Tasigna is the first and only tyrosine kinase inhibitor (TKI) to include information on stopping therapy in Ph+ CML-CP patients in the EU product information
Approval based on Novartis trials evaluating TFR with Tasigna in Ph+ CML-CP patients in both the first-line setting and after switching from Glivec®
Addition of TFR data to label provides patients and physicians with important clinical information for potential approach to managing Ph+ CML-CP
Basel, June 6, 2017- Novartis announced today that the European Commission (EC) has approved the inclusion of Treatment-free Remission (TFR) data in the Tasigna® (nilotinib) Summary of Product Characteristics (SmPC). TFR is the ability to maintain molecular response (MR) after stopping tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) patients in chronic phase (CP). This is an important milestone for the Ph+ CML community because Tasigna is now the first and only TKI to include information on TFR in the European Union (EU) label.
"For more than 15 years, Novartis has been committed to improving upon the standard of care in Ph+ CML," said Bruno Strigini, CEO, Novartis Oncology. "With this EU approval, we are pleased that results of two studies from our large international Ph+ CML clinical trial program assessing Tasigna discontinuation, ENESTfreedom and ENESTop, now provide physicians with important clinical information for discontinuing therapy in certain patients."
The approval by the EC was based on efficacy and safety findings from the 48-week analyses of two open label trials, ENESTfreedom and ENESTop, which showed that more than 50% of Ph+ CML-CP patients who met the rigorous predefined response criteria of the trials were able to maintain TFR after stopping Tasigna in both in the first-line setting and after switching from Glivec® (imatinib)*,. No new major safety findings were observed in these studies at the 48-week analyses in patients treated with Tasigna beyond those in the known safety profile of Tasigna,.
An important part of the ENESTfreedom and ENESTop trials was regular and frequent molecular monitoring of BCR-ABL levels with a well-validated assay able to measure BCR-ABL transcript levels down to MR4.5 (BCR-ABL1 International Scale [IS] <= 0.0032%). Frequent patient monitoring after discontinuation of Tasigna allows timely determination of loss of MR4.0 (BCR-ABL1 IS <= 0.01%) and major molecular response (MMR; BCR-ABL1 IS <= 0.1%) and need for treatment re-initiation,.
About Ph+ CML CML is a type of cancer in which the body produces cancerous white blood cells. Almost all patients with CML have an abnormality known as the Philadelphia chromosome, which produces a protein called BCR-ABL. BCR-ABL causes malignant white blood cells to proliferate. Worldwide, CML is responsible for approximately 10% to 15% of all adult cases of leukemia, with an incidence of one to two cases per 100,000 people per year.
Novartis Commitment to CML Over the past several decades, Novartis research in Ph+ CML has helped transform the disease from a fatal leukemia to a chronic condition in most patients, and today, the company continues its long-standing commitment to the global CML community. Novartis follows the science and builds upon existing evidence to explore what could be the next major contribution in the treatment of Ph+ CML. The company is evaluating more than 1,000 patients as part of the Tasigna TFR studies, which include ENESTfreedom and ENESTop as well as two other ongoing company-sponsored TFR studies and multiple investigator-initiated studies, as well as investigational compounds.
About ENESTfreedom ENESTfreedom (Evaluating Nilotinib Efficacy and Safety in Clinical Trials - Following REsponsE in De nOvo CML-CP Patients) is an open label Phase II study involving 215 Ph+ CML-CP patients, conducted at 132 sites across 19 countries. The trial evaluated stopping treatment in 190 adults with Ph+ CML-CP after the patients had achieved a response of MR4.5 with Tasigna and a sustained deep molecular response for one year as a first-line treatment.
Results from the ENESTfreedom study showed that more than half (51.6%) of 190 Ph+ CML-CP patients in the trial (confidence interval [CI] 95%: 44.2%-58.9%) were able to discontinue therapy and remain in TFR at the 48 week analysis. ENESTfreedom did not meet its primary endpoint, the percentage of patients in MMR at 48 weeks in the TFR phase, per the original statistical assumption that the lower limit of the 95% CI will be equal to or greater than 50%. The median treatment duration in this trial was 3.6 years.
