The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for Jakavi (INC424, ruxolitinib) for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis.

Globally, there are few available treatments for myelofibrosis, an uncommon, life-threatening blood cancer characterized by multiple severe complications such as bone marrow failure, enlarged spleen (splenomegaly) and shortened survival.

Jakavi (INC424, ruxolitinib) is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinases. As part of the Novartis clinical development programme, Jakavi is being investigated in primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Jakavi is also being investigated in clinical trials for the treatment of polycythemia vera.

"The Committee's positive opinion validates the strong data in support of Jakavi and the very high unmet need in treating myelofibrosis," said Hervé Hoppenot, president, Novartis Oncology. "The recommendation for European Commission approval of Jakavi also marks a significant step forward in bringing the first and only JAK 1 and JAK 2 inhibitor to patients with very limited options. Novartis is committed to advancing novel, targeted treatments for rare diseases, and we are invested in continuing research to determine other haematological diseases where Jakavi may address unmet patient needs."

In the European Union (EU), the European Commission generally follows the recommendations of the CHMP and usually delivers its final decision within three months of the CHMP recommendation. The decision will be applicable to all 27 EU member states. The European Commission granted Jakavi orphan drug designation for myelofibrosis.

The CHMP opinion was based on positive findings from the COMFORT (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) programme, which represents the largest myelofibrosis clinical development program to date. Jakavi directly targets the underlying mechanism of disease, significantly reducing splenomegaly and improving symptoms regardless of JAK mutational status, disease subtype or any prior treatment, including hydroxyurea.

In the COMFORT-I trial, 41.9% of Jakavi treated patients achieved at least a 35% reduction in spleen volume at 24 weeks from baseline compared to 0.7% of patients in the placebo group (p<0.001). An early analysis of COMFORT-I shows Jakavi treatment resulted in an overall survival benefit as compared to placebo (hazard ratio=0.50 [95% confidence interval: 0.25, 0.98]). The most frequently reported grade 3 or higher adverse events were haematologic. One patient in each group discontinued treatment for thrombocytopenia or for anemia, respectively. The most common non-haematologic  adverse events of any grade reported for patients receiving Jakavi or placebo respectively were fatigue (25% vs 34%), diarrhoea (23% vs 21%), peripheral edema (19% vs 22%) and ecchymosis (19% vs 9%). COMFORT-I was conducted in the US by Incyte under the worldwide collaboration and license agreement for INC424 (ruxolitinib).  

In COMFORT-II, Jakavi produced a volumetric spleen size reduction of 35% or greater (roughly equivalent to a reduction in palpable spleen size by 50%) in 28.5% of patients compared to 0% of patients in the best available therapy (BAT) group at 48 weeks (p<0.001). The BAT is any commercially available agent (such as monotherapy or in combination) or no therapy at all. At week 24, 32% of Jakavi patients demonstrated a 35% or greater volumetric spleen size reduction compared to 0% of patients treated with the BAT (p<0.001) for the key secondary endpoint. Jakavi was associated with improvements in myelofibrosis symptoms at each evaluation as compared to the BAT.

Continuous Jakavi therapy also provided a marked and durable improvement in overall quality of life measures, functioning and symptoms, including loss of appetite, dyspnea (shortness of breath), fatigue, insomnia and pain, at week 48 compared to a worsening of symptoms in BAT-treated patients. For Jakavi, the most frequently reported adverse event was increased frequency of anaemia and thrombocytopenia. The most frequently reported serious adverse event for Jakavi was anemia (5%). Pneumonia was reported in 1% of patients taking Jakavi.

In the EU, the disease affects about 0.75 out of every 100,000 people annually. Myelofibrosis has a poor prognosis and limited treatment options. Symptoms include extreme fatigue, fever, night sweats, itchy skin, bone or muscle pain, abdominal pain or discomfort and weight loss.

Studies show that patients with myelofibrosis have a decreased life expectancy, with a median survival of 5.7 years. Although allogeneic stem cell transplantation may cure myelofibrosis, the procedure is associated with significant morbidity and transplant-related mortality and is available to less than 5% of patients who are young and fit enough to undergo the procedure.

Novartis licensed INC424 (ruxolitinib) from Incyte for development and potential commercialization outside the US. Incyte has retained rights for the development and commercialization of INC424 (ruxolitinib) in the US. Both the European Commission and the US Food and Drug Administration (FDA) granted INC424 (ruxolitinib) orphan drug status for myelofibrosis. Incyte received FDA approval for INC424 (ruxolitinib) in November 2011 under the name Jakafi for the treatment of patients with intermediate or high-risk myelofibrosis.