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Date: 2015-03-11

Type of information: Granting of a Market Authorisation in the EU

Product name: Jakafi® (USA)/Jakavi® (UE)

Compound: ruxolitinib

Therapeutic area: Cancer - Oncology - Rare diseases

Action mechanism:

kinase inhibitor. Jakafi® inhibits enzymes called JAK 1 and 2 (Janus Associated Kinase) that are involved in regulating blood and immunological functioning. Myelofibrosis is associated with the deregulation of JAK 1 and 2.  Novartis and Incyte Corporation have a worldwide collaboration and license agreement for Jakafi® - INC424 (ruxolitinib).

Company: Incyte (USA - DE) Novartis (Switzerland)

Disease:

treatment of patients with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea

 

Latest news:

* On March 17, 2015, Novartis announced that the European Commission has approved Jakavi® (ruxolitinib) for the treatment of adult patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea. Jakavi is the first targeted treatment approved by the European Commission for these patients. The approval is based on data from the pivotal Phase III RESPONSE clinical trial demonstrating that a significantly greater proportion of patients achieved the composite primary endpoint of hematocrit control without use of phlebotomy and spleen size reduction, key measures of disease control, when treated with Jakavi compared to best available therapy (21% compared to 1%, respectively; p<0.0001). In the study, a 50% or more improvement in PV-related symptoms was seen in 49% of Jakavi-treated patients compared to 5% of patients treated with best available therapy. 

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 Jakavi (starting dose of 10 mg twice daily) or best available therapy, which was defined as investigator-selected monotherapy or observation only. The Jakavi dose was adjusted as needed throughout the trial. In the Jakavi 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 the modified European LeukemiaNet (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% and had increased three or more percentage points from the time they entered the trial (e.g., at baseline), or hematocrit greater than 48%. 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). Overall, non-hematologic adverse events (AEs) were consistent with those previously seen in other Jakavi studies in PV and myelofibrosis. Within the first 32 weeks of treatment, the most common Grade 3 or 4 hematologic AEs in the Jakavi-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%). 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. 

* On 22 January 2015, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a variation to the terms of the marketing authorisation for Jakavi®. The CHMP adopted a new indication as follows:" Jakavi is indicated for the treatment of adult patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea.”
For information, the full indications for Jakavi will be as follows:
Myelofibrosis (MF): Jakavi is indicated for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythaemia vera, myelofibrosis or post essential thrombocythaemia myelofibrosis.
Polycythaemia vera (PV): Jakavi is indicated for the treatment of adult patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea.”

* On December 4, 2014, the FDA approved ruxolitinib (Jakafi®, Incyte Corporation) for the treatment of patients with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea. The approval was based on demonstration of a composite endpoint of durable hematocrit control and spleen volume reduction and in achieving a relatively high rate of durable hematocrit control that obviated the need for regular phlebotomy. The multicenter, open-label, active-control trial (Protocol CINC424B2301) leading to the approval, enrolled 222 patients with PV resistant to or intolerant of HU. Patients were randomized to receive either ruxolitinib 10 mg twice daily (n=110) or best available care (n=112). 

Ruxolitinib was superior to best available therapy in achieving durable hematocrit control and spleen volume reduction at week 32 (21% vs 1%, p<0.0001) and at week 48 (19% vs 1%, p<0.0001), and in achieving a relatively high rate of durable hematocrit control (week 48) (55%, 95% CI 45%-64%). Safety through week 32 was evaluated in the 110 subjects randomized to ruxolitinib. The most common hematologic adverse reactions (incidence > 20%) were thrombocytopenia and anemia. The most common nonhematologic adverse events (incidence >10%) were headache, abdominal pain, diarrhea, dizziness, fatigue, pruritus, dyspnea and muscle spasms. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with ruxolitinib.

The recommended starting dose of ruxolitinib is 10 mg twice daily (5 mg twice daily for patients taking strong CYP3A4 inhibitors and for those patients with moderate-to-severe renal impairment or with hepatic impairment). Doses may be titrated based on subsequent safety and efficacy evaluations.

 * On August 5 2014, Incyte announced that the FDA has accepted for filing the supplemental New Drug Application (sNDA) for ruxolitinib as a potential treatment of patients with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea. The sNDA includes results from the RESPONSE Phase III trial, which were recently presented at the 2014 American Society of Clinical Oncology (ASCO) annual meeting. RESPONSE was conducted under a Special Protocol Assessment (SPA) from the FDA. The Prescription Drug User Fee Act (PDUFA) date for the sNDA for ruxolitinib is set for December 5, 2014.

 Jakafi® (ruxolitinib) is already approved by the FDA to treat people with intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF and post–essential thrombocythemia MF. The drug is marketed by Incyte in the United States and by Novartis as Jakavi® (ruxolitinib) outside the United States.

* On 7-9 January 2014, the Committee for Orphan Medicinal Products (COMP) has recommended the granting of an orphan designation for ruxolitinib for treatment of polycythaemia vera.

Patents:

Submission of marketing authorization application USA :

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2014-12-04

UE authorization: 2015-03-11

Favourable opinion UE: 2015-01-22

Favourable opinion USA:

Orphan status USA: 2010-03-26

Orphan status UE: 2014-02-19

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes