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Mocetinostat (MGCD103)

Image: The Rationale and Therapeutic Promise of Combining HDAC Inhibitors with Immune Checkpoint Inhibitors
Targets: Class I & IV HDAC Inhibitor
Indications: NSCLC and other solid tumors
 
Status: Phase 1/2
Mocetinostat (MGCD103) is an orally-bioavailable, spectrum-selective Class I & IV HDAC inhibitor currently being studied in a Phase 2 trial as a combination therapy with durvalumab, targeting the programmed death ligand 1 (PD-L1) pathway, which has been implicated in advanced lung cancers. In preclinical models, mocetinostat with durvalumab demonstrated significant reduction in tumor volume compared to either agent alone.

Mirati retains worldwide rights to Mocetinostat (MGCD103) with the exception of certain Asian territories where the program is partnered with Taiho.

AACR 2016:  Abstract 4021: "The class I HDAC inhibitor, mocetinostat, induces expression of PD-L1 and tumor antigen presentation machinery and modifies tumor immune cellular subsets providing a rationale for immune checkpoint inhibitor combinations"  click to view


Non-Small Cell Lung Cancer (NSCLC)

The overall five year survival rate for patients with NSCLC is only 16.8% and NSCLC results in the greatest number of cancer deaths in the United States. Over recent years, new therapies have been approved that target gene pathways implicated in progression of NSCLC, including EGFR kinase inhibitors, EML4-ALK inhibitors, and immune checkpoint inhibitors. However, these targets represent only a fraction of the growing list of cancer genes that play a role in NSCLC. There remains a significant unmet medical need to develop new therapies that inhibit multiple targets, particularly those that also inhibit novel targets for which no therapy exists. Backed by a strong scientific rationale, we believe that Mocetinostat (MGCD103), combined with durvalumab (an investigational anti-PD-L1 immune checkpoint inhibitor), may result in synergistic and immune enhancing anti-tumor effect.

Clinical Development

Mocetinostat (MGCD103) has completed 13 clinical trials which have enrolled more than 400 patients with hematologic malignancies and solid tumors.

Mocetinostat (MGCD103) in combination with immunotherapy

A Phase 1-2 study of Mocetinostat (MGCD103), in combination with durvalumab (an investigational anti-PD-L1 immune checkpoint inhibitor), is anticipated to start in 2016. The study will evaluate the safety and efficacy of the combination in patients with non-small cell lung cancer (NSCLC).

 

Mocetinostat (MGCD103) + durvalumab Proof-of-Concept Phase 2 Trial in NSCLC Initiating 1H 2016

 

Mocetinostat (MGCD103) Clinical Trials

Scientific Rationale

In combination with immunotherapy

Preclinical data suggests that spectrum-selective HDAC inhibitors, such as Mocetinostat (MGCD103), may enhance the anti-tumor activity of checkpoint inhibiting antibodies (anti-programmed cell death (PD-1) and anti-programmed cell death ligand (PD-L1) inhibitors) by increasing tumor cell immunogenicity and decreasing cell types that limit the T-cell mediated tumor immune response. In addition, evidence suggests that Mocetinostat (MGCD103) enhances tumor cell immunogenicity by selectively inhibiting Class I HDACs, which results in increased human leukocyte antigen (HLA) expression, can increase PD-L1 expression, and decrease immunosuppressive tumor myeloid derived suppressor cells and T regulatory cells. Lastly, in contrast to other HDAC inhibitors, Mocetinostat (MGCD103) does not inhibit Class II HDACs which may limit the efficacy of immunotherapy and are associated with significant side effects. These data indicate that Mocetinostat (MGCD103) could potentially be used to enhance the efficacy of immune check-point inhibitors, such as PD-1 or PD-L1 antagonists.

Select Background Reading

  1. Cancer Genome Atlas Research Network, 'Comprehensive molecular characterization of urothelial bladder carcinoma' , 507 ( ): Nature2013 ; 315 - 322
  2. Magner, W.J., et al., 'Activation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitors,' . J Immunol . 165:7017-24, 2000
  3. Park, Jeenah, et al., 'Epigenetic modulation with histone deacetylase inhibitors in combination with immunotherapy,' 7(4), Epigenomics 2015: 641-652
  4. Park, Jeenah, et al., 'Eradication of solid tumors using histone deacetylase inhibitors combined with immune-stimulating antibodies,' Proc Natl Acad Sci USA. 108:4141-6, 2011
  5. West, A.C., et al., 'An Intact Immune System Is Required for the Anticancer Activities of Histone Deacetylase Inhibitors,' 7(4), Cancer Res 2013
  6. Woods, D.M., et al., 'HDAC Inhibition Upregulates PD-1 Ligands in Melanoma and Augments Immunotherapy with PD-1 Blockade,' Cancer Immunol Res. 2015 Dec;3(12):1375-85
  7. West, A., C. et al, 'The combination of histone deacetylase inhibitors with immune-stimulating antibodies has potent anti-cancer effects,' 1:3, OncoImmunology; 376-378

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