EPIGENETICS PHARMA

Treating cancer by upregulating tumor suppressor genes and stimulating an antitumor immune response



Background



The central feature of cancer is increasingly thought to be an unstable and disrupted epigenome, including aberrant methylation that suppresses gene expression (pubmed.ncbi.nlm.nih.gov). DNA methyl transferase inhibitors (DNMTI) are a class of drugs approved for the treatment of hematologic cancers that aim to express aberrantly silenced genes, but until now have not been very effective against solid tumors.


iMN013 and its prodrug iMN041 (iMN041 is an inactive form converted in the body to iMN013) have been invented and developed by Epigenetics Pharma. iMN013 combines a DNMTI and a ribonucleotide reductase inhibitor (RNRI) in a novel molecule. The immune response that is generated after administration of iMN041 has a unique and “ideal” profile based on the current knowledge of antitumor immunology.



Vision






The goal of Epigenetics Pharma is to treat cancer patients with iMN041. A molecule that has been shown to be a potent DNMTI and RNRI. This translates into iMN041 being a uniquely effective immunotherapeutic to treat tumors such as triple negative breast cancer or pancreatic cancer by harnessing the patient's own antitumor immune response.



Findings



Delivering on the promise of Epigenetics through immunotherapy





Epigenetics Pharma has developed a drug (iMN013) and its prodrug (iMN041) that address the shortcomings of currently approved drugs or those under development:




1. iMN041 has been shown to have a significant impact on the antitumor immune response, and acts on multiple arms of the immune system in concert, as opposed to current immunotherapeutics that only have effect on one arm of the immune system, sometimes adversely impacting others (e.g., www.nature.com ). iMN041 upregulates both the innate and the adaptive immune system, while decreasing the possibility of tumor immune escape.


  • iMN041 increases the amount of the enzyme Granzyme B in natural killer cells, NK and NKT, and leads to their proliferation. NK cells are the major component of the innate antitumor immune response, while NKT cells bridge the gap between NK and CD8-T cells. Granzyme B is a serine protease that leads to tumor cell death by apoptosis (programed cell death). This upregulation of NKT has not previously been described in the medical literature.


  • Cytotoxic T-lymphocytes (CTL, CD8-T) are thought to be one of the key cells for antitumor activity. T-helper cells (CD4-T) are important in modulating the antitumor immune response. T-regulatory cells (Treg) are immune suppressive cells and blunt the anti-tumor immune response. Current DNMTI upregulate Treg cells, while iMN041 downregulates them, mediated by RNRI. iMN041 is the first DNMTI reported to increase the ratio of CD8-T cells to Treg cells, and CD4-T cells to Treg cells, enhancing the antitumor immune response. A favorable CD8-T/Treg is one of the best predictors of cancer patient outcome.


  • Myeloid derived suppressor cells (MDSC) have a potent mechanism to inhibit the activity of T-cells and NK cells, and promote tumor growth. iMN041 has been shown to significantly inhibit the population of such cells.


  • MAGE-A is a protein that is not expressed on normal cells, except the testis, but is expressed on many cancer cells. As such it has been thought of as a target for immunotherapy. iMN041 has been shown to significantly decrease the number of tumor cells expressing MAGE-A in an animal model of renal cancer, by enhancing the targeting of such cells by the immune system. This is the first molecule to demonstrate this activity in vivo.


2. iMN013/041 also function by derepressing genes that turn immortal cancer cells into normal cells that undergo apoptosis at very low drug concentrations. One of the key genes that is not expressed in the setting of cancer is p53. It is often referred to as the “guardian of the genome” because it is associated with reduced tumor cell proliferation, cell differentiation, cell senescence and death. It is not expressed in cancer cells, either because of mutation (p53 null or mutant) or because of hypermethylation (p53 wild type). About half of human cancers are p53 wild type. In this case, the gene can be expressed in the presence of a DNMTI. iMN013 has demonstrated a unique ability to treat p53 wild type cells mediated through RNRI, though it is more effective than other DNMTI against p53 null cells as well.



3. This dual activity of iMN041 has translated into efficacy in mouse models of human cancer, and in particular, the most difficult to treat solid tumors. For mice to not reject human tumors, it is necessary to implant the tumor in animals without T-cells (so called nude mice).


  • Originally, iMN013 demonstrated significant activity against leukemia and colon cancer.


  • More recently iMN041 has shown significant activity against some of the most difficult to treat cancers, including non-small cell lung cancer, renal cell cancer, pancreatic cancer (as an example see below) and triple negative breast cancer. As nude mice lack T-cells, the expectation is that iMN041 will further inhibit tumor growth in immunocompetent hosts.


In Summary



iMN041 offers a new paradigm for treating solid and hematogenous tumors by upregulating the patient’s own antitumor immune response and ending the immortally of cancerous cells.



CURRENT STAGE OF DEVELOPMENT





iMN041 has been administered to mice, rats and dogs and is ready for IND enabling toxicology, a prelude to clinical testing. The carrier moiety of the molecule has already had extensive multispecies toxicology performed.



Publications



iMN013





Daifuku R, Hu Z, Saunthararajah Y. iMN013: a novel nucleoside DNA methyl transferase inhibitor and ribonucleotide reductase inhibitor for the treatment of cancer. Pharmaceuticals (Basel).


www.mdpi.com



IMN041





Daifuku R., Grimes S., Stackhouse M. iMN041, a prodrug of the DNA methytransferase inhibitor 5-aza-2’,2’-difluorodeoxycytidine (iMN013), leads to tumor regression in a model of non-small cell lung cancer. Pharmaceuticals (Basel).


www.mdpi.com



Pharmacoepigenetics





Daifuku R. Pharmacoepigenetics of novel nucleoside DNA methyltransferase inhibitors. In: Pharmacoepigenetics. Cacabellos R (Ed.). Elsevier. 2019

www.sciencedirect.com


Daifuku R. Pharmacoepigenetics of novel nucleoside DNA methyltransferase inhibitors. In: Pharmacoepigenetics (2nd Ed). Cacabellos R (Ed.). Elsevier. 2024. In Press.



iMN041





Daifuku, R., Zhang, Y., Wang, J. et al. iMN041 is an immunotherapeutic and an effective treatment in mouse xenograft models of pancreatic cancer, renal cancer and triple negative breast cancer. Transl Med Commun. 9, 2 (2024).


www.biomedcentral.com



Patents issued / applications





Silylated pyrimidine compounds and methods of their use.
WO2016057828A1.



Method of treatment of TP53 wild-type tumors with 2’,2’-difluoro-5-aza-2’-deoxycytidine or prodrugs thereof.
WO2017143453A1



Pyrimidine prodrugs formulations and methods of uses thereof.
PCT/US24/20088



Behind the scenes



Richard Daifuku MD-PhD has experience in multiple corporate roles, including Chief Executive Officer, Chief Medical Officer, and Chief Scientific Officer, resulting in a broad skillset in company management, fund raising and scientific research. Other professional background includes work as a consultant for biopharmaceutical companies and a venture firm. Phase I to III clinical development experience includes research with proteins, small molecules and gene therapy primarily in the subspecialties of oncology and infectious diseases. Discovery experience in the field of small molecules has lead to multiple issued and pending patents. He is the inventor of such molecules as KP-1212, KP-1461, iMN013, VEP-gemcitabine and the co-inventor of iMN041.


The preclinical development of iMN013 and iMN041 is being carried out by leading contract research organizations in the United States and abroad .



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iMN013/iMN041 is available for licensing, please contact us for further information








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