RU2802628C2 - Use of low-volume plasmapheresis for the treatment of early and middle stages of alzheimer's disease - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to the use of a composition containing human albumin at a concentration of 5% (w/v) to 25% (w/v) for the treatment of mild and moderate Alzheimer's disease by small volume plasmapheresis. The use of a composition containing human albumin at a concentration of 5% (w/v) to 25% (w/v) for the treatment of mild to moderate Alzheimer's disease (AD) by low volume plasmapheresis (LVPE), wherein the said LVPE regimen includes blood volumes from 600 ml to 900 ml.

EFFECT: above invention improves cognitive function in patients with mild to moderate Alzheimer's disease.

13 cl, 12 dwg

Description

The present invention relates to the medical field, in particular to the use of small volume plasmapheresis for the treatment of Alzheimer's disease in the early and middle stages.

Alzheimer's disease (AD) is the most common cause of dementia in adults. The presence of intracellular neurofibrillary tangles (NFTs) deposits of phosphorylated tau protein, as well as amyloid plaques formed from extracellular aggregates of amyloid β-peptides (Ap), are hallmarks of AD pathology. Although both NFTs and amyloid deposits are hypothesized to be responsible for cell death in AD brains, the underlying biological trigger for the pathology has not been fully identified to date. 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 an agent with disease-modifying properties. This hypothesis suggests that the production and deposition of amyloid plaques in the brain leads to the pathogenesis of AD.

Large amounts of Aβ are neurotoxic to cells in many ways, including activation of apoptosis and induction of oxidative stress associated with the production of free radicals, which leads to changes in oxidative metabolism. The pathological metabolism leading to the accumulation of Aβ peptide in the brain is initiated in the amyloid precursor protein (APP), which is processed by several distinct proteases (secretases) followed by a constitutive non-amyloidogenic pathway or a pathogenic amyloidogenic pathway. In the amyloid ore 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 in turn is cleaved by γ-secretase to produce the intracellular soluble protein domain -amyloid precursor (AICD) and heterogeneous formation of insoluble Aβ peptides, the most common being Aβ _1-40 and Aβ _1-42 . The hydrophobic properties of Aβ facilitate the formation of amyloid plaque in the brain, especially Aβ _1-42 , because it is less soluble and more toxic compared to Aβ _1-40 . Conversely, in the non-amyloidogenic pathway, APP is constitutively cleaved by α-secretase at the Aβ sequence; thus preventing the formation of amyloidogenic Aβ.

There are only symptomatic treatments approved for the treatment of AD, including cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. Treatments to prevent the accumulation of amyloid deposits or reduce existing plaque are currently being investigated for the treatment of AD, and several molecular targets of the amyloidogenic pathway are or have been tested. Therefore, interfering with factors that regulate upstream steps of APP production may influence intracellular APP levels and thus reduce overall Aβ levels.

Likewise, inhibition or modulation of key players involved in the neurotoxic formation of Aβ, such as β-secretase and γ-secretase, appear to be key therapeutic targets against AD. Alternatively, subsequent strategies targeting amyloid deposits in brain tissue may inhibit Aβ aggregation or disrupt plaque already formed. Finally, there is clearance of Aβ using both passive and active immunotherapy (direct use of anti-Aβ monoclonal antibody and stimulation of the immune system by vaccination with Aβ peptide fragments, respectively).

Unfortunately, clinical trials with small molecule pharmacotherapies and immunotherapies to reduce Aβ levels in the brain have not demonstrated effectiveness. Consistent failures have led researchers to develop new therapeutic strategies for AD aimed at reducing the accumulation of Aβ in the brain by altering the transport of Aβ across the blood-brain barrier.

