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Methods and compositions for treating a serpinc1-associated disorder

a serpinc1-associated disorder and composition technology, applied in the field of methods and compositions for treating a serpinc1-associated disorder, can solve the problems of refractory to replacement coagulation factor, difficult treatment of bleeds in such subjects, and inability to properly control bleeds, etc., to inhibit or reduce the expression of the serpinc1 gene

Pending Publication Date: 2022-01-20
GENZYME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is based on the discovery that very small amounts of a special type of double-stranded RNAi agent can effectively and durably inhibit the expression of a gene called Serpinc1. This invention is useful for treating disorders that would benefit from reducing the activity of this gene. The invention also shows that certain modifications to the RNAi agent make it more effective and durable in silencing the gene. Additionally, the invention shows that the treatment reduces the bleed rate in subjects with the disorder.

Problems solved by technology

Although at present there is no cure for hemophilia, it can be controlled with regular infusions of the deficient clotting factor, e.g., factor VIII in hemophilia A. However, some hemophiliacs develop antibodies (inhibitors) against the replacement factors given to them and, thus, become refractory to replacement coagulation factor.
Accordingly, bleeds in such subjects cannot be properly controlled.
The development of high-titer inhibitors to, for example, factor VIII and other coagulation factors is the most serious complication of hemophilia therapy and makes treatment of bleeds very challenging.
Currently, the only strategies to stop bleeds in such subjects are the use of “bypassing agents” such as factor eight inhibitor bypass activity (FEIBA) and activated recombinant factor VII (rFVIIa), plasmapheresis, continuous factor replacement, and immune tolerance therapy, none of which are completely effective.

Method used

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  • Methods and compositions for treating a serpinc1-associated disorder
  • Methods and compositions for treating a serpinc1-associated disorder
  • Methods and compositions for treating a serpinc1-associated disorder

Examples

Experimental program
Comparison scheme
Effect test

example 1

ation of a Single Dose of AD-57213 to Healthy Human Subjects

[0774]Twenty-four healthy human volunteers, in cohorts of 3:1 (active: placebo), were administered a single dose of 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 0.6 mg / kg, or 1.0 mg / kg of AD-57213 (Sense (5′ to 3′): GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAfL96 (SEQ ID NO: 13); Antisense (5′ to 3′): usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcsasg (SEQ TD NO: 14)). Plasma samples were collected at days 0, 1, 2, 3, 7, 10, 14, 21, 28, 42, 56, and 70 after administration to monitor AT protein levels, AT activity, and duration duration of AT protein silencing. AT protein levels were monitored using ELISA and AT activity levels were monitored by generation of thrombin generation curves using a Calibrated Automated Thrombinoscope (tissue factor=1 pM). Fold change in peak thrombin was calculated relative to the average peak thrombin value for two pre-dose values for each subject.

[0775]There were no serious adverse events, 3 mild adverse events that were not li...

example 2

ation of Multiple Doses of AD-57213 to Human Patients Having Hemophilia A or B

Phase I—Parts B, C, and D Clinical Trial

[0778]In Part B of a Phase I clinical trial of AD-57213 (Sense (5′ to 3′): GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAfL96 (SEQ ID NO:13); Antisense (5′ to 3′): usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcsasg (SEQ ID NO:14)), three patients having Hemophilia A (n=2) or B (n=1) were subcutaneously administered 0.015 mg / kg weekly for three weeks (15 micrograms / kg qw×3; 15 mcg / kg) of AD-57213; six patients having Hemophilia A were subcutaneously administered 0.045 mg / kg weekly for three weeks (45 micrograms / kg qw×3; 45 mcg / kg) of AD-57213; and three patients having Hemophilia A (n=2) or B (n=1) were subcutaneously administered 0.075 mg / kg weekly for three weeks (75 micrograms / kg qw×3; 75 mcg / kg) of AD-57213.

[0779]In Part C of a Phase I clinical trial of AD-57213 (Sense (5′ to 3′): GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAfL96 (SEQ ID NO:13); Antisense (5′ to 3′): usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcs...

example 3

ation of Multiple Doses of AD-57213 to Human Patients Having Hemophilia A or B

Phase II Open Label Extension (OLE) Clinical Trial

[0798]In a Phase II OLE study of AD-57213 (Sense (5′ to 3′): GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAfL96 (SEQ ID NO:13); Antisense (5′ to 3′): usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcsasg (SEQ ID NO:14)), patients without inhibitors previously administered AD-57213 in the Phase I Part B and C clinical trials described above, were eligible to be enrolled into a Phase II open-label extension (OLE) study. Twelve patients from the Phase I Part B study having Hemophilia A or B that had been subcutaneously administered 0.015 mg / kg weekly for three weeks (15 micrograms / kg qw×3; 15 mcg / kg) of AD-57213; or had been subcutaneously administered 0.045 mg / kg weekly for three weeks (45 micrograms / kg qw×3; 45 mcg / kg) of AD-57213; or had been subcutaneously administered 0.075 mg / kg weekly for three weeks (75 micrograms / kg qw×3; 75 mcg / kg) of AD-57213; and 18 patients from the Phase I P...

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Abstract

The invention relates to iRNA, e.g., double stranded ribonucleic acid (dsRNA), compositions targeting the Serpinc1 gene, and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of Serpinc1 and to treat subjects having a Serpinc1-associated disease, e.g., a bleeding disorder, such as a hemophilia.

Description

RELATED APPLICATIONS[0001]This application is a division of U.S. patent application Ser. No. 15 / 371,300, filed Dec. 7, 2016, which claims the benefit of priority to U.S. Provisional Patent Application 62 / 264,013, filed Dec. 7, 2015, U.S. Provisional Patent Application 62 / 315,228, filed Mar. 30, 2016, U.S. Provisional Patent Application 62 / 366,304, filed Jul. 25, 2016, and U.S. Provisional Patent Application 62 / 429,241, filed Dec. 2, 2016. The contents of each of the foregoing patent applications are incorporated herein by reference in their entirety.[0002]This application is related to U.S. Provisional Patent Application 61 / 992,057, filed May 12, 2014, U.S. Provisional Patent Application 62 / 089,018, filed Dec. 8, 2014, U.S. Provisional Patent Application 62 / 102,281, filed Jan. 12, 2015, and PCT Patent Application PCT / US2015 / 030337, filed May 12, 2015. The contents of each of the foregoing patent applications are incorporated herein by reference in their entirety.[0003]In addition, t...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N15/113A61K31/713A61K47/54
CPCC12N15/113A61K31/713A61K47/549C12N2320/35C12N2310/351C12N2310/315C12N2310/321C12N2310/346C12N2310/14A61P43/00A61P7/04C12N2310/3521C12N2310/322C12N2310/3533C12N2310/335C07H21/04A61K48/00
Inventor AKINC, AKINSORENSEN, BENNYGARG, PUSHKALROBBIE, GABRIEL
Owner GENZYME CORP
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