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IgPro20, the Polyneuropathy and Treatment with Hizentra® study (PATH), and the treatment of chronic inflammatory demyelinating polyradiculoneuropathy with subcutaneous IgG

    Melvin Berger

    *Author for correspondence:

    E-mail Address: Mel.Berger@cslbehring.com

    CSL Behring, LLC. King of Prussia, PA 19406, USA

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    ,
    Thomas Harbo

    Department of Neurology, Aarhus University Hospital, Aarhus, Denmark

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    ,
    David R Cornblath

    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

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    &
    Orell Mielke

    CSL Behring, GmbH. Marburg, Germany

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    Published Online:16 May 2018https://doi.org/10.2217/imt-2018-0036

    Abstract

    Subcutaneous IgG (SCIG) administration may be preferred over the intravenous route (IVIG) in chronic inflammatory demyelinating polyneuropathy (CIDP) because it minimizes ‘end of cycle’ treatment-related fluctuations, reduces systemic adverse effects, improves convenience/quality of life and potentially lowers overall costs. Early reports of the use of highly concentrated SCIG preparations suggested they were effective and well-tolerated in chronic inflammatory demyelinating polyneuropathy. This was confirmed in the Polyneuropathy and Treatment with Hizentra® study of 172 subjects randomized to receive maintenance therapy with placebo or one of two doses of IgPro20 (20% IgG stabilized with L-Proline) for 6 months. Risk of relapse was reduced by SCIG in a dose-related manner as compared with placebo. A total of 88% of polyneuropathy and treatment with hizentra subjects felt the subcutaneous method was ‘easy to learn’. Local adverse events were mostly mild or moderate, and systemic adverse events were infrequent. Some patients may prefer maintenance therapy with SCIG over IVIG.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Berger M, Rojavin M, Kiessling P, Zenker O. Pharmacokinetics of subcutaneous immunoglobulin and their use in dosing of replacement therapy in patients with primary immunodeficiencies. Clin. Immunol. 139(2), 133–141 (2011).Crossref, Medline, CAS, Google Scholar
    • 2 Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clin. Immunol. 112(1), 1–7 (2004).Crossref, Medline, CAS, Google Scholar
    • 3 Berger M, McCallus DE, Lin CS. Rapid and reversible responses to IVIG in autoimmune neuromuscular diseases suggest mechanisms of action involving competition with functionally important autoantibodies. J. Peripher. Nerv. Syst. 18(4), 275–296 (2013). • Good review of mechanisms which underlie rapidly reversible effects of IgG therapy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).Crossref, Medline, CAS, Google Scholar
    • 4 Pollard JD, Armati PJ. CIDP - the relevance of recent advances in schwann cell/axonal neurobiology. J. Peripher. Nerv. Syst. 16(1), 15–23 (2011).Crossref, Medline, Google Scholar
    • 5 Querol L, Devaux J, Rojas-Garcia R, Illa I. Autoantibodies in chronic inflammatory neuropathies: diagnostic and therapeutic implications. Nat. Rev. Neurol. 13(9), 533–547 (2017).Crossref, Medline, CAS, Google Scholar
    • 6 Allen JA, Berger M, Querol L, Kuitwaard K, Hadden RD. Individualized immunoglobulin therapy in CIDP. J. Peripher. Nerv. Syst. doi:10.1111/jns.12262 (2018) (Epub ahead of print).Google Scholar
    • 7 Markvardsen LH, Christiansen I, Andersen H, Jakobsen J. Headache and nausea after treatment with high-dose subcutaneous versus intravenous immunoglobulin. Basic Clin. Pharmacol. Toxicol. 117(6), 409–412 (2015).Crossref, Medline, CAS, Google Scholar
    • 8 Nicolay U, Kiessling P, Berger M et al. Health-related quality of life and treatment satisfaction in North American patients with primary immunedeficiency diseases receiving subcutaneous IgG self-infusions at home. J. Clin. Immunol. 26(1), 65–72 (2006).Crossref, Medline, CAS, Google Scholar
