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Positive Phase III Data Reported for Jakafi (Ruxolitinib) in Patients With Rare Blood Cancer

Treatment currently approved for myelofibrosis patients in U.S.

In a pivotal phase III trial, Jakafi (ruxolitinib, Incyte Corp.) compared with best available therapy has met its primary endpoint of maintaining hematocrit control (red blood cell volume) without the need for phlebotomy and reducing spleen size in patients with polycythemia vera (PV) resistant to or intolerant of hydroxyurea.

PV is a chronic, incurable blood cancer associated with an overproduction of blood cells. This leads to a thickening of the blood and increased risk of blood clots. These clots can cause serious cardiovascular complications, such as stroke and heart attack, resulting in increased morbidity and mortality. Patients with PV often have an enlarged spleen and additional debilitating symptoms. Many treated patients become intolerant of or resistant to commonly available therapies, which can lead to an increased of risk of disease progression.

The phase III RESPONSE trial was a global, randomized, open-label study conducted in 222 patients with PV that was resistant to or intolerant of hydroxyurea. The patients were randomly assigned to receive either ruxolitinib (10 mg twice daily) or best available therapy, which was defined as investigator-selected monotherapy or observation only. The dose of ruxolitinib was adjusted as needed throughout the study.

The trial’s primary endpoint was the proportion of patients whose hematocrit was controlled without phlebotomy and whose spleen volume was reduced by 35% or more from baseline, as assessed by imaging at 32 weeks. In addition to safety, key secondary endpoints include a durable response and complete hematological remission.

Ruxolitinib is an oral inhibitor of the Janus kinase 1 (JAK1) and JAK2 tyrosine kinases. The JAK pathway has many different molecules that contribute to the signaling process. The balance of the activity among these components is critical to normal myeloid cell growth, cell survival, and differentiation of blood cells as well as to the maintenance of a functioning immune system. Dysregulation of JAKs or any other components of the pathway may lead to imbalances in blood-cell production or immune function.

The JAK2 V617F mutant allele is present in more than 95% of cases of PV. This mutation results in constitutive activation of the JAK pathway. Although JAK2 mutational status is helpful in the diagnosis of myeloproliferative neoplasms (MPNs), it is not a predictive marker of a response to JAK inhibitor treatment. This may be partly due to other mechanisms of dysregulation of JAK signaling, such as excess cytokines or other receptor or kinase mutations, implicated in MPNs. Therefore, inhibition of the JAK pathway represents a promising approach in the research into these disorders, regardless of the patient's mutational status.

Ruxolitinib is a selective JAK1 and JAK2 inhibitor that is currently under investigation for the treatment of MPNs. As a dual JAK1 and JAK2 inhibitor, the drug has the potential to modulate two important kinases that play a role in MPNs.

In the U.S., Jakafi (Incyte Corp.) is indicated for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. The treatment is approved in Europe under the trade name Jakavi (Novartis) for patients with disease-related splenomegaly or symptoms in adult patients with chronic idiopathic myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis.

The recommended starting dose for Jakafi (ruxolitinib) in patients with myelofibrosis is 20 mg given orally twice daily for patients with a platelet count greater than 200 x 109/L, and 15 mg twice daily for patients with a platelet count between 100 x 109/L and 200 x 109/L. The starting dose is 5 mg twice daily for patients with a platelet count between 50 x 109/L and less than 100 x 109/L.

Ruxolitinib is an investigational compound for PV. Its safety and efficacy have not been established outside the approved indication.

Sources: Novartis; March 7, 2014; Jakafi Prescribing Information; November 2013; and About Ruxolitinib; May 2012.

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