Thus, there is still a need for successful treatments for AD. The present inventors conducted a clinical study involving 496 patients suffering from mild to moderate AD from centers of 41 institutions, 19 in Spain and 22 in the United States of America, in which patients received various doses of albumin through therapeutic plasmapheresis and small volume plasmapheresis ( LVPE), possibly combined with intravenous immunoglobulin (IVIG), and unexpectedly found that change from baseline in cognitive scores measured using the Alzheimer's Disease Assessment Scale in cognition (ADAS-Cog) (Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984;141:1356-64) and Alzheimer's Disease Cooperation Studies-Activities of Daily Living (ADCS protocol) -ADL (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's Dis Assoc Disord. 1997;11:33-9) improves in patients suffering from mild to moderate AD. Surprisingly, this improvement is enhanced in patients suffering from mild AD. The LVPE treatment regimen requires smaller volumes than traditional therapeutic plasmapheresis, shorter duration and single venipuncture, reduced patient discomfort and reduced treatment side effects.

To facilitate understanding, the present invention will be described in more detail below with reference to the accompanying drawings, which are provided by way of example, and with reference to an example that is illustrative and not limiting.

Fig. 1 is a schematic representation of clinical studies in accordance with the present invention (TPE: therapeutic plasma exchange; LVPE: small volume plasma exchange; F: Phlebogamma 5% DIF (intravenous immunoglobulin); A: Albumin 5% - 20% (albumin); S: treatment placebo; B: baseline visit; IV: intermediate visit; FV: final visit).

Fig. 2 is a graph illustrating the change in ADAS-Cog from baseline over time in the four groups of patients enrolled in the clinical trial.

Fig. 3 is a graph illustrating the change in ADCS-ADL from baseline over time in the four groups of patients enrolled in the clinical trial.

Fig. 4 is a graph illustrating the change in ADAS-Cog from baseline over time in all treated patients compared to the control group.

Fig. 5 is a graph illustrating the change in ADCS-ADL from baseline over time in all treated patients compared to the control group.

Fig. 6 is a graph illustrating the change from baseline in ADAS-Cog over time in treated patients suffering from mild AD (MMSE (Mini-Mental State Examination) 22-26), compared with controls group.

Fig. 7 is a graph illustrating the change in ADCS-ADL from baseline over time in treated patients suffering from mild AD (MMSE 22-26) compared to controls.

Fig. 8 is a graph illustrating the change in ADAS-Cog from baseline over time in treated patients suffering from mild AD (MMSE 18-21) compared to controls.

Fig. 9 is a graph illustrating the change in ADCS-ADL from baseline over time in treated patients suffering from mild AD (MMSE 18-21) compared to controls.

Fig. 10 is a graph illustrating the change in ADCS-ADL from baseline over time in patients suffering from moderate AD (MMSE 18-21) for the three treatment groups compared to the control group.

Fig. 11 is a graph illustrating CSF (cerebrospinal fluid) levels of Aβ _1-42 at the end of each of two treatment periods for all patients treated (A) in patients suffering from mild AD (MMSE 22-26) (B) , and suffering from moderate AD (MMSE 18-21) (C).

Fig. 12 is a graph illustrating CSF levels of T-tau (A) and P-tau (B) at the end of each of two treatment periods in patients suffering from mild AD (MMSE 18-21).

In a first aspect, the present invention relates to the use of human albumin at a concentration of 5% (w/v) to 25% (w/v) for the treatment of mild to moderate Alzheimer's disease (AD) by low volume plasmapheresis (LVPE).

As used herein, the term “small volume plasmapheresis” refers to plasmapheresis treatments involving blood volumes of 600 ml to 900 ml.

As used here, the term “mild AD” refers to individuals having a Mini-Mental State Examination (MMSE) score at the baseline visit (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) from 22 to 26.

As used herein, the term “moderate AD” refers to individuals having an MMSE score at the baseline visit of 18 to 21.

In one embodiment, treatment in accordance with the present invention includes additional administration of intravenous immunoglobulins (IGIV). Preferably, 10 g to 20 g of immunoglobulins are used during plasmapheresis in one of the LVPE rounds, but are never administered together with albumin.