    • 9 van Schaik IN, Bril V, van Geloven N et al. Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebo-controlled, Phase III trial. Lancet Neurol. 17, 35–46 (2018). •• The Phase III PATH study proved the efficacy and safety of IgPro20 in CIDP, resulting in regulatory approval of IgPro20 for use in CIDP.Crossref, Medline, Google Scholar
    • 10 Bolli R, Woodtli K, Bartschi M, Hofferer L, Lerch P. L-Proline reduces IgG dimer content and enhances the stability of intravenous immunoglobulin (IVIG) solutions. Biologicals 38(1), 150–157 (2010).Crossref, Medline, CAS, Google Scholar
    • 11 Spycher MO, Bolli R, Hodler G et al. Well-tolerated liquid intravenous immunoglobulin G preparations (IVIG) have a low immunoglobulin G dimer (IgG-dimer) content. J. Autoimmun. 96(Suppl. 1), 2–13 (1999).Google Scholar
    • 12 Hizentra Prescribing Information, CSL Behring LLC, King of Prussia, PA. www.hizentra.com/prescribing-information.Google Scholar
    • 13 Maeder W, Lieby P, Sebald A, Spycher M, Pedrussio R, Bolli R. Local tolerance and stability up to 24 months of a new 20% proline-stabilized polyclonal immunoglobulin for subcutaneous administration. Biologicals 39(1), 43–49 (2011). • Describes development characteristics of L-Proline stabilized high concentration ‘IgPro20’.Crossref, Medline, CAS, Google Scholar
    • 14 Berger M. L-proline-stabilized human IgG: privigen®10% for intravenous use and Hizentra® 20% for subcutaneous use. Immunotherapy 3(2), 163–176 (2011).Link, CAS, Google Scholar
    • 15 Trejo SR, Hotta JA, Lebing W et al. Evaluation of virus and prion reduction in a new intravenous immunoglobulin manufacturing process. Vox Sang. 84(3), 176–187 (2003).Crossref, Medline, CAS, Google Scholar
    • 16 Jolles S. Subcutaneous and intramuscular immune globulin therapy. www.uptodate.com/contents/subcutaneous-and-intramuscular-immune-globulin-therapy.Google Scholar
    • 17 Bonilla FA. Pharmacokinetics of immunoglobulin administered via intravenous or subcutaneous routes. Immunol. Allergy Clin. North Am. 28(4), 803–19; ix (2008). • Excellent presentation of the pharmacokietics of intravenous and subcutaneous IgG.Crossref, Medline, Google Scholar
    • 18 Waldmann TA, Strober W. Metabolism of immunoglobulins. Prog. Allergy 13, 1–110 (1969).Medline, CAS, Google Scholar
    • 19 Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 44(2), 223–226 (1994).Crossref, Medline, CAS, Google Scholar
    • 20 Reinhart WH, Berchtold PE. Effect of high-dose intravenous immunoglobulin therapy on blood rheology. Lancet 339(8794), 662–664 (1992).Crossref, Medline, CAS, Google Scholar
    • 21 Yu Z, Lennon VA. Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases. N. Engl. J. Med. 340(3), 227–228 (1999).Crossref, Medline, CAS, Google Scholar
    • 22 Wasserman RL, Melamed I, Nelson RP Jr et al. Pharmacokinetics of subcutaneous IgPro20 in patients with primary immunodeficiency. Clin. Pharmacokinet. 50(6), 405–414 (2011).Crossref, Medline, CAS, Google Scholar
    • 23 Berger M. Adverse effects of IgG therapy. J. Allergy Clin. Immunol. Pract. 1(6), 558–566 (2013).Crossref, Medline, Google Scholar
    • 24 Stiehm ER. Adverse effects of human immunoglobulin therapy. Transfus. Med. Rev. 27(3), 171–178 (2013).Crossref, Medline, Google Scholar
    • 25 Borte M, Quinti I, Soresina A et al. Efficacy and safety of subcutaneous vivaglobin(R) replacement therapy in previously untreated patients with primary immunodeficiency: a prospective, multicenter study. J. Clin. Immunol. 31(6), 952–961 (2011).Crossref, Medline, CAS, Google Scholar
    • 26 Misbah SA, Baumann A, Fazio R et al. A smooth transition protocol for patients with multifocal motor neuropathy going from intravenous to subcutaneous immunoglobulin therapy: an open-label proof-of-concept study. J. Peripher. Nerv. Syst. 16(2), 92–97 (2011).Crossref, Medline, CAS, Google Scholar
    • 27 Buclin T, Nicod M, Kellenberger S. Pharmacokinetics: repeated administration. https://sepia.unil.ch/pharmacology/index.php?id=70.Google Scholar
    • 28 dersdorfer CB, Bexon M, Edelman J et al. Pharmacokinetic modeling and simulation of biweekly subcutaneous immunoglobulin dosing in primary immunodeficiency. Postgrad. Med. 125(6), 53–61 (2013).Crossref, Google Scholar
