Use of low-volume plasma exchange to treat early and intermediate stages of Alzheimer's disease

Abstract

The present invention relates to a composition comprising human albumin at a concentration between 5% (w / v) and 25% (w / v) for treating mild and moderate Alzheimer's disease using low-volume plasma exchange (LVPE).

Description

[Technical field]

[0001] explanation The present invention relates to the medical field, in particular to the use of low-volume plasma exchange for treating early and intermediate stages of Alzheimer's disease. [Background technology]

[0002] Alzheimer's disease (AD) is the most common cause of dementia in adults. Intracellular neurofibrillary tangles (NFTs) of phosphorylated tau protein deposits and amyloid plaques formed from extracellular aggregates of amyloid-β peptide (Aβ) are hallmarks of AD symptoms. Both NFTs and amyloid deposits are suspected to cause cell death in AD brains, but the initial biological triggers of the condition have not been fully elucidated. The amyloid cascade hypothesis has been widely studied to explain the pathogenesis observed in AD. It has served as a target for many drug development programs in search of drugs with disease-modifying properties. The hypothesis proposes that the production and deposition of amyloid plaques in the brain drives AD pathogenesis.

[0003] Large amounts of Aβ are neurotoxic to cells in a variety of ways, including the activation of apoptosis and induction of oxidative stress associated with the production of free radicals, which results in alterations in oxidative metabolism. The pathological metabolism that leads to Aβ peptide accumulation in the brain is initiated in the amyloid precursor protein (APP), which is processed by several different proteases (secretases) according to either the constitutive nonamyloidogenic pathway or the pathogenic amyloidogenic pathway. In the amyloidogenic pathway, APP is cleaved by β-secretase to release a soluble N-terminal fragment (sAPP-β) and a membrane-bound C-terminal fragment (C99), which is subsequently cleaved by γ-secretase to generate the soluble amyloid precursor protein intracellular domain (AICD), which then degrades Aβ. 1~40 and Aβ 1~42 is the most common, resulting in the heterogeneous generation of insoluble Aβ peptides.1~42 is Aβ 1~40 The hydrophobic nature of Aβ may contribute to the formation of amyloid plaques in the brain, particularly Aβ, due to its low solubility and high toxicity in naphthalene. 1~42 Conversely, in the nonamyloidogenic pathway, APP is constitutively cleaved by α-secretase within the Aβ sequence, thus preventing the formation of amyloidogenic Aβ.

[0004] For the treatment of AD, only symptomatic treatments, including cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists, have been approved. Therapies that prevent the accumulation of amyloid deposits or reduce existing plaques are currently being investigated for the treatment of AD, and several molecular targets of the amyloidogenic pathway are under investigation or have been investigated. Therefore, interference with factors that regulate the most upstream APP production may affect the intracellular level of APP and therefore reduce the overall level of Aβ.

[0005] Similarly, inhibition or modulation of key players involved in neurotoxic Aβ generation, such as neurogenic β-secretase and γ-secretase, appears to be important therapeutic targets for AD. Alternatively, downstream strategies targeting amyloid deposits in brain tissue may inhibit Aβ aggregation or destroy already formed plaques. Finally, clearance of Aβ using both passive and active immunotherapy (direct use of anti-Aβ monoclonal antibodies and stimulation of the immune system by vaccination with Aβ peptide fragments, respectively) is seen.

[0006] Unfortunately, clinical trials with small molecule pharmacotherapies and immunotherapies to reduce brain Aβ have not shown efficacy. Persistent failure has led researchers to develop new therapeutic strategies for AD that aim to reduce Aβ accumulation in the brain by altering the transport of Aβ across the blood-brain barrier. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984;141:1356–64 [Non-Patent Document 2] Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, et al. An Inventory to Assess Activities of Daily Living for Clinical Trials in Alzheimer's Disease. Alzheimer Dis Assoc Disord. 1997;11:33-9 [Non-Patent Document 3] Folstein MF, Folstein SE, McHugh PR. Mini-mental state, A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98 Summary of the Invention [Problem to be solved by the invention]

