The prospects of epigenetics are questionable
It was no accident that Roche gave up the rights to an experimental inhibitor of lysine-(K)-specific demethylase 1A (LSD1)
Roche did not want to license its leading candidate drug for the treatment of acute myeloid leukemia and solid tumors from the Spanish Oryzon Genomics. The decision to throw overboard ORY-1001, an inhibitor of lysine-specific histone demethylase 1A (KDM1A), also known as lysine-(K)-specific demethylase 1A (LSD1), was reflected in a 30 percent drop in shares of Orizn: investors could not digest the loss of a potential 500 million-plus dollars that the Swiss pharmaceutical giant could pay within the framework of the agreement of the April 2014 sample.
Everything would be fine, but we should consider the issue much more broadly, realizing that we are talking about the future of epigenetics. The latter is associated with functionally relevant changes in the genome that do not involve changes in the nucleotide sequence. Epigenetic mechanisms may include, for example, DNA methylation or histone modification that alter gene expression without affecting the underlying DNA sequence. Epigenetic alterations can persist throughout the entire life cycle of a cell, as well as in many of its generations.
Lysine-(K)-specific demethylase 1A, engaged in histone demethylation, is an indispensable epigenetic regulator involved in the management of key cellular processes such as proliferation and differentiation. LSD1 is also called an "eraser": by removing methyl groups, it eliminates signals in histones, thereby provoking changes in the context of reading the chromosome and disabling genes. Aberrant activity of the "eraser" can lead to oncological diseases.
Epigenetics is of great interest to pharmaceutical companies: complex signaling pathways can be switched and regulated using low-molecular compounds. However, the market thinks otherwise. Thus, the histone deacetylase inhibitors "Solinza" (Zolinza, vorinostat) and "Beleodaq" (Beleodaq, belinostat), which are engaged in "Merck & Co." (Merck & Co.) and "Spectrum Pharmaceuticals" (Spectrum Pharmaceuticals) /"Onxeo" (Onxeo) — the first approved epigenetic drugs — alas, not shot. And the stock price of Epizyme, focused on epigenetic therapy, has been falling incessantly over the past five years — without looking back at the support from GlaxoSmithKline, Eisai and Roche.
Roche, in addition to agreements with Orizn and Episaim, even bought a thematic Tensha Therapeutics in January 2016 for $ 115 million in advance and another possible $ 420 million as projects develop. In December 2014, Merck & Co. paid $110 million for Oncoethix, promising it an additional $265 million.
Ori-zn will continue to study ORY-1001, although it will need financial support from some new partner. In phase I clinical trials, the molecule demonstrated an objective response in 36% of patients (n=5/14) with acute myeloid leukemia, and in a subpopulation with translocations between chromosomes 9 and 11 [(t(9;11)], stabilization of the disease was recorded in two cases, and also provided evidence of morphological blast differentiation in two thirds of participants (n=9/14).
ORY-2001, a dual inhibitor of LSD1 and monoamine oxidase-B (MAOB), which is being investigated in the treatment of Alzheimer's disease, Parkinson's disease, Huntington's disease and multiple sclerosis, is on the assembly line of ORI. However, it is included in the group of risky molecules, since it is focused on diseases of the central nervous system, the effective management of which is difficult to this day.
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24.07.2017