Basel, December 13, 2011 - Novartis today announced additional results from two pivotal Phase III trials evaluating Janus kinase (JAK) inhibitor INC424 (ruxolitinib) in myelofibrosis. These data demonstrate the important potential role of INC424 in treating patients with myelofibrosis, a life-threatening blood cancer characterized by bone marrow failure, enlarged spleen (splenomegaly) and debilitating symptoms.
Results are being presented at the 53rd Annual Meeting of the American Society of Hematology (ASH) in San Diego. Novartis and Incyte Corporation have a worldwide collaboration and license agreement for INC424.
A post-hoc analysis from the COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) study evaluated patient-reported health-related quality of life (HRQoL) measures for INC424 versus best available therapy (BAT). The results showed a substantial improvement in HRQoL and myelofibrosis symptoms compared with baseline for patients receiving INC424 but remained the same or worsened for patients receiving BAT. Results were based on a broad range of validated QoL instruments.[1]
"Myelofibrosis is a life-shortening disease with symptoms that significantly compromise patients' everyday lives," said Claire Harrison, MD, Guy's and St. Thomas' NHS Foundation Trust, Guy's Hospital, London, lead investigator for the COMFORT-II study. "As a result, therapies that address the severe burden of myelofibrosis are urgently needed. Data from large Phase III studies continue to show INC424 alleviates the manifestations and associated symptoms of myelofibrosis, potentially representing a major advance."
In the second Phase III study, COMFORT-I researchers evaluated INC424 versus placebo in symptom improvement and spleen volume reduction, as well as overall survival. Results showed that patients receiving INC424 had higher response rates based on reductions in spleen volume and Total Symptom Score (TSS). The TSS evaluated changes in symptoms, such as abdominal discomfort, pain under the ribs on the left side, early satiety, itching, night sweats and bone or muscle pain. These benefits were consistent across all patient subgroups, including myelofibrosis disease subtype, age, risk group, presence or absence of JAK2 mutation, hemoglobin, spleen size and TSS.
In the COMFORT-I updated analysis, INC424 also demonstrated an overall survival advantage over placebo. A total of 13 INC424 and 24 placebo patients died during the study or during extended follow up after median follow up of 51 and 52 weeks, respectively, representing a hazard ratio (95% CI) of 0.499 (0.254, 0.98) (p=0.0395). Survival was estimated by the Kaplan-Meier method.[2]
"These data reinforce the dramatic effect INC424 has on improving the overall quality of life of patients battling this debilitating blood cancer," said Hervé Hoppenot, President, Novartis Oncology. "We are committed to developing innovative therapies to address this unmet patient need and further support our ongoing research in myelofibrosis and other myeloproliferative neoplasms."
COMFORT-II Predictors of Response and Post-Hoc HRQoL Study Details
A detailed analysis of predictors of spleen response in various patient subsets indicated that INC424 was more effective than BAT for all patient subgroups. In particular, responses to INC424 occurred and were superior to BAT regardless of the JAK2 mutation status.
The COMFORT-II study included an assessment of HRQoL and myelofibrosis symptoms using validated instruments, including the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym). Scores from these instruments were measured at baseline and weeks 8, 16, 24 and 48. A total of 219 patients were included in two treatment groups: INC424 (n=146) and BAT (n=73).
Based on a detailed analysis of the patterns of change of QoL scales over time, and compared with the BAT arm, INC424-treated patients experienced significant improvement in Global Health Status/QoL and in symptoms measured by the FACT-Lym symptom subscale including pain, swelling, fever, night sweats, itching, trouble sleeping, fatigue, weight loss, loss of appetite and trouble concentrating compared to BAT. In addition, the EORTC QLQ-30 showed that treatment differences in physical functioning, role functioning, fatigue and appetite loss were significantly better for INC424-treated patients as early as week 8 (p<0.05), and this effect was sustained throughout 48 weeks (p<0.05).[1]
The COMFORT-II trial was conducted by Novartis in Europe.
COMFORT-I Study Details for Symptom and Overall Survival Analyses
Patients were randomized to start INC424 or placebo at doses of 15 mg or 20 mg PO BID, depending on baseline platelet count (100-200 X109/L or >200X109/L, respectively). A total of 309 patients were randomized, 155 to INC424 and 154 to placebo. The dose was optimized for efficacy and safety during treatment.[2]
The COMFORT-I study was conducted by collaboration partner Incyte Corporation in the US, Canada and Australia.
About Myelofibrosis
Myelofibrosis is an uncommon, life-threatening blood cancer characterized by bone marrow failure, enlarged spleen (splenomegaly), debilitating symptoms, such as fatigue, night sweats and pruritus, poor quality of life, weight loss as well as shortened survival.[4] In the EU, the disease affects about 0.75 out of every 100,000 people annually.[5],[6] In the US, myelofibrosis affects about 1.5 out of every 100,000 people annually.[7] Myelofibrosis has a poor prognosis and limited treatment options.[3],[4]
Studies show that within 10 years of diagnosis, up to approximately 20% of myelofibrosis patients progress to fatal secondary acute myelogenous leukemia, which is virtually untreatable.[8],[9] Although allogeneic stem cell transplantation may cure myelofibrosis, the procedure is associated with significant morbidity and mortality.[10] The five-year survival rate after transplantation is approximately 50%.[10]
About INC424 (ruxolitinib)
The investigational compound INC424 is an oral inhibitor of the JAK1 and JAK2 tyrosine kinases.[3] As part of Novartis' clinical development program, INC424 is being investigated in primary myelofibrosis as well as post-polycythemia vera myelofibrosis (PPV-MF) and post-essential thrombocythemia myelofibrosis (PET-MF). INC424 is also being investigated in clinical trials for the treatment of polycythemia vera (PV).
Novartis licensed INC424 from Incyte for development and potential commercialization outside the US. Incyte has retained rights for the development and potential commercialization of INC424 in the US. Both the European Commission (EC) and the US Food and Drug Administration (FDA) have granted INC424 orphan drug status for myelofibrosis, and INC424 was recently approved by the FDA in the US under the name Jakafi(TM).
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