[0008] Thus, there remains a need for successful treatment of AD. The inventors carried out a clinical trial involving 496 patients with mild to moderate AD from 41 centres, 19 in Spain and 22 in the USA, in which patients received different doses of albumin by therapeutic plasma exchange and low-volume plasma exchange (LVPE), optionally combined with intravenous immunoglobulin (IVIG), and surprisingly demonstrated improved cognitive and cognitive outcomes in patients with mild and moderate AD, as measured by the Alzheimer's Disease Assessment Scale for Cognition (ADAS-Cog scale) (Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984;141:1356-64) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL Inventory) (Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M et al. An Inventory to Assess Activities of Daily Living for Clinical It has been found that the change from baseline in cognitive scores as measured using the LVPE Plasma Exchange Test (Vol. 11, No. 3, pp. 33-9, Trials in Alzheimer's Disease. Alzheimer Dis Assoc Disord. 1997). Surprisingly, the improvement is enhanced in patients with moderate AD. The LVPE treatment regimen requires a smaller volume, shorter duration and a single venipuncture than traditional therapeutic plasma exchange, reducing patient discomfort and reducing adverse effects of the treatment. [Means for solving the problem]

[0009] To facilitate understanding, the inventor will now be described in more detail with reference to the accompanying drawings, given by way of example and with reference to illustrative, but non-limiting, examples. [Brief description of the drawings]

[0010] [Figure 1]FIG. 1 is a schematic diagram of clinical trial interventions according to the present invention (TPE: therapeutic plasma exchange; LVPE: low-volume plasma exchange; F: Flebogamma 5% DIF [intravenous immunoglobulin]; A: albumin 5%-20% [albumin]; S: sham treatment; B: baseline visit; IV: interim visit; FV: final visit). [Diagram 2] FIG. 1 is a graph showing the ADAS-Cog change from baseline over time in the four groups of patients included in the clinical trial. [Diagram 3] 1 is a graph showing ADCS-ADL change from baseline over time in the four groups of patients included in the clinical trial. [Figure 4] FIG. 1 is a graph showing the ADAS-Cog change from baseline over time in all treated patients compared to the control group. [Diagram 5] FIG. 1 is a graph showing ADCS-ADL change from baseline over time for all treated patients compared to the control group. [Figure 6] FIG. 13 is a graph showing ADAS-Cog change from baseline over time in treated patients with mild AD (MMSE 22-26) compared to controls. [Figure 7] FIG. 13 is a graph showing ADCS-ADL change from baseline over time in treated patients with mild AD (MMSE 22-26) compared to controls. [Figure 8] FIG. 13 is a graph showing ADAS-Cog change from baseline over time in treated patients with moderate AD (MMSE 18-21) compared to controls. [Figure 9] FIG. 13 is a graph showing ADCS-ADL change from baseline over time in treated patients with moderate AD (MMSE 18-21) compared to controls. [Figure 10] FIG. 13 is a graph showing ADCS-ADL change from baseline over time in patients with moderate AD (MMSE 18-21) in the three treatment groups compared to the control group. [Figure 11]Graphs showing levels of Aβ1-42 in CSF at the end of each of the two treatment periods for all treated patients (A), for patients with mild AD (MMSE 22-26) (B), and for patients with moderate AD (MMSE 18-21) (C). [Figure 12] Graphs showing T-tau (A) and P-tau (B) levels in CSF at the end of each of the two treatment periods in patients with moderate AD (MMSE 18-21). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] In a first aspect, the present invention refers to the use of human albumin at a concentration between 5% (w / v) and 25% (w / v) for the treatment of mild and moderate Alzheimer's Disease (AD) by low-volume plasma exchange (LVPE).

[0012] As used herein, the term "low volume plasma exchange" refers to plasma exchange treatment involving a blood volume between 600 mL and 900 mL.

[0013] As used herein, the term "mild AD" refers to individuals with a Mini-Mental State Examination (MMSE) score (Folstein MF, Folstein SE, McHugh PR. Mini-mental state, A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-98) of 22-26 at the baseline visit.

