Novartis, a Swiss pharmaceutical giant, announced that five-year treatment with Jakavi (ruxolitinib) suggested an overall survival advantage for patients with myelofibrosis (MF), despite crossover to Jakavi from the best available therapy arm after the primary analysis at 48 weeks (intent-to-treat analysis: 33 per cent reduction in risk of death, hazard ratio=0.67 [95 per cent confidence interval (CI), 0.44-1.02], crossover-corrected hazard ratio=0.44 [95 per cent CI, 0.18-1.04]).

In the COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) phase III study, more than half of the patients with MF (53.4 per cent) also experienced significant reductions (>=35 per cent) in spleen size with Jakavi therapy, and sustained this benefit over prolonged periods of time (median duration of 3.2 years). Findings from this study were presented at the 57th American Society of Hematology Meeting (ASH) in Orlando, Florida.

"Given that patients with myelofibrosis have shortened survival expectations and are at an increased risk of complications, the five-year findings from COMFORT-II demonstrate a long-term benefit with Jakavi therapy that is meaningful to the community," said Claire Harrison, MD, study investigator and consultant hematologist, Guy's and St. Thomas' NHS Foundation Trust, London.

"These data help to confirm the important role Jakavi plays in these difficult-to-treat patients."

In addition to the Jakavi data presented at ASH, Novartis announced that a separate phase III study met its primary endpoint-patients with polycythemia vera (PV) resistant to or intolerant of hydroxyurea who did not have an enlarged spleen who were treated with Jakavi maintained hematocrit control without the need for phlebotomy. In the phase III RESPONSE 2 (Randomized Study of Efficacy and Safety in POlycythemia Vera with JAK INhibitor Ruxolitinib VerSus BEst Available Care) study, the safety profile of Jakavi was consistent with previous studies. Full results from the trial continue to be evaluated and will be presented at a future medical congress.

"The growing body of research confirms the benefit of Jakavi for patients with rare blood cancers, such as myelofibrosis and polycythemia vera, who have limited treatment options," said Alessandro Riva, MD, global head, Novartis Oncology Development and Medical Affairs.

"In addition to exhibiting long-term benefits in myelofibrosis, Jakavi also showed potential to benefit a broader population of patients with polycythemia vera, bringing hope to another underserved patient community."

COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) is a randomized, open-label, phase III study of 219 patients with primary MF, post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF) in 56 study locations in Europe. Two-thirds of patients (146) received Jakavi twice daily and one-third of patients (73) received best available therapy, which was administered at doses and schedules determined by the investigator. Best available therapy was selected by the investigator for each patient and could have included a combination of available agents to treat the disease and/or its symptoms. Of the patients on the best available therapy arm, 61.6 per cent crossed over to receive Jakavi upon protocol-defined progression following the primary analysis after week 48. All patients randomized to best available therapy have crossed over or discontinued. An analysis of the study at five years was performed to evaluate the safety and efficacy of Jakavi in patients with MF.

In the phase III trial, fibrosis grades, a key indicator of disease control in MF, improved (15.8 per cent) or were maintained (32.2 per cent) in nearly half of patients with long-term Jakavi treatment. Nearly one-quarter of patients (26.7 per cent from Jakavi treatment arm; 24.4 per cent who crossed over from best available treatment arm) remained on treatment with Jakavi for five years. All adverse events (AEs) were consistent with previous analyses of treatment with Jakavi in patients with MF. The most common AEs in Jakavi-treated patients either after randomisation or after crossing over from best available therapy were thrombocytopenia (52.4 per cent), anemia (49.2 per cent), diarrhea (35.6 per cent) and peripheral edema (33.0 per cent). The most common grade 3/4 AEs included anemia (22.5 per cent), thrombocytopenia (15.2 per cent), pneumonia (5.8 per cent), general physical health deterioration (4.2 per cent) and shortness of breath (4.2 per cent).