In accordance with specific embodiments, each round of LVPE includes automated plasmapheresis using a single venipuncture. Any extracorporeal plasmapheresis device known in the art can be used in accordance with the present invention. For example, the device may include an input port for obtaining whole blood from a patient, means for separating blood plasma from cellular blood components, and means for returning cellular blood components through an input port through which the cellular blood components exit the device, and an output port through which blood plasma exits the device. Preferably, the means for separating the blood plasma from the cellular components of the blood is a means for centrifugation (ie, a centrifuge). More preferably, the means for separating the blood plasma from the cellular components of the blood is a filtration means (ie, a filter such as that used in double filtration plasmapheresis).

In accordance with specific embodiments, the treatment regimen includes administering to the patient three or more than three rounds of LVPE, four or more than four rounds of LVPE, five or more than five rounds of LVPE, six or more than six rounds of LVPE, seven or more than seven rounds of LVPE, eight or more than eight rounds of LVPE, nine or more than nine rounds of LVPE, or ten or more than ten rounds of LVPE, eleven or more than eleven rounds of LVPE, or twelve or more than twelve rounds of LVPE.

In yet another specific embodiment, prior rounds of conventional therapeutic plasmapheresis (TPE) may be performed prior to the LVPE treatment regimen. Preferably, said TPE regimen may be administered at a frequency of 1 TPE per week, more preferably for at least 6 weeks. The term "TPE" refers to plasmapheresis, in which 2500 to 3000 ml of the patient's blood plasma is replaced with the same volume of replacement fluid.

In accordance with specific embodiments, each subsequent round of LVPE is conducted 10-45 days after the previous round. Preferably, each subsequent round of LVPE is conducted 15-35 days after the previous round, more preferably conducted 30 days after the previous round.

In accordance with specific embodiments, from 10 g to 40 g of albumin can be used for plasmapheresis in each round of LVPE, preferably from 20 g to 40 g of albumin in each round of LVPE.

Example 1: Clinical Study

General research plan

The clinical trial was a multicenter, randomized, placebo-blind, placebo-controlled, parallel-group clinical trial involving 496 patients suffering from mild to moderate AD from sites at 41 institutions, 19 in Spain and 22 in the United States. This study included four groups of patients: three PE-treated groups receiving varying doses of albumin and IVIG, and one control group (placebo). Control patients were subjected to sham PE using a noninvasive procedure (placebo) that mimics plasmapheresis, but no fluid is changed and no albumin or IVIG is administered. Patients, caregivers, and raters were blinded to information regarding therapy received. A single code was used to deidentify patients.

The study strictly complied with the ethical standards adapted from the XVIII World Medical Assembly Declaration of Helsinki (and subsequent editions) and the European Union standards of Good Clinical Practice (GCP) relevant to research involving medicinal products. The Institutional Review Board (IRB) or Ethics Committees of the sites and health authorities of both countries approved the protocol, informed consent form, and patient information sheets.

The safety of the intervention was strictly monitored. All serious and/or unexpected adverse reactions were reported, as well as any additional information that may change the study plan or pose a risk to the patient.

Study group selection

Participants in the clinical study were men or women aged 55-85 years at the time of signing the informed consent. They must be diagnosed with AD according to the National Institute of Neurological and Communication Disorders and Stroke and Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria and have Mini-Mental State Examination (MMSE) score of 18 to 26, and have been treated with acetylcholinesterase inhibitors (AchEIs) and/or memantines for the previous three months at a constant dose. In addition, patients did not suffer from cerebrovascular disease according to cerebral computed axial tomography (CAT) or magnetic resonance imaging (MRI) scans performed within 12 months before selection. MRI required during the screening period is used to rule out any factor that could affect patient safety, such as microhemorrhage, infarction, hematoma, stroke, or brain tumors including meningioma. Exclusion criteria include any condition in which plasmapheresis is contraindicated or not possible, such as behavioral disorders, difficult venous access or abnormal coagulation parameters, or replacement products cannot be administered, such as a history of frequent adverse reactions or thromboembolic disorders associated with blood components , in particular, hypersensitivity to albumin, or allergies to any of the components of Albutein ^® or Phlebogamma ^® DIF. Other exclusion criteria due to impact on patient safety include IgA deficiency; low hemoglobin level (less than 10 g/dl); high level of plasma creatinine (more than 2 mg/dl); uncontrolled hypertension (systolic equal to 160 mmHg or higher, diastolic equal to 100 mmHg or higher despite regular treatment in the last 3 months), liver disease (ORT more than 2.5 x ULN, or bilirubin more than 2 mg/dL), heart disease, a disease with a life expectancy of less than one year, drug or alcohol addiction; and pregnancy or breastfeeding. RE interventions

