Pharmion and MethylGene has announced the formation of an international licensing agreement potentially worth $272 million (€224 million) for new class of compounds that inhibits gene expression providing a tumour and haematological malignancy treatment platform.
The agreement represents a growing band of companies that see epigenetic control of cancer as the way forward treatment-wise. Epigenetics refers to changes in the regulation of gene expression. Epigenetic changes can silence gene expression and, unlike DNA mutations, may be reversed by targeting the enzymes involved.
The epigenetic approach to cancer therapy is that rather than using molecules that kill normal and tumour cells, the silenced genes are reactivated through targeted epigenetic therapy, re-establishing the cancer cell's natural mechanisms to control abnormal growth.
"There is tremendous potential to be explored in the combination of demethylating agents and HDAC inhibitors in the treatment of cancer," said Alan List, director, Heamatologic Malignancies Program at the H. Lee Moffitt Cancer Centre and Research Institute.
"Both agents demonstrate specific effects on the regulation of gene expression, and the potential synergies of these agents in combination, which is being explored with Vidaza and MGCD0103 in the clinic, could ultimately transform certain cancers into more chronically managed diseases."
MethylGene have combined this drug candidate with Vidaza after previous research indicated that the drug could reverse the effects of DNA hypermethylation with subsequent gene re-expression.
Likewise MGCD0103 has been shown, in vivo, to reverse the effects of inappropriate deacetylation resulting in gene expression reactivation.
HDAC inhibitors are a new class of compounds that inhibit histone deacetylation, a process that regulates gene expression. MGCD0103 is an oral compound currently in multiple Phase I clinical trials in solid tumours and haematological malignancies and one combination Phase I/II trial with Vidaza (azacitidine for injectable suspension) for high-risk myelodysplastic syndromes (MDS) and acute myelogenous leukaemia (AML).
MGCD0103 is isotype-selective, inhibiting a subset of the eleven HDAC isotypes. Inhibition of HDAC enzymes by MGCD0103 has resulted in significant tumour inhibition in preclinical animal models, with the potential for a favourable safety profile when compared to traditional chemotherapies.
Under the terms of the agreement, MethylGene will receive from Pharmion up front payments totalling $25 million, consisting of a $20 million license fee and a $5 million equity investment in MethylGene common shares.
Pharmion's milestone payments to MethylGene for MGCD0103 could reach $145 million, based on the achievement of significant development, regulatory and sales goals, with the nearest-term milestone of $4 million to be paid upon enrollment of the first patient in a Phase II trial.
Furthermore, up to $100 million for each additional HDAC inhibitor may be paid, also based on the achievement of significant development, regulatory and sales milestones.
In addition, Pharmion will provide one year of research support ($2 million) for a team of eight MethylGene scientists who are identifying second-generation clinical candidates in addition to MGCD0103.
Additional terms of the agreement will see MethylGene, who have previously executed an agreement for MGCD0103 (and its second generation oncology HDAC inhibitors) with Taiho Pharmaceutical, form a global development committee alongside Pharmion and Taiho to share data and coordinate the development program.
Histones are protein complexes around which DNA is wrapped, which play an important role in gene regulation. The histone arrangement specifically has an impact on the accessibility of DNA for transcription.
Histones and DNA together are called chromatin. Histone acetylation exposes DNA so that gene expression can occur. Conversely, histone deacetylation leads to dense packing of chromatin and gene silencing.
These processes are regulated by enzyme families called histone acetylases (HATs) and histone deacetylases (HDACs). In many cancerous tissues, through the activity of DNA methylation and histone deacetylation, tumour suppressor genes are silenced and not expressed.
Using HDAC inhibitors, such as MGCD0103, the effect of HDACs may be blocked and tumour suppressor genes re-expressed to inhibit cancer progression. In humans, there are eleven different forms, or isotypes, of HDACs.
Previous research has suggested that only a subset may be involved in cancer progression.