Novartis AG Data Shows Treatment-Free Remission Rates Are Consistently Above 50% Regardless Of Reason For Switch To Tasigna From Gleevec

EAST HANOVER, N.J., Dec. 5, 2016 /PRNewswire/ -- Novartis today announced at the 58th American Society of Hematology (ASH) Annual Meeting & Exposition new data from the Tasigna^® (nilotinib) ENESTop Treatment-free Remission (TFR) study, which demonstrate that TFR rates are consistent among Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) patients who switched from Gleevec^® (imatinib mesylate)* due to intolerance, resistance or physician preference. ENESTop evaluated stopping Tasigna treatment in eligible Ph+ CML adults with chronic phase disease after they achieved and sustained deep molecular response (MR) for at least one year with Tasigna but had not achieved and sustained this response previously with Gleevec^1,2. Results of this post-hoc analysis were presented today in an oral session (ASH Abstract #792).

"Findings from this post-hoc analysis of ENESTop suggest that the reason for switching from Gleevec to Tasigna did not impact a patient's chance of maintaining TFR," said Timothy P. Hughes, MD, ENESTop study investigator, Cancer Theme Leader at the South Australian Health and Medical Research Institute and Clinical Professor at the University of Adelaide, Australia. "CML is considered a chronic disease due to the success of tyrosine kinase inhibitors (TKIs), but there remains a need for continued advancements and these findings are an exciting and important contribution to clinical research in CML treatment."

This new post-hoc analysis of ENESTop evaluated rates of TFR at 48 weeks after stopping treatment with Tasigna among subgroups of patients who switched from Gleevec due to intolerance, resistance or physician preference. The analysis, which included 125 patients, found that more than 50% of patients in each of the subgroups maintained TFR at 48 weeks and that the proportion of patients who maintained TFR at 48 weeks was similar across the three subgroups: 30 of 51 (58.8%; 95% confidence interval [CI], 44.2%-72.4%) in the intolerance subgroup, 16 of 30 (53.3%; 95% CI, 34.3%-71.7%) in the resistance subgroup, and 27 of 44 (61.4%; 95% CI, 45.5%-75.6%) in the physician preference subgroup¹. One patient who stopped treatment in the ENESTop trial was found to have had atypical transcripts and was excluded from this analysis³.

ENESTop is part of a larger Tasigna TFR clinical trial program to evaluate the potential to maintain molecular response after stopping therapy in adult patients with Ph+ CML in the chronic phase who achieved a sustained deep level of molecular response with Tasigna. In the primary analysis of ENESTop, nearly 6 out of 10 (57.9%) patients (95% CI, 48.8%-66.7%) who achieved a sustained deep molecular response following at least three years of Tasigna therapy maintained a molecular response 48 weeks after stopping treatment³. No new major safety findings were observed in ENESTop in patients treated with Tasigna beyond those in the known safety profile of Tasigna. 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. These results were previously presented at the American Society of Clinical Oncology (ASCO) Annual Meeting and the Annual Congress of European Hematology Association (EHA) in June 2016. Results from additional studies in the Tasigna TFR clinical trial program were also presented at ASH in poster sessions, including ENESTpath (Abstract #3094) and ENESTfreedom (Abstract #3066).

"Our mission at Novartis is to help transform cancer therapy through bold science and innovation, and there is no better example of this than our support of eight TFR studies in patients with CML," said Bruno Strigini, CEO of Novartis Oncology. "Our further exploration of results from the ENESTop trial, beyond the primary analysis, reinforces our ongoing commitment to CML patients and contributes to the growing body of science that goes into treating this cancer."

Regular and frequent molecular monitoring with a well-validated assay able to measure BCR-ABL transcript levels down to MR4.5 is an important part of Tasigna TFR studies. Frequent patient monitoring during TFR allows timely determination of loss of MR4.0 or major molecular response (MMR) and the need for treatment initiation³.

Stopping CML treatment is currently not a clinical recommendation and should only be attempted in the context of a clinical study. Discontinuation of treatment in ENESTop was conducted under the conditions of the trial and in patients who met the rigorous predefined criteria of the trial³.

Novartis commitment to CML
Novartis is supporting eight studies as part of its TFR clinical trial program, which includes ENESTop, as well as three other ongoing company-sponsored TFR studies and four investigator-initiated studies that are now underway in more than 100 global sites across 40 countries. Over the past several decades, Novartis research in Ph+ CML has helped transform the disease from a fatal leukemia to a chronic condition 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 through these TFR trials as well as investigational compounds.

