RU-2861586-C2 - COMPOSITIONS AND METHODS FOR TREATING LATE-ONSET POMPE DISEASE

Abstract

FIELD: chemistry; pharmaceutics. SUBSTANCE: invention relates to a method of treating late-onset Pompe disease (LOPD) in a human subject in need thereof. According to the proposed method, a human subject whose first symptoms of Pompe disease manifest at the age of at least 18 years is administered a pharmaceutical composition comprising an oligosaccharide-protein conjugate, which is avalglucosidase alfa, and a pharmaceutically acceptable carrier, at a dose of 20 mg/kg for 49 weeks, resulting in (compared to treatment with alglucosidase alfa at a dose of 20 mg/kg for 49 weeks) an increase in one or more of: percentage of forced vital capacity (FVC%) in the upright position; distance in the 6-minute walk test (6MWT); percentage of the predicted 6MWT distance (6MWT%); percentage of predicted maximum inspiratory pressure (MIP%) or percentage of predicted maximum expiratory pressure (MEP%) in the upright position; hand-held dynamometry (HHD) measurement for lower or upper limbs; total score in the quick motor function test (QMFT); health-related physical component summary (PCS) score of the 12-item Short Form Health Survey (SF-12®); mental component summary (MCS) score of SF-12®, and/or a decrease in urinary hexose tetrasaccharide (HEX4) level, creatine kinase level, alanine aminotransferase (ALT) level, aspartate aminotransferase (AST) level. EFFECT: more effective treatment of LOPD. 53 cl, 70 dwg, 4 tbl, 2 ex

Inventors

• FINN, PATRICK
• HAMED, Alaa
• AN HAACK, Kristina
• WILSON, CATHERINE

Dates

Publication Date

20260506

Application Date

20210611

Priority Date

20200614

Claims (20)

