Immunoglobulin products for use in the treatment of chronic inflammatory demyelinating polyneuropathy - Patent Application 2007023333

Abstract

To provide immunoglobulin products for use in treatment of chronic inflammatory demyelinating polyneuropathy, and specifically, provide efficacious dosing regimens.SOLUTION: The present invention provides immunoglobulin products for use in treatment of chronic inflammatory demyelinating polyneuropathy (CIDP), where the immunoglobulin products are to be administered at a fixed dose chosen in the range of 0.1-0.4 g / kg patient weight every 5-10 days.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an immune globulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy. In particular, the present invention provides an effective dosing regimen. [Background technology]

[0002] Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease that specifically targets the myelin sheath of peripheral nerves, causing progressive weakness and sensory loss. Nerve root swelling is also a hallmark of the disease. CIDP can occur at any age and gender, but is more common in young adults and more common in men than women.

[0003] CIDP causes peripheral neuropathy manifested by loss of sensation, weakness, or pain alone or in combination in the upper and lower limbs, or other parts of the body. It can cause symmetric or multifocal neuropathy, affecting proximal or distal muscles. CIDP may be associated with certain other diseases. For example, CIDP is recognized to be diagnosed in one-third of human immunodeficiency virus (HIV)-seropositive patients referred for peripheral neuropathy. CIDP also occurs in subjects with lupus, paraproteinemia, lymphoma, or diabetes. The course of CIDP can vary greatly between individuals. Some patients experience attacks of CIDP and subsequently recover spontaneously, while others experience many attacks and only partially recover between relapses.

[0004] CIDP is diagnosed based on the clinical picture, evidence of demyelination on electrodiagnostic testing or pathologic testing of biopsied nerves, and exclusion of other known causes of neuropathy, such as genetic defects, osteosclerosing myeloma, or IgM monoclonal gammopathy.

[0005] If untreated, CIDP is characterized by an ever-increasing number of disabilities requiring physical and occupational therapy, orthotics, and long-term care. Early intervention can prevent permanent damage and disability. Current treatments for CIDP include the administration of corticosteroids, such as prednisone, prescribed alone or in combination with immunosuppressants. Immunosuppressants may also be administered in the absence of steroids. Individualized intravenous immunoglobulin (IVIG) therapy is also effective and is currently used to treat CIDP. However, such current IVIG treatments require laborious adjustment of dosing regimens to each individual patient. Summary of the Invention [Problem to be solved by the invention]

[0006] Thus, there is a need in the art for standardized, effective immunoglobulin treatments for CIDP. [Means for solving the problem]

[0007] The present invention is based on the unexpected discovery that low, fixed doses of immune globulin exhibit therapeutic efficacy in the treatment of chronic inflammatory demyelinating polyneuropathy.

[0008] The present invention provides an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, said immunoglobulin product for administration at a fixed dose selected from the range of 0.1-0.4 g / kg of patient body weight every 5-10 days. In a preferred embodiment, the immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy is In an additional preferred embodiment, the immune globulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy is administered at a fixed dose of 0.2 g / kg of patient body weight once per week.

[0009] In a preferred embodiment of the present invention, the immune globulin product is administered subcutaneously. In an additional preferred embodiment, the patient self-administers the immune globulin product. Furthermore, a single dose of the immune globulin product may be administered all at once. Alternatively, a single dose of the immune globulin product may be divided into multiple portions and administered at different times during a single administration interval. Thus, the product is convenient for the patient to use, which is beneficial for patient compliance.

[0010] The provided treatment may be administered for a variety of periods, including weeks, months, and years. It is effective and well tolerated. The provided treatment exhibits a favorable side effect profile, specifically, minimal local reactions at the injection site. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 shows the study design. [Diagram 2] Flowchart of subject disposition;CIDP = chronic inflammatory demyelinating polyneuropathy;IVIG = intravenous immunoglobulin;PP-PSDS = Per-protocol pre-randomization Safety Data Set;PPS = Per-protocol Analysis Set;PSDS = Pre-randomization Safety Analysis Set;RSDS = Rescue Drug Safety Analysis Set;SDS = Safety Analysis Set. Figure 1 shows exclusion of subjects from the RSDS and PPS. [Diagram 3] FIG. 1 shows CIDP recurrence. [Figure 4] FIG. 1 shows time to CIDP recurrence by Kaplan-Meier plot. [Diagram 5] FIG. 1 shows a summary of adverse events. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) CIDP is an acquired polyneuropathy in the peripheral nervous system with a presumed immune-mediated etiology. CIDP is characterized by symmetric weakness in both proximal and distal muscles that progressively worsens. The condition is usually, but not always, accompanied by sensory impairment, absent or decreased tendon reflexes, elevated cerebrospinal fluid protein levels, and altered electrophysiological parameters. Nerve biopsy specimens are characterized by signs of demyelination. The clinical course is either relapsing or chronic and progressive (see, e.g., Mathey EK et al., J Neurol Neurosurg Psychiatry 2015;86:973-985; Koller H et al., N Engl J Med. 2005;352(13):1343-1356), the former being much more common in young adults. CIDP is a rare disease with an estimated prevalence of approximately 1.6-8.9 per 100,000 adults and 0.5 per 100,000 children. CIDP may be diagnosed as described by the Joint Task Force of the EFNS and the PNS (Journal of the Peripheral Nervous System 15:1-9 (2010)).

[0013] The following conditions are considered to be identical or essentially identical to CIDP and are therefore encompassed within the scope of the claims: "chronic relapsing polyneuropathy," "chronic idiopathic demyelinating polyneuropathy," "chronic inflammatory demyelinating polyradiculoneuropathy," and "chronic acquired demyelinating polyneuropathy" ("CADP").

