Novartis Tasigna(R) (nilotinib) Trial Shows Superior Results to Glivec(R) (imatinib) in Newly Diagnosed, Chronic Phase Chronic Myeloid Leukaemia

Wednesday, December 9, 2009 Research News
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FRIMLEY, England, December 8

- Nilotinib Surpassed imatinib in Key Measures of Treatment Effectivenessin the Trial, in Patients With Newly-Diagnosed Disease(1)

- At 12-Months, Significantly Fewer Patients Progressed to Later Stagesof the Disease on nilotinib (300mg Twice-Daily and 400mg Twice-Daily) Than onimatinib 400mg Once-Daily(1)

- Nilotinib was Generally Well Tolerated; Only a Small Number of PatientsDiscontinued Due to Adverse Events(1)

- Novartis Plans to File for Use in Newly Diagnosed Patients With Ph+ CMLin the EU in 2010

In a large clinical trial, nilotinib demonstrated greater efficacy overthe current gold standard treatment, imatinib, in adult patients with newlydiagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+CML) in the chronic phase.(1)

In the first head-to-head study of these two oral treatments as initialtherapy for this life-threatening leukaemia, nilotinib demonstratedstatistically significant improvement over imatinib in key measures ofeffectiveness used in the trial.(1) These new data were presented as a latebreaker abstract at the 51st annual meeting of the American Society ofHaematology (ASH), held 5-8 December 2009, in New Orleans, USA.(1)

CML accounts for more than one in six leukaemias in adults, with around600 new cases being registered in England and Wales each year.(2) Theestimated prevalence of CML in 2003 in England and Wales was 2,660patients.(2)

The trial showed that at 12 months, significantly fewer patients onnilotinib 300mg twice-daily progressed from the initial chronic phase of thedisease to the later accelerated or blast crisis phases than those onimatinib 400mg once-daily.(1) This demonstrates that nilotinib providedsignificantly better control of the disease compared to imatinib.

Nilotinib was generally well tolerated in the study.(1) A small number ofpatients discontinued due to adverse events.(1)

"The impressive rates of response observed in this study, combined withthe very low rate of disease progression seen in nilotinib-treated patientsare very encouraging," said Professor Richard Clark, Consultant Haematologistat Royal Liverpool University Hospital and a trialist involved in this study."Continued improvement in the treatment of Ph+ CML is very important andthese results indicate that nilotinib may provide long-term improvement inprogression-free survival."

95% of patients with CML have an abnormality known as the Philadelphiachromosome. This chromosome produces a type of protein called Bcr-Abl, whichis responsible for the overproduction of the cancerous white blood cells thatare the main feature in Ph+ CML.(3) Nilotinib is a potent and selectiveinhibitor of the Bcr-Abl protein, thereby inhibiting the production of thesecancerous cells.(4,5)

"Novartis has been at the forefront of research on the molecular originof Ph+ CML and this has led to the development of treatments withunprecedented effectiveness and safety," said Panos Alexakos, OncologyBusiness Unit Head for Novartis UK. "These data are exciting and the deepermolecular response demonstrated provides hope for further improvement inoutcomes for patients with Ph+ CML in the future."

Novartis plans to file worldwide applications for approval of nilotinibas a treatment for adult patients with newly diagnosed Ph+ CML. Nilotinib iscurrently approved in more than 80 countries including the European Union(EU), United States and other countries for the treatment of adult patientswith Ph+ CML in chronic phase or accelerated phase who are resistant orintolerant to prior treatment including imatinib.

Notes to editors

Study details

The clinical trial, Evaluating Nilotinib Efficacy and Safety in ClinicalTrials of Newly Diagnosed Ph+ CML Patients (ENESTnd), is a Phase IIIrandomised, open-label, multicentre trial comparing the efficacy and safetyof nilotinib versus imatinib in adult patients with newly diagnosed Ph+ CMLin the chronic phase.(1) It is the largest global randomised comparison oftwo oral therapies ever conducted in newly diagnosed Ph+ CML patients.

ENESTnd is being conducted at 220 global sites, including five sites inthe UK, in total 846 patients are enrolled. Patients were randomised toreceive nilotinib 400mg twice-daily (n = 281), nilotinib 300mg twice-daily (n= 282) or imatinib 400mg once-daily (n = 283).(1) The primary endpoint wasMMR at 12 months; a secondary endpoint was CCyR by 12 months. It is plannedthat patients are followed up for five years. Patients on the imatinibtreatment arm who had suboptimal response or treatment failure will be ableto escalate dose and/or switch to nilotinib via a protocol extension.