    • 29 Gouilleux-Gruart V, Chapel H, Chevret S et al. Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: correlations with clinical phenotype and polymorphism of the neonatal Fc receptor. Clin. Exp. Immunol. 171(2), 186–194 (2013).Crossref, Medline, CAS, Google Scholar
    • 30 Lucas M, Lee M, Oksenhendler E, Chapel H. The ratio of mean daily IgG increment/mean daily dose in immunoglobulin replacement therapy in primary antibody deficiencies. J. Allergy Clin. Immunol. Pract. 3(6), 998.e2–1000.e2 (2015).Crossref, Google Scholar
    • 31 Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society–First Revision. J. Peripher. Nerv. Syst. 15(1), 1–9 (2010).Crossref, Google Scholar
    • 32 Nobile-Orazio E. Chronic inflammatory demyelinating polyradiculoneuropathy and variants: where we are and where we should go. J. Peripher. Nerv. Syst. 19(1), 2–13 (2014).Crossref, Medline, CAS, Google Scholar
    • 33 Lin CS, Krishnan AV, Park SB, Kiernan MC. Modulatory effects on axonal function after intravenous immunoglobulin therapy in chronic inflammatory demyelinating polyneuropathy. Arch. Neurol. 68(7), 862–869 (2011).Crossref, Medline, Google Scholar
    • 34 Boerio D, Creange A, Hogrel JY, Gueguen A, Bertrand D, Lefaucheur JP. Nerve excitability changes after intravenous immunoglobulin infusions in multifocal motor neuropathy and chronic inflammatory demyelinating neuropathy. J. Neurol. sci. 292(1–2), 63–71 (2010).Crossref, Medline, CAS, Google Scholar
    • 35 Lichtenstein T, Sprenger A, Weiss K et al. MRI biomarkers of proximal nerve injury in CIDP. Ann. Clin. Transl. Neurol. 5(1), 19–28 (2018).Crossref, Medline, CAS, Google Scholar
    • 36 Goedee HS, van der Pol WL, van Asseldonk JH et al. Diagnostic value of sonography in treatment-naive chronic inflammatory neuropathies. Neurology 88(2), 143–151 (2017).Crossref, Medline, Google Scholar
    • 37 Uncini A, Vallat JM. Autoimmune nodo-paranodopathies of peripheral nerve: the concept is gaining ground. J. Neurol. Neurosurg. Psychiatry (2017).Crossref, Google Scholar
    • 38 Smith KJ, Bostock H, Hall SM. Saltatory conduction precedes remyelination in axons demyelinated with lysophosphatidyl choline. J. Neurol. sci. 54(1), 13–31 (1982).Crossref, Medline, CAS, Google Scholar
    • 39 Hellmann MA, Mosberg-Galili R, Lotan I, Steiner I. Maintenance IVIg therapy in myasthenia gravis does not affect disease activity. J. Neurol. sci. 338(1–2), 39–42 (2014).Crossref, Medline, CAS, Google Scholar
    • 40 Harbo T, Andersen H, Hess A, Hansen K, Sindrup SH, Jakobsen J. Subcutaneous versus intravenous immunoglobulin in multifocal motor neuropathy: a randomized, single-blinded cross-over trial. Eur. J. Neurol. 16(5), 631–638 (2009).Crossref, Medline, CAS, Google Scholar
    • 41 Harbo T, Andersen H, Jakobsen J. Acute motor response following a single IVIG treatment course in chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 39(4), 439–447 (2009). •• Prospective study of intravenous immunoglobulin (IVIG) treatment-related fluctuations in motor function with illustrations of individual subject's responses.Crossref, Medline, CAS, Google Scholar
    • 42 Hughes RA, Donofrio P, Bril V et al. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol. 7(2), 136–144 (2008). •• Randomized study which led to first regulatory approval of IVIG for CIDP.Crossref, Medline, CAS, Google Scholar
    • 43 Latov N, Deng C, Dalakas MC et al. Timing and course of clinical response to intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy. Arch. Neurol. 67(7), 802–807 (2010).Crossref, Medline, Google Scholar
    • 44 Bril V, Banach M, Dalakas MC et al. Electrophysiologic correlations with clinical outcomes in CIDP. Muscle Nerve 42(4), 492–497 (2010).Crossref, Medline, Google Scholar
    • 45 Broyles R, Rodden L, Riley P, Berger M. Variability in intravenous immunoglobulin G regimens for autoimmune neuromuscular disorders. Postgrad. Med. 125(2), 65–72 (2013).Crossref, Medline, Google Scholar
    • 46 Rajabally YA, Seow H, Wilson P. Dose of intravenous immunoglobulins in chronic inflammatory demyelinating polyneuropathy. J. Peripher. Nerv. Syst. 11(4), 325–329 (2006).Crossref, Medline, CAS, Google Scholar
