Richard Levy, MD
The FDA has assigned a priority review designation to the JAK1/2 inhibitor ruxolitinib as treatment for patients with polycythemia vera who are resistant or intolerant to hydroxyurea. Under this program, the agency will make a decision on the application by December 5, 2014.
The priority review is based on results from the phase III RESPONSE trial that examined oral ruxolitinib at 10 mg twice daily (BID) or best available therapy in patients who were resistant or intolerant to treatment with hydroxyurea. The primary endpoint of the trial looked specifically at the number of patients who achieved hematocrit control without phlebotomy from week 8 to 32 and experienced greater than a 35% reduction in spleen volume by week 32. Overall, 21% of patients in the ruxolitinib arm met this criteria compared with 1% for best available therapy, according to results presented at the 2014 ASCO Annual Meeting.
“We are pleased to have received the acceptance of our sNDA [supplemental new drug application] filing by the FDA, and we believe that the submission contains a robust data set,” Richard Levy, MD, executive vice president and chief drug development and medical officer of Incyte, said in a statement. “We look forward to working with the FDA to complete its review of this application."
In the RESPONSE trial, 222 patients with polycythemia vera were randomized to ruxolitinib (n = 110) or best available therapy (n = 112), which included hydroxyurea, interferon, observation, and other treatments. By week 32, ruxolitinib was administered at 10 mg BID for 33.7% of patients and 32.7% received the drug at 15 mg. Doses ranged from <10 mg to 25 mg BID.
Approximately 95% of patients in both arms tested positive for a mutation in JAK2
V617F. Altogether, 96 patients in the best available therapy arm crossed over to receive ruxolitinib. Patient characteristics were balanced between the two arms.
Hematocrit control without phlebotomy was achieved for 60% of patients treated with ruxolitinib compared with 20% receiving best available therapy. Spleen volume was reduced by ≥35% in 38% of patients receiving ruxolitinib compared with 1% for best available therapy.
At week 32, 24% of patients treated with ruxolitinib achieved a complete hematologic remission (CHR) compared with 9% for best available therapy (P
= .003). Additionally, 88.5% of patients maintained a CHR at week 48.
In total, 91% of patients maintained a response to ruxolitinib following 48 weeks of treatment. The probability of maintaining a primary response to ruxolitinib for 1 year was 94%. At a median follow-up of 81 weeks, 85% of patients randomized to ruxolitinib remained on therapy.
The rates of grade 3/4 anemia and thrombocytopenia were less in the ruxolitinib arm compared with best available therapy (1.8% vs 5.5% and 0% vs 3.6%, respectively). Symptom improvement by Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) favored ruxolitinib, with 49% of patients experiencing a ≥50% improvement from baseline compared with 5% for best available therapy.
“An interesting observation is that the rate of thromboembolic events appears to be lower in the ruxolitinib group so far,” lead investigator Srdan Verstovsek, MD, PhD, from a professor at The University of Texas MD Anderson Cancer Center, said when the results were presented. "Hematocrit control is a key therapeutic goal. It has been shown before in many studies that maintaining hematocrit to below 45% significantly decreases the risk of cardiovascular death and major thrombotic events."
The FDA first approved ruxolitinib as a treatment for patients with intermediate and high risk myelofibrosis in November 2011. This approval included the treatment of primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. This approval was based on results from two studies that demonstrated a reduction in spleen size with the treatment.