Regulatory Decision Summary for JAKAVI

Polycythemia vera (PV) is a chronic disease and patients may require prolonged periods of treatment. The safety and efficacy of Jakavi for the control of haematocrit in adult patients with PV resistant to or intolerant of a cytoreductive agent was demonstrated in a phase III pivotal study (RESPONSE trial). The primary endpoint of the single pivotal trial was a composite endpoint evaluating the impact of Jakavi on hematocrit control (absence of phlebotomy eligibility) and the reduction (≥35%) of splenomegaly at week 32. Significantly more patients randomized to Jakavi met the primary endpoint at week 32 when compared to patients randomized to Best Available Therapy (BAT) (20.9% versus [vs.] 0.9% respectively, p <0.0001). Spleen volume reduction of at least 35% from baseline was achieved in 38.2% (95% confidence interval [CI]: 29.1, 47.9) vs. 0.9% (95% CI: 0.0, 4.9) of the patients in the Jakavi arm vs. the BAT arm, respectively. Most importantly, hematocrit control was achieved by 60.0% (95% CI: 50.2, 69.2) vs. 19.6% (95% CI: 12.7, 28.2) of the patients in the Jakavi arm vs. the BAT arm, respectively.

The efficacy of Jakavi appears to be durable since most patients who achieved a primary response at week 32 (number of patients [n] = 23) maintained their response at week 48 (n = 21) and the probability of maintaining the response at 80 weeks was 0.94 (95% CI: 0.65, 0.99). In a supporting study, hematocrit was well controlled at week  92 (3.7 years), with 23 (67.7%) of PV patients achieving hematocrit control in the absence of phlebotomy. However, there is no data available on the efficacy of Jakavi for the long-term prevention of thrombotic complications.

The proposed clinical population depends on phlebotomy to control their hematocrit. Considering that hematocrit control is currently the main therapeutic target in the management of PV, the efficacy findings are clinically relevant for the proposed indication.

Almost all patients from both arms experienced at least one adverse event. Grade 3-4 adverse events were reported with comparable frequency in both arms. The most frequent adverse events with a higher frequency in the Jakavi group compared to the BAT group were: anemia, diarrhea, dizziness, muscle spasms, dyspnea, constipation, and cough. However, Jakavi was generally well tolerated in this patient population.

The long-term efficacy of Jakavi is acceptable and the safety profile is manageable. The recommended dose and schedule are fully supported by the pivotal study data. They also support the proposed dose titration based on safety and efficacy. The overall results from the clinical development program and the revised labelling support the proposed indication and recommendation of use.