Ruxolitinib - Treatment of Myelofibrosis, United States of America
Key Data
Ruxolitinib is an oral janus kinase (JAK) inhibitor indicated for the treatment of myelofibrosis. It is being developed by Incyte Corp in collaboration with Novartis.
Ruxolitinib obtained orphan drug designation both from the European Commission and the US Food and Drug Administration (FDA) for treating myelofibrosis.
Incyte submitted a new drug application to the FDA in June 2011, based on positive results from two Phase III trials. The drug was accepted for review and awarded priority designation in August 2011. The review is expected to be completed in six months.
Myelofibrosis
Myelofibrosis is a kind of blood cancer that affects the bone marrow.
The disease restrains blood forming tissues and disrupts the normal production of blood cells.
It results in extensive scarring in bone marrow, which leads to anaemia, weakness, fatigue, and often, an enlarged spleen and liver.
According to estimates in the US, the incidence of the disease is less than two in every 100,000 inhabitants. The disease generally develops in individuals aged over 50.
Ruxolitinib mechanism of action
Ruxolitinib contains JAK1 and JAK2 inhibitors that are used for treating myelofibrosis. The drug works by inhibiting the signalling of cytokines (small cell-signalling protein molecules) and growth factor receptors that use JAK1 and JAK2 for signalling. The drug restrains the growth of malignant cells and also controls the cytokines that contribute to hypermetabolic state.
Clinical trials
Incyte conducted phase I clinical trials on ruxolitinib in May 2007.
In May 2011, a Phase II trial was initiated on myelofibrosis patients with platelet counts of 50x109/L to 100x109/L to determine the effect of drug in improving the overall survival rate and its side affects.
Recruitment started in June 2011 and the trials will involve around 150 patients. The primary myelofibrosis, post-essential thrombocythemia-myelofibrosis (PET-MF) and post-polycythemia vera-myelofibrosis (PPV-MF) patients will be administered 5mg of ruxolitinib to study the reductions in the myelofibrosis -associated symptoms, inflammatory cytokine and splenomegaly levels. The entire study is expected to be completed by July 2012.
Another Phase II trial was initiated in March 2011 to determine the safety and tolerability of the drug through sustained release formulation. Around 40 myelofibrosis patients have been recruited. The trial will evaluate the safety, efficacy and tolerability of the drug in patients with myelofibrosis, PPV-MF and PET-MF. Patients will be administered once-daily doses of Ruxolitinib for 16 weeks and the results will be compared with immediate release formulation. The trial is expected to be completed by January 2013.
In July 2011, Novartis Pharmaceuticals initiated a multinational, open-label Phase II trial in Asian myelofibrosis patients. Around 110 patients have been recruited and the entire study is expected to be completed by February 2016. Primary outcomes measured will be reduced volume in spleen, safety and tolerability of the drug.
Incyte and Novartis initiated a phase III clinical study called RESPONSE on ruxolitinib in October 2010. The randomised study is being conducted in multiple centres within and outside the US. Incyte is responsible for the trials within the US while Novartis is responsible for those outside the US. The trials are scheduled to be completed by July 2013.
The RESPONSE study will enrol 300 patients. The primary and secondary outcome measures of the study include finding the proportion of subjects achieving a response rate and hematologic remission respectively at week 32.
Incyte carried out the first pivotal phase III clinical trial named COMFORT-I (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Treatment) on the drug between August 2009 and January 2011. The randomised, double-blind and placebo-controlled study was conducted in 112 study centres across the US and enrolled 309 myelofibrosis patients. The trials were conducted under a Special Protocol Assessment agreement with the US FDA.
The results of the study showed that the drug met both the primary and secondary endpoints. The primary endpoint was attaining more than 35% reduction in spleen volume in 24 weeks.
Computerised tomography and magnetic resonance imaging techniques were used to compare the response rates in the ruxolitinib-administered patient group with that of placebo-administered group. The ruxolitinib-treated patient group achieved a response rate of 42%. The response rate in placebo-administered patients was, however, just less than 1%.
Novartis conducted the second pivotal phase III clinical trials on ruxolitinib between July 2009 and December 2010. Named COMFORT-II, the study was conducted across 56 centres in Europe and enrolled 219 patients.
Two-thirds of the patients were administered with ruxolitinib and the remaining were treated with the best available therapy. The final results of the study, announced in March 2011, demonstrated that the patients who were treated with ruxolitinib achieved 35% reduction in spleen volume from baseline at week 48. The change in response rates in patients was measured by MRI or CT scans.
Marketing commentary
Incyte holds the rights to develop and market ruxolitinib in the US. Novartis obtained rights to develop and market ruxolitinib in other parts of the world excluding the US. The collaboration and licence agreement was signed by the two companies in November 2009.