1. 1. A method for treating late-onset Pompe disease (LOPD) in a human subject in need thereof, comprising administering to the human subject a pharmaceutical composition comprising an oligosaccharide-protein conjugate and a pharmaceutically acceptable carrier, wherein the oligosaccharide-protein conjugate is avalglucosidase alfa,
2. in this case, the pharmaceutical composition is administered at a dose of 20 mg/kg,
3. where the human individual exhibits the first symptoms of Pompe disease at an age of at least 18 years, and
4. wherein administration of said pharmaceutical composition to a human individual for 49 weeks results in one or more of the following:
5. (a) the human subject has an increase in standing forced vital capacity (FVC%) that is at least 2.43% higher than the increase in standing FVC% in the human subject treated with alglucosidase alfa;
6. (b) the human subject is characterized by an increase in 6-minute walk test (6MWT) distance of at least 30.01 meters compared to the increase in 6MWT distance in the human subject treated with alglucosidase alfa;
7. (c) the human subject has a 6MWT distance percentage (6MWT%) increase from the predicted value that is at least 4.71% greater than the 6MWT% increase in the human subject treated with alglucosidase alfa;
8. (d) the human subject has an increase in maximum inspiratory pressure (MIP%) of predicted in the upright position that is at least 4.40% higher than the increase in MIP% in the human subject treated with alglucosidase alfa;
9. (e) the human subject has an increase in maximum expiratory pressure (MEP%) of predicted in the upright position that is at least 2.51% greater than the increase in MEP% in the human subject treated with alglucosidase alfa;
10. (f) the human subject has an increase in lower limb hand strength (HHD) that is at least 106.97 Newtons greater than the increase in lower limb HHD in the human subject treated with alglucosidase alfa;
11. (g) the human subject has an increase in upper limb HHD that is at least 63.87% Newton greater than the increase in upper limb HHD in the human subject treated with alglucosidase alfa;
12. (h) the human subject has an increase in the total score on the Quick Motor Function Test (QMFT) that is at least 2.08 times greater than the increase in the total score on the QMFT in the human subject treated with alglucosidase alfa;
13. (i) the human subject has an increase in the health-related physical component score (PCS) of the Short Form 12-Item Quality of Life (SF-12®) that is at least 0.77 times greater than the increase in the SF-12® PCS score of the human subject treated with alglucosidase alfa;
14. (j) the human subject has an increase in the SF-12® mental component score (MCS) that is at least 2.12 times greater than the increase in the SF-12® MCS score of a human subject treated with alglucosidase alfa;
15. (k) the human subject is characterized by a decrease in the level of hexose tetrasaccharide (HEX4) in urine that is at least 43.14% lower compared to the decrease in the level of HEX4 in the human subject treated with alglucosidase alfa;
16. (l) the human subject has a decrease in creatine kinase that is at least 23.89% lower than the decrease in creatine kinase in a human subject treated with alglucosidase alfa;
17. (m) the human subject has a decrease in alanine aminotransferase (ALT) that is at least 33.9% lower than the decrease in ALT in a human subject treated with alglucosidase alfa; and
18. (n) the human subject has a decrease in aspartate aminotransferase (AST) level that is at least 32.28% lower than the decrease in AST level in a human subject treated with alglucosidase alfa;
19. In this case, a human subject treated with alglucosidase alfa was administered alglucosidase alfa at a dose of 20 mg/kg for 49 weeks.
20. 2. The method according to claim 1, wherein the age of the human individual is at least 45 years.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [1] This application claims the benefit of priority to U.S. Provisional Patent Application Nos. 63/038,857, filed June 14, 2020, 63/076,037, filed September 9, 2020, 63/147,629, filed February 9, 2021, and 63/157,490, filed March 5, 2021, the contents of each of which are incorporated herein by reference in their entirety. AREA OF TECHNOLOGY [2] This application relates to compositions and methods for the treatment of late-onset Pompe disease (LOPD). BACKGROUND OF THE INVENTION [3] Pompe disease (also known as glycogen storage disease type II or GSD-II) is a rare, autosomal recessive, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase (GAA), the enzyme responsible for the breakdown of glycogen. The resulting abnormal accumulation of glycogen in lysosomes leads to cellular dysfunction; progressive damage to the respiratory, cardiac, skeletal, and smooth muscles; and functional impairment. [4] In late-onset Pompe disease (LOPD), symptoms can present at any age but without the cardiomyopathy that is common in patients with infantile onset. With multiple system involvement, respiratory muscle dysfunction and failure lead to significant morbidity and mortality in patients with LOPD. In untreated patients with LOPD, progressive muscle damage causes breathing and mobility problems that occur with varying frequency and, in many patients, ultimately lead to the need for respiratory support and wheelchair use. There is a need for effective and safe therapies for LOPD. ESSENCE OF THE INVENTION [5] The present application provides methods and compositions for treating late-onset Pompe disease (LOPD) in an individual in need thereof. [6] In one aspect of the present application, there is provided a method of treating LOPD in a human subject, comprising administering to the subject a pharmaceutical composition comprising an oligosaccharide-protein conjugate and a pharmaceutically acceptable carrier, wherein the oligosaccharide-protein conjugate is characterized by the structure of formula I: wherein GAA is acid α-glucosidase, L is a chemical linker connecting the oligosaccharide and GAA, and n is from 1 to 10, and wherein the pharmaceutical composition is administered at a dose of approximately 20 mg/kg. [7] In some embodiments, according to any of the methods described above, the individual is at least about 45 years old (e.g., at least 50, 60, 65, or more). In some embodiments, the individual is between about 18 and about 45 years old. In some embodiments, the individual is no more than 18 years old (e.g., no more than 16, 12, 8, or 5). [8] In some embodiments, according to any of the methods described above, the individual is diagnosed with Pompe disease at an age of at least about 18 (e.g., at least 25, 30, 35, 40, 45, or more) years. In some embodiments, the individual is diagnosed with Pompe disease at an age of no more than about 18 (e.g., no more than about 16, 12, 8, or 5) years. [9] In some embodiments, according to any of the methods described above, the individual is characterized by the first symptoms of Pompe disease at an age of at least about 18 (e.g., at least 25, 30, 35, 40, 45, or more) years. In some embodiments, the individual is characterized by the first symptom of Pompe disease at an age of no more than about 18 (e.g., no more than about 16, 12, 8, or 5) years. [10] In one aspect of the present application, there is provided a method of treating late-onset Pompe disease (LOPD) in a human subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an oligosaccharide-protein conjugate and a pharmaceutically acceptable carrier, wherein the oligosaccharide-protein conjugate is characterized by the structure of formula I: where GAA is acid α-glucosidase, L is a chemical linker connecting the oligosaccharide and GAA, and n is from 1 to 10, wherein the pharmaceutical composition is administered at a dose of approximately 20 mg/kg, in this case, the individual is characterized by one or more of the following characteristics: (a) the age of the individual at the time of initiation of treatment is between 3 and 18 years; (b) the individual has a forced vital capacity (FVC) percentage of predicted value of between approximately 30% and approximately 50% prior to treatment, and (c) the individual can walk from about 40 to about 50 meters without stopping or using an assistive device before receiving treatment. In some embodiments, the individual is between 3 and 18 years old at the time of treatment. In some embodiments, the individual has a forced vital capacity (FVC) percentage of the predicted value of between about 30% and about 50% before receiving treatment. In some embodiments, the individual can walk from 40 to 50 meters without stopping or using an assistive device before receiving treatment. [11] In some embodiments according to the methods disclosed above, administering the phar