Compositions containing albumin for use in the treatment of amyotrophic lateral sclerosis (ALS) by plasma exchange

Abstract

The present invention relates to a composition comprising albumin for use in the treatment of amyotrophic lateral sclerosis (ALS), which is administered to a patient by plasma exchange twice weekly for the first 3 weeks and once weekly for the following 21 weeks for a total period of 24 weeks, using an amount of the composition equal to approximately 100% of the volume of plasma withdrawn from the patient.

Description

[Technical Field]

[0001] The present invention relates to compositions comprising albumin for use in the treatment of amyotrophic lateral sclerosis (ALS) by plasma exchange. [Background technology]

[0002] Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that affects approximately 3 in 100,000 people annually in the United States. ALS is a chronic, progressive, and fatal degenerative neurological disease that causes the death of motor neurons that control voluntary muscles. In 90% of cases, the cause of the disease is unknown and it is sporadic. Despite extensive research into the disease, its etiology has not been identified and no effective treatment has been found.

[0003] As mentioned above, ALS is usually progressive, resulting in upper and lower motor paralysis, with a median survival time of three years from the onset of the disease. Difficult and painful medical problems generally arise during the course of the disease, which has motivated the use of a wide range of treatments, including toxic drugs, inactivated cobra venom, and plasmapheresis, among others.

[0004] Plasmapheresis is a common medical procedure in which plasma from a patient is separated from whole blood. This has been used to treat patients suffering from various chronic diseases. Once the plasma is separated from the blood cells, the cells can be returned to the patient with or without a replacement fluid. During treatment of a patient with therapeutic plasmapheresis, a catheter is placed in a major vein, such as in the arm, and a second catheter is placed in another vein, such as in the foot or hand. Blood then exits the patient's body through the catheter and is pumped into a separation device, where the plasma is separated from the blood cells. Plasma-free blood, optionally containing a replacement fluid, is returned to the patient through the second catheter. Instead of two peripheral catheters, a dual-channel central venous catheter or peripheral catheter can also be used.

[0005] The use of plasmapheresis to treat ALS has been reported. For example, Silani et al. used plasma exchange with frozen plasma and saline for six months to treat four ALS patients (Silani, V., Scarlato, G., Valli, G., and Marconi, M. "Plasma Exchange Ineffective in Amyotrophic Lateral Sclerosis," Arch. Neurol. (1980) 37:511-513). However, the treatment was unsuccessful and did not alter the course of the disease. Furthermore, in a subsequent study by Kelemen et al., the use of plasma exchange with 5% albumin in combination with immunosuppressants to treat ALS failed to produce any beneficial effect on the disease or clinical improvement in any of the four patients studied (Kelemen, J., Hedlund, W., Orlin, JB, Berkman, EM, and Munsat TL, "Plasmapheresis with immunosupression in Amyotrophic Lateral Sclerosis," Arch. Neurol. (1983), 40:752-753).

[0006] Such previous research explains why the use of plasma exchange in the treatment of ALS is considered a lower category IV in the American Society for Apheresis Guidelines for the Use of Therapeutic Apheresis in Clinical Practice (Schwartz, J., Winters, JL, Padmanabhan, A., Balogun, RA, Delaney, M., Linenberger, ML, Szczepiorkowski, ZM, Williams, ME, Wu, Y., Shaz BH, "Guidelines on the use of therapeutic apheresis in clinical practice—evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue," J. Clin. Apher. 2013 July; 28(3):145-284). Category IV refers to disorders for which published evidence demonstrates or suggests that apheresis is ineffective or harmful.

[0007] More recently, Spanish Patent ES201530074 has shown that the use of a composition containing albumin to treat ALS by plasma exchange has some beneficial effects on the course of the disease. In this Spanish patent, ALS patients received 14 weeks of treatment with a composition containing 5% (w / v) human albumin by plasma exchange three times a week for the first two weeks and once a week for the remaining 12 weeks. The effects of this specific treatment were evaluated using ALS functional assessments starting 12 months before treatment and ending two months after the end of treatment. The results of the functional assessments showed a tendency toward stabilization of the disease course over time, which was unexpected, given the well-known tendency for ALS patients' condition to consistently worsen.