In ENESTfreedom, 24.7% of patients experienced musculoskeletal pain during the first year of the TFR phase versus 16.3% while still taking Tasigna in the one-year consolidation phase. No patients progressed to advanced phase/blast crisis in the study.
About ENESTop ENESTop (Evaluating Nilotinib Efficacy and Safety Trial) is an open label Phase II study involving 163 Ph+ CML-CP patients, conducted at 63 sites across 18 countries. The trial evaluated stopping treatment in 126 adults with Ph+ CML-CP after patients had been treated with Glivec, and then switched to treatment with Tasigna, and had achieved and sustained deep molecular response for one year with Tasigna.
ENESTop showed that nearly 6 out of 10 (57.9%) patients in the trial (95% CI: 48.8%-66.7%) maintained a molecular response at 48 weeks after stopping treatment. The study met its primary endpoint of the proportion of patients without confirmed loss of MR4.0 or loss of MMR within 48 weeks of Tasigna discontinuation in the TFR phase.
In ENESTop, the rates of all grade musculoskeletal pain were 42.1% in the first year of the TFR phase versus 14.3% while still taking Tasigna in the consolidation phase. No patients progressed to advanced phase/blast crisis in the study.
About Tasigna (nilotinib) Tasigna® (nilotinib) is approved in more than 122 countries for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to at least one prior therapy, including Glivec® (imatinib), and in more than 110 countries for the treatment of adult patients with newly diagnosed Ph+ CML in chronic phase.
IMPORTANT SAFETY INFORMATION for TASIGNA® (nilotinib) Capsules Use with caution in patients with uncontrolled or significant cardiac disease and in patients who have or may develop prolongation of QTc. Low levels of potassium or magnesium must be corrected prior to Tasigna administration. Monitor closely for an effect on the QTc interval. Baseline ECG is recommended prior to initiating therapy and as clinically indicated. Cases of sudden death have been reported in clinical studies in patients with significant risk factors. Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors. Avoid food 2 hours before and 1 hour after taking dose. Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving TKI treatment.
Use with caution in patients with liver impairment, with a history of pancreatitis and with total gastrectomy. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not use Tasigna. Tasigna may cause fetal harm in pregnant women. If pregnancy is planned during the treatment-free remission phase, the patient must be informed of a potential need to re-initiate treatment with Tasigna during pregnancy. Women taking Tasigna should not breastfeed.
Cases of cardiovascular events included ischemic heart disease-related events, peripheral arterial occlusive disease, and ischemic cerebrovascular events have been reported. Serious cases of hemorrhage from various sites including gastrointestinal were reported in patients receiving Tasigna. Grade 3 or 4 fluid retention including pleural effusion, pericardial effusion, ascites and pulmonary edema have been reported. Cases of tumor lysis syndrome have been reported in Tasigna-treated patients who were resistant or intolerant to prior CML therapy.
Eligible patients who are confirmed to express the typical BCR-ABL transcripts, e13a2/b2a2 or e14a2/b3a2, can be considered for treatment discontinuation. Frequent monitoring of BCR-ABL transcript levels in patients eligible for treatment discontinuation must be performed with a quantitative diagnostic test validated to measure molecular response levels with a sensitivity of at least MR4.5 (BCR-ABL/ABL <=0.0032% IS). BCR-ABL transcript levels must be assessed prior to and during treatment discontinuation. Loss of major molecular response (MMR=BCR-ABL/ABL <=0.1%IS) or confirmed loss of MR4 (two consecutive measures separated by at least 4 weeks showing loss of MR4 (MR4=BCR-ABL/ABL <=0.01%IS)) will trigger treatment re-initiation within 4 weeks of when loss of remission is known to have occurred. It is crucial to perform frequent monitoring of BCR-ABL transcript levels and complete blood count with differential in order to detect possible loss of remission. For patients who fail to achieve MMR after three months of treatment re initiation, BCR-ABL kinase domain mutation testing should be performed.