[0014] As used herein, the term "moderate AD" refers to individuals with an MMSE score of 18-21 at the baseline visit.

[0015] In one embodiment, the treatment of the invention further comprises administration of intravenous immunoglobulin (IGIV). Preferably, between 10 g and 20 g of immunoglobulin is used for replacement in one session of LVPE, but is not administered simultaneously with albumin.

[0016] According to certain embodiments, each LVPE involves automated plasma exchange using a single venipuncture. Any extracorporeal plasma exchange device known in the art may be used according to the present invention. For example, the device may include an inlet port for receiving whole blood from a patient, a means for separating plasma from cellular components of the blood, a means for returning the cellular components of the blood through the inlet port where the cellular components of the blood exit the device, and an outlet port where the plasma exits the device. Preferably, the means for separating plasma from cellular components of the blood is a centrifugation means (i.e., a centrifuge). More preferably, the means for separating plasma from cellular components of the blood is a filtration means (i.e., a filter such as those used in double filtration plasma exchange).

[0017] According to certain embodiments, the treatment regimen comprises administering to the patient 3 or more doses of LVPE, 4 or more doses of LVPE, 5 or more doses of LVPE, 6 or more doses of LVPE, 7 or more doses of LVPE, 8 or more doses of LVPE, 9 or more doses of LVPE, or 10 or more doses of LVPE, 11 or more doses of LVPE, or 12 or more doses of LVPE.

[0018] In another specific embodiment, a prior conventional therapeutic plasma exchange (TPE) may be performed prior to the LVPE treatment regimen. Preferably, the TPE regimen may be performed at a frequency of one TPE per week, more preferably for at least six weeks. The term "TPE" refers to plasma exchange in which 2500-3000 mL of the patient's plasma is replaced with an equal volume of replacement fluid.

[0019] According to a particular embodiment, each subsequent round of LVPE is performed 10 to 45 days after the previous round. Preferably, each subsequent round of LVPE is performed 15 to 35 days after the previous round, more preferably 30 days after the previous round.

[0020] According to a particular embodiment, between 10 g and 40 g of albumin may be used for each substitution in LVPE, preferably between 20 g and 40 g of albumin for each substitution in LVPE. EXAMPLES

[0021] Clinical Trials Comprehensive research design The clinical trial was a multicenter, randomized, blinded, placebo-controlled, parallel-group trial with the enrollment of 496 patients with mild to moderate AD from 41 centers, 19 in Spain and 22 in the United States. The study included four groups of patients: three PE treatment groups receiving different doses of albumin and IVIG, and one control (placebo) group. Control patients underwent simulated PE (sham), a non-invasive procedure that mimics plasma exchange, but in which neither albumin nor IVIG was administered and neither fluid was replaced. Patients, caregivers and assessors were blinded as to the treatment they received. A single code was used for patient anonymization.

[0022] The study will strictly adhere to the ethical standards adopted by the XVIII World Medical Assembly Declaration of Helsinki (and subsequent amendments) and the European Union standards of Good Clinical Practice (GCP) for clinical trials, including formulation. The Institutional Review Board (IRB) or ethics committee of the site and the health authorities of both countries have approved the protocol, informed consent forms, and patient information sheets.

[0023] The safety of the intervention was closely monitored. All serious and / or unexpected adverse reactions and any further information that may have altered the study design or involved risks to the patient were reported.