About ENESTop
ENESTop (Evaluating Nilotinib Efficacy and Safety Trial) is an open-label Phase II study involving 163 Ph+ CML patients, conducted at 63 sites across 18 countries. The trial evaluated stopping treatment in 126 adults with Ph+ CML in the chronic phase after patients had achieved and sustained deep molecular response for one year with Tasigna following Gleevec. The study is ongoing with planned follow-up to evaluate the ability of patients to sustain remission for longer durations following discontinuation of Tasigna.

About Tasigna
TASIGNA^® (nilotinib) is approved for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of TASIGNA for this indication is based on major molecular response and cytogenetic response rates at 12 months.

TASIGNA is also approved in more than 122 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 Gleevec, and in more than 120 countries for the treatment of adult patients with newly diagnosed Ph+ CML in chronic phase. The effectiveness of TASIGNA for this indication is based on hematologic and cytogenetic response rates.

IMPORTANT SAFETY INFORMATION for TASIGNA^® (nilotinib) Capsules

• Myelosuppression: Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter
• Cardiac and Vascular Events: Cases of cardiovascular events included ischemic heart disease-related events, peripheral arterial occlusive disease, and ischemic cerebrovascular events have been reported
• Pancreatitis and Elevated Serum Lipase:  TASIGNA can cause increases in serum lipase.  Caution is recommended in patients with a history of pancreatitis
• Hepatotoxicity: The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase
• Electrolyte Abnormalities: TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia
• Drug Interactions: The concomitant use of strong CYP3A4 inhibitors or anti -arrhythmic drugs and other drugs that may prolong the QT interval should be avoided.  Grapefruit products should also be avoided
• The concomitant use of strong CYP3A4 inducers should be avoided. The concomitant use of proton pump inhibitors with TASIGNA is not recommended
• When the concurrent use of a H2 blocker is necessary, administer approximately 10 hours before and approximately 2 hours after the TASIGNA dose. If necessary, an antacid may be  administered  approximately  2  hours  before  or  approximately  2  hours  after  the TASIGNA dose
• Food Effects: TASIGNA must be taken on an empty stomach. No food should be consumed for at least 2 hours before the dose and for at least 1 hour after the dose is taken
• Hepatic Impairment: TASIGNA exposure is increased in patients with impaired hepatic function
• Tumor Lysis Syndrome: Cases of tumor lysis syndrome have been reported in TASIGNA-treated patients who were resistant or intolerant to prior CML therapy. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with TASIGNA
• Total Gastrectomy: The exposure of TASIGNA is reduced in patients with total gastrectomy
• Lactose: Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption
• Monitoring Laboratory Tests: Chemistry panels, including electrolytes, calcium, magnesium, lipid profile, and glucose should be checked prior to therapy and periodically
• Embryo-Fetal Toxicity: Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do
• Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving TKI treatment.
• ADVERSE REACTIONS: The most commonly reported non-hematologic adverse reactions (20% in patients) were nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats. Hematologic adverse drug reactions include myelosuppression: thrombocytopenia, neutropenia and anemia
• DOSE ADJUSTMENTS OR MODIFICATIONS: TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hematologic toxicities that are not related to underlying leukemia, clinically significant moderate or severe non hematologic toxicities, laboratory abnormalities or concomitant use of strong CYP3A4 inhibitors

Please see full Prescribing Information including Boxed WARNING.

About Gleevec
Gleevec^® (imatinib mesylate) tablets are indicated for newly diagnosed adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase (CP). Gleevec is also indicated for the treatment of patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in CP after failure of interferon-alpha therapy.

GLEEVEC Important Safety Information
GLEEVEC 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.

GLEEVEC is often associated with edema (swelling) and serious fluid retention. Studies have shown that edema (swelling) tended to occur more often among patients who are 65 and older or those taking higher doses of GLEEVEC.

Cytopenias (reduction or lack of certain cell elements in blood circulation), such as anemia, have occurred. If the cytopenia is severe, your doctor may reduce your dose or temporarily stop your treatment with GLEEVEC.

Severe congestive heart failure and left ventricle dysfunction have been reported, particularly in patients with other health issues and risk factors. Patients with heart disease or risk factors or history of renal failure will be monitored and treated for the condition. Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving TKI treatment.

