Novartis International AG /Longer-term Phase III data show Novartis drug Tasigna® continues to surpass Glivec® in slowing disease progression in patients with newly diagnosed CML Processed and transmitted by Thomson Reuters.the issuer is solely responsible for the content of this announcement.
* Fewer patients taking Tasigna for Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase progressed to advanced stages of the disease * 24-month analysis confirms Tasigna induces deeper and more durable cytogenetic and molecular responses * Tasigna now approved in the US and Switzerland for this indication; regulatory submissions under review in EU, Japan and other countries worldwide
Basel, December 6, 2010 – Novartis announced today 24-month data showing thatTasigna(®) (nilotinib) continues to surpass Glivec(®) (imatinib)* in thetreatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase[1]. these new data, from the first Phase III comparison of the two oral therapies as initialtreatment for this blood cancer, were presented at the 52(nd) Annual Meeting andExposition of the American Society of Hematology (ASH) in Orlando, Florida.
With this longer-term follow-up at 24 months, first-line treatment with Tasignaat 300 mg twice daily was found to result in a lower incidence of progression toaccelerated phase and blast crisis, compared to the standard approved dose ofGlivec 400 mg once daily. Patients receiving Tasigna also had a lower incidenceof suboptimal response and treatment failure as defined by study criteria[1].
These data also showed that Tasigna induced deeper and more durable completecytogenetic response (CCyR) and major molecular response (MMR) compared toGlivec, as well as a significantly higher rate of an even deeper response – atrace amount of 0.0032% or less of the Bcr-Abl protein that causes Ph+ CML, which is considered a complete molecular response (CMR)[1]. Fewer patientstaking Tasigna in the study discontinued treatment due to adverse eventscompared to Glivec[1]. Tasigna and Glivec were generally well tolerated.
“These 24-month Phase III data extend the evidence of clinical benefit for newlydiagnosed patients with chronic phase Ph+ CML treated with Tasigna, compared toGlivec, ” said Timothy P. Hughes, MD, ENESTnd study investigator and ClinicalProfessor at the University of Adelaide, Australia. “Now we can begin toevaluate the long-term treatment outcomes of patients who achieve and maintaindeep reductions in Bcr-Abl on Tasigna.”
Rates of MMR and CCyR remain statistically higher for Tasigna versus Glivec atthe 24-month minimum follow-up. MMR was achieved by 71% of patients takingTasigna 300 mg twice daily and 67% of patients taking Tasigna 400 mg twicedaily, compared to 44% of patients taking Glivec by 24 months. Durable MMR rateswere statistically significantly higher in the Tasigna 300 mg twice daily andTasigna 400 mg twice daily arms compared to Glivec 400 mg once daily (42%, 39%and 21% respectively). Significantly more patients achieved CCyR in the Tasigna300 mg and 400 mg arms compared to the Glivec arm at 87% and 85% vs. 77%respectively by 24 months.
The US Food and Drug Administration (FDA) and Swissmedic have approved Tasignain this first-line indication. In September, Novartis received a positiveopinion from the Committee for Medicinal Products for Human Use (CHMP)recommending European Commission approval for Tasigna for this indication.Regulatory submissions are under review in the European Union, Japan and othercountries worldwide.
This year, Novartis also began a collaboration with molecular diagnosticscompany Cepheid to develop a new FDA cleared/approved Bcr-Abl test, whichadheres to the International Scale. the goal of the collaboration is to helpdoctors more reliably monitor Ph+ CML patients. Cepheid and Novartis also willdevelop a next generation test, which is expected to enable even more sensitivetesting, indicating the depth of a patient´s response to tyrosine kinaseinhibitors, including Tasigna and Glivec. Currently there are no FDAcleared/approved tests to monitor for Bcr-Abl.
“The creation and introduction of Glivec revolutionized the treatment of Ph+ CMLby substantially improving overall survival rates for patients, ” said HervéHoppenot, President, Novartis Oncology. “We are encouraged by the ongoingclinical development of Tasigna as a new treatment showing that at 24 months itcontinues to surpass Glivec in slowing disease progression in patients withnewly diagnosed chronic phase Ph+ CML.”
