Methods and compositions for treating myelofibrosis
Inventors
Kumar, Ravindra • Suragani, Rajasekhar Naga Venkata Sai
Assignees
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Publication Number
US-12194076-B2
Publication Date
2025-01-14
Expiration Date
Abstract
In part, the present disclosure relates methods for treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis (extramedullary hematopoiesis, splenomegaly, anemia, and fibrosis). In certain aspects, the disclosure provides ActRIIB antagonists for use in treating, preventing, or reducing the progression rate and/or severity of one or more complications associated with Janus kinase inhibitor therapy in a patient (e.g., anemia).
Core Innovation
The disclosure relates to a method for treating myelofibrosis by administering an effective amount of ruxolitinib and an ActRIIB polypeptide to a patient in need thereof. The ActRIIB polypeptide comprises an amino acid sequence at least 98% identical to the amino acid sequence of SEQ ID NO: 53 and includes an E or D at the position corresponding to position 79 of SEQ ID NO: 1. The ActRIIB polypeptide inhibits myostatin and/or GDF11 in a cell-based assay.
The method further requires administering one or more blood cell transfusions prior to the start of ActRIIB polypeptide treatment. The disclosure specifies that the method decreases blood cell transfusions by greater than about 30% for 4 to 8 weeks relative to the equal time period prior to the start of ActRIIB polypeptide treatment. The context includes anemia management and patients treated with JAK inhibitors such as ruxolitinib.
The disclosure also characterizes therapeutic use of ActRIIB antagonists, including an ActRIIB/GDF trap, aimed at ameliorating myelofibrosis complications such as splenomegaly, extramedullary hematopoiesis, and fibrosis. It further describes antagonizing ActRIIB signaling, including by inhibiting GDF11 and/or GDF8 and related TGF-beta superfamily ligands.
Claims Coverage
The consolidated claim coverage identifies one independent claim. It combines ruxolitinib with a structurally defined ActRIIB polypeptide, requires prior blood cell transfusions, and specifies a reduction in transfusion burden over 4 to 8 weeks, supported by a cell-based assay inhibition requirement.
Ruxolitinib plus sequence-defined ActRIIB polypeptide for myelofibrosis
Administering to a patient in need thereof an effective amount of ruxolitinib and an ActRIIB polypeptide comprising an amino acid sequence at least 98% identical to SEQ ID NO: 53, wherein the polypeptide comprises an E or a D at the position corresponding to position 79 of SEQ ID NO: 1, and wherein the ActRIIB polypeptide inhibits myostatin and/or GDF11 in a cell-based assay.
Prior blood cell transfusions and reduction of transfusions
Administering one or more blood cell transfusions prior to the start of ActRIIB polypeptide treatment, wherein the method decreases blood cell transfusions by greater than about 30% for 4 to 8 weeks relative to the equal time period prior to the start of ActRIIB polypeptide treatment.
The independent claim centers on treating myelofibrosis with ruxolitinib plus a sequence-constrained ActRIIB polypeptide that functionally inhibits myostatin and/or GDF11 in a cell-based assay, together with prior transfusions and a quantified decrease in transfusion requirement.
Stated Advantages
Decreases blood cell transfusions by greater than about 30% for 4 to 8 weeks relative to the equal time period prior to the start of ActRIIB polypeptide treatment.
Inhibits myostatin and/or GDF11 in a cell-based assay.
Ameliorates complications of myelofibrosis, including splenomegaly, extramedullary hematopoiesis, and fibrosis.
Documented Applications
Treating myelofibrosis in a patient in need thereof, including patients receiving JAK inhibitors such as ruxolitinib and experiencing anemia and transfusion dependence.
Reducing transfusion burden in patients requiring one or more blood cell transfusions prior to starting ActRIIB polypeptide treatment.
Therapeutic use of ActRIIB antagonists, including an ActRIIB/GDF trap, in the context of myelofibrosis complications such as splenomegaly, extramedullary hematopoiesis, and fibrosis.
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