RESPONSE 2 (Randomized Study of Efficacy and Safety in POlycythemia Vera with JAK INhibitor Ruxolitinib VerSus BEst Available Care) is a multi-center, open label, randomized, phase IIIb study evaluating the efficacy and safety of Jakavi versus best available therapy. The trial randomized 149 patients with PV who were resistant to or intolerant of hydroxyurea, dependent on phlebotomy for hematocrit control and did not have an enlarged spleen. Patients were randomized 1:1, by stratification (based on hydroxyurea resistance or intolerance) to receive either Jakavi (10 mg twice daily) or best available therapy, which was defined as investigator selected monotherapy or observation only. The dose was adjusted as needed throughout the study.

MF is part of a group of related rare blood cancers known as myeloproliferative neoplasms (MPNs) where a patient's bone marrow can no longer produce enough normal blood cells, causing the spleen to enlarge. As a result, patients with MF may suffer from debilitating symptoms and have a poor quality of life. After diagnosis, patients with MF have a decreased life expectancy, with an average survival of approximately five to six years. Although allogeneic stem cell transplantation may cure MF, the procedure is associated with significant morbidity and transplant-related mortality, and is available to less than 5 per cent of patients who are young and fit enough to undergo the procedure.

Also an MPN, PV is associated with an overproduction of blood cells in the bone marrow and affects roughly one to three people per 100,000 globally. The disease is driven by the dysregulation of the JAK-STAT pathway. It is typically characterized by elevated hematocrit, the volume percentage of red blood cells in whole blood, which can lead to a thickening of the blood and an increased risk of blood clots, as well as an elevated white blood cell and platelet count. This can cause serious cardiovascular complications, such as stroke and heart attack, resulting in increased morbidity and mortality. Approximately 60 to 70 per cent of patients with PV do not have enlarged spleen.

A common PV treatment includes phlebotomy, a procedure to remove blood from the body to reduce the concentration of red blood cells, which is used to help maintain a hematocrit level below 45 per cent. However, for a subset of patients, including those with high-risk PV, phlebotomy is usually unsuitable as a permanent treatment option due to its inability to control symptoms or effectively manage the overproduction of red blood cells, therefore cytoreductive agents, such as hydroxyurea, may be added. For patients requiring phlebotomy in combination with hydroxyurea, hematocrit may fluctuate and remain at unsafe levels for significant periods of time. Unfortunately, approximately 25 per cent of patients with PV become resistant to or intolerant of hydroxyurea treatment according to European LeukemiaNet (ELN) criteria, resulting in inadequate disease control and an increased risk of progression.

Jakavi (ruxolitinib) is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinases. Jakavi is approved by the European Commission for the treatment of adult patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea and for the treatment of disease-related splenomegaly or symptoms in adult patients with primary MF (also known as chronic idiopathic MF), post-polycythemia vera MF or post-essential thrombocythemia MF. Jakavi is approved in more than 95 countries for patients with MF, including countries in the European Union, Canada, Japan and countries in Asia, Latin and South America, and in 49 countries for patients with PV, including countries in the European Union, Japan and Canada. The exact indication for Jakavi varies by country. Additional worldwide regulatory filings are underway in MF and PV.

Novartis licensed ruxolitinib from Incyte Corporation for development and commercialisation outside the United States. Jakavi is marketed in the United States by Incyte Corporation as Jakafi for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea and for the treatment of patients with intermediate or high-risk MF.

The recommended starting dose of Jakavi in PV is 10 mg given orally twice daily. The recommended starting dose of Jakavi in MF is 15 mg twice daily for patients with a platelet count between 100,000 cubic millimeters (mm3) and 200,000 mm3, and 20 mg twice daily for patients with a platelet count of >200,000 mm3. Doses may be titrated based on safety and efficacy. There is limited information to recommend a starting dose for MF and PV patients with platelet counts between 50,000/mm3 and <100,000/mm3. The maximum recommended starting dose in these patients is 5 mg twice daily, and patients should be titrated cautiously.