Another study will be presented at this year´s annual ASH meeting which providesfurther support for the use of Tasigna in patients with newly diagnosed Ph+ CML.the Gruppo Italiano Malattie Ematologiche dell´Adulto (GIMEMA) study, anongoing, open-label, single-stage, multicenter Phase II clinical trial, will bepresented on Monday, December 6, 2010[2].
ENESTnd Study DetailsThe clinical trial, ENESTnd (Evaluating Nilotinib Efficacy and Safety inClinical Trials of Newly Diagnosed Ph+ CML Patients), is a Phase III randomized, open-label, multicenter trial comparing the efficacy and safety of Tasignaversus Glivec in adult patients with newly diagnosed Ph+ CML in chronicphase[1]. it is the largest global randomized comparison of two oral therapiesever conducted in newly diagnosed Ph+ CML patients.
ENESTnd is being conducted at 217 global sites with 846 patients enrolled.Patients were randomized to receive Tasigna 300 mg twice daily (n = 282), Tasigna 400 mg twice daily (n = 281) or Glivec 400 mg once daily (n = 283). Theprimary endpoint was MMR at 12 months; the key secondary endpoint was durableMMR at 24 months (patients having MMR when evaluated at both 12 and 24months)[1]. MMR was defined in the study as reduction in the level of theabnormal Bcr-Abl gene to less than or equal to 0.1% of the pretreatment levelbased on an internationally agreed standard(1). Planned follow-up is for fiveyears. Patients on the Glivec treatment arm who had suboptimal response ortreatment failure were allowed to escalate dose and/or switch to Tasigna via aprotocol extension. these data, presented at ASH, were the 24-month minimumfollow-up.
Results showed that fewer patients progressed to accelerated phase or blastcrisis while on treatment with Tasigna at 300 mg twice daily (n = 2) and 400 mgtwice daily (n = 3) versus Glivec at 400 mg once daily (n = 12)[1] with 24months of minimum follow-up demonstrating a significant improvement in diseasecontrol.
These data also showed that nearly three times more patients taking Tasigna 300mg twice daily achieved CMR – defined as a trace amount of 0.0032% or less ofthe Bcr-Abl protein that causes Ph+ CML – with Tasigna 300 mg twice daily (n =70) than with Glivec (n = 25) by 24-months[1].
All patients had a minimum of 24 months of treatment or discontinued early; themedian follow-up was 25 months. overall, 75%, 78% and 68% of patients remainedin the study on Tasigna 300 mg twice daily, Tasigna 400 mg twice daily andGlivec 400 mg once daily, respectively[1].
Both Tasigna and Glivec were generally well tolerated overall. Rates ofdiscontinuation due to adverse events or laboratory abnormalities were 9% forTasigna 300 mg twice daily, 13% for Tasigna 400 mg twice daily and 11% forGlivec 400 mg once daily[1]. no patients treated with Tasigna in the study hadprolongation of QT interval >500 milliseconds[1]. no sudden deaths occurred inany of the treatment arms[1].
About Philadelphia Chromosome-Positive Chronic Myeloid Leukemia (Ph+ CML)Chronic myeloid leukemia is a disease in which the body produces cancerous whiteblood cells. Almost all patients with CML have an abnormality known as thePhiladelphia chromosome, which produces a protein called Bcr-Abl. Bcr-Abl causesmalignant white blood cells to proliferate[3]. Worldwide, CML is responsible forapproximately 10% to 15% of all adult cases of leukemia[4], with an incidence ofone to two cases per 100,000 people per year[5].
About Tasigna[6]()Tasigna has been approved in over 85 countries for the treatment of chronicphase and accelerated phase Ph+ CML in adult patients resistant or intolerant toat least one prior therapy, including Glivec. the effectiveness of Tasigna forthis indication is based on confirmed hematologic and unconfirmed cytogeneticresponse rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.
Tasigna is not approved in the EU for the treatment of newly diagnosed Ph+ CML-CP.
Tasigna important Safety InformationTasigna should be taken twice daily at an interval of approximately 12 hoursapart and must not be taken with food. no food should be consumed for two hoursbefore the dose and for at least one hour after the dose. Avoid grapefruit juiceand other foods that are known to inhibit CYP3A4.
