ruxolitinib

Top-line results from a Phase II trial showed that its JAK inhibitor Jakafi (ruxolitinib), in combination with Roche’s Xeloda (capecitabine), improved survival in some patients with recurrent or treatment refractory advanced pancreatic cancer

http://www.pharmatimes.com/Article/13-08-

22/Big_boost_for_Incyte_as_Jakafi_shines_in_PhII.aspx

Ruxolitinib (trade names Jakafi and Jakavi, by Incyte Pharmaceuticals and Novartis) is a drug for the treatment of intermediate or high-risk myelofibrosis, a type of bone marrow cancer.It is also being investigated for the treatment of other types of cancer (such as lymphomas and pancreatic cancer), for polycythemia vera, and for plaque psoriasis.
The phase III Controlled Myelofibrosis Study with Oral JAK Inhibitor-I (COMFORT-I) and COMFORT-II trials showed significant benefits by reducing spleen size, relieving debilitating symptoms, and improving overall survival.

Mechanism of action

Ruxolitinib is a Janus kinase inhibitor with selectivity for subtypes 1 and 2 of this enzyme.
Side effects

Immunologic side effects have included herpes zoster (1.9%) and case reports of opportunistic infections.[10] Metabolic side effects have included weight gain (7.1%). Laboratory abnormalities have included alanine transaminase (ALT) abnormalities (25.2%), aspartate transaminase (AST) abnormalities (17.4%), and elevated cholesterol levels (16.8%).
Legal status

In November 2011, ruxolitinib was approved by the USFDA for the treatment of intermediate or high-risk myelofibrosis based on results of the COMFORT-I and COMFORT-II Trials.

Some analysts believe this to be a potential blockbuster drug.[3] As of the end of March 2012, and according to an Incyte spokesman, approximately 1000 physicians had prescribed the drug in the United States, out of a total 6500 hematologists and oncologists nationwide.

The US Food and Drug Administration had approved Incyte’s Jakafi (ruxolitinib) to treat patients with the bone marrow disease myelofibrosis (MF).  Jakafi is the first and only drug granted license specifically for the treatment of the rare blood cancer.

Jakafi approved by FDA to treat rare bone marrow disease

Posted By Edward Su On November 17th, 2011

MF is a rare, potentially life-threatening blood cancer with limited treatment methods. Patients with the bone marrow disoder, characterized by bone marrow failure, enlarged spleen (splenomegaly), suffer from the symptoms of fatigue, night sweats and pruritus, poor quality of life, weight loss and shortened survival. The US drug firm Incyte estimates the disease affects about 16,000-18,500 people in the USA. Currently,  the disease is treated with chemotherapy or bone marrow transplant.

Incyte’s Jakafi, the first drug to reach market from the Wilmington-based drug company, was approved by the FDA as a twice-a-day pill for the treatment of patients with intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF.  The US regulators reviewed Jakafi under its priority review program for important new therapies.

The approval of  Jakafi was based on the results from two clinical studies involved 528 patients with the disease. Patients in the Jakafi treatment arm experienced a significant reduction in the size of their spleen as well as a 50 percent decrease in symptoms, including pain, discomfort and night sweats.

Jakafi, generically known as ruxolitinib,  works by blocking JAK1 and JAK2 enzymes associated with the disease. The company has co-developed the drug with Novartis as part of their collaboration signed in 2009. The Swiss drug firm has the rights to market Jakafi in other countries.

“The availability of Jakafi is a significant medical advancement for people living with myelofibrosis, a debilitating disease,” said Paul A. Friedman, M.D., President and Chief Executive Officer of Incyte. “This milestone marks a tremendous achievement for Incyte because a scientific discovery from our research laboratories has become the first JAK inhibitor to reach the market and provide a clinical benefit to patients.”

Richard Pazdur, director of the Office of Hematology and Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, said that Jakafi “represents another example of an increasing trend in oncology where a detailed scientific understanding of the mechanisms of a disease allows a drug to be directed toward specific molecular pathways”.

Incyte says Jakafi will be available next week, and the drug will cost $7,000 per month, or $84,000 for a year’s supply for insured patients. The company plans to provide Jakafi free to uninsured patients and will offer co-pay assistance to patients with financial need.

(JAK1, JAK2) inhibitor, developed by the Incyte Corporation, trade name Jakafi.
Ruxolitinib synthetic route as shown below. 4 – bromo-pyrazole ( 1 ) with ethyl vinyl ether ( 2 ) to protect, and then with a Grignard reagent to a halogen – exchanged with isopropyl magnesiumpinacol ester ( 3 ) quenching to obtain 4 . Compound 5 is obtained consisting of hydrogen is protected 6 , and then with a boronic acid ester 4 Suzuki coupling occurs under acidic conditions after removal of the protecting group pyrazolyl 7 , 7 and α, β-unsaturated aldehyde 8 chiral catalyst 9 of under the catalysis of asymmetric Michael addition to give ( R ) -10 (90% EE). ( R) -10 , after reaction with ammonia to obtain an imine oxidation with iodine nitrile 11 , respectively, with different conditions for the final removal of the protecting group to afford Ruxolitinib.