XL019

Stage

Phase 1

Status

A phase 1 trial in patients with myelofibrosis is ongoing. A phase 1 trial in patients with polycythemia vera is planned for the second half of 2008.

Indications

Myeloproliferative Disorders

Principal Targets

Cell proliferation, differentiation, migration, and survival: JAK2

• Activating mutations of JAK2 occur frequently in a variety of myeloproliferative disorders including:
  • Polycythemia vera
  • Essential thrombocytosis
  • Idiopathic myelofibrosis
• JAK2 signaling is upregulated in several types of lymphoma and a number of solid tumors.

Preclinical Data

XL019 is a selective inhibitor of JAK2, a cytoplasmic tyrosine kinase. JAK2 is activated by cytokine and growth factor receptors, and phosphorylates members of the STAT family of inducible transcription factors. Activation of the JAK/STAT pathway promotes cell growth and survival, and is a common feature of human tumors. JAK2 is activated by mutation in the majority of patients with polycythemia vera, myelofibrosis, and essential thrombocythemia, and appears to drive the inappropriate proliferation of blood cells in these conditions. XL019 is a potent and selective JAK2 inhibitor with favorable pharmacodynamic properties.

Clinical Data

Preliminary data from an ongoing phase 1 dose-escalation trial of XL019 in patients with myelofibrosis were presented at the American Society of Hematology 49th Annual Meeting and Exposition in December 2007.

Unaudited data from cohort 1 (100 mg), cohort 2 (200 mg), and cohort 3 (300 mg) were presented and the key findings by investigators included:

• XL019 was generally well tolerated.
• Adverse events included Grade 1 nausea, headaches, equilibrium imbalance, dizziness, chest discomfort, visual disturbances, fatigue, and hypertension.
• Grade 2 adverse events of lightheadedness and decreased sensation in soles and one serious adverse event of confusion in a patient with baseline history of dementia were also observed.
• No evidence of myelosuppression was observed.
• Preliminary pharmacokinetics (PK) analyses indicate a long plasma half-life (27 hours) and dose-linear exposure were observed.
• Preliminary PK/pharmacodynamics analyses indicate a correlation between XL019 exposure and decreased phosphorylation of STAT5, a marker for JAK2 activity.
• Preliminary clinical activity was observed in most subjects, including:
  • Reduction in spleen size of 33% to 100% in five of six evaluated patients with either a JAK2 or Mpl mutation.
  • Reduction in erythropoietin-independent colony formation of up to 39% in BFU-E, and up to 100% in CFU-E in two patients evaluated.
  • Relief of constitutional symptoms, including pruritus, fatigue, back pain, and abdominal fullness.
  • Trend towards reduction in the number of cells with the JAK2 V617F mutation (allele burden) were observed.

Further follow-up and analyses indicated that symptoms consistent with neuropathy were observed at all doses tested to date, and the onset appeared to be dose-related. Because even the lowest administered dose appeared to have beneficial activity, we believe that lower-doses and/or alternative dosing schedules may retain activity while reducing or eliminating the neuropathies we have seen. Currently, we are working to identify a dose and schedule that will support efficacy and safety profiles that could position XL019 as a leading selective JAK2 inhibitor. Once the optimization is completed, we intend to initiate a pivotal trial in myelofibrosis and further studies in polycythemia vera and other indications.

The maximum tolerated dose has not been identified. The phase 1 dose-ranging clinical trial in patients with myelofibrosis continues.

Information on Clinical Trials

Information about ongoing clinical trials of Exelixis' investigational product candidates is available at ClinicalTrials.gov, a service of the U.S. National Institutes of Health. General information about clinical trials and issues related to participating in clinical trials also is available at ClinicalTrials.gov.

Related Publications

For publication information related to this compound, please see the Related Publications page.