Tasigna should not be used in patients who are hypersensitive to nilotinib orany of the excipients.
Treatment with Tasigna has been associated with hematological side effects, suchas thrombocytopenia, neutropenia and anemia which was generally reversible andusually managed by withholding Tasigna temporarily or dose reduction. Completeblood counts should be performed every two weeks for the first two months andthen monthly thereafter as clinically indicated.
Tasigna should be used with caution in patients with uncontrolled or significantcardiac disease (e.g., recent heart attack, congestive heart failure, unstableangina or clinically significant bradycardia), as well as in patients who haveor may develop prolongation of QTc. these include patients with abnormally lowpotassium or magnesium levels, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other drugs that may lead to QTprolongation. Low levels of potassium or magnesium must be corrected prior toTasigna administration. Close monitoring for an effect on the QTc interval isadvisable and a baseline electrocardiography is recommended prior to initiatingtherapy with Tasigna and as clinically indicated. Uncommon cases (0.1 to 1%) ofsudden death have been reported in clinical studies in patients with significantrisk factors.
Tasigna should be used with caution in patients with liver impairment, inpatients with a history of pancreatitis and in patients with total gastrectomy.Patients with rare hereditary problems of galactose intolerance, severe lactasedeficiency or glucose-galactose malabsorption should not use Tasigna. Tasignashould not be used during pregnancy unless clearly necessary and breast feedingis not recommended during treatment.
The most frequent Grade 3 or 4 adverse events for Tasigna were primarilyhematological in nature and included neutropenia and thrombocytopenia.Elevations seen in bilirubin, liver function tests, lipase enzymes and bloodsugar were mostly transient and resolved over time. these cases were easilymanaged and rarely led to discontinuation of treatment. Pancreatitis wasreported in less than 1% of cases. the most frequent non-hematologic drug-related adverse events were rash, pruritus, nausea, fatigue, headache, alopecia, myalgia, constipation and diarrhea. most of these adverse events were mild tomoderate in severity.
About Glivec[7]Glivec is approved in more than 90 countries, including the US, EU and Japan, for the treatment of all phases of Ph+ CML. Glivec is also approved in the US, EU and other countries for the treatment of patients with Kit (CD117)-positivegastrointestinal tumors (GIST), which cannot be surgically removed and/or havealready spread to other parts of the body (metastasized). In the US and EU, Glivec is now approved for the post-surgery treatment of adult patientsfollowing complete surgical removal of Kit (CD117)-positive gastrointestinalstromal tumors. In the EU, Glivec is also approved for the treatment of adultpatients with newly diagnosed Ph+ acute lymphoblastic leukemia (Ph+ ALL) incombination with chemotherapy and as a single agent for patients with relapsedor refractory Ph+ ALL. Glivec is also approved for the treatment of adultpatients with unresectable, recurrent and/or metastatic dermatofibrosarcomaprotuberans (DFSP) who are not eligible for surgery. Glivec is also approved forthe treatment of patients with myelodysplastic/myeloproliferative diseases(MDS/MPD). Glivec is also approved for hypereosinophilic syndrome and/or chroniceosinophilic leukemia (HES/CEL).
The effectiveness of Glivec is based on overall hematological and cytogeneticresponse rates and progression-free survival in CML, on hematological andcytogenetic response rates in Ph+ ALL, MDS/MPD, on hematological response ratesin systemic mastocytosis, HES/CEL, on objective response rates and progression-free survival in unresectable and/or metastatic GIST, on recurrence freesurvival in adjuvant GIST and on objective response rates in DFSP. Increasedsurvival in controlled trials has been demonstrated only in newly diagnosedchronic phase CML and GIST.
Not all indications are available in every country.
Glivec important Safety InformationThe majority of patients treated with Glivec in clinical trials experiencedadverse events at some time. most events were of mild to moderate grade andtreatment discontinuation was not necessary in the majority of cases.