[0014] Immunoglobulin Products The term "immunoglobulin product" is intended to mean all polyclonal antibody fractions. In this regard, the term "antibody" may be used interchangeably with the term "immunoglobulin". The immunoglobulin product is obtained from mammalian, preferably human, plasma. In certain embodiments, the plasma of multiple (generally 1000 or more) healthy donors is pooled and, optionally, further processed. The term "healthy individual" refers to an individual who meets the current (at the time of donation) standard eligibility criteria for donating blood, keeping in mind that such eligibility criteria are subject to continuous improvement and modification. In some embodiments, the immunoglobulin fraction is enriched from the pooled plasma. Preferably, the immunoglobulin is purified from the pooled plasma. More preferably, the immunoglobulin is purified and enriched. In various embodiments, purified and enriched immunoglobulin G (IgG) is used.

[0015] In certain embodiments, the immunoglobulin product may contain trace amounts of immunoglobulins of different Ig classes, such as IgA or IgM. In one embodiment, the IgA concentration is 50 μg or less per 100 mg of immunoglobulin. In a preferred embodiment, the IgA concentration is 25 μg or less per 100 mg of immunoglobulin. A small amount of IgA is desirable to avoid adverse events in patients with IgA deficiency. In one embodiment, the IgM concentration is 10 μg or less per 100 mg of immunoglobulin. In a preferred embodiment, the IgM concentration is 5 μg or less per 100 mg of immunoglobulin. In various embodiments, the immunoglobulin product exhibits a protein fraction purity of greater than 90% IgG, more preferably greater than 95% IgG, and even more preferably greater than 98% IgG. In various embodiments, the immunoglobulin product exhibits a content of immunoglobulin monomers and dimers of greater than 90%, more preferably greater than 95%, and even more preferably greater than 98%. The provided product preferably exhibits a native IgG subclass distribution. In one embodiment, the immunoglobulin subclass distribution of the immunoglobulin product is 62-74% IgG1, 22-34% IgG2, 2-5% IgG3, and 1-3% IgG4. The immunoglobulin product may contain additional components such as stabilizers, for example, amino acids such as proline or glycine, or sucrose, maltose, sorbitol, albumin, nicotinamide, PEG, polysorbate 80, or others. A preferred stabilizer is an amino acid, specifically proline. In various embodiments, the immunoglobulin product comprises 10-30% (w / v) immunoglobulin. In certain embodiments, the immunoglobulin product is provided as a solution comprising at least 10% (w / v) immunoglobulin, more preferably at least 15% (w / v) immunoglobulin, and most preferably about 20% (w / v) immunoglobulin. The immunoglobulin product may comprise about 30% (w / v) immunoglobulin.Immune globulin products are virally safe against enveloped (eg, HIV, HBV, and HCV) and non-enveloped (eg, HAV and parvovirus B19) viruses.

[0016] The immune globulin product may be provided as a liquid product or a lyophilized product. In a preferred embodiment, the immune globulin product is provided as a liquid product. Such liquid products are ready to use, i.e., there is no need to reconstitute the product prior to administration. Liquid products are convenient to use as they do not require reconstitution. Thus, liquid products are particularly suitable for self-administration by the patient.

[0017] The immunoglobulin products provided exhibit shelf stability over extended periods of time. In one embodiment, the immunoglobulin products exhibit shelf stability in liquid form for at least 12 months when stored at a maximum temperature of 25° C. In a preferred embodiment, the immunoglobulin products exhibit shelf stability for at least 12 months when stored at a maximum temperature of 25° C. In liquid form, the immunoglobulin product exhibits storage stability for at least 24 months when stored at an elevated temperature of 25° C. In additional preferred embodiments, the immunoglobulin product exhibits storage stability for at least 30 months when stored at a maximum temperature of 25° C. As used herein, the term “storage stability” refers to maintaining one or more properties of an immunoglobulin product over a storage period. For example, storage stability is indicated by the absence of aggregation of immunoglobulins. In one embodiment, the immunoglobulin product's immunoglobulin monomers and dimers retain greater than 95% content during at least 12 months of storage when stored at a maximum temperature of 25° C. In additional embodiments, the immunoglobulin product's immunoglobulin monomers and dimers retain greater than 95% content during at least 24 months of storage when stored at a maximum temperature of 25° C. In one embodiment, the immunoglobulin product's immunoglobulin monomers and dimers retain greater than 98% content during at least 12 months of storage when stored at a maximum temperature of 25° C. In additional embodiments, the immunoglobulin monomers and dimers of the immunoglobulin product retain greater than 98% integrity during storage for at least 24 months when stored at a maximum temperature of 25°C.

[0018] A preferred immunoglobulin product is a product for subcutaneous administration (SCIG). The term "subcutaneous immunoglobulin G", or SCIG for short, refers to a therapeutic preparation of pooled immunoglobulin G formulated for subcutaneous administration. SCIG refers to the product as well as the preferred route of administration (subcutaneous administration). In a particular embodiment, the SCIG is VIVAGLOBIN® or HIZENTRA® (both manufactured and sold by CSL Behring).

[0019] The immune globulin product may be a product for intravenous administration (IVIG). IVIG refers to the product as well as the preferred route of administration (intravenous administration). In a particular embodiment, the IVIG is PRIVIGEN® or SANDOGLOBULIN® / CARIMUNE® (both manufactured and sold by CSL Behring).

[0020] Dosing Scheme The present invention provides a fixed dose, weight-based, immunoglobulin product that is effective in treating chronic inflammatory demyelinating polyneuropathy. As used herein, the term "fixed dose" refers to a specific weight-based dose that can be administered to every patient. The use of such a fixed dose eliminates the need for individual dose adjustments.