[0008] However, the study was conducted in only one patient whose disease course was maintained but never improved.

Prior Technical Literature

Charter Documents

[0009] [Patent Document 1] スペイン License ES201530074

Non-licensed literature

[0010]

Non-patent document 1

Non-patent document 2

Non-patent document 3

[0011] Therefore, there remains a need for a treatment of ALS by plasma exchange that can circumvent the usual progression of the disease and even improve the functional status of patients. [Means for solving the problem]

[0012] The inventors of the present invention have surprisingly found that the use of compositions comprising albumin to treat ALS by plasma exchange can actually ameliorate the progression of the disease by using certain treatment conditions.

[0013] Thus, in a first aspect, the present invention relates to a composition comprising albumin for use in the treatment of ALS by plasma exchange.

[0014] Preferably, the albumin concentration in the composition is between 5% and 25% (w / v). More preferably, the albumin concentration is about 5%, 10%, 15%, 20%, or 25% (w / v). Even more preferably, the albumin concentration is about 5% (w / v).

[0015] The albumin can be either recombinant or purified from human plasma, hi a preferred embodiment, the albumin is purified from human plasma.

[0016] In a preferred embodiment of the present invention, a composition comprising albumin for use in treating ALS is administered to a patient in need thereof by plasma exchange using a volume of said composition equal to approximately 100% of the volume of plasma withdrawn from the patient. In a preferred embodiment, said composition is administered to a patient by plasma exchange twice weekly for the first 3 weeks and once weekly for the following 21 weeks for a total period of 24 weeks.

[0017] In the present invention, treatment with a composition comprising albumin is preferably carried out by plasma exchange, i.e., the composition comprising albumin is used as a replacement fluid and returned to the patient together with blood cells previously separated from the plasma by plasmapheresis. Generally, a predetermined amount of plasma is withdrawn from the patient, and plasma exchange with a composition comprising albumin is carried out using an amount of the composition equal to approximately 100% of the amount of plasma withdrawn from the patient. Those skilled in the art will understand that slight variations of approximately ±10% of this amount fall within the scope of the present invention.

[0018] One major difference between the use of a composition containing albumin in the treatment of ALS according to the present invention and treatments known in the prior art is that the present treatment does not require the use of immunosuppressants before, during, or after the treatment. In the prior art, ALS has been linked to immune system abnormalities, such as abnormalities in surface antigens, T lymphocyte and macrophage migration (Kelemen J. et al., supra), which may suggest the use of immunosuppressant treatments simultaneously with any ALS treatment. However, it is demonstrated herein that the use of immunosuppressants together with the treatment of the present invention is not required to achieve satisfactory results for the treatment of ALS. Thus, in some embodiments, the use of immunosuppressants is not required during treatment with the compositions of the present invention. However, in other embodiments, the use of immunosuppressants during treatment of ALS with the compositions of the present invention is still possible if required by another condition of the patient.

[0019] In the treatment of the present invention, plasma exchange using a composition containing albumin as a replacement fluid is performed twice a week for the first 3 weeks and once a week for the following 21 weeks, which corresponds to a total period of 24 weeks.

[0020] During the treatment period of the present invention, patients can at least experience a tendency to stabilize the course of the disease. In other words, since ALS is a disease whose progression is rapid and gradual once ALS symptoms occur, achieving stabilization of the progression during the treatment period can be considered a very positive result. In addition, the treatment of the present invention also demonstrates an improvement in functional status in some patients, thus reversing the progression of the disease to a less advanced stage.

[0021] In a second aspect, the present invention relates to a method for treating ALS in a patient in need thereof, comprising administering a composition comprising albumin by plasma exchange. Preferably, the plasma exchange is performed using an amount of the composition equal to approximately 100% of the amount of plasma withdrawn from the patient. Those skilled in the art will appreciate that slight variations in this amount, of approximately ±10%, fall within the scope of the present invention. In some preferred embodiments, the method for treating ALS is performed twice weekly for the first three weeks and once weekly for the following 21 weeks, for a total period of 24 weeks.