    • 47 Kuitwaard K, van Doorn PA, Vermeulen M et al. Serum IgG levels in iv. immunoglobulin treated chronic inflammatory demyelinating polyneuropathy. J. Neurol. Neurosurg. Psychiatry 84(8), 859–861 (2013).Crossref, Medline, Google Scholar
    • 48 Debs R, Reach P, Cret C et al. A new treatment regimen with high-dose and fractioned immunoglobulin in a special subgroup of severe and dependent CIDP patients. Int. J. Neurosci. 127(10), 864–872 (2017).Crossref, Medline, CAS, Google Scholar
    • 49 Berger M, Allen JA. Optimizing IgG therapy in chronic autoimmune neuropathies: a hypothesis driven approach. Muscle Nerve 51(3), 315–326 (2015).Crossref, Medline, CAS, Google Scholar
    • 50 Immune Deficiency Foundation. Treatment experiences and preferences of patients with primary immune deficiency diseases: first national survey. https://primaryimmune.org/wp-content/uploads/2011/04/Treatment-Experiences-and-Preferences-of-Patients-with-Primary-Immune-Deficiency-Disease-First-National-Survey-2002.pdf.Google Scholar
    • 51 Rojavin MA, Hubsch A, Lawo JP. Quantitative evidence of wear-off effect at the end of the intravenous IgG (IVIG) dosing cycle in primary immunodeficiency. J. Clin. Immunol. 36(3), 210–219 (2016).Crossref, Medline, CAS, Google Scholar
    • 52 Markvardsen LH, Harbo T. Subcutaneous immunoglobulin treatment in CIDP and MMN. Efficacy, treatment satisfaction and costs. J. Neurol. sci. 378, 19–25 (2017).Crossref, Medline, CAS, Google Scholar
    • 53 Markvardsen LH, Debost JC, Harbo T et al. Subcutaneous immunoglobulin in responders to intravenous therapy with chronic inflammatory demyelinating polyradiculoneuropathy. Eur. J. Neurol. 20(5), 836–842 (2013).Crossref, Medline, CAS, Google Scholar
    • 54 Markvardsen LH, Sindrup SH, Christiansen I et al. Subcutaneous immunoglobulin as first-line therapy in treatment-naive patients with chronic inflammatory demyelinating polyneuropathy: randomized controlled trial study. Eur. J. Neurol. 24(2), 412–418 (2017).Crossref, Medline, CAS, Google Scholar
    • 55 Racosta JM, Sposato LA, Kimpinski K. Subcutaneous versus intravenous immunoglobulin for chronic autoimmune neuropathies: a meta-analysis. Muscle Nerve 55(6), 802–809 (2017).Crossref, Medline, CAS, Google Scholar
    • 56 Markvardsen LH, Christiansen I, Jakobsen J. Improvement of hemoglobin levels after a switch from intravenous to subcutaneous administration of immunoglobulin in chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. Transfusion 56(10), 2443–2448 (2016).Crossref, Medline, CAS, Google Scholar
    • 57 Cocito D, Romagnolo A, Peci E et al. Subcutaneous vs. intravenous immunoglobulin in CIDP: pharmacokinetic and clinical response. J. Peripher. Nerv. Syst. 21(2), 114–116 (2016).Crossref, Medline, Google Scholar
    • 58 Harbo T, Andersen H, Jakobsen J. Long-term therapy with high doses of subcutaneous immunoglobulin in multifocal motor neuropathy. Neurology 75(15), 1377–1380 (2010).Crossref, Medline, CAS, Google Scholar
    • 59 Cocito D, Merola A, Romagnolo A et al. Subcutaneous immunoglobulin in CIDP and MMN: a different long-term clinical response? J. Neurol. Neurosurg. Psychiatry 87(7), 791–793 (2016).Crossref, Medline, Google Scholar
    • 60 Markvardsen LH, Harbo T, Sindrup SH et al. Subcutaneous immunoglobulin preserves muscle strength in chronic inflammatory demyelinating polyneuropathy. Eur. J. Neurol. 21(12), 1465–1470 (2014).Crossref, Medline, CAS, Google Scholar
    • 61 Lazzaro C, Lopiano L, Cocito D. Subcutaneous vs intravenous administration of immunoglobulin in chronic inflammatory demyelinating polyneuropathy: an Italian cost-minimization analysis. Neurol. sci. 35(7), 1023–1034 (2014).Crossref, Medline, Google Scholar
    • 62 van Schaik IN, van Geloven N, Bril V et al. Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (The PATH Study): study protocol for a randomized controlled trial. Trials 17(1), 345 (2016). • Discussion of the rationale for design of the PATH study.Crossref, Medline, Google Scholar
    • 63 RMC Trial Group. Randomised controlled trial of methotrexate for chronic inflammatory demyelinating polyradiculoneuropathy (RMC trial): a pilot, multicentre study. Lancet Neurol. 8(2), 158–164 (2009).Crossref, Medline, Google Scholar