[0021] Specifically, the present invention provides an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, said immunoglobulin product for administration at a fixed dose selected from the range of 0.1-0.4 g / kg of patient body weight, from the range of 0.1-0.3 g / kg of patient body weight, from the range of 0.15-0.25 g / kg of patient body weight, or from the range of 0.18-0.22 g / kg of patient body weight, or at a fixed dose of 0.2 g / kg of patient body weight, every 5-10 days, every 6-8 days, or every week.

[0022] Provided herein is an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, the immunoglobulin product being administered at a fixed dose selected from the range of 0.1-0.4 g / kg of patient weight per 5-10 days. Also provided is an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, the immunoglobulin product being administered at a fixed dose selected from the range of 0.1-0.4 g / kg of patient weight per 6-8 days. Also provided is an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, the immunoglobulin product being administered at a fixed dose selected from the range of 0.1-0.4 g / kg of patient weight per week.

[0023] Provided herein is an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, the immunoglobulin product being administered at a fixed dose selected from the range of 0.1-0.3 g / kg of patient weight per 5-10 days. Also provided is an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, the immunoglobulin product being administered at a fixed dose selected from the range of 0.1-0.3 g / kg of patient weight per 6-8 days. Also provided is an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, the immunoglobulin product being administered at a fixed dose selected from the range of 0.1-0.3 g / kg of patient weight per week.

[0024] Provided herein is an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, the immunoglobulin product being administered at a fixed dose selected from the range of 0.15-0.25 g / kg of patient weight per 5-10 days. Also provided is an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, the immunoglobulin product being administered at a fixed dose selected from the range of 0.15-0.25 g / kg of patient weight per 6-8 days. Also provided is an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, the immunoglobulin product being administered at a fixed dose selected from the range of 0.15-0.25 g / kg of patient weight per week.

[0025] Provided herein is an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, the immunoglobulin product being administered at a fixed dose selected from the range of 0.18-0.22 g / kg of patient weight per 5-10 days. Also provided is an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, the immunoglobulin product being administered at a fixed dose selected from the range of 0.18-0.22 g / kg of patient weight per 6-8 days. Also provided is an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, the immunoglobulin product being administered at a fixed dose selected from the range of 0.18-0.22 g / kg of patient weight per week.

[0026] Provided herein is an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, the immunoglobulin product for administration at a fixed dose of 0.2 g / kg patient weight per 5-10 days. Also provided is an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, the immunoglobulin product for administration at a fixed dose of 0.2 g / kg patient weight per 6-8 days. Also provided is an immunoglobulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy, the immunoglobulin product for administration at a fixed dose of 0.2 g / kg patient weight per week.

[0027] Further provided is a method of treating chronic inflammatory demyelinating polyneuropathy (CIDP), comprising administering an immune globulin product to a patient in need thereof, wherein the immune globulin product is administered at a fixed dose selected from the range of 0.1-0.4 g / kg of patient body weight per 5-10 days. The particular dosing schemes described herein for immune globulin products for use in treating chronic inflammatory demyelinating polyneuropathy apply equally to any method of treating chronic inflammatory demyelinating polyneuropathy.

[0028] The immune globulin product may be administered in any suitable manner. In one embodiment, the immune globulin product is administered intravenously. In a preferred embodiment, the immune globulin product is administered subcutaneously. Subcutaneous administration may be by subcutaneous bolus injection or subcutaneous infusion. Subcutaneous infusions may be administered using an infusion pump. Subcutaneous administration of immune globulin products is advantageous because it results in a lower peak-to-trough ratio in the patient. Thus, IgG administered via subcutaneous administration remains at relatively stable levels in the patient. Such stable levels ensure optimal therapeutic efficacy.

[0029] In additional preferred embodiments, the patient self-administers the immune globulin product. Self-administration increases patient compliance; no visit to a treatment facility is required. Moreover, the administration can be integrated into the patient's daily routine at the patient's convenience.

[0030] The entire fixed dose of the immune globulin product may be administered at once, i.e. without any interruption in administration. This dose may be divided into several portions, which are administered separately, with breaks in between. Such stepwise administration may take place over the course of one day or over the course of several days. In one embodiment, the fixed dose of the immune globulin product is divided into two or more portions, which are administered over the course of one to seven days. Thus, the patient may individually decide whether they prefer to be administered the entire dose at once or to have this dose administered in several portions, over the course of one or several days.

[0031] In one embodiment, the fixed dose of the immune globulin product is administered over the course of 1 to 7 days. In additional embodiments, the fixed dose of the immune globulin product is administered over the course of 1 day. In additional embodiments, the fixed dose of the immune globulin product is administered over the course of 2 days. In additional embodiments, the fixed dose of the immune globulin product is administered over the course of 3 days. In additional embodiments, the fixed dose of the immune globulin product is administered over the course of 4 days. In additional embodiments, the fixed dose of the immune globulin product is administered over the course of 5 days. In additional embodiments, the fixed dose of the immune globulin product is administered over the course of 6 days. In additional embodiments, the fixed dose of the immune globulin product is administered over the course of 7 days.

[0032] In another embodiment, two or more fixed doses are combined and administered at correspondingly extended intervals.In such combinations, the total dose per time is maintained the same.For example, the total dose per week is 0.2g / kg patient weight, and 0.4g / kg can be administered every other week.

[0033] In one embodiment, the fixed dose of immune globulin product is doubled and is administered every 14 days. In an additional embodiment, the fixed dose of immune globulin product is tripled and is administered every 21 days. In an additional embodiment, the fixed dose of immune globulin product is quadrupled and is administered every 28 days.