[0024] Selection of study population Participants in the clinical trial were males or females between 55 and 85 years of age at the time of signing the informed consent document. Participants in the clinical trial must have a diagnosis of AD according to the National Institute of Neurological and Communication Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria, have a Mini-Mental State Examination (MMSE) score of 18-26, and have been treated with a stable dose of an acetylcholinesterase inhibitor (AchEI) and / or memantine in the last 3 months. In addition, patients were free of cerebrovascular disease evident by brain computed axial tomography (CAT) or magnetic resonance imaging (MRI) studies obtained 12 months prior to screening. MRIs required during the screening period will be used to exclude any findings that may affect patient safety, such as microbleeds, infarcts, hematomas, strokes, or brain tumors, including meningiomas. Exclusion criteria include any condition in which plasma exchange is contraindicated or not feasible, such as behavioral disorders, difficult venous access, or abnormal coagulation parameters, or any condition in which the replacement product cannot be administered, such as a history of frequent adverse reactions or thromboembolic complications associated with blood components, particularly hypersensitivity to albumin or allergy to any of the components of Albutein® or Flebogamma® DIF. Other exclusion criteria due to the impact on patient safety include IgA deficiency, low hemoglobin (<10 g / dL), high plasma creatinine (>2 mg / dL), poorly controlled hypertension (systolic ≥160 mmHg, diastolic ≥100 mmHg, despite regular treatment during the final 3 months), liver disease (GPT >2.5×ULN, or bilirubin >2 mg / dL), cardiac disease, illness with a predicted survival of less than 1 year, drug or alcohol dependency, and pregnancy or lactation.

[0025] PE intervention After the screening visit, patients were randomized to one of three treatment or control (sham) groups according to a [1:1:1:1] scheme. As outlined in Figure 1, the intervention regimen included an initial 6-week phase of intensive treatment with conventional therapeutic plasma exchange (TPE) at one session per week, where all patients assigned to one of the treatment groups followed the same treatment regimen, followed by a second 12-month phase of maintenance treatment with low-volume plasma exchange (LVPE) at one session per month. Between these two treatment periods, there was an interim visit to evaluate the patient's condition and collect further study-related data. At the corresponding PE session, sufficient EDTA-blood was collected for all clinical tests. CSF samples were collected before and after both treatment periods for all clinical tests. Aliquots of both plasma and CSF were stored at -70°C for further analysis. At the end of the maintenance period, patients underwent a final visit to evaluate the same variables as the screening and interim visits.

[0026] Depending on the randomization of the treatment group, during TPE, 2500-3000 ml of the patient's plasma was replaced with the same volume of Albutein® 5% (GRIFOLS, SA), while during LVPE, only 650-880 ml of the patient's plasma was replaced with 100 or 200 ml of Albutein® 20% (GRIFOLS, SA). There were three groups of LVPE: in one group, only 20 grams of Albutein® 20% was used for replacement in LVPE, while in the other two groups, the Albutein® 20% replacement (20 or 40 grams) was alternated with Flebogamma® DIF 5% (10 or 20 grams, GRIFOLS, SA).

[0027] TPE was performed using a commercially available continuous flow cell separator, using either centrifugation or filtration-based techniques. Peripheral nerve access (e.g. radial / cubital vein) or central nerve access (e.g. subclavian / jugular vein) was used based on the patient's individuality. Venous access implantation and maintenance was performed according to the standard procedures used at each center, and the correct placement of the central venous catheter was always confirmed by chest X-ray. The volume of plasma removed and replaced depended on the patient's characteristics (i.e. sex, height, weight, and hematocrit). The volume of plasma removed and replaced was approximately 35-45 mL / kg, corresponding to a volume of 2500-3000 mL. LVPE was performed through the peripheral nervous system using a prototype apheresis device based on the Auto-C™ device (Fenwal, Lake Zurich, IL, USA) or a newer version of the Auto-C™, the Aurora™ device (Fresenius Kabi, Bad Homburg, Germany). The plasma volume removed was equivalent to the volume of plasma transfusion (650–880 mL) and was dependent on the patient's weight. The volume of albumin infused matched the treatment groups as described above. Saline was used when there was a negative balance between the volume of plasma removed and the volume of albumin infused.

[0028] For the control group (sham TPE), the tip of a cut catheter was sewn to a colostomy adhesive patch (acting as a "second skin") and placed in the subclavian or jugular region. The patch with the catheter tip sewn to it was then covered with a gauze dressing and adhesive film. The cut catheter had similar characteristics to the catheters used in the treatment group. The conventional PE device was loaded with an iron-stained saline solution to mimic plasma and operated in a closed-loop mode without any fluid interchange between the device and the subject. For the control group, a sham LVPE Autopheresis-C or Aurora-based prototype provided seemingly realistic operating conditions, where expired human blood from the local blood bank was circulated in a closed-loop mode.