Severe liver problems (hepatotoxicity) may occur. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of GLEEVEC.

Bleeding may occur. Severe gastrointestinal (GI) bleeding has been reported in patients with KIT+ GIST. GI tumor sites may be the cause of this bleeding; therefore, GI symptoms should be monitored at the start of treatment.

In patients with hypereosinophilic syndrome (a condition with increased eosinophils, which are a type of white blood cell) and heart involvement, cases of heart disease (cardiogenic shock/left ventricular dysfunction) have been associated with the initiation of GLEEVEC therapy.

Skin reactions, such as fluid-filled blisters, have been reported with the use of GLEEVEC.

Clinical cases of hypothyroidism (reduction in thyroid hormones) have been reported in patients taking levothyroxine replacement with GLEEVEC.

Long-term use may result in potential liver, kidney, and/or heart toxicities; immune system suppression may also result from long-term use.

GI perforation (small holes or tears in the walls of the stomach or intestine), in some cases fatal, has been reported.

Growth retardation has been reported in children taking GLEEVEC. The long-term effects of extended treatment with GLEEVEC on growth in children are unknown.

Cases of tumor lysis syndrome (TLS), which refers to a metabolic and electrolyte disturbance caused by the breakdown of tumor cells, have been reported and can be life-threatening in some cases. Correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of GLEEVEC.

Reports of motor vehicle accidents have been received in patients receiving GLEEVEC. Caution patients about driving a car or operating machinery.

Almost all patients treated with GLEEVEC experience side effects at some time. Some common side effects you may experience are fluid retention, muscle cramps or pain and bone pain, abdominal pain, loss of appetite, vomiting, diarrhea, decreased hemoglobin, abnormal bleeding, nausea, fatigue and rash.

GLEEVEC is sometimes associated with stomach or intestinal irritation. GLEEVEC should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including deaths, of stomach or intestinal perforation (a small hole or tear).

If you are experiencing any of the mentioned side effects, please be sure to speak with your doctor immediately.

Do not take any other medications without talking to your doctor or pharmacist first, including Tylenol^® (acetaminophen); herbal products (St. John's wort, Hypericum perforatum); Coumadin^® (warfarin sodium); rifampin; erythromycin; metoprolol; ketoconazole; and Dilantin^® (phenytoin). Taking these with GLEEVEC may affect how they work, or affect how GLEEVEC works. 

You should also tell your doctor if you are taking or plan to take iron supplements. Patients should also avoid grapefruit juice and other foods that may affect how GLEEVEC works.

Please see full Prescribing Information.

Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as "commitment," "exciting," "potential," "mission," "exploration," "growing," "currently," "continues," "could be," "investigational," "ongoing," "planed," or similar terms, or by express or implied discussions regarding potential new indications or labeling for Tasigna or Gleevec, or regarding potential future revenues from Tasigna and Gleevec. 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 either Tasigna or Gleevec 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 either Tasigna or Gleevec will be commercially successful in the future. In particular, management's expectations regarding Tasigna and Gleevec could be affected by, among other things, the uncertainties inherent in research and development, including unexpected clinical trial results and additional analysis of existing clinical data; unexpected 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 pressures; unexpected 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 Pharmaceuticals Corporation researches, develops, manufactures and markets innovative medicines aimed at improving patients' lives.  We offer a broad range of medicines for cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, neurological disease, organ transplantation, psychiatric disease, respiratory disease and skin conditions. The company's mission is to improve people's lives by pioneering novel healthcare solutions.

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which 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, eye care and cost-saving generic pharmaceuticals. Novartis is the only global company with leading positions in these areas. In 2015, the Group achieved net sales of USD 49.4 billion, while R&D throughout the Group amounted to approximately USD 8.9 billion (USD 8.7 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 118,000 full-time-equivalent associates. Novartis products are available in more than 180 countries around the world. For more information, please visit http://www.novartis.com.

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*Known as Glivec^® (imatinib) outside the US, Canada and Israel.

References

1. Hughes, T.P. et al. Treatment-Free Remission in Patients with Chronic Myeloid Leukemia in Chronic Phase According to Reasons for Switching from Imatinib to Nilotinib: Subgroup Analysis from ENESTop. Oral Presentation. Abstract #792. 58^th American Society of Hematology Annual Meeting & Exposition in San Diego, CA, USA.
2. 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.
3. 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.

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