[0034] In one embodiment, the immune globulin product is administered in a flexible dosing regimen. In such a flexible dosing regimen, the total dose of immune globulin product administered over time remains constant. Thus, the same amount of immune globulin product is administered over time, whether it is administered less frequently (longer dosing intervals) or more frequently (shorter dosing intervals). The dosing intervals may be longer or shorter than one week, but the total weekly dose is maintained. The invention is further illustrated by the following embodiments: -The recommended subcutaneous dose is 0.2 to 0.4 g / kg (1 mL to 2 mL / kg) of body weight per week. - Initiate therapy with an immune globulin product 1 week after the last IGIV infusion. - Any dose from daily to every other week (every 2 weeks) provided the total weekly dose is maintained A dosing interval can be used that will result in systemic serum IgG exposure equivalent to treatment with a weekly immune globulin product. - Every other week: multiply the calculated weekly dose of immune globulin product by 2. -Frequent dosing (2 to 7 times per week): Divide the calculated weekly dose by the desired number of times per week (e.g., for 3 doses per week, divide the weekly dose by 3).

[0035] The treatment offered is therefore very flexible for the patient with regard to drug administration schedules.

[0036] The treatment provided may be for an extended period of time ranging from several weeks to several years. In one embodiment, the treatment is for at least 3 months. In an additional embodiment, the treatment is for at least 6 months. In another embodiment, the treatment is for at least 12 months. In yet another embodiment, the treatment is for at least 24 months.

[0037] The offered treatment is well tolerated: at low doses, e.g. 0.2 g / kg patient weight, subcutaneous administration of immunoglobulin causes only infrequent local reactions at the injection site.

[0038] Patients who do not respond to immune globulin therapy may undergo individual dose adjustments to achieve therapeutic efficacy.

[0039] Treatment effect The treatment provided may result in various therapeutic effects. These effects include: INCAT score, R-ODS score, mean grip strength, MRC total score (8 muscle groups), and electrophysiological parameters: distal and proximal latency, compound action potential (CMAP) amplitude, nerve conduction velocity, and conduction block in three motor nerves. These effects are obtained using any of the dose ranges provided herein. In one embodiment, the effect is obtained using a fixed dose selected from the range of 0.1-0.4 g / kg patient weight per 6-8 days. In a preferred embodiment, the effect is obtained using a fixed dose selected from the range of 0.18-0.22 g / kg patient weight per 6-8 days.

[0040] The INCAT score is a 10-point rating scale covering upper and lower limb functionality and has been used successfully to assess treatment efficacy in various CIDP trials. The score for upper limb impairment ranges from 0 ("no problems with upper limbs") to 5 ("neither limb can be used for any purposeful movement"), and the score for lower limb impairment ranges from 0 ("no effect on walking") to 5 ("limited to wheelchair and unable to stand or take a few steps with assistance"). The INCAT (total) score is the sum of these two scores and ranges from 0 to 10. In the "adjusted" INCAT score, changes in upper limb function from 0 (normal) to 1 (mild symptoms) or from 1 to 0 are not recorded as worsening or improving, as these changes are considered clinically insignificant (Hughes R et al., Ann Neurol.2001;50(2):195-201;Hughes RA et al., Lancet Neurol.2008;7(2):136-144;Hughes RA, Expert Rev Neurother.2009;9(6):789-795).

[0041] The R-ODS centile score is an outcome measure capturing activity and social participation in subjects with Guillain-Barré syndrome, CIDP, and monoclonal gammopathy of unknown significance (MGUSP) associated with polyneuropathy (van Nes SI et al., Neurology. 2011;76(4):337-345). This 24-item questionnaire based on Rasch analysis ranges from the easiest tasks, such as "reading a newspaper / book" and "eating," to the most difficult tasks, such as "running" or "standing for several hours." The survey covers a wide range of everyday tasks, from basic to advanced tasks, and each task is rated as either "not possible to do," "doing with difficulty," or "doing easily."

[0042] Mean grip strength may be measured by a Martin Vigorimeter. The Martin (Tuttlingen, Germany) handheld Vigorimeter is a device that measures the strength of the small muscles of the hand, i.e., grip strength. Subjects squeeze a rubber ball placed in the palm of their hand between their thumb and index finger. Pressure is recorded via a rubber tube on a pressure gauge and expressed in kilopascals. At each assessment, subjects squeeze three times with each hand. The mean grip strength of each hand is determined.

[0043] An adapted version of the MRC sum score (Leger JM et al., Brain. 2001;124(Pt1):145-153) may be used. The MRC sum score scale may range from 0 ("no visible contraction") to 5 ("normal"). The following eight bilateral muscle pairs are assessed and the individual muscle scores and their sum score recorded: shoulder abduction, elbow flexion, wrist extension, index finger abduction, hip flexion, knee extension, ankle dorsiflexion, and big toe dorsiflexion.

[0044] Electrophysiological parameters may be assessed. Three motor nerves (two in the upper limbs and one in the lower limbs) are measured: median, ulnar, and peroneal. Stimulation points are as follows: ulnar nerve: wrist, above elbow; median nerve: wrist, elbow; peroneal nerve: ankle, below the peroneal head, lateral popliteal fossa.