[0029] Result judgment The coprimary efficacy variables were i) the change from baseline in cognitive scores as measured using the ADAS-Cog scale, and ii) the change from baseline in functional scores as measured by the ADCS-ADL inventory. In both cases, six measurements were performed: once at weeks -3, -2 or -1 (baseline), once at weeks 7-8 (end of the intensive treatment period), and once each at months 6, 9, 12 and 14 (end of the maintenance treatment period). Month 14 was the end point for the main efficacy analysis (see Figure 1). Aβ levels before and after each PE were significantly increased in the 14-month period. 1~40 and Aβ 1~42 Changes in plasma levels of Aβ between the completion and initiation of each of the two treatment periods 1~40 and Aβ 1~42 Secondary efficacy variables were also measured: change in cerebrospinal fluid (CSF) levels of T-tau, change in CSF levels of T-tau and P-tau throughout the study, assessment of structural changes in hippocampal volume, posterior cingulate volume, and other regions of interest as shown by magnetic resonance imaging (MRI), and assessment of functional changes in the brain as detected by positron emission tomography using 18F-fludeoxyglucose.

[0030] Specific methodology for cognitive / behavioral assessment The ADAS-Cog is an instrument specifically designed to assess the severity of underlying alterations in cognitive and behavioral function characteristic of patients with AD. Functional ability is assessed using the ADCS-ADL test, which provides a detailed description of each activity and asks the informant to describe the observed actions or behaviors, as explained above.

[0031] Safety Considerations PE is a safe technique that may induce expected and therefore preventable and controllable adverse reactions (e.g., hypocalcemia, hypotension). Given the special vulnerability of the patients studied, vital signs and laboratory parameters were monitored more frequently than in a normal clinical setting to minimize risks. In addition, patients were asked to remain in the center for a longer time than usual before and after the PE procedure, and caregivers were present except during the actual procedure to maintain the blinding. In rare cases, agitated or anxious patients were accompanied by a caregiver during the procedure to ease the patient's anxiety. However, the blinding protocol was maintained for both patients and caregivers.

[0032] The main criterion for safety evaluation was the proportion of TPE and LVPE procedures (including infusion of albumin and IVIG) associated with at least one adverse event (AE) (adverse reaction) that could be related to the study procedure. In addition, vital signs (blood pressure, heart rate, respiratory rate, and temperature) and clinical laboratory parameters (blood count, platelet count, prothrombin time [Quick], activated partial thromboplastin time [aPTT], fibrinogen, total protein, and calcium) were recorded before, during, and after each PE session. AEs were coded according to the World Health Organization (WHO) (MeDRA current version) classification of adverse events and described by synonym (lowest level term) and affected organ / system, intensity, causality, and severity.

[0033] result The changes from baseline in the ADAS-Cog score and the ADCS-ADL inventory were analyzed over time using a mixed model for repeated measures (MMRM) approach. Efficacy was determined by the change in the total ADAS-Cog score and the change in the ADCS-ADL inventory score from baseline to the 14-month follow-up. As shown in Figure 2, the changes in ADAS-Cog in the three dose groups (low albumin without IGIV, low albumin with IGIV, and high albumin with IGIV) were lower than the control group after 14 months of treatment (-1.6, -2.4, and -2.4, respectively). The same behavior is observed for ADCS-ADL (see Figure 3), (-2.8, -4.7, and -3.1, respectively). No statistical differences were observed between all the treatment groups. Figures 4 and 5 show the graphs of the treatment groups grouped and compared with the control group. Changes from baseline of 2.1 and 3.5 were observed in ADAS-Cog and ADCS-ADL, respectively.