The most frequent Grade 3 or 4 adverse events are hematological (neutropenia, thrombocytopenia, anemia) which are generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. Chemistry panels, including electrolytes, lipid profile, liver enzymes, and glucose should be checked prior to therapy and periodically. Tasigna can cause increases in serum lipase. The most frequent non-hematologic adverse events were rash, pruritus, nausea, fatigue, headache, alopecia, myalgia, constipation and diarrhea.
Musculoskeletal pain, myalgia, pain in extremity, arthralgia, bone pain and spinal pain may occur upon discontinuing treatment with Tasigna within the framework of attempting treatment-free remission.
Please see full Prescribing Information including Boxed WARNING at www.tasigna.com.
About Glivec Glivec is approved in more than 110 countries, for the treatment of adult patients in all phases of Ph+ CML, for the treatment of patients with KIT (CD117)-positive gastrointestinal tumors (GIST), which cannot be surgically removed and/or have metastasized and for the treatment of adult patients following complete surgical removal of KIT+ GIST.
Not all indications are available in every country.
Glivec Important Safety Information Glivec is contraindicated in patients who are hypersensitive to imatinib or any of the excipients.
Glivec can cause fetal harm when administered to a pregnant woman. Women should not become pregnant, and should be advised of the potential risk to the unborn child.
Glivec has been associated with severe edema (swelling) and serious fluid retention. Cytopenias (anemia, neutropenia, thrombocytopenia) are common, generally reversible and usually managed by withholding Glivec or dose reduction. Monitor blood counts regularly. Severe congestive heart failure and left ventricle dysfunction, severe liver problems including cases of fatal liver failure and severe liver injury requiring liver transplants have been reported. Caution in patients with cardiac dysfunction and hepatic dysfunction. Monitor carefully. Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving TKI treatment.
Bleeding may occur. Severe gastrointestinal (GI) bleeding has been reported in patients with KIT+ GIST. Skin reactions, hypothyroidism in patients taking levothyroxine replacement, GI perforation, in some cases fatal, tumor lysis syndrome which can be life threatening have also been reported with Glivec. Correct dehydration and high uric acid levels prior to treatment. Long-term use may result in potential liver, kidney, and/or heart toxicities; immune system suppression may also result from long-term use. In patients with hypereosinophilic syndrome and heart involvement, cases of heart disease have been associated with the initiation of Glivec therapy. Growth retardation has been reported in children taking Glivec. The long-term effects of extended treatment with Glivec on growth in children are unknown.
The most common side effects include fluid retention, muscle cramps or pain and bone pain, abdominal pain, loss of appetite, vomiting, diarrhea, decreased hemoglobin, abnormal bleeding, nausea, fatigue and rash. Glivec should be taken with food and a large glass of water.
*Known as Gleevec® (imatinib mesylate) tablets in the US, Canada and Israel.
Disclaimer The foregoing release contains forward-looking statements that can be identified by words such as "potential," "committed," "commitment," "builds," "explore," "could," "evaluating," "ongoing," "investigational," or similar terms, or by express or implied discussions regarding potential new indications or labeling for Tasigna or Glivec, or regarding potential future revenues from Tasigna and Glivec. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that Tasigna or Glivec will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that Tasigna or Glivec will be commercially successful in the future. In particular, management's expectations regarding Tasigna and Glivec could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain proprietary intellectual property protection; general economic and industry conditions; global trends toward health care cost containment, including ongoing pricing and reimbursement pressures; safety, quality or manufacturing issues, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.
About Novartis Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2016, the Group achieved net sales of USD 48.5 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 118,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com.
References  Hughes, T.P. and Ross, D.M. Moving treatment-free remission into mainstream clinical practice in CML. Blood. 2016. Advance online publication. doi# 10.1182/blood-2016-01-694265.  Hochhaus, A. et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 17 March 2017. Advance online publication. doi# 10.1038/leu.2017.63.  Hughes, T.P. et al. Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with second-line nilotinib (NIL): First results from the ENESTop study. Poster Presentation. Abstract #7054. 2016 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL, USA.  Central European Leukemia Study Group. About CML. 2007. Available at: http://www.cml-info.com/de/healthcare-professionals/about-cml.html. Accessed March 2017.
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