[0045] In one embodiment, the treatment provided results in at least a 10% improvement in one or more of the INCAT score, R-ODS score, average grip strength, MRC total score, and electrophysiological parameters relative to placebo treatment. In a further embodiment, the treatment provided results in at least a 20% improvement in one or more of the INCAT score, R-ODS score, average grip strength, MRC total score, and electrophysiological parameters relative to placebo treatment. In a further embodiment, the treatment provided results in at least a 30% improvement in one or more of the INCAT score, R-ODS score, average grip strength, MRC total score, and electrophysiological parameters relative to placebo treatment. In a further embodiment, the treatment provided results in at least a 40% improvement in one or more of the INCAT score, R-ODS score, average grip strength, MRC total score, and electrophysiological parameters relative to placebo treatment. In additional embodiments, the treatment provided results in at least a 50% improvement in one or more of the INCAT score, R-ODS score, average grip strength, MRC total score, and electrophysiological parameters relative to placebo treatment. In additional embodiments, the treatment provided results in at least a 60% improvement in one or more of the INCAT score, R-ODS score, average grip strength, MRC total score, and electrophysiological parameters relative to placebo treatment. In additional embodiments, the treatment provided results in at least a 70% improvement in one or more of the INCAT score, R-ODS score, average grip strength, MRC total score, and electrophysiological parameters relative to placebo treatment. In additional embodiments, the treatment provided results in at least an 80% improvement in one or more of the INCAT score, R-ODS score, average grip strength, MRC total score, and electrophysiological parameters relative to placebo treatment.In additional embodiments, the treatment provided results in at least a 90% improvement in one or more of the INCAT score, R-ODS score, mean grip strength, MRC total score, and electrophysiological parameters relative to placebo treatment. In additional embodiments, the treatment provided results in at least a 100% improvement in one or more of the INCAT score, R-ODS score, mean grip strength, MRC total score, and electrophysiological parameters relative to placebo treatment.

[0046] The provided treatment results in a reduction in CIDP relapse rate in CIDP patients. In one embodiment, the provided treatment with a fixed dose selected from the range of 0.1-0.4 g / kg per 6-8 days results in a reduction in relapse rate of more than 20%, preferably more than 30%, more preferably more than 40% or even more than 50% when compared to placebo. In an additional embodiment, the provided treatment with a fixed dose selected from the range of 0.18-0.22 g / kg per 6-8 days results in a reduction in relapse rate of more than 20%, preferably more than 30%, more preferably more than 40% when compared to placebo.

[0047] In one embodiment, the treatment provided with a fixed dose selected from the range of 0.18-0.22 g / kg per 6-8 days results in a greater than 20% reduction in relapse rate when compared to placebo. In one embodiment, the treatment provided with a fixed dose selected from the range of 0.18-0.22 g / kg per 6-8 days results in a greater than 30% reduction in relapse rate when compared to placebo. In one embodiment, the treatment provided with a fixed dose selected from the range of 0.18-0.22 g / kg per 6-8 days results in a greater than 40% reduction in relapse rate when compared to placebo. In one embodiment, the treatment provided with a fixed dose of 0.2 g / kg once a week results in a greater than 20% reduction in relapse rate when compared to placebo. In one embodiment, the treatment provided with a fixed dose of 0.2 g / kg once a week results in a greater than 30% reduction in relapse rate when compared to placebo. In one embodiment, the treatment provided using a fixed dose of 0.2 g / kg once weekly results in a greater than 40% reduction in relapse rate when compared to placebo.

[0048] The provided treatment results in an increase in patients who do not experience a CIDP relapse. In one embodiment, the provided treatment with a fixed dose selected from the range of 0.1-0.4 g / kg per 6-8 days results in a greater than 30%, preferably greater than 40%, more preferably greater than 60% or even greater than 80% increase in patients who do not experience a CIDP relapse when compared to placebo. In one embodiment, the provided treatment with a fixed dose selected from the range of 0.18-0.22 g / kg per 6-8 days results in a greater than 30%, preferably greater than 40%, more preferably greater than 50% or even greater than 60% increase in patients who do not experience a CIDP relapse when compared to placebo.

[0049] The provided treatment results in a reduced probability of CIDP relapse in CIDP patients over time, when compared to placebo-treated patients. In one embodiment, the provided treatment with a fixed dose selected from the range of 0.1-0.4 g / kg per 6-8 days results in a greater than 10% reduction in the probability of relapse after 5 weeks of treatment, when compared to placebo, preferably greater than 15%, more preferably greater than 20% or even greater than 25%. In one embodiment, the provided treatment with a fixed dose selected from the range of 0.18-0.22 g / kg per 6-8 days results in a greater than 10% reduction in the probability of relapse after 5 weeks of treatment, when compared to placebo, preferably greater than 12%, more preferably greater than 13% or even greater than 15%. In one embodiment, the treatment provided with a fixed dose selected from the range of 0.1-0.4 g / kg per 6-8 days results in a reduction in the probability of relapse after 14 weeks of treatment of more than 10%, preferably more than 20%, more preferably more than 30% or even more than 40% when compared to placebo. In one embodiment, the treatment provided with a fixed dose selected from the range of 0.18-0.22 g / kg per 6-8 days results in a reduction in the probability of relapse after 14 weeks of treatment of more than 10%, preferably more than 15%, more preferably more than 18% or even more than 2 ... The provided treatment with a fixed dose selected from the range of 0.1-0.4 g / kg results in a reduction in the probability of relapse after 24 weeks of treatment of more than 10%, preferably more than 20%, more preferably more than 30% or even more than 35% when compared to placebo. In one embodiment, the provided treatment with a fixed dose selected from the range of 0.18-0.22 g / kg per 6-8 days results in a reduction in the probability of relapse after 24 weeks of treatment of more than 15%, preferably more than 20%, more preferably more than 23% or even more than 24% when compared to placebo. EXAMPLES

[0050] patient Patients were eligible if they were aged 18 years or older, had a definite or presumed diagnosis of CIDP according to the European Federation of Neurological Societies / Peripheral Nerve Society (EFNS / PNS) criteria 2010 (Van den Bergh PYK et al.; Eur J Neurol 2010;17:356-63), and had responded to IVIg treatment as assessed by the treating physician within 8 weeks prior to enrollment. The protocol was amended five times during the conduct of the study. Other than an increase in the number of subjects, these amendments did not affect the randomized treatment period.

