Resminostat is an orally administered histone deacetylase (HDAC) inhibitor with an innovative epigenetic mechanism of action that potentially represents a novel therapy for a broad spectrum of oncology indications, both in monotherapy and particularly in combination with other anti-cancer drugs.
In preclinical models, resminostat has shown selectivity for class I, IIB and IV HDAC enzymes with a particular specificity toward inhibiting the protein HDAC6, which is active in metastasis of cancer cells, thus targeting epigenetic changes observed in tumor cells. Resminostat has the potential to provide significant benefit to patients by inhibiting tumor progression and metastasis, inducing tumor regression and enhancing the body’s own immune response to cancer.
Clinical development profile
The clinical development of resminostat is currently focused on two primary indications: cutaneous T-cell lymphoma (CTCL) and liver cancer (hepatocellular carcinoma, HCC). Resminostat is also being investigated by 4SC and its Japanese partner Yakult Honsha in several indications such as, Hodgkin’s Lymphoma (HL), colorectal cancer (CRC), and non-small-cell lung cancer (NSCLC) through a broad clinical development program. The compound’s safety profile has been assessed in more than 300 Western and Asian patients to date, with further evaluation ongoing.
Studies have shown that resminostat is well tolerated in various indications in monotherapy and combination therapy. The most frequent adverse events are gastrointestinal disorders (i.e. nausea, vomiting and diarrhea), fatigue, and thrombocytopenia (low platelet count in the blood). The majority of adverse events were mild to moderate, manageable and reversible. In addition, resminostat has shown clinical efficacy in various Phase II studies which 4SC is evaluating further in advanced clinical studies.
Resminostat is a potent inhibitor of class I, IIb and IV HDACs, including a pronounced activity against HDAC6. In pharmacology studies, resminostat dose-dependently inhibited HDACs and induced acetylation of histone and non-histone proteins resulting in changes in gene expression levels in tumor cells and the deregulation of pathways involved in cell differentiation, such as WNT signaling. Changes in cell differentiation are very often the cause for tumor progression, metastasis and acquired resistance to anti-cancer treatment.
Resminostat also demonstrated similar in vitro effects in cutaneous T cell lymphoma (CTCL) derived cell lines. Resminostat was able to stabilize less advanced malignantly transformed T cells or even revert advanced stages of disease back to less advanced stages, indicating a unique potential for both maintenance therapy as well as the treatment of progressive CTCL.
Beside these effects on the differentiation of tumor cells, resminostat leads to an increased immunogenicity of tumors by enhancing natural killer (NK) cell recognition and killing, increasing expression and presentation of tumor-associated antigens that support T-cell functions, and reducing unspecific immunosuppressive mechanisms.
In vivo, resminostat showed significant anti-tumor activity in various human xenograft mice tumor models. Resminostat in combination with established therapies, such as irinotecan or sorafenib, generated additive, synergistic anti-tumor effects.