Data from two pivotal Phase III trials evaluating Janus kinase (JAK) inhibitor INC424 (ruxolitinib; Jakafi? Novartis, Incyte) in myelofibrosisshows a clinical relevant and statistically significant improvement in symptoms compared to the best available therapy (BAT). The results of these trials demonstrate a potential role of INC424 in the treatment of myelofibrosis.

Myelofibrosis is an uncommon, life-threatening Philadelphia chromosome?negative myeloproliferative neoplasm characterized by bone marrow failure, splenomegaly (enlarged spleen) and a range of debilitating symptoms, such as fatigue, night sweats and pruritus, a generally poor quality of life, weight loss as well as reduced survival.[1] In the EU, the disease affects about 0.75 out of every 100,000 people annually.[2],[3] In the US, myelofibrosis affects about 1.5 out of every 100,000 people annually.[4] Myelofibrosis has a poor prognosis and limited treatment options.[5],[1]

The investigational compound INC424 is an oral inhibitor of the JAK1 and JAK2 tyrosine kinases.[5] 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).

Orphan Drug Status
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?.

Compromising patients lives
“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 (Controlled Myelofibrosis Study with Oral JAK Inhibitor Therapy). “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.”

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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.[6],[7] Although allogeneic stem cell transplantation may cure myelofibrosis, the procedure is associated with significant morbidity and mortality.[8] The five-year survival rate after transplantation is approximately 50%.[8]

Australian studies
In the COMFORT I study conducted by collaboration partner Incyte Corporation in the US, Canada and Australia, 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.[9]

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.[9]

Improving overall Quality of Life
“These data reinforce the dramatic effect INC424 has on improving the overall quality of life of patients battling this debilitating blood cancer,” said Herv? 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.”

More improvements
Results from a post-hoc analysis of the COMFORT-II trial presented during the 53rd Annual Meeting of the American Society of Hematology(ASH) in San Diego, showed a substantial improvement in patient-reported health-related quality of life (HRQoL) and disease symptoms compared with baseline for patients treated with INC424. Results for patients treated with BAT (best available therapy) remained the same or worsened.

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 results were based on a broad range of validated QoL instruments. [10] The trial was conducted by Novartis in Europe and 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).[10]

[1] Mesa RA, Schwagera S, Radia D, et al. The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res. 2009;33:1199-1203;
[2] Girodon F, Bonicelli G, Schaeffer C, et al. Significant increase in the apparent incidence of essential thrombocythemia related to new WHO diagnostic criteria: a population-based study. Haematologica. 2009; 94(6):865-869.
[3] McNally RJQ, Rowland D, Roman E, Cartwright RA. Age and sex distributions of hematological malignancies in the U.K. He
matol Oncol. 1997;15:173-189
[4] Mesa RA, Silverstein MN, Jacobsen SJ, et al. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995. Am J Hematol. 1999;61:10-15.
[5] Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and Efficacy of JAK1 & JAK2 Inhibitor, INCB018424, in Myelofibrosis. New Eng J Med. 2010 September 16;363:1117-1127.
[6]Abdel-Wahab O, Manshouri T, Patel J, et al. Genetic analysis of transforming eventsthat convert chronic myeloproliferative neoplasms to leukemia. Cancer Res. 2010;70(2):447-452.
[7] Beer PA, Green AR. Pathogenesis and management of essential thrombocythemia. Hematology Am Soc Hematol Educ Program. 2009;621-628.[Full text]
[8] Tefferi A. Allogeneic hematopoietic cell transplantation versus drugs in myelofibrosis: the risk-benefit balancing act. Bone Marrow Transplant. 2010;45(3):419-421.
[9] Verstovsek S, Mesa RA, Gotlib J, Levy RA, Gupta V, et al. Consistent Benefit of Ruxolitinib Over Placebo in Spleen Volume Reduction and Symptom Improvement Across Subgroups and Overall Survival Advantage: Results from COMFORT-I. American Society of Hematology 2011 Annual Meeting. Blood 2011 118: Abstract #278.
[10] Harrison CN, Kiladjian, Al-Ali HK, Gisslinger H, Knoops L, Waltzman RJ, Mendelson ET, et al. Health-Related Quality of Life and Symptoms in Myelofibrosis Patients Treated with Ruxolitinib versus Best Available Therapy. American Society of Hematology 2011 Annual Meeting. Blood 2011 118: Abstract #795

For more information also read:
– COMFORT-I, a Pivotal Phase III Trial of INCB18424in Myelofibrosis, Meets Primary and Key Secondary Endpoints.
– Ruxolitinib Shows Statistically Significant Positive Outcomes in Myelofibrosis

Also watch:
– COMFORT II – Why is Spleen Volume So Important? and Other Questions with Dr. Claire Harrison.
– What do the Results of the COMFORT-I and II Trial Mean to Patients? (Video 5 of 5).

Prescribing information
Jakafi? (ruxolitinib; Incyte) tablets, for oral use. Initial U.S. Approval 2011

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