[0051] Clinical Trial Design The study conducted was an international, multicenter, double-blind, randomized, placebo-controlled, phase III study. After screening, all eligible patients progressed through the IgG-dependent study period. Only patients determined to be IgG-dependent were enrolled in the IVIG restabilization period. This period was performed with IgPro10 (Privigen®, CSL Behring, Bern, Switzerland) at the recommended doses in the EFNS / PNS guidelines (Van den Bergh PYK et al.; Eur J Neurol 2010;17:356-63). Only patients who improved to at least the INCAT total score recorded at the screening visit and who maintained a stable INCAT total score during the last 3 weeks of the restabilization period were eligible for randomization (Figure 1).

[0052] Patients were randomly assigned in a 1:1:1 ratio to high-dose or low-dose IgPro20 (Hizentra®, CSL Behring, Bern, Switzerland) or placebo using a block randomization of 6 patients per block, stratified for region (Japan / non-Japan) using a voice / web automated response system. All patients visited the clinic at the end of the study after completing SC or dropping out for any reason during the SC treatment period.

[0053] Treatment and blinding IgPro20 or placebo was self-administered or administered by a home caregiver after appropriate site training. During the SC treatment period, the total dose / volume for all groups was based on body weight. One group received IgPro20 at 0.4 g / kg, one group received IgPro20 at 0.2 g / kg plus placebo to match volumes across all three groups, and one group received placebo alone. Weekly SC infusions were performed using an infusion pump on either 1 or 2 consecutive days during the 2 sessions. All patients and study personnel were blinded and unaware of treatment allocation. Standard measures were used to ensure adequate blinding of placebo (2% human albumin solution) and IgPro20. A "two-investigator" approach reduced the possibility of unblinding the study, minimizing bias. The "treating" physician is the first point of contact with the patient and handles all patient-related questions, adverse event (AE) evaluations, and other The first investigator was responsible for the study-related tasks. A second "evaluating" investigator was responsible for the efficacy evaluation. The evaluating investigators did not have access to any of the data collected by the treating investigators.

[0054] Outcome measures and data collection The primary outcome was defined as the percentage of patients who experienced a CIDP relapse during SC treatment or dropped out of the study for any reason during SC treatment.

[0055] CIDP relapse was defined as a worsening (i.e., increase) of at least 1 point from baseline in the adjusted INCAT total score (Hughes RA et al.; The Lancet Neurol 2008;7:136-44). Baseline score was defined as the score assessed at the end of the IVIg restabilization period. Secondary outcomes of the SC treatment period included time to the primary endpoint, between-group difference in median change from baseline to end-of-study visit in INCAT score, mean grip strength in each hand assessed using a handheld Martin Vigorimeter (Vanhoutte EK et al.; Eur J Neurol 2013;20:748-55), Medical Research Council (MRC) total score (Kleyweg RP et al.; Muscle & Nerve 1991;14:1103-9), and Inflammatory Neuropathy-Rasch-built Overall Disability Scale (Rasch-built Overall Disability Scale). The Interventional Retrograde Response Scale (I-RODS) (Van Nes SI et al; Neurology 2011;76:337-45) was used. Primary and secondary outcome measures were assessed at screening; during the IgG-dependent study and before IVIg infusion during the IVIg restabilization phase; at baseline; at all visits during the SC treatment period, including the end-of-study visit; and at all scheduled outpatient visits.

[0056] Quality of life was assessed using the EuroQoL 5-Dimension Questionnaire (EQ-5D), the Treatment Satisfaction Questionnaire for Medication (SAS-M), and the EQ-5D-M. Patients were assessed using the Time-Spreading Questionnaire for Medication (TSQM) and the Work Productivity and Activity Impairment Questionnaire for General Health (WPAI-GH) (van Schaik IN et al; Trials 2016;17:345).

[0057] To evaluate the safety and tolerability of IgPro20 vs. placebo, adverse events (AEs) per infusion and the number and percentage of patients with AEs were determined. All outcomes in the two prerandomization periods, rescue treatments, and other exploratory outcomes will be reported separately.

[0058] statistical analysis The sample size calculation was based on the null hypothesis that the percentage of patients who relapsed or dropped out during SC treatment did not increase from placebo to the low and high dose groups, and that at least one of the SCIg dose groups studied had a strictly lower percentage than the placebo group. The percentage of patients who reached the primary endpoint was assumed to be 35% for the high dose, 52% for the low dose, and 65% for placebo (van Schaik IN et al.; Trials 2016;17:345). These figures are based on data from the extension period of the ICE trial (Hughes RA et al.; The Lancet Neurol 2008;7:136-44). Using equal interval scores and an exact Cochran-Armitage trend test with a one-sided significance level of 0.025, a 90% power was required to detect a 90% increase in each treatment group in the intention-to-treat analysis based on the above hypothesis. A sample size of 58 was required. Taking into account IgG-dependence testing and patients who would not pass the IVIg restabilization period, it was estimated that up to 350 patients would be required for screening to ensure 174 patients for randomization.

[0059] For the primary outcome examining trends across the three study arms, an exact Cochran-Armitage trend test with a one-sided type I error of 0.025 was used. If the hypothesized superiority was proven, one-sided Fisher's exact test was used for subsequent pairwise comparisons: placebo vs low dose, placebo vs high dose, and low dose vs high dose. Proportions for each treatment group and corresponding two-sided 95% Wilson score confidence intervals were calculated. For all pairwise treatment comparisons, point estimates for the difference in proportions and corresponding two-sided exact 95% confidence intervals were calculated. Three prespecified sensitivity analyses using a modified definition of the primary end point examined potential bias for any reason other than CIDP recurrence (van Schaik IN et al; Trials 2016;17:345). As a complement to the primary and sensitivity analyses, two time-to-event analyses were performed, yielding Kaplan-Meier estimates. In the first analysis, patients who dropped out for other reasons were considered to have reached the end point, and in the second analysis, dropout for other reasons was a censored outcome.

