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Therapeutic regimens for treatment of paroxysmal nocturnal hemoglobinuria

Inactive Publication Date: 2019-02-07
ACHILLION PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method for treating a condition called paroxysmal nocturnal hemoglobinuria (PNH) by using a combination of a complement component C5 inhibitor, a complement component C3 inhibitor, or a complement factor B (CFB) inhibitor with a small molecule complement factor D (CFD) inhibitor. This combination has been found to significantly improve the inhibition of intravascular hemolysis associated with PNH and to prevent the upstream C3 convertase assembly and C3 fragment deposition that contributes to extravascular hemolysis. The use of a CFD inhibitor in combination with a C5 inhibitor or a C3 inhibitor provides an improved therapeutic approach for treating PNH subjects who are suboptimal responders to a C5 inhibitor or are susceptible to extravascular hemolysis.

Problems solved by technology

While eculizumab binds to C5 and blocks the terminal pathway of complement upstream of CD59, it does not address the deposition of C3 fragments as a result of the complement alternative pathway due to the absence of CD55 on PNH erythrocytes.
As a result, PNH erythrocytes accumulate C3 fragment and are susceptible to extravascular hemolysis by opsonization.

Method used

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  • Therapeutic regimens for treatment of paroxysmal nocturnal hemoglobinuria
  • Therapeutic regimens for treatment of paroxysmal nocturnal hemoglobinuria
  • Therapeutic regimens for treatment of paroxysmal nocturnal hemoglobinuria

Examples

Experimental program
Comparison scheme
Effect test

example 1

y Activity of Compound 1 in Combination with Eculizumab as Assessed Via a CAP-Mediated Hemolysis Assay with PNH Erythrocytes

[0214]The inhibitory activity of Compound 1 and the humanized monoclonal antibody Eculizumab was assessed via a CAP-mediated hemolysis assay with PNH erythrocytes from subjects (described in Example 3). The CAP-mediated hemolysis assay with PNH erythrocytes was conducted two independent times and then analyzed by the method of Prichard and Shipman (described in Example 4). The inhibition of CAP activity for each experiment is shown in Table 2. The analytical results for each experiment, along with summary information, are shown in Table 3. The three-dimensional surface-graphs used in the analysis method of Prichard and Shipman are shown in FIGS. 1A-1B.

TABLE 2Inhibition of CAP activity of Compound 1 and EculizumabEculiz-Compound 1 (μM)umaba00.02340.04690.09380.1880.3750.751.5Inhibition (%), Experiment #140034373536567691972002531293155708898100122518234164879750...

example 2

y Activity of Compound 1 in Combination with Compstatin as Assessed Via a CAP-Mediated Hemolysis Assay with PNH Erythrocytes

[0216]The inhibitory activity of Compound 1 and the complement C3 inhibitor Compstatin was assessed via a CAP-mediated hemolysis assay with PNH erythrocytes from subjects (described in Example 3). The CAP-mediated hemolysis assay with PNH erythrocytes was conducted two independent times and then analyzed by the method of Prichard and Shipman (described in Example 4) and by the method of Chou and Talalay (described in Example 5). The inhibition of CAP activity for each experiment is shown in Table 4. The analytical results for each experiment are shown in Table 5. The three-dimensional surface-graphs used in the analysis method of Prichard and Shipman are shown in FIGS. 2A-2B.

TABLE 4Inhibition of CAP activity of Compound 1 and Compstatin measured using the CAP-mediated hemolysis assay with PNH ErythrocytesComp-statin(μM)Compound 1 (μM)Inhibition (%), Experiment ...

example 3

ted Hemolysis Assay with Erythrocytes from PNH Subject A

[0219]Combination studies of Compound 1 with Eculizumab (results are described in Example 1) and Compound 1 with Compstatin (results are described in Example 2) were performed using the CAP-mediated hemolysis assay with erythrocytes from PNH subject A and blood group ABO-compatible serum (NHS-AB, final assay concentration 20%). PNH Subject hematologic characteristics are shown in Table 6.

TABLE 6Characteristics of Subject AAge, Gender52, FBlood typeBErythrocyte clone size Type II / III (%)3.1 / 88Granulocyte clone size (%)99LDH (U / L)293Hemoglobin (g / dL)9.8Direct Coombs C3PosDirect Coombs IgGNegAbsolute reticulocyte count (K / cu mm)288.3Start of Eculizumab useStarted March 2011

[0220]Compound 1 and Compstatin were prepared as 15 mM stocks in DMSO. Eculizumab was obtained as a 10 mg / mL stock in buffered saline. Complement-preserved normal human serum (NETS) from an individual donor of ABO blood group type AB (NHS-AB) was purchase from B...

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Abstract

Provided herein are methods for treating a subject with PNH comprising administering to a subject a therapeutically effective amount of complement component C5 (C5) inhibitor, complement component C3 (C3) inhibitor, or complement factor B (CFB) inhibitor in combination with a therapeutically effective amount of small molecule complement factor D (CFD) inhibitor of Formula I or Formula II, or a pharmaceutically acceptable salt thereof.

Description

STATEMENT OF RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 62 / 540,451, filed on Aug. 2, 2017, and U.S. Provisional Application No. 62 / 593,669, filed Dec. 1, 2017. The entirety of each of these applications is incorporated herein by reference for all purposes.FIELD OF THE INVENTION[0002]This invention is in the area of therapeutic regimens for the treatment of the complement-mediated disorder paroxysmal nocturnal hemoglobinuria (PNH).BACKGROUND OF THE INVENTION[0003]The complement system is a part of the innate immune system which does not adapt to changes over the course of the host's life, but is recruited and used by the adaptive immune system. For example, it assists, or complements, the ability of antibodies and phagocytic cells to clear pathogens. This sophisticated regulatory pathway allows rapid reaction to pathogenic organisms while protecting host cells from destruction. Over thirty proteins and protein fragments make up t...

Claims

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Application Information

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IPC IPC(8): A61K31/506A61K39/395C07K16/18A61P7/00
CPCA61K31/506A61K39/3955C07K16/18A61P7/00A61K2039/505C07K2317/76A61K2300/00
Inventor HUANG, MINGJUNPATEL, DHARABENPODOS, STEVEN D.
Owner ACHILLION PHARMA INC
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