After the selection visit, patients were randomly assigned to one of three treatment groups or a control group (placebo) according to a [1:1:1:1] design. The intervention regimen consisted first of a 6-week intensive treatment phase with one round of conventional therapeutic plasmapheresis (TPE) per week, in which all patients allocated to either treatment group followed the same treatment regimen, followed by a second 12-month maintenance phase with one round of low volume plasmapheresis (LVPE) per month, as summarized in FIG. 1. Between these two treatment periods there was an interim visit to assess the patient's condition and collect additional study-related data. During the respective PE rounds, sufficient EDTA (ethylenediaminetetraacetic acid) blood was collected for laboratory testing. CSF samples were collected before and after both treatment periods for all laboratory tests. Aliquots of both plasma and CSF were stored at -70°C for subsequent analysis. At the end of the maintenance period, the patient had a final visit, during which the same variables were assessed as at the screening and interim visits.

During the TPE process, 2500 to 3000 ml of the patient's blood plasma was replaced with the same volume of Albutein ^® 5% (GRIFOLS, SA), whereas during LVPE, only 650 ml to 880 ml of the patient's blood plasma was replaced with 100 ml or 200 ml of Albutein ^® 20 % (GRIFOLS, SA), depending on the randomization of treatment groups. There were three LVPE groups: in one group, only 20 grams of Albutein ^® 20% was used as a replacement in the LVPE, while in the other two groups, Albutein ^® 20% (20 or 40 grams) was opposed to Phlebogamma ^® DIF 5% (10 or 20 grams; GRIFOLS ,SA).

TPE was carried out using a commercially available flow cell separator with centrifugation or filtration based technology. Peripheral (eg, radial/median ulnar vein) or central access (eg, subclavian/jugular vein) was used, depending on individual patient characteristics. Implantation for venous access and maintenance was performed according to standard techniques used at each center, and correct placement of the central catheter was always confirmed by chest radiography. The volume of blood plasma removed and recovered depended on patient characteristics (ie, sex, height, weight, and hematocrit). It was approximately 35-45 ml/kg, corresponding to a volume of 2500-3000 ml. LVPE was performed by the peripheral line using a prototype apheresis device based on the Auto-C™ device (Fenwal hie, Lake Zurich, IL, USA) or the Aurora™ device (Fresenius Kabi, Bad Homburg, Germany), which is a newer variant of the Auto -C™. The volume of blood plasma removed was close to the volume of donor blood plasma (650-880 ml) and depended on the patient’s weight. The volume of albumin infused was consistent with the treatment group as described above. Normal saline was used when there was a negative balance between the volume of plasma removed and the volume of albumin infused.

For the control group (TPE placebo), the tip of the cut catheter was sutured to an adhesive colostomy patch (acting as a “second skin”), which was placed over the subclavian or jugular region. The patch with the catheter tip attached was then covered with a gauze bandage and an adhesive film. The cut catheter had characteristics similar to those used for the treatment group. The conventional PE device was filled with intravenous iron-stained saline, simulating blood plasma, and operated in a closed circuit without any exchange of fluids between the device and the subject. For the LVPE placebo control group, a prototype based on Autopheresis-C or Aurora provided a seemingly realistic operating condition in which expired human blood from a local blood bank circulated in a closed loop.

