JAK2 Inhibitor Shows Promise in Myelofibrosis

Beth Fand Incollingo @fandincollingo
Published: Wednesday, May 08, 2013
Dr. Tal Zaks

Tal Zaks, MD, PhD
Vice President
Head of Development
Sanofi Oncology
Cambridge, MA

The strategy of targeting aberrant signaling in the Janus kinase (JAK) pathway appears promising thus far for SAR302503, an oral agent in development for the treatment of myelofibrosis. Recruitment for the phase III JAKARTA trial is complete, and initial results are scheduled to be reported later this year, according to Sanofi, which is developing the drug.

SAR302503 is a selective inhibitor of JAK2, a member of the JAK family of nonreceptor tyrosine kinases whose activity can promote cancer-causing processes, including proliferation. The drug is being evaluated in patients with primary myelofibrosis, polycythemia vera (PV), or essential thrombocythemia (ET).

Mutations in the JAK2 gene are found in approximately half of patients with primary myelofibrosis, 50% of patients with ET, and 95% of patients with PV, researchers have indicated.

In the JAKARTA trial, 225 patients with high-risk or intermediate-risk level 2 disease were randomized to receive either 400 mg or 500 mg of SAR302503 once a day for six 28-day cycles, or a daily placebo on the same dosing schedule (Figure). The primary endpoint is the response rate, defined as the proportion of patients who have achieved a ≥35% reduction in spleen size volume at the end of cycle 6.1

Figure. JAKARTA Study Design

Key Patient Criteria

  • Primary MF, post-PV MF, or post-ET MF
  • High-risk or intermediate risk level 2 disease
  • Spleen palpable ≥5 cm below costal margin
  • ECOG status 0-2
  • No splenectomy
  • No prior JAK2 inhibitor treatment
 
225
patients
Randomized
 
 
 
 
75 patients
75 patients
75 patients
 
 
 
500 mg SAR302503
once a day for
six 28-day cycles
400 mg SAR302503
once a day for
six 28-day cycles
Placebo
once a day for
six 28-day cycles
 
 
 
End of cycle 6
Crossover to
400 mg or 500 mg
SAR302503
End of cycle 6 or
disease progression
 
End of treatment
 
ECOG indicates Eastern Cooperative Oncology Group; ET, essential thrombocythemia; MF, myelofibrosis; PV, polycythemia vera.

The JAKARTA trial. Sanofi Oncology website. http://www.jakartastudy.com/Hcp/default.aspx. Updated January 2012. Accessed March 27, 2013.
The rationale for continued development of SAR302503 was supported by phase II trial results in a similar patient population, according to research presented during the 54th Annual Meeting and Exposition of the American Society of Hematology (ASH), held in December in Atlanta, Georgia.2


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