[0034] In addition to the above results, treated patients with mild AD (MMSE 22-26) were compared with the control group, as shown in Figures 6 and 7. Changes from baseline in ADAS-Cog and ADCS-ADL of 1.1 and 0.7, respectively, were observed. However, as shown in Figures 8 and 9, the changes from baseline in ADAS-Cog and ADCS-ADL in treated patients with moderate AD (MMSE 18-21) were 3.9 and 8.6, respectively. This is a very surprising result, as it suggests that better results can be obtained in more advanced stages of AD.

[0035] Correction showed lower plasma Aβ in the PE-treated group after each treatment period. 1~42 levels (P<0.05) and CSF Aβ 1~42 levels (marginal P=0.072 after final PE compared with baseline).

[0036] Furthermore, neuroimaging studies confirmed that PE-treated patients had less hypoperfusion in the frontal, temporal, and parietal areas than controls, and had a stabilization of perfusion (P<0.05) in Brodmann's area BA38-R during the PE treatment period. BA38 is postulated to play an important role in language.

[0037] On the other hand, as shown in Figure 11, Aβ levels in the CSF at the end of each of the two treatment periods 1~42 Level changes were demonstrated.

[0038] As shown in FIG. 11A, Aβ in CSF 1~42 Figure 11B shows that Aβ levels in CSF are reduced in all patients treated with conventional therapeutic plasma exchange (TPE) and low-volume plasma exchange (LVPE) when compared to untreated patients (placebo group) (N=299). 1~42 Figure 11B shows that Aβ levels in the CSF were decreased in patients with mild AD (MMSE 22-26) treated with TPE when compared to untreated patients (N=145). 1~42 Finally, Figure 11C shows that Aβ levels in the CSF are maintained in patients with mild AD (MMSE 22-26) treated with LVPE when compared to untreated patients (N=145). 1~42 Levels are shown to be decreased in patients with moderate AD (MMSE 18-21) treated with TPE and LVPE when compared to untreated patients (N=154).

[0039] Furthermore, as shown in FIG. 12, changes in T-tau and P-tau levels in the CSF at the end of each of the two treatment periods were demonstrated.

[0040] FIG. 12 shows that CSF T-tau (FIG. 12A) and P-tau (FIG. 12B) levels are reduced in patients with moderate AD (MMSE 18-21) treated with TPE and LVPE compared to untreated patients (placebo group) (N=154).

Claims

1. 1. A composition comprising human albumin at a concentration between 5% (w / v) and 25% (w / v) for treating moderate Alzheimer's disease (AD) (Mini-Mental State Examination) (MMSE) score 18-21) by low-volume plasma exchange (LVPE), characterized in that a preceding round of conventional therapeutic plasma exchange (TPE) is performed prior to said treatment of LVPE.

2. The composition of claim 1, wherein the LVPE comprises plasma exchange for a blood volume between 600 mL and 900 mL.

3. 3. The composition according to claim 1 or 2, characterized in that the treatment comprises a step of performing LVPE on the patient three or more times.

4. 4. The composition according to claim 1, wherein the TPE is carried out at a frequency of one TPE per week.

5. 5. The composition according to claim 4, characterized in that the TPE is carried out for at least 6 weeks.

6. The composition according to any one of claims 1 to 5, characterized in that each subsequent LVPE is carried out 10 to 45 days after the previous one.

7. The composition according to claim 6, characterized in that each subsequent LVPE is carried out 15 to 35 days after the previous one.

8. 8. The composition according to claim 7, characterized in that each subsequent LVPE is carried out 30 days after the previous one.

9. Composition according to any one of claims 1 to 8, characterized in that between 10 g and 40 g of albumin are used for each substitution in LVPE.

10. The composition according to claim 9, characterized in that between 20 g and 40 g of albumin are used for each substitution in LVPE.

11. 11. The composition according to any one of claims 1 to 10, characterized in that the treatment further comprises intravenous immunoglobulin (IGIV).

12. The composition according to claim 11, characterized in that between 10 g and 20 g of immunoglobulin are used for replacement in one LVPE session, but are not administered simultaneously with albumin.

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