Following a priority review, the US Food and Drug Administration (FDA) has approved nilotinib (Tasigna?) for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase. With this approval, nilotinib becomes the first new therapeutic option for newly diagnosed patients since the introduction of imatinib (Glivec?), providing a major advance for patients with this blood cancer.

The US approval was based on results of the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients) Phase III clinical trial, which were published today in The New England Journal of Medicine (NEJM).

“With the faster and deeper responses we are seeing with Tasigna, newly diagnosed CML patients will have a new and more effective treatment option,” said Herv? Hoppenot, President, Novartis Oncology.

Nilotinib is a potent and selective inhibitor of the Bcr-Abl protein that causes production of cancer cells in Ph+ CML[2,3]. It is also active against a broad spectrum of Bcr-Abl mutations associated with resistance to imatinib[4]. The first clinical trials of nilotinib began only 21 months after its discovery, with the drug receiving its first regulatory approval as a second-line treatment in 2007.

In its pivotal head-to-head trial against imatinib, nilotinib surpassed imatinib in key measures of treatment efficacy, as has been previously reported. Nilotinib eliminated Bcr-Abl faster than imatinib, resulting in lower rates of cancer progression even as early as 12 months[1]. Deep reduction of Bcr-Abl, known as a major molecular response, is considered to be a critical therapeutic milestone associated with good long-term outcomes for patients with Ph+ CML[5-7]. Treatment with nilotinib led to higher rates of both major molecular response and complete cytogenetic response (elimination of the Philadelphia chromosome that is the hallmark of the cancer) compared with imatinib[1].

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The randomized, open-label, multicenter ENESTnd trial compared the efficacy and safety of nilotinib versus imatinib in adult patients with newly diagnosed Ph+ CML in chronic phase[1]. It is the largest global randomized comparison of two oral therapies ever conducted in newly diagnosed Ph+ CML patients in chronic phase.

Two patients on the nilotinib arm progressed to either accelerated phase or blast crisis while 17 patients on the imatinib arm progressed to either accelerated phase or blast crisis. In the study, nilotinib was well tolerated. Fewer patients discontinued due to adverse events from the nilotinib 300 mg twice daily arm of the study compared to the imatinib 400 mg once daily arm. No patients in the study had a prolongation of the QT interval >500 milliseconds[1]. In addition, no sudden deaths occurred with either treatment[4].

Regulatory submissions for nilotinib in the first-line indication are under way worldwide, with applications currently filed in the EU, Switzerland and Japan.

Nilotinib has been approved in more than 80 countries for the treatment of chronic phase and accelerated phase Ph+ CML in adult patients resistant or intolerant to at least one prior therapy, including imatinib. The effectiveness of nilotinib for this indication is based on confirmed hematologic and unconfirmed cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

More Information:
[1] Giuseppe Saglio, M.D., Dong-Wook Kim, M.D., Ph.D., Surapol Issaragrisil, M.D., F.R.C.P., F.A.C.P., F.R.C.P.A., F.R.C.Path., Philipp le Coutre, M.D., Gabriel Etienne, M.D., Clarisse Lobo, M.D., Ricardo Pasquini, M.D., Richard E. Clark, M.A., M.D., F.R.C.P., F.R.C.Path., Andreas Hochhaus, M.D., Timothy P. Hughes, M.D., M.B.B.S., Neil Gallagher, M.D., Ph.D., Albert Hoenekopp, M.D., Mei Dong, M.D., M.S, Ariful Haque, M.S., Richard A. Larson, M.D., and Hagop M. Kantarjian, M.D.4 on behalf of the ENESTnd investigators – ENESTnd: A Randomized Comparison of Nilotinib and Imatinib for Newly Diagnosed Chronic Myeloid Leukemia – The New England Journal of Medicine 2010 June 17;362(24): Pages 2251-2259.[2] Tasigna? (nilotinib) European Summary of Product Characteristics. Novartis AG.[3] Novartis data on file.[4] Swords R, Mahalingam D, Padmanabhan S, et al. Nilotinib: optimal therapy for patients with chronic myeloid leukemia and resistance or intolerance to imatinib. Drug Des Devel Ther. 2009 Sep 21;3:89-101.[5] Hochhaus A, O’Brien SG, Guilhot F,et al. IRIS Investigators. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009 Jun;23(6):1054-61.[6] M?ller MC, Hanfstein B, Erben P, et al. Molecular response to first line imatinib therapy is predictive for long term event free survival in patients with chronic phase chronic myelogenous leukemia – an interim analysis of the randomized German CML Study IV. Blood (ASH Annual Meeting Abstracts) 2008., 112: Abstract 333.[7] Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009 Dec 10;27(35):6041-51.[8] Glivec? (imatinib) prescribing information. Basel, Switzerland: Novartis International AG; March 2009.

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