Performance criteria

Covariates of effectiveness were: 1) change from baseline in cognitive scores measured by the ADAS-Cog; and 2) change from baseline in functional scores measured by the ADCS-ADL questionnaire. In both cases, 6 measurements were taken: one per week at weeks -3, -2 or -1 (baseline), one per week at weeks 7-8 (end of the intensive treatment period), and one per month at 6, 9, 12 and 14 months (end of maintenance treatment period). The fourteenth month represented the end point for the primary efficacy analysis (see Fig. 1). Secondary efficacy variables were changes in plasma Aβ _1-40 and Aβ _1-42 levels before and after each PE, changes in cerebrospinal fluid (CSF) Aβ _1-40 and Aβ _1-42 levels between the end and start of each two treatment periods, changes in CSF T-tau and P-tau levels during the study, assessment of structural changes in the volume of the hippocampus, volume of the cingulate cortex and other areas of interest according to magnetic resonance imaging (MRI), and assessment of functional changes in the brain detected using 18F-fludeoxyglucose positron emission tomography.

Specific methodology for assessing cognition/behavior

The ADAS-Cog is a tool specifically designed to assess the severity of fundamental changes in cognitive and behavioral function that characterize patients suffering from AD. Functional ability is assessed using the ADCS-ADL, which provides detailed descriptions of each activity and asks the subject to describe observed activities or behaviors, as explained above.

Safety Considerations

PE is a safe method that may cause expected and therefore preventable and controllable adverse reactions (eg hypocalcemia, hypotension). Considering the particular vulnerability of the study patients, vital signs and laboratory test values were monitored more frequently to minimize risks than in a typical clinical trial. In addition, patients were required to remain at the center before and after the PE procedure for longer periods of time than usual, and a caregiver was present except during the actual procedure to maintain blinding characteristics of the study. In rare cases, anxious or anxious patients were accompanied by a caregiver during the procedure to alleviate patient anxiety. However, a blinding protocol was maintained for both patient and caregiver.

The primary safety outcome was the percentage of TPE and LVPE procedures (including albumin and IVIG infusion) associated with at least one adverse event (AE) that could be attributed to the study procedure (adverse event). In addition, vital signs (blood pressure, heart rate, respiratory rate and body temperature) and laboratory test parameters (blood cell count, platelet count, prothrombin time (Quick), activated partial thromboplastin time (APTT), fibrinogen, total protein content and calcium content) were recorded before, during and after each round of PE. AEs were coded according to the World Health Organization (WHO) classification of adverse effects (current version of MeDRA), and described by synonym (Low Level Term) and organ/system affected, intensity, causes, and severity.

results

Changes from baseline in ADAS-Cog and ADCS-ADL questionnaire scores were analyzed over time using a mixed model for repeated measures (MMRM) approach. Efficacy was determined by changes in ADAS-Cog total score and ADCS-ADL questionnaire score from baseline to 14 months. As shown in FIG. 2 The change in ADAS-Cog in the three drug-dose groups (low albumin without IGIV; low albumin with IGIV; and high albumin with IGIV) was lower than in the control group (respectively -1.6; -2. 4; and -2.4) after 14 months of treatment. The same was found for ADCS-ADL (see Figure 3), (-2.8; -4.7; and 3.1, respectively). There was no statistical difference found between all treatment groups. In fig. Figures 4 and 5 show a graph in which the treatment groups were grouped and compared with the control group. Changes from baseline were found to be 2.1 and 3.5 according to ADAS-Cog and ADCS-ADL, respectively.

In addition to the above results, as demonstrated in FIGS. 6 and 7, patients suffering from mild AD (MMSE 22-26) who were treated were compared with a control group. Changes from baseline were found to be 1.1 and 0.7 according to ADAS-Cog and ADCS-ADL, respectively. However, as demonstrated in FIG. 8 and 9, the change from baseline according to ADAS-Cog and ADCS-ADL in treated patients with moderate AD (MMSE 18–21) was 3.9 and 8.6, respectively. The latter result is quite surprising as it suggests that better results may be achieved in later stages of AD.

