pipeline
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Over 1.3 million people in the United States will be diagnosed with cancer in 2005, and over 500,000 Americans are expected to die from the disease in 2005, translating to about 1,500 deaths per day from cancer. In addition to the pain and suffering inflicted by cancer, the economic costs – including medical expenses, lost productivity and death – were estimated at $190 billion in 2004. There is clear need for better treatments in various cancers, as the 5-year survival rate for all cancers combined is 64%. |
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CYT997: a vascular disrupting agent (VDA) for various cancers
Cytopia has discovered a new class of orally bioavailable drugs that disrupt microtubule formation by interacting with tubulin. Compounds of this chemical series are highly potent anticancer agents which are not susceptible to multi-drug resistance. Importantly, they appear to act by a mechanism distinct from other drugs that work on this molecular target, and have shown vascular disrupting activity.
Microtubules play an essential role in cell division and thus drugs that interfere with the normal function of microtubules disrupt the life cycle of cells, ultimately causing cell death. There are currently three main classes of tubulin-binding drugs; colchicine analogues; vinca-alkaloids; and taxanes. While certain taxanes and the vinca-alkaloids are widely used anticancer agents, the acquisition of multi-drug resistance (MDR+) by cancer cells is a significant impediment to their ongoing clinical use.
We have also shown that CYT997 posesses in vivo efficacy in a several orthotopic models of solid tumor cancers and in a childhood t-cell acute lymphoblastic leukaemia model, including a strong dose dependence demonstration of efficacy in a metastasising colon cancer model.
Cytopia successfully concluded its first Phase I study for CYT997 in late 2007, administered intravenously. Enrolment in a second Phase I study, where CYT997 is administered as a capsule dose, is ongoing. The company has now received FDA approval and has commenced a Phase II study of CYT997 in patients with relapsed or refractory multiple myeloma
and will shortly commence another Phase II study in patients with glioma
.
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Myeloproliferative diseases (MPDs) and JAK2
Myeloproliferative diseases, including polycythemia vera (PV) and essential thrombocythemia (ET), are relatively rare, but 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 to be present in >95% of patients with PV and ~50% of patients with ET and a third MPD, Idiopathic myelofibrosis. Cytopia is developing selective JAK2 inhibitors to stop the over-activity of the mutant JAK2 with a drug candidates expected to enter formal development in 2008. Preliminary data using samples derived from MPD patients has shown very promising activity in suppressing the over-activity of the mutant JAK2 enzyme and in the case of PV, the over-production of red blood cells.
Cytopia has selected a lead JAK2 drug for further development. Formal development activities are currently underway and the company intends filing regulatory dossiers with US and Australian authorities in the fourth quarter of 2008. Subject to regulatory approval, clinical trials will commence in early 2009
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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 cancer cells, particularly those in haematological malignancies such as acute lymphoblastic leukaemia. Again, Cytopia's anticancer JAK2 programme is well advanced, with formal pre-clinical development expected to commence in early 2009.
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JAK3 in immunology and inflammatory disease
Cytopia, through its access to crystal structures of members of the JAK family of kinases and chemistry capabilities, has been successful in developing a portfolio of small molecule inhibitors of JAK3 that are both potent and specific.
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 lymphoid cells. 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.
These compounds are being further developed through a partnership with Novartis Pharma AG, for application into the different therapeutic areas mentioned above, with a primary focus on transplantation and rheumatoid arthritis.
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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 etiology 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 ($40,000 to over $200,000 per patient per year depending on severity), 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.
In PAH animal models, a specific JAK2 inhibitor has also shown disease-modifying activity and further development studies with highly potent and specific inhibitors of JAK2 are ongoing.
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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