Date: 2017-02-27
Type of
information: Presentation of results at a congress
phase: preclinical
Announcement: presentation of results at the 2nd Annual Conference of the “Americas Committee for Treatment and Research in Multiple Sclerosis” (ACTRIMS)
Company: Oryzon Genomics (Spain)
Product: ORY-2001
Action
mechanism: enzyme inhibitor/LSD1 inhibitor. ORY-2001 is a selective inhibitor of Lysine Specific Demethylase-1 (LSD1, aka KDM1), an epigenetic modulator that regulates gene expression by demethylating specifically some lysines in the histones (lysine K4 and K9 in histone H3). LSD1 forms part of protein complexes involved in transcriptional regulation, and misregulation of these transcriptional complexes may result in disease. This orally-active subnanomolar specific LSD1 inhibitor reduces leukemic stem cell potential, potently inhibits colony formation, overcomes the differentiation block in AML cell lines, and induces apoptosis / inhibits proliferation at sub-nanomolar concentrations in selected AML cell lines.
Disease: multiple sclerosis
Therapeutic
area: Neurodegenerative diseases
Country:
Trial
details:
Latest
news:
- • On February 27, 2017, Oryzon Genomics announced that the company has presented new preclinical data of
therapeutic activity in multiple sclerosis of ORY-2001 at the 2nd Annual Conference of the “Americas Committee for Treatment and Research in Multiple Sclerosis” (ACTRIMS) in Orlando. Dr. Tamara Maes, Vice President and Chief Scientific Officer of the Company, presented positive preclinical data expanding on those previously presented at the ECTRIMS European Conference last September in
London. The poster entitled "ORY-2001 Reduces Lymphocyte Egress and Demyelination in Experimental
Autoimmune Encephalomyelitis and Highlights the Epigenetic Axis in Multiple Sclerosis" showed results
produced in the Experimental Autoimmune Encephalomyelitis model. In that model mice are injected with fragments of a peptide (MOG) that triggers a very specific autoimmune reaction, which in turn produces a
violent inflammatory reaction and the production of antibodies against the myelin protecting the motor
neurons of the animal. As a consequence, there is a gradual demyelination and a development of different degrees of paralysis that can become extremely severe. The results presented at ACTRIMS demonstrate that ORY-2001, administered in a wide range of doses from the moment the mice begin to show the first symptoms, provides an effective and long lasting protection in terms of survival and mobility of the animals even at the lower doses of ORY-2001 (0.05 mg/kg).Analysis of spleenocytes from ORY-2001-treated animals showed that MOG-induced but not alpha-CD3-induced T cell proliferation was significantly decreased, pointing at a selective effect on specific MOG-induced
immune response but not a general systemic immunosuppressive effect. The histopathological analysis,
carried out 2 weeks after the first symptoms, showed a strong reduction of infiltration of inflammatory cells and demyelination plaques in the lumbar region of the spinal cord and its total disappearance in the cervical region in animals treated with 0.5 mg/kg of ORY-2001 compared to vehicle-treated animals. In addition, treatment with ORY-2001 resulted in a significant increase in the number of immune cells retained in the spleen and lymph nodes of treated animals, suggesting a reduced egress of lymphocytes
from immune tissues. ORY-2001 also caused a reduction in the levels of various pro-inflammatory cytokines such as IL-6 and IL-1beta and of chemokines such as IP-10 and MCP-1, which are involved in the recruitment of the inflammatory and encephalitogenic cells known as Th1 into the spinal cord leading to the destruction of motor neurons. Whole Genome Microarray and Pathway analysis of the spinal cord
shows that 39 out of 48 down-regulated genes are linked to pathways related to the immune system. Although the main mechanisms of action characterized to explain the therapeutic effect of drugs recently approved for the treatment of mutliple sclerosis such as fingolimod and dimethylfumarate are not epigenetic, there is now evidence in the scientific literature demonstrating that these drugs also act on epigenetic modulators known as histone deacetylases (HDACs). Interestingly, certain HDACs and LSD1, the target of ORY-2001, often act together in the same protein complexes that regulate gene expression in brain cells and other
organs. The data obtained with ORY-2001, an inhibitor of LSD1 and MAOB, point to a convergence in the mechanism of action of these drugs and reveal the existence of an epigenetic axis, hitherto unknown, that could control the disease or could be used to manage the disease.
In addition, ORY-2001 produces the observed effects at doses that do not produce haematological or lymphocytic effects and without signs of gastrointestinal toxicity, which are some of the various adverse effects common in these approved drugs, suggesting that drugs acting on LSD1 could be cleaner than current drugs acting on HDACs. Several experimental HDAC inhibitors have been linked to beneficial memory
effects in various Alzheimer's disease and other dementia models. It has also been recently shown that fingolimod, used at high doses improves memory in other mouse models. This
is consistent with Oryzon’s data obtained with ORY-2001 showing that this drug enhances memory in Alzheimer's disease and produces a potent and lasting protection in the EAE-MS model, and ratifies the hypothesis that epigenetic mechanisms may underlie different phenomena in the brain including memory function and neuroinflammatory pathways.
The ongoing Phase I trial with ORY-2001, initiated in early 2016 to determine its safety, tolerability and kinetics in healthy volunteers, will be completed in a few weeks. Shall the preliminary results be confirmed, Oryzon's clinical development plan contemplates the initiation of several Phase II studies later this year to assess its safety and efficacy in diseases such as Multiple Sclerosis, Alzheimer's and
other neurodegenerative or neuroinflammatory diseases.
- • On September 12, 2016, Oryzon Genomics announced it will present efficacy data on its proprietary oral epigenetic drug ORY-2001 in a preclinical multiple sclerosis animal model. The data will be presented at the 32nd congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) to be held in London (UK) on September 14-17 in the Poster entitled “LSD1 inhibition, a potential epigenetic therapeutic approach for the treatment of multiple sclerosis”. In a widely used multiple sclerosis model, the Experimental Autoimmune Encephalomyelitis (EAE) mice model, treatment with ORY-2001 during the effector phase greatly inhibited the development of EAE and reduced disease incidence and severity. This represents the first report of the benefit of epigenetic modulation of histone demethylation in an autoimmune disorder and points at a potential of ORY-2001 for the treatment of multiple sclerosis.
Is
general: Yes
