The new, open-label, dose-escalating, Phase I/II trial, which is being conducted at Mayo Clinic in Rochester, Minnesota, is designed to investigate the safety and tolerability of CYT387, an orally-administered ATP-competitive small molecule that potently inhibits JAK1/JAK2 kinases, administered as a daily oral capsule dose in 30-60 patients with myelofibrosis. The study will also allow preliminary assessment of the compound's activity in these patients including its effect on spleen size, hematological symptoms, quality-of-life and markers of aberrant JAK2 activity in blood. Dr. Ayalew Tefferi, Professor of Hematology at Mayo Clinic will be Study Chairman for the program with Dr. Animesh Pardanani acting as Lead Investigator. Initial safety data from the trial are expected in mid-2010.
Importance of JAK
Hyperactivity of the JAK2 enzyme is known to cause a number of heterogeneous hematological conditions known as myeloproliferative neoplasms (MPN), a group of diseases including myelofibrosis, polycythemia vera (PV) and essential thrombocythemia.
Myeloproliferative neoplasms were initially thought to include four different diseases: chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (IMF). However, recently hypereosinophilic syndrome (HES) and chronic neutrophilic leukemia (CNL) were included in the classification of MPNs.
Characteristics
These disorders are hematological malignancies that arise from the transformation of a multipotent hematopoietic stem cell. Clonal hematopoiesis is characteristics of chronic myeloid leukemia, polycythemia vera , chronic idiopathic myelofibrosis and, at least, some cases of essential thrombocythemia . Except for IMF, all MPNs are generally characterized by increased levels of blood cell production with predominance of one myeloid cell lineage and no marked alterations in cellular maturation.
Each of the MPNs has a predisposition to progress towards acute leukemia, yet they differ with respect to the rate of transformation to blast crisis. Many complications of the MPNs, such as thrombosis in essential thrombocythemia and polycythemia vera, are characterized by cytokine hypersensitivity and overproduction of mature blood cells.
Research
Clinical evidence suggests that JAnus Kinase 2 or JAK2 is involved in the pathogenesis of PV because it is implicated in the intracellular signaling following the exposure to cytokines to which PV progenitors display hypersensitivity (Epo, GM-CSF, IL-3,TPO and more or less SCF and IGF-1).
Dual JAK1/JAK2 inhibition is likely to increase the clinical benefit in these disease indications and broaden the therapeutic opportunities for CYT387. JAK kinase inhibitors with similar profiles are also being trialed in inflammatory diseases such as rheumatoid arthritis. CYT387 possesses optimized JAK1/JAK2 inhibition while minimizing unwanted activity seen with other JAK2 inhibitors in clinical development.
CYT387 is a pyrimidine derivative, with low nanomolar activity against JAK1/2 in biochemical assays and a very narrow scope of additional targets. Studies have shown that it inhibits the growth of JAK2-dependent cell lines in the high nanomolar – low micromolar dose range.
Studies have shown that CYT387 is active in a murine model of JAK2-V617F-positive MPD, with normalization of blood counts and spleen size, without apparent toxicity. However, residual disease remained detectable and relapse occurred upon discontinuation of drug, reminiscent of preliminary data from studies of JAK2 inhibitors in humans.
"The utility of JAK2 inhibitors may be broadly applicable and is not limited to myelofibrosis. Additional potential indications include other MPNs, graft-vs-host disease, solid tumors and inflammatory conditions. To suitably address this large potential requirement, the development of multiple JAK2 inhibitor candidates may be warranted," said Dr. Ayalew Tefferi. "Patient safety is very important with this class of compounds and can be reliably predicted only by testing in humans. It is premature to select the best JAK2 inhibitors in clinical development as there is a need for longer follow-up data on safety and efficacy than is currently available. As such, the results of this study could yield important data on the potential for this molecule and possibly the entire class."
The trials are sponsored by Cytopia, an Australian biotechnology company focused on the discovery and development of new drugs to treat cancer and other diseases
"Given the broad potential of JAK inhibitors, the human clinical safety data generated from this first clinical trial could be pivotal to the further development of CYT387 and its differentiation within the class. Limited data is available on the use of JAK 2 inhibitors in this patient population but a strong rationale exists to pursue this approach," said David Allan, Chairman and CEO of YM BioSciences, a life sciences product development company, currently awaiting the results of a merger proposal with Cytopia which pending approval by Cytopia shareholders, Australian court and other regulatory approvals.
"This program has also been an opportunity for productive collaboration between the YM and Cytopia teams to further advance Cytopia's pipeline," Allan noted.
Debilitating conditions
CYT387 is reported to potently inhibit the JAK2 enzyme, a mutated form of which has been implicated in a variety of MPNs including myelofibrosis, polycythemia vera and essential thrombocythemia. CYT387 has reportedly demonstrated the ability to attenuate MPN symptoms in preclinical models and disrupt JAK2 hyperactivity in cells from patients with MPNs. These data suggest that the compound may exert a profound effect on the human diseases. Over-activity of the JAK2 enzyme has also been noted in certain cancers and in inflammatory conditions, such as rheumatoid arthritis and psoriasis.
Myelofibrosis is a chronic, debilitating condition where the patient's bone marrow is replaced by scar tissue. This compromises the ability of patients to produce sufficient blood cells and creates a reliance on organs other than the bone marrow, including the liver and spleen, to produce blood cells. Typical symptoms include an enlarged spleen, progressive anemia and poor overall survival.
"The commencement of our CYT387 clinical study is another significant milestone delivered by Cytopia and we look forward to its progress under the guidance of Dr. Tefferi and his colleagues," said Mr. Andrew Macdonald, CEO of Cytopia. "The combination of JAK1 and JAK2 inhibitory activity in this compound represents a potential advantage over JAK2 inhibitors. JAK1 is hypothesized to have an effect on cytokines and cachexia, and thus may improve the quality of life in patients with JAK2 mediated diseases. Cytopia will seek to demonstrate the activity of CYT387 in other diseases where JAK1 and JAK2 activity may be important."
Commercial interest
There has been considerable commercial interest in the JAK2 target with no selective JAK inhibitors having yet successfully completed late stage clinical trials and few compounds in development that meet a desirable product profile. A similar JAK2 inhibitor in clinical development was recently licensed by Onyx Pharmaceuticals for $550 million including a $25 million up-front payment and double-digit royalties.
For more information, please review these PubMed Abstracts:
- Spivak JL. MPDs: it's all in the family. Blood. 2008 Sep 15;112(6):2173-4.
- Pardanani A, Lasho T, Smith G, Burns CJ, et al. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia 2009 Aug;23(8):1441-5. Epub 2009 Mar 19.
- Cross NC, Reiter A. Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Leukemia. 2002;16:1207–1212
- Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387–397
- Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in Polycythemia Vera (PV). J Biol Chem. 2005; 280:22788–22792.
- Steensma DP, Dewald GW, Lasho TL, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and the myelodysplastic syndrome. Blood. 2005;106:1207–1209
- Spivak JL. Polycythemia vera: myths, mechanisms, and management. Blood. 2002;100:4272–429
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