG. It is not approved for use in the US.

41. Pharmacokinetics of Enzyme-Facilitated IGSC Infusion
(Animal Model)
Concentrations of radiolabeled IgG1 (10 mg/kg) administered via IV,
intradermally (ID), or ID + rHuPH20 in rodent model.
Gamma counting expressed as counts per minute (Counts) per mL of blood.
1.81 E+06
1.61 E+06
IgG Serum Levels (Counts/mL) Time (Hours)
IgG 10 mg/kg ID
IgG 10 mg/kg ID + rHuPH20
IgG 10 mg/kg IV
0 10 20 30 40 50 60 80 90 100 110 120 130
1.41 E+06
1.21 E+06
1.01 E+06
8.10 E+05
6.10 E+05
4.10 E+05
2.10 E+05
1.00 E+04
70
rHuPH20 increases Cmax and decreases Tmax for large molecule therapeutics
More rapid absorption (Ka) results in shorter residence time and increased systemic bioavailability
Adapted from: Bookbinder LH, Hofer A, Haller MF, et al. J Control Release. 2006.

42. IGSC vs IGHy Infusion
IGSC site 15ml

43. IGHy Pivotal Trial
• Primary outcome
– Less than 1 serious acute bacterial infection per
patient year
• Secondary outcomes
– Infuse an IV equivalent dose (3 or 4 week)
– Infuse at an IV equivalent rate
– Any infection
– Local adverse events
– Systemic adverse events
Wasserman RL, Melamed I, Stein MR, et al.
J. Allergy Clin Immunol. 2012. 130:951-57.

44. PKiv vs PKsq for IGHy Study Patient
AUC IV vs SC 97.3%

45. IGHy Pivotal Trial Data
• Primary outcome met: < 1 serious acute bacterial
infection per patient year
• Secondary outcomes
– Any infections – fewer than during IGIV phase
– IV dose achieved in 96.6% of patients
– Maximum dose per site 600 mL
– Mean infusion duration 2.2 hours
– Mean infusion rate 163.2 mL/hr
– Infusion site reaction rate 0.03/infusion
– Systemic reaction rate 9% of infusions

46. CASE PRESENTATIONS

47. Case Presentation 1
• 24-year-old female with CVID
– IGIV therapy for 14 years
– Current dose 575 mg/kg/mo
– Recent IgA 41 mg/dL, IgG 997 mg/dL, IgM 17 mg/dL
• Complains of malaise and fatigue
– Decreased intellectual function before infusion
– Begins 5 days before infusion, resolves day after infusion
– Six episodes of antibiotic-responsive purulent rhinorrhea
in the past 12 months

48. Case Presentation 2
• 27-month-old, new diagnosis of common
variable immunodeficiency, weight 12 kg
• “In label” IGSC therapy
– Intravenous infusion of 6 g
– One week later begin IGSC 2 g/week
• Alternative approaches to initiating IGSC
– 2 g daily for 4 days then weekly

49. Case Presentation 3
• 32-year-old male CVID patient treated with
IGIV for 6 years
– Debilitating migraines begin 6 hours after infusion
for the past 6 months
– Pre-medications (steroids, NSAIDs, antihistamines)
provide limited benefit
– No difference with 3 different products
• Alternatives in treatment

50. Case Presentation 4
• 18-year-old XLA patient has done well on IGIV
for 16 years.
– Requires treatment antibiotics less than once a
year
– No problems with IV access or IgG side effects
• Leaves to attend college out of town
– Therapeutic alternatives

51. Summary
• The correct IgG dose is the dose that keeps the
patient well
• The ideal dose, route of administration, and dosing
interval is individual to the patient
• IGIV allows infrequent dosing but results in
significant variations in IgG level between infusions
• IGSC may be given from daily to every 14 days
enhancing patient control and maybe adherence
• For some patients, IGHY may represent the
advantages of both IV and SC administration