Novartis announced that a pivotal phase III trial of the investigational Janus kinase (JAK) inhibitor INC424 (also known as INCB018424 and INCB18424) has met its primary endpoint of significantly reducing spleen volume in patients with myelofibrosis (MF).

The study, called COMFORT-1 (COntrolled MyeloFibrosis Study with Oral JAK Inhibitor Therapy), showed treatment with INC424 provided a statistically significant reduction in spleen size in patients with primary MF, post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF). The study also met the secondary endpoint of symptomatic improvement as measured by the modified Myelofibrosis Symptom Assessment Form Diary. Further, the safety profile of INC424 was consistent with previous studies, which included reversible thrombocytopenia and anaemia. Results from COMFORT-1 are planned to be submitted for presentation at an upcoming medical congress.

These results support findings from a phase I/II study published in the September 16, 2010 issue of The New England Journal of Medicine showing that treatment with INC424 resulted in marked and durable clinical benefits in patients with MF. These benefits included alleviation of debilitating symptoms and reduction of spleen size, an accepted measurement for the clinical improvement in MF.

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 US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have granted INC424 orphan drug status for MF.

Myelofibrosis is an uncommon, life-threatening blood cancer characterized by bone marrow failure, enlarged spleen (splenomegaly), debilitating symptoms including fatigue, night sweats and pruritus, poor quality of life, weight loss and shortened survival. Myelofibrosis has a poor prognosis and limited treatment options. Although allogeneic stem cell transplantation may cure MF, 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 approximately 50% .

"Throughout its clinical development, INC424 has demonstrated the potential to fill a critical need for patients with myelofibrosis, who currently have limited treatment options," said Hervé Hoppenot, president, Novartis Oncology. "This promising JAK inhibitor is an important part of our rich pipeline of innovative new therapies that address unmet needs in haematology and cancer treatment."

A separate phase III clinical trial conducted in Europe, COMFORT-II, has completed enrolment and will evaluate the benefits of treatment with INC424 compared with best available care in patients with primary MF, PPV-MF or PET-MF. Results are expected in the first half of 2011 and along with COMFORT-I may form the basis of worldwide regulatory filings.

The JAK family of enzymes are key players in a number of important biologic processes, including the regulation of immune function and the formation and development of blood cells. A strong association exists between abnormal JAK signalling and the development of MF, polycythemia vera and essential thrombocythemia, a related group of conditions referred to as Philadelphia-chromosome negative myeloproliferative neoplasms. Patients with these diseases can progress to secondary acute myelogenous leukemia, which is virtually untreatable and is associated with a dismal prognosis. The discovery of JAK mutations common to MF, 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.

COMFORT-I is a randomized, double-blind, placebo-controlled Phase III study of INC424 that enrolled 309 patients with primary MF, PPV-MF or PET-MF. Half received INC424 (starting dose 15 or 20 mg twice-daily) and half received placebo. The primary endpoint is the proportion of patients achieving a reduction in spleen volume of 35% or more from baseline to week 24 as measured by a magnetic resonance imaging (MRI), or computed tomography (CT) scan in applicable patients. COMFORT-I was sponsored by Incyte Corporation and has 112 study locations in the US, Canada and Australia.

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