There was a modification for plasma Aβ _1-42 levels, which were lower in the PE-treated group after each treatment period (P less than 0.05), and for CSF Aβ _1-42 levels (borderline P equal to 0.072 after the last PE compared to baseline).

In addition, neuroimaging studies confirmed that patients treated with PE demonstrated less underperfusion in the frontal, temporal and parietal regions compared with controls, and stabilization of perfusion in the FJA38-R Brodmann area during the period of PE treatment (P less than 0 .05); BA38 has been suggested to play an important role in speech.

On the other hand, as shown in FIG. 11 demonstrates changes in CSF Aβ _1-42 levels at the end of each of the two treatment periods.

In fig. 11A shows that CSF Aβ _1-42 levels are reduced in all patients treated with conventional therapeutic plasma exchange (TPE) and patients treated with low volume plasma exchange (LVPE) compared with patients not treated (placebo group). ) (N=299). In fig. 11 B shows that CSF levels of Aβ _1-42 are reduced in patients suffering from mild AD (MMSE 22-26) treated with TPE compared with patients not treated (N=145). However, in FIG. 11 B shows that CSF levels of Aβ _1-42 are maintained in patients suffering from mild AD (MMSE 22-26) treated with LVPE compared with patients not treated (N=145). Finally, in FIG. 11C shows that CSF levels of Aβ _1-42 are reduced in patients suffering from mild AD (MMSE 18-21) treated with TPE and LVPE compared to patients not treated (N=154).

In addition, as shown in FIG. 12 demonstrates changes in CSF T-tau and P-tau levels at the end of each of the two treatment periods.

In fig. 12 shows that CSF levels of T-tau (FIG. 12A) and P-tau (FIG. 12B) are reduced in patients suffering from mild AD (MMSE 18-21) treated with TPE and LVPE compared to patients who were not treated (placebo group) (N=154).

Claims (13)

1. The use of a composition containing human albumin at a concentration of from 5% (wt./vol.) to 25% (wt./vol.), for the treatment of mild to moderate Alzheimer's disease (AD) by low volume plasmapheresis (LVPE), where the specified LVPE regimen includes blood volumes from 600 ml to 900 ml. 2. The use of claim 1, wherein said treatment regimen includes administering three or more than three rounds of LVPE to the patient. 3. Use according to claim 1 or 2, characterized in that the LVPE treatment regimen is preceded by previous rounds of conventional therapeutic plasmapheresis (TPE). 4. Application according to claim 3, characterized in that the specified TPE regimen can be carried out with a frequency of 1 TPE per week. 5. Application according to claim 3 or 4, characterized in that said TPE regimen is carried out for at least 6 weeks. 6. Application according to any one of paragraphs. 1-5, characterized in that each subsequent round of LVPE is carried out 10-45 days after the previous round. 7. Application according to claim 6, characterized in that each subsequent round of LVPE is carried out 15-35 days after the previous round. 8. Application according to claim 7, characterized in that each subsequent round of LVPE is carried out 30 days after the previous round. 9. Application according to any one of paragraphs. 1-8, characterized in that from 10 g to 40 g of albumin are used for replacement in each round of LVPE. 10. Use according to claim 9, characterized in that from 20 g to 40 g of albumin is used for replacement in each round of LVPE. 11. Application according to any one of paragraphs. 1-10, characterized in that said treatment additionally includes intravenous administration of immunoglobulins (IGIV). 12. Use according to claim 11, characterized in that from 10 g to 20 g of immunoglobulins are used for replacement in one of the rounds of LVPE, but are never administered simultaneously with albumin. 13. Application according to any one of paragraphs. 1-12, characterized in that it is intended for the treatment of patients suffering from moderate Alzheimer's disease (AD).