Results from a phase I/II study of the Novartis Janus kinase (JAK) inhibitor with the investigational name INC424 (also known as INCB018424 and INCB18424) were published in The New England Journal of Medicine, demonstrating marked and durable clinical benefits in patients with myelofibrosis. Novartis has 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.

Myelofibrosis is a rare, life-threatening blood cancer characterized by bone marrow failure, enlarged spleen (splenomegaly), debilitating symptoms, poor quality of life, weight loss and shortened survival. Both the US Food and Drug Administration and the European Medicines Agency have granted INC424 orphan drug status for myelofibrosis.

The phase I/II study of 153 patients showed that approximately 75 per cent of myelofibrosis patients receiving INC424 twice-daily experienced rapid reduction in spleen size, which was durable for more than one year of follow-up. After only one month of therapy, patients with debilitating symptoms including fatigue, night sweats and pruritus (itching) also achieved more than 50 per cent improvement in symptom scores, as measured by the Myelofibrosis Symptom Assessment Form. Patients, particularly those with weight loss, experienced a clinically meaningful gain in total body weight following treatment. Additional clinical benefits observed in the study included improved functional status and increased exercise capacity. These clinical benefits were accompanied by reductions in circulating cytokines, inflammation-causing proteins in the blood that are markedly elevated in patients with myelofibrosis.

Two phase III clinical trials, COMFORT-I in the US, Canada and Australia, and COMFORT-II in Europe, have completed enrollment and are evaluating the benefits of treatment with INC424 compared to either placebo or best available care.

"Effective therapies are desperately needed for patients with myelofibrosis, which has a poor prognosis, especially when advanced," said lead investigator Srdan Verstovsek, MD, PhD, of MD Anderson Cancer Center, Houston, Texas. "We currently have no therapeutic options for these patients in the US, and the rapid and durable clinical benefits observed in this study show a real potential to provide a way to alleviate suffering."

A strong association exists between abnormal JAK signaling and the development of myelofibrosis, polycythemia vera and essential thrombocythemia, a related group of conditions referred to as myeloproliferative neoplasms. Patients with these diseases can progress to secondary acute myelogenous leukaemia, which is virtually untreatable and is associated with a dismal prognosis. The discovery of JAK mutations common to myelofibrosis, polycythemia vera and essential thrombocythemia has linked them on a molecular level and has led to the development of INC424, a potent, selective inhibitor of the JAK1 and JAK2 tyrosine kinases.

"Complementing our rich haematology-oncology pipeline in rare diseases, this promising JAK inhibitor exemplifies the Novartis commitment to developing new therapies for patients with unmet medical needs," said Alessandro Riva, MD, Global Head, Oncology Development & Medical Affairs, Novartis Oncology. "We are pleased to contribute our expertise to the global development of INC424, complementing and leveraging Incyte's work for myelofibrosis patients in the US."

The open-label, non-randomized, dose-escalation Phase I/II study, conducted by Incyte, included 153 patients with myelofibrosis, and was undertaken at MD Anderson Cancer Center and Mayo Clinic. Primary outcome measures were safety and tolerability. The secondary outcome measure was preliminary effectiveness.

In this study, a starting dose of 15 mg twice-daily with individualized dose titration was found to be the most effective and safest dose of INC424. Median duration of therapy exceeded one year. Notably, improvements occurred in patients regardless of JAK mutational status. Investigators observed that treatment with INC424 reduced levels of inflammatory cytokines in the blood, which they believe could provide a rational biological explanation for the mutation-independent response to therapy.

INC424 provided rapid and sustained reduction in splenomegaly, resolution of constitutional symptoms, improvement of performance status and exercise capacity and weight gain. At the starting dose of 15 mg twice-daily, 48 per cent of patients achieved at least a 35 per cent reduction in spleen volume. Symptoms of myelofibrosis not directly related to splenomegaly, including night sweats, fevers, fatigue, weight loss and pruritus, also improved in response to INC424. Other clinical benefits included normalization of elevated platelet and white cell counts. Reduction in cytokine levels while on therapy, presumably through JAK1 inhibition, paralleled improvements in patients' systemic symptoms.

At the time of the data analysis, the median duration of therapy for 153 patients enrolled in the study was 14.7 months and 115 (75 per cent) were still receiving INC424. Non-haematologic side effects related to therapy were infrequent (<10 per cent) and of low grade. Haematologic side effects included anaemia and thrombocytopenia (reduced platelet counts). Thrombocytopenia was the dose-limiting toxicity of the drug. Mean haemoglobin levels decreased during the first three to four cycles of therapy and then stabilized or improved with continued treatment. Serious adverse events occurred in 59 patients, of whom 12 experienced serious adverse events that were considered at least possibly related to treatment.

Myelofibrosis is a Philadelphia chromosome-negative myeloproliferative neoplasm associated with bone marrow failure, splenomegaly, debilitating symptoms and shortened survival. Of the JAK-associated myeloproliferative neoplasms, myelofibrosis carries the greatest risk of a poor prognosis, including transformation to fatal acute myelogenous leukaemia. For myelofibrosis patients in general, clinical findings such as splenomegaly, anaemia and constitutional symptoms may significantly reduce quality of life.

The disease has a high unmet medical need. Although allogeneic stem cell transplantation may cure myelofibrosis, the procedure is associated with significant morbidity and mortality and is usually appropriate only in younger patients. The five-year survival rate after transplantation is about 50 per cent.