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Generation 2.5 antisense drug

ION674, formerly known as IONIS-EZH2-2.5Rx, is an epigenetic modulator as the catalytic subunit of the polycomb repressive complex 2 (PRC2). It functions as a histone methyltransferase which catalyzes the mono- through tri-methylation of lysine 27 residue of histone 3 (H3K27me3) and suppresses the transcription of specific genes. It is involved in early embryogenesis, self-renewal and proliferation of embryo and adult stem cells. Increased expression or activity of EZH2 has been reported in multiple solid tumors as well as hematological malignancies, which associates with poor prognosis. Aberrant expression of EZH2 can be caused by multiple mechanisms in a variety of cancer types. For example, activating mutations leading to enhanced catalytic activity of EZH2 are found in certain types of B-cell lymphoma including GCB-DLBCL and follicular lymphoma. There is also evidence that solid tumors with a loss of function in tumor suppressor genes such as SWI/SNF complex, BAP1, and UTX are highly dependent on EZH2 for their growth. Finally, EZH2 can promote tumor growth by creating immune-suppressive tumor microenvironment such as T cell exhaustion. Collectively, selective depletion of EZH2 by ASO is expected to be highly efficacious in treating tumors with aberrant expression of EZH2.

GCB-DLBCL and Follicular Lymphoma

GCB-DLBCL and follicular lymphoma belong to B-cell non-Hodgkin lymphoma (NHL), a lymphoproliferative disorder originating in B lymphocytes. Even though the initial response rate to the standard of care treatment composed of chemotherapy in combination with anti-CD20 antibody (R-CHOP) is relatively good, the disease either relapses or becomes refractory to the therapy. Heterozygous somatic mutations leading to increased EZH2 activity have been found in approximately 20% of patients with GCB-DLBCL and follicular lymphoma, where EZH2 plays an important role in promoting tumor growth, suggesting that these tumor types might be sensitive to antisense inhibition by EZH2 production.