[0060] Secondary endpoints are presented as median changes from baseline and were compared between the three groups using the asymptotic Jonckheere-Terpstra test (Jonckheere AR; Biometrika 1954;41:133-45). Pairwise comparisons based on median changes from baseline were performed using the one-sided Wilcoxon rank-sum test. Adjustments for multiple testing of statistical tests were made only for the primary endpoint. For this reason, all other comparisons are considered exploratory.

[0061] Primary outcomes, including all sensitivity analyses, were assessed in the intention-to-treat (ITTS) and per-protocol (PPS) populations (van Schaik IN et al; Trials 2016;17:345). Safety was assessed in the safety population, which included all randomized patients who received at least one dose of IgPro20 / placebo.

[0062] result patient Patients were enrolled at 69 sites worldwide between March 2012 and November 2015, with the last patient visit in September 2016. A total of 276 unique patients were screened. A total of 172 patients were randomized (Figure 2). All 172 patients received their assigned treatment, and 99.7% of the planned volume was actually administered. Patients tolerated a maximum volume of 50 mL per injection site with 2 to 8 parallel injection sites and a maximum infusion rate of 50 mL / hour / site, for a maximum total infusion volume of 140 mL. Infusion duration was approximately 1 hour. No patients were lost to follow-up. Table 1 shows the baseline characteristics of all randomized patients.

[0063] [Table 1]

[0064] efficacy Seventy-seven patients had a recurrence of CIDP or dropped out of the study: 36 (63%) in the placebo group, 22 (39%) in the low-dose group, and 19 (33%) in the high-dose group (Figure 3, Table 2). The absolute risk reduction (ARR) for reaching the primary endpoint was 24.6% (95% CI 6.2, 40.7) in the low-dose group and 30.4% (12.2, 46.0) in the high-dose group compared with the placebo group. Comparing the low dose with the high dose, the ARR was 5.8 (-11.4, 22.6). Both doses of SCIG were superior to placebo (p=0.007 and p<0.001). Sensitivity analysis showed that patients dropping out for reasons other than recurrence did not affect the primary endpoint outcome (Table 2).

[0065] [Table 2]

[0066] The probability of reaching the primary endpoint, assessed by time-to-event analysis, was significantly lower in both SCIG groups than in the placebo group (hazard ratio, low-dose vs. placebo: 0.49 (95% CI 0.29 to 0.84, p = 0.007); high-dose vs. placebo: 0.38 (0.22 to 0.67, p < 0.001); Figure 4; Table 2).

[0067] A complementary time to relapse analysis was performed, censoring all dropouts at dropout. Kaplan-Meier estimates of CIDP relapse alone were 22% for high-dose SCIg, 35% for low-dose SCIg, and 59% for placebo patients (Table 2). Both doses of IgPro20 were associated with lower relapse rates compared with placebo, and the probability of relapse was lower at all time points between SC weeks 3 and 25 in IgPro20-treated patients when compared with placebo-treated patients. All per-protocol analyses confirmed the results of the intention-to-treat analysis.

[0068] In the secondary outcome variables, the median changes from baseline showed a similar pattern to the primary outcomes between the different treatment groups (Table 3). In the I-RODS score, all median changes with the high and low doses were significantly better than with placebo, except for the median change with the low dose. No significant differences were observed between the two dose groups.

[0069] [Table 3]

[0070] Measures of health-related quality of life generally showed better outcomes in both SCIG arms compared with placebo (details of patients for whom outcomes were reported were not available).

[0071] safety In the placebo group, 21 patients (36.8%) had 52 adverse events over 1514 infusions; in the low-dose group, 33 patients (57.9%) had 158 adverse events over 2007 infusions; in the high-dose group, 30 patients (51.7%) had 16 adverse events over 2007 infusions. There were 114 adverse events observed over 2218 infusions. Local reactions at the infusion site occurred in 18.6% of patients and were more frequent in the SCIg group (19% of low-dose and 29% of high-dose patients compared with 7% of placebo patients; Figure 5). All local reactions were either mild (94.5%) or moderate (5.5%) and decreased in frequency during the first 8 infusions, with none leading to study discontinuation. Eleven serious AEs occurred in one placebo patient, three low-dose patients, and two high-dose patients. Only one of these 11 SAEs was assessed as causally related: one patient in the low-dose group developed an acute allergic skin reaction. This SAE led to treatment discontinuation. No hemolysis or thrombosis occurred during the SC treatment period.

[0072] Consideration The reported study provides evidence of efficacy and safety of IgPro20 in preventing CIDP relapse. Superiority of both doses of IgPro20 over placebo was demonstrated by statistically significant differences for both doses of IgPro20 during a 24-week randomized, placebo-controlled SC treatment period.

[0073] The absolute risk reduction of CIDP recurrence was 25% with the 0.2 g / kg IgPro20 dose and 30% with the 0.4 g / kg IgPro20 dose compared with placebo, using conservative endpoints that included not only CIDP recurrence but also subjects who dropped out for any other reason.

