Nilotinib - Tasigna®
Rationale
Enhanced BCR-ABL binding specificity
Tasigna (nilotinib, formerly AMN107) is a next-generation targeted therapy for treatment of patients with Ph+ CML in CP or accelerated phase (AP) who are resistant to or intolerant of at least one prior therapy including imatinib.1 The rationale for the design of Tasigna was to modify the chemical structure of imatinib to enhance the target specificity of this next-generation inhibitor. The resulting molecule, nilotinib, which is the active ingredient of Tasigna, demonstrated a 20- to 50-fold higher potency for inhibition of proliferation of cells expressing BCR-ABL compared with imatinib in preclinical studies.1-4
Inhibition of imatinib-resistant BCR-ABL mutants
Nilotinib inhibits all tested imatinib-resistant mutants of BCR-ABL, except the T315I mutant.1,5These findings suggested that Tasigna may have activity in imatinib-resistant patients and were the scientific foundation for clinical investigations with Tasigna.
Phase I studies of Tasigna in patients with CML, in any disease phase, resistant to or intolerant of imatinib resulted in favorable response rates and tolerability.4 A phase II trial confirmed these results.6-8 In imatinibresistant or imatinib-intolerant patients with CML-CP or CML-AP, Tasigna produced high rates of major cytogenetic response (MCyR).Responses were achieved in patients with and without imatinib-resistant BCR-ABL mutations at baseline. Importantly, Tasigna was generally well tolerated, inducing acceptable levels
of myelosuppression that were readily managed.6-8 Phase I and II studies, taken together, demonstrate that Tasigna is a safe and effective therapy, and possibly the best alternative, for patients with CML-CP or CML-AP who are resistant to or intolerant of at least one prior therapy including imatinib.
References:
1. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7:129-141.
2. O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005;65:4500-4505.
3. O’Hare T, Walters DK, Deininger MW, Druker BJ. AMN107: tightening the grip of imatinib. Cancer Cell. 2005;7:117-119.
4. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosomepositive ALL. N Engl J Med. 2006;354:2542-2551.
5. Cortes J, O’Brien S, Quintas A, et al. Erythropoietin is effective in improving the anemia induced by imatinib mesylate therapy in patients with chronic myeloid leukemia in chronic phase. Cancer. 2004;100:2396-2402.
6. Tasigna® (nilotinib) Summary of Product Characteristics. Basel, Switzerland: Novartis; 2007.
7. Kantarjian H, Giles F, Gattermann M, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007:110:3540-3546.
8. le Coutre P, Ottman OG, Giles F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or intolerant accelerated phase chronic myelogenous leukemia [published online ahead of print December 10, 2007]. Blood. doi:blood-2007-04-083196v2.