[0022] Preferably, the albumin concentration in the composition is between 5% and 25% (w / v). More preferably, the albumin concentration is about 5%, 10%, 15%, 20%, or 25% (w / v). Even more preferably, the albumin concentration is about 5% (w / v).

[0023] The albumin can be either recombinant or purified from human plasma, hi a preferred embodiment, the albumin is purified from human plasma.

[0024] In some embodiments, the use of immunosuppressants is not necessary during the methods of treating ALS of the present invention.

[0025] Hereinafter, the present invention will be described in more detail with reference to illustrative examples, which do not constitute limitations of the present invention. DETAILED DESCRIPTION OF THE INVENTION [Example]

[0026] Plasma exchange (PE) with albumin 5% (Albutein®, Grifols, SA, Spain) in patients diagnosed with ALS.

[0027] Men and women aged 18 to <70 years with a definite, probable, or probable diagnosis of ALS according to El Escorial / Airlie House diagnostic criteria and a forced vital capacity (FVC) >70% of predicted were eligible for this prospective, single-arm, single-center pilot study.

[0028] Patients underwent PE treatment with 5% albumin (Albutein® 5%) for 6 months in Phase 2: an intensive phase included PE sessions twice a week for 3 weeks, followed by a maintenance phase included PE sessions once a week for 21 weeks. The follow-up period was 6 months.

[0029] Endpoints were changes in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score and FVC. Based on a typical survival time of 3 to 5 years from the time of ALS symptom onset and a typical decline of 1 point / month in the ALSFRS-R total score, disease progression was defined into three categories: "moderate," "slow," and "rapid," depending on whether the ALSFRS-R slope was between -0.8 and -1.33 points / month, less than -0.8 points / month, or more than -1.33 points / month, respectively.

[0030] Thirteen adults with ALS were enrolled and evaluated. The median (IQR) total score at baseline was 42.0 (37.0, 44.0). ALSFRS-R scores declined throughout the study, but the median decline was less than predicted in untreated patients. Seven patients had a slower decline than predicted at the end of treatment and five patients at the end of the study. Six patients remained in the same "progressor" category, while four improved in that category at the end of treatment. The median (IQR) FVC and percent predicted FVC at baseline were 3.9 (3.0, 4.9) L and 87.0% (76.0, 96.0), respectively. Median FVC declined significantly during the study. The treatment was well tolerated.

[0031] Plasma exchange with albumin replacement was safe and well tolerated in ALS patients. Although functional impairment progressed, most patients showed a slower than expected rate of decline at the end of treatment. Regarding progression, most patients either remained stable (54.5%) or showed improvement in their disease status (36.4%).

[0032] Thus, the treatment of the present invention has been found to not only stabilize the course of the disease, but also improve the patient's condition, thus reversing the progression of the disease to a less advanced stage.

[0033] While the present invention has been described with respect to preferred embodiments, this should not be construed as limiting the invention, which is defined by the broadest interpretation of the following claims.

Claims

1. 1. A composition comprising albumin for use in the treatment of amyotrophic lateral sclerosis (ALS) in a patient in need thereof, comprising: A composition comprising albumin is administered to the patient by plasma exchange, twice weekly for the first 3 weeks and once weekly for the following 21 weeks for a total period of 24 weeks, using the composition as a replacement fluid in an amount equal to 100±10% of the volume of plasma withdrawn from the patient.

2. 2. The composition for use according to claim 1, wherein the concentration of albumin in the composition is between 5% and 25% (w / v).

3. 3. The composition for use according to claim 2, wherein the concentration of albumin in the composition is 5% (w / v).

4. 4. The composition for use according to any one of claims 1 to 3, wherein the albumin is recombinant or purified from human plasma.

5. 5. A composition for use according to any one of claims 1 to 4, which does not require the use of immunosuppressants.