[0074] Considering only CIDP recurrences, the 0.2 g / kg IgPro20 dose prevented CIDP recurrence in 67% of subjects and the 0.4 g / kg IgPro20 dose prevented CIDP recurrence in 81% of subjects (Figure 3). The absolute risk reductions compared to placebo were 23% for the 0.2 g / kg IgPro20 dose and 37% for the 0.4 g / kg IgPro20 dose. Based on the reciprocal of these absolute risk reductions, the number of subjects needing treatment to prevent CIDP recurrence is 4-5 for the 0.2 g / kg IgPro20 dose and 2-3 for the 0.4 g / kg IgPro20 dose.

[0075] Time to CIDP recurrence (Figure 4) was evaluated, and the corresponding probabilities of CIDP recurrence based on Kaplan-Meier estimates were: placebo, 58.8%; 0.2 g / kg body weight IgPro20, 35.0%; and 0.4 g / kg body weight IgPro20, 22.4%. Hazard ratios (95% CI) for the low and high doses compared with placebo were 0.48 (0.27, 0.85) and 0.25 (0.12, 0.49), respectively. The differences observed between the 0.2 g / kg body weight IgPro20 and 0.4 g / kg body weight IgPro20 groups did not reach statistical significance.

[0076] The risk of CIDP recurrence was lower in each dose group of IgPro20 compared with placebo at all time points between weeks 3 and 25. Based on the hazard ratios, the risk of CIDP recurrence in subjects in the placebo group was two times higher than in subjects in the 0.2 g / kg IgPro20 group and four times higher than in subjects in the 0.4 g / kg IgPro20 group.

[0077] Secondary endpoints INCAT score, R-ODS centile score, mean grip strength, and MRC total score were more favorable for both doses of IgPro20 versus placebo, as were quality of life and electrophysiological parameters.

[0078] No statistically significant differences were observed on any measure between the doses of IgPro20. Surprisingly, the 0.2 g / kg IgPro20 dose is as efficacious as the 0.4 g / kg IgPro20 dose.

[0079] Over 88% of subjects indicated that the SC injection was easy to use.

[0080] Overall, SC treatment with IgPro20 was not only efficacious in preventing CIDP recurrence but also preferable to IVIG.

[0081] Adverse events, laboratory parameters, and vital signs observed during the study were consistent with the known safety profile of IgPro20. The most common AEs were local reactions, which occurred more frequently in IgPro20-treated subjects than in placebo-treated subjects. The incidence of local reaction AEs was lower with 0.2 g / kg IgPro20 compared with 0.4 g / kg IgPro20. The incidence of local reaction AEs was generally highest during the initial infusions during the SC treatment period and decreased thereafter. The incidence of causally related AEs was low, the majority of AEs were mild or moderate, and few SAEs were reported.

[0082] SC treatment was well tolerated when administered at high volumes of up to 140 mL per injection session. Subjects generally used 4 injection sites (max: 9 sites) and injected an average of 20 mL per site at an injection rate of 20 mL / hour (max: 50 mL / hour). Infusion times were approximately 1 hour.

[0083] In summary, the available evidence in this study demonstrates the efficacy and safety of IgPro20 in preventing CIDP recurrence in subjects.

Claims

1. 1. A method of manufacturing an immune globulin product for use in the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP), comprising formulating the immune globulin product in liquid or lyophilized form, wherein the immune globulin preparation is administered subcutaneously at a fixed dose of 0.2 g / kg patient weight per week, wherein the treatment results in at least a 20% improvement versus placebo treatment in one or more of INCAT score, R-ODS score, mean grip strength, MRC total score, and electrophysiological parameters, and wherein the treatment achieves a greater than 20% reduction in relapse rate compared to placebo.

2. 13. The method of claim 1, wherein the fixed dose of immune globulin product is formulated to be administered over the course of 1 to 7 days.

3. 3. The method of claim 2, wherein the doses of the immune globulin product are formulated to be administered over the course of a day.

4. The method according to any one of claims 1 to 3, wherein the treatment is carried out for at least 3 months, preferably the treatment is carried out for at least 6 months.

5. 5. The method of any one of claims 1 to 4, wherein the treatment results in at least a 50% improvement relative to placebo treatment in one or more of the following: INCAT score, R-ODS score, mean grip strength, MRC total score, and electrophysiological parameters.

6. 6. The method of any one of claims 1 to 5, wherein the immune globulin product is a ready-to-use liquid product and / or the immune globulin product does not need to be reconstituted into a liquid form prior to administration.

7. 7. The method according to any one of claims 1 to 6, wherein the immunoglobulin product exhibits a storage stability in liquid form of at least 12 months, preferably at least 24 months, when stored at a maximum temperature of 25°C.

8. The method of any one of claims 1 to 7, wherein the patient self-administers the immune globulin product.

9. The method according to any one of claims 1 to 5, wherein the immunoglobulin product is a lyophilized product.

10. The method according to any one of claims 1 to 9, wherein the immunoglobulin product has an immunoglobulin concentration of 10 to 30%.

11. 11. The method of claim 10, wherein the immunoglobulin product has an immunoglobulin concentration of 20%.

12. 12. The method of any one of claims 1 to 11, wherein the immunoglobulin subclass distribution of the immunoglobulin product is 62-74% IgG1, 22-34% IgG2, 2-5% IgG3, and 1-3% IgG4.

13. The method according to any one of claims 1 to 12, wherein the IgA concentration is less than or equal to 50 µg per 100 mg of immunoglobulin.

14. 14. The method of claim 13, wherein the IgA concentration is less than or equal to 25 μg per 100 mg of immunoglobulin.

15. The method of any one of claims 1 to 14, wherein the immunoglobulin product comprises a stabilizer.

16. 16. The method of claim 15, wherein the stabilizer is an amino acid, preferably the stabilizer is proline.

17. The method according to any one of claims 1 to 16, wherein the immunoglobulin product is obtained from human plasma or a human plasma concentrate.

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