Key drug programs
CYT997: VDA anti-cancer program
Cytopia is developing CYT997, a new anti-cancer agent that disrupts tumour blood vessels. CYT997 is currently being investigated in Phase II clinical trials in a variety of cancers.
Cytopia’s lead anti-cancer agent is CYT997, a novel compound synthesized by Cytopia’s chemistry team which possesses potent vascular disrupting properties against tumour blood vessels.
Studies in several cancer models have demonstrated that the compound ablates the blood vessels which serve growing tumours whilst sparing normal, healthy blood vessels. By attacking tumour vessels, the compound can lead to blood flow arrest, starvation of rapidly dividing tumour cells and tumour death. As well as its potent anti-vascular properties, the compound also directly effects tumour cell replication via its inhibition of the cellular structural protein, tubulin.
Unlike many other antivascular agents, including those more advanced in clinical development (e.g. Zybrestat from Oxigene and ASA404 from Antisoma), CYT997 can be administered both intravenously and orally, allowing patients to be dosed more frequently and more conveniently by mouth.
Following a period of preclinical development, Cytopia successfully concluded its first Phase I study for CYT997 administered intravenously in late 2007. Seven of the 31 end-stage cancer patient enrolled in this study achieved stable disease for a period of approximately 4 to 5 months. Two patients with symptomatic progressive disease were stabilized for approximately 5 to 6 months. Analysis of measures of vascular damage indicated that CYT997 disrupts the tumour vasculature, leading to decreased tumour blood flow in a number of patients. These findings were presented at the ASCO meeting in Chicago in June 2008.
Enrolment in a second Phase I study, where CYT997 is administered as a capsule dose has also concluded. Data from this study confirmed that CYT997 is well absorbed in cancer patients when presented as a capsule dose.
Enrolment into the first of the company’s Phase II studies in highly, vascular tumour indications is underway. This study will investigate the activity of CYT997 in patients with relapsed glioblastoma multiforme (GBM; glioma) an aggressive form of brain tumour. CYT997 will be administered intravenously in combination with carboplatin every three weeks. Patients will be monitored for changes in their tumour as well as progression-free survival. Enrolment into this study is underway at centres in Melbourne, Sydney and Adelaide.
The company is also enrolling into a Phase II programme in relapsed or refractory multiple myeloma.
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JAK2 and Myeloproliferative diseases (MPDs)
Myeloproliferative disorders (MPDs) are debilitating, and potentially fatal, diseases of blood cell production. Cytopia is developing JAK2 inhibitors for the treatment of myeloproliferative disease, cancer and pulmonary hypertension (PAH). The company's lead drug, CYT387, will enter a Phase I/II clinical trial in late 2009.
Myeloproliferative diseases, including polycythemia vera (PV) and essential thrombocythemia (ET), are highly debilitating disorders for which there are limited and poorly efficacious therapeutic options.
A genetic mutation in the JAK2 enzyme, that results in continual activity of the enzyme, has been shown present in >95% of patients with PV and approximately 50% of patients with ET and a third MPD, idiopathic myelofibrosis. Cytopia has designed and synthesized CYT387, a selective JAK2 inhibitor to suppress the over-activity of the mutant JAK2. The compound possesses an excellent selectivity and safety profile and preliminary data using samples derived from MPD patients has shown very promising activity in suppressing the over-activity of the mutant JAK2 enzyme. In an in vivo model of the disease CYT387 showed excellent activity essentially reversing a number of the hallmarks of the disease.
Formal development activities are currently underway and the company has recently submitted an Investigational New Drug (IND) application with the US FDA. Subject to regulatory approval, the company’s clinical study will commence in October, 2009.
JAK2 Movie
Refer link to MPD Foundation: http://www.mpdfoundation.org/
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JAK2 in cancer
JAK2 and its related biochemical pathways are now known to play a key role in the proliferation of certain types of cancer cells such as prostate, breast and liver cancers, and haematological cancers such as multiple myeloma. Cytopia is undertaking extensive pre-clinical research to examine the activity of CYT387, and other JAK2 inhibitors in its portfolio, in these indications.
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JAK2 in cardiovascular disease
Cytopia is developing JAK2 inhibitors for the treatment of pulmonary hypertension (PAH) and other cardiovascular diseases.
PAH, a disease with distinctly different aetiology and pathology from systemic hypertension is a highly debilitating disease of the lungs characterized by endothelial and smooth muscle cell proliferation in the pulmonary arterioles leading to very high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs.
The average survival after diagnosis for untreated patients is about three years. Current treatments are often cumbersome, expensive and fraught with complications and side effects. This leads to a high unmet medical need, with over 100,000 patients worldwide affected by this disease.
Selected compounds from Cytopia’s JAK2 inhibitor collection have demonstrated promising activity in laboratory tests representative of the disease. In in-vivo PAH models, a specific JAK2 inhibitor has also shown disease-modifying activity.
It is intended that the PAH program will be out-licensed to a partner with specialist development capability to effectively and efficiently progress it through clinic studies.
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JAK3 in immunology and inflammatory disease
Cytopia has partnered its JAK3 program with Novartis, one of the world's largest pharmaceutical companies, for the development of new anti-rejection drugs for transplantation, as well as for treatment of auto-immune diseases. JAK3 is a key enzyme necessary for the function of white blood cells which mediate transplant rejection.
Many cytokine receptors critical for the activity of immune cells, signal through JAK3. Unlike its family members (JAK1, JAK2 and TYK2), JAK3 is only expressed in cells of the immune system. Thus, the pivotal role of JAK3 coupled with its selective distribution, makes the enzyme a key target for inflammatory disorders such as rheumatoid arthritis, asthma and psoriasis and for autoimmune disorders and transplantation rejection.
Cytopia and Novartis have worked jointly to identify potent and selective JAK3 inhibitors, and formal development of compounds from this collaboration will be progressed by Novartis.
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FMS in cancer
Macrophages are key mediators of an immune response and their over activity has been implicated in the progression of and metastatic spread of certain cancers and in the progression of inflammatory diseases. FMS is a kinase involved solely with signaling of the CSF1 receptor, which in turn controls the proliferation and function of macrophages.
Cytopia has discovered a panel of highly potent inhibitors of the FMS enzyme that show promising activity in laboratory tests. Further pre-clinical studies on these compounds are ongoing.
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