Novartis’ Jakavi recommended by CHMP for EU approval to treat polycythemia vera

If approved in the EU, ruxolitinib could provide the first targeted treatment option for these patients.

PV is a chronic, incurable blood cancer associated with an overproduction of blood cells that can cause serious cardiovascular complications, such as stroke and heart attack.

In PV, patients with resistance to or intolerance of hydroxyurea are considered to have uncontrolled disease, which is typically defined as hematocrit levels greater than 45%, elevated white blood cell count and/or platelet count, and may be accompanied by debilitating symptoms and/or enlarged spleen. Elevated white blood cell count and hematocrit are also associated with an increased risk of blood clots.

"This positive CHMP opinion is encouraging news for patients with polycythemia vera who need effective treatment options," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs.

"If approved, ruxolitinib will be the first-ever targeted therapy for polycythemia vera in the EU, a positive step forward for the rare blood cancer community in Europe and a major development in Novartis’ continued commitment to help patients with high unmet needs."

In the EU, the European Commission generally follows the recommendations of the CHMP and delivers its final decision within three months of the CHMP recommendation.

The decision will be applicable to all 28 EU member states plus Iceland, Norway and Liechtenstein. Global regulatory applications for ruxolitinib in PV are currently ongoing, and further regulatory filings are under review by health authorities.

Ruxolitinib, which is marketed in the US by Incyte Corporation as Jakafi®, received approval in December 2014 from the US Food and Drug Administration (FDA) for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea.

The CHMP recommendation was based on results from the pivotal Phase III RESPONSE clinical trial demonstrating that a significantly greater proportion of patients achieved the composite primary endpoint of hematocrit control (volume percentage of red blood cells in whole blood) without use of phlebotomy (a procedure to remove blood from the body to reduce the concentration of red blood cells) and spleen size reduction when treated with ruxolitinib compared to best available therapy (21% compared to 1%, respectively; p<0.0001).

In addition, a greater proportion of patients in the ruxolitinib treatment arm achieved complete hematologic remission, as defined by the modified 2009 European LeukemiaNet (ELN) criteria, when compared to the standard therapy arm (24% compared to 9%, respectively; p=0.003). The data also showed more patients treated with ruxolitinib had a durable primary response at week 48 compared to patients treated with standard therapy (19% compared to 1%, respectively; (p<0.0001).

Overall, ruxolitinib was well tolerated, and non-hematologic adverse events (AEs) were consistent with those previously seen in ruxolitinib studies in PV and myelofibrosis. Within the first 32 weeks of treatment, the most common Grade 3 or 4 hematologic AEs in the ruxolitinib treatment arm were anemia (1.8%) and thrombocytopenia (5.5%).

The most common non-hematologic AEs were dizziness (15.5%), constipation (8.2%) and herpes zoster (6.4%)[2]. The three most frequent non-hematological laboratory abnormalities (any Grade) were hypercholesterolemia (30.0%), raised alanine aminotransferase (22.7%) and raised aspartate aminotransferase (20.9%), which were mainly Grade 1 and 2.

RESPONSE is a global, randomized, open-label trial conducted at more than 90 trial sites. 222 patients with PV resistant to or intolerant of hydroxyurea were randomized 1:1 to receive either ruxolitinib (starting dose of 10 mg twice daily) or best available therapy, which was defined as investigator-selected monotherapy or observation only.

Ruxolitinib dose was adjusted as needed throughout the trial. In the ruxolitinib arm, patients had a PV diagnosis for a median of 8.2 years and had previously received hydroxyurea for a median of approximately three years. Most patients (>80%) had received at least two phlebotomies in the last 24 weeks prior to screening. Patients were classified as intolerant or resistant to hydroxyurea based on modified ELN defined criteria.

The primary endpoint of the trial was the proportion of patients whose hematocrit was controlled without phlebotomy eligibility from week 8 through 32 (with no more than one phlebotomy eligibility between randomization and week 8) and whose spleen volume was reduced by 35% or more from baseline as assessed by imaging at week 32.

Patients in the trial who were deemed to be eligible for phlebotomy had hematocrit that was greater than 45% or had increased 3 or more percentage points from the time they entered the trial (e.g., at baseline).

In addition, efficacy was further assessed using two key secondary endpoints: durable primary response and complete hematological remission. Other endpoints include safety and symptom improvement (as measured by the MPN-SAF 14-item total symptom score).