The safety profile of Glivec was similar in all indications. the most commonside effects included nausea, superficial edema, muscle cramps, skin rash, vomiting, diarrhea, abdominal pain, myalgia, arthralgia, hemorrhage, fatigue, headache, joint pain, cough, dizziness, dyspepsia and dyspnea, dermatitis, eczema and fluid retention, as well as neutropenia, thrombocytopenia and anemia.Glivec was generally well tolerated in all of the studies that were performed, either as monotherapy or in combination with chemotherapy, with the exception ofa transient liver toxicity in the form of transaminase elevation andhyperbilirubinemia observed when Glivec was combined with high dosechemotherapy.
Rare/serious adverse reactions include: sepsis, pneumonia, depression, convulsions, cardiac failure, thrombosis/embolism, ileus, pancreatitis, hepaticfailure, exfoliative dermatitis, angioedema, Stevens-Johnson syndrome, renalfailure, fluid retention, edema (including brain, eye, pericardium, abdomen andlung), hemorrhage (including brain, eye, kidney and gastrointestinal tract), diverticulitis, gastrointestinal perforation, tumor hemorrhage/necrosis and hiposteonecrosis/avascular necrosis.
Patients with cardiac disease or risk factors for cardiac failure should bemonitored carefully and any patient with signs or symptoms consistent withcardiac failure should be evaluated and treated. Cardiac screening should beconsidered in patients with HES/CEL, and patients with MDS/MPD with high levelof eosinophils (echocardiogram, serum troponin level).
Glivec is contraindicated in patients with known hypersensitivity to imatinib orany of its excipients. Women of childbearing potential should be advised toavoid becoming pregnant while taking Glivec.
DisclaimerThe foregoing release contains forward-looking statements that can be identifiedby terminology such as “under review, ” “expected, ” “goal, ” or similarexpressions, or by express or implied discussions regarding potential newindications or labeling for Tasigna or regarding potential future revenues fromTasigna or Glivec. You should not place undue reliance on these statements. Suchforward-looking statements reflect the current views of management regardingfuture events, and involve known and unknown risks, uncertainties and otherfactors that may cause actual results with Tasigna or Glivec to be materiallydifferent from any future results, performance or achievements expressed orimplied by such statements. There can be no guarantee that Tasigna will beapproved for any additional indications or labeling in any market. Nor can therebe any guarantee that Tasigna or Glivec will achieve any particular levels ofrevenue in the future. In particular, management´s expectations regardingTasigna and Glivec could be affected by, among other things, unexpectedregulatory actions or delays or government regulation generally; unexpectedclinical trial results, including unexpected new clinical data and unexpectedadditional analysis of existing clinical data; the company´s ability to obtainor maintain patent or other proprietary intellectual property protection;competition in general; government, industry and general public pricingpressures; the impact that the foregoing factors could have on the valuesattributed to the Novartis Group´s assets and liabilities as recorded in theGroup´s consolidated balance sheet, and other risks and factors referred to inNovartis AG´s current Form 20-F on file with the US Securities and ExchangeCommission. should one or more of these risks or uncertainties materialize, orshould underlying assumptions prove incorrect, actual results may varymaterially from those anticipated, believed, estimated or expected. Novartis isproviding the information in this press release as of this date and does notundertake any obligation to update any forward-looking statements contained inthis press release as a result of new information, future events or otherwise.
About NovartisNovartis provides healthcare solutions that address the evolving needs ofpatients and societies. Focused solely on healthcare, Novartis offers adiversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines, diagnostic tools andconsumer health products. Novartis is the only company with leading positions inthese areas. In 2009, the Group´s continuing operations achieved net sales ofUSD 44.3 billion, while approximately USD 7.5 billion was invested in R&Dactivities throughout the Group. Headquartered in Basel, Switzerland, NovartisGroup companies employ approximately 100,000 full-time-equivalent associates andoperate in more than 140 countries around the world. For more information, please visitnovartis.com.
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*Known as Gleevec(®) (imatinib mesylate) tablets in the US, Canada and Israel.
References 1. Hughes T, et al. ENESTnd Update: Continued Superiority of Nilotinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP). 52nd Annual Meeting of the American Society of Hematology. Abstract no. 207. December 6, 2010. 2. Rosti G, et al. Excellent Outcomes at 3 Years with Nilotinib 800 Mg Daily In Early Chronic Phase, Ph+ Chronic Myeloid Leukemia (CML): Results