One of the key effectiveness measures used in the study was called majormolecular response (MMR). This is defined as the reduction in levels of theBcr-Abl protein to less than or equal to 0.1% of the level seen beforetreatment. MMR is an important measure in CML, as data show that patients whoachieve MMR are unlikely to progress to the later stages of the disease.(6)With nilotinib 300mg twice-daily, the rate of MMR at 12 months was twice thatof patients receiving imatinib 400mg once-daily (44% vs. 22%, p < 0.0001).(1)

Another effectiveness measure used in the study was called completecytogenetic response (CCyR). CCyR indicates that no CML cells containing thePh chromosome can be seen in a sample of bone marrow taken from the patient.80% of patients achieved CCyR with nilotinib versus 65% with imatinib 400mgonce-daily (p < 0.0001).(1) Responses were achieved faster in the nilotinibgroup than in the imatinib group.(1)

All patients had a minimum of 12 months of treatment or discontinuedearly; the median follow-up was 14 months. Overall, 84%, 82% and 79% ofpatients remained in the study on nilotinib 300mg twice-daily, nilotinib400mg twice-daily and imatinib 400mg once-daily, respectively.(1)

About Ph+ CML

CML is a disease in which the body produces cancerous (leukaemic) whiteblood cells. 95% of patients with CML have an abnormality known as thePhiladelphia chromosome. This chromosome produces a protein called Bcr-Abl,which is responsible for the proliferation of leukaemic white blood cells inPh+ CML.(3)

CML accounts for more than one in six leukaemias in adults, with around600 new cases being registered in England and Wales each year.(2) Theestimated prevalence of CML in 2003 in England and Wales was 2,660patients.(2)

About Tasigna (nilotinib)

Nilotinib, a second generation TKI, is a potent and selective inhibitorof the Bcr-Abl protein, which is responsible for the proliferation ofleukaemic white blood cells in Ph+ CML.(4,5) Nilotinib is indicated for thetreatment of adults with chronic phase and accelerated phase Ph+ CML withresistance or intolerance to prior therapy including imatinib. Efficacy datain patients with CML in blast crisis are not available.(5)

For nilotinib summary of product characteristics, please see:

(Due to the length of this URL, it may be necessary to copy and pastethis hyperlink into your Internet browser's URL address field. Remove thespace if one exists.)

About Glivec (imatinib)(7)

Imatinib is approved in the EU for the treatment of all phases of Ph+CML. Imatinib is also indicated for the treatment of adult patients with Kit(CD 117) positive unresectable and/or metastatic malignant gastrointestinalstromal tumours (GIST) and the adjuvant treatment of adult patients who areat significant risk of relapse following resection of Kit (CD117)-positiveGIST.

Furthermore, imatinib is approved for the treatment of adult patientswith newly diagnosed Philadelphia chromosome positive acute lymphoblasticleukaemia (Ph+ ALL) integrated with chemotherapy, adult patients withrelapsed or refractory Ph+ ALL as monotherapy, adult patients withmyelodysplastic/myeloproliferative diseases (MDS/MPD) associated withplatelet-derived growth factor receptor (PDGFR) gene re-arrangements, adultpatients with advanced hypereosinophilic syndrome (HES) and/or chroniceosinophilic leukaemia (CEL) with FIP1L1-PDGFR alpha rearrangement and thetreatment of adult patients with unresectable dermatofibrosarcoma protuberans(DFSP) and adult patients with recurrent and/or metastatic DFSP who are noteligible for surgery.For imatinib summary of product characteristics, please see: References (1) Saglio G, Kim DW, Issaragrisil S, Philipp le Coutre, et al. Nilotinib Demonstrates Superior Efficacy Compared with Imatinib in Patients with Newly Diagnosed Chronic Myeloid Leukaemia in Chronic Phase: Results from the International Randomized Phase III ENESTnd Trial. American Society of Hematology 2009. Abstract number LBA-1 (2) NICE Guidance on the use of imatinib for chronic myeloid leukaemia - Technology Appraisal 70. October 2003 (3) Faderl S; Talpaz M; Estrov Z; O'Brien S; Kurzrock R; Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med. 341:164-72, 1999. (4) National Cancer Institute. General Information about Chronic Myelogenous Leukaemia (PDQ). Accessed March 2009.l 1: definition of PCR. (5) Tasigna (nilotinib) European Summary of Characteristics. Novartis AG. 20hard%20capsules. 21/09/2009 (Due to the length of this URL, it may be necessary to copy and paste this hyperlink into your Internet browser's URL address field. Remove the space if one exists.) (6) Hughes et al. Reduction of BCR-ABL Transcript Levels at 6, 12, and 18 Months (mo) Correlates with Long-Term Outcomes on Imatinib (IM) at 72 Mo: An Analysis from the International Randomized Study of Interferon versus STI571 (IRIS) in Patients (pts) with Chronic Phase Chronic Myeloid Leukemia (CML-CP). ASH. 2008. Abstract #334 (7) Glivec (imatinib) European Summary of Characteristics. Novartis AG. 03/06/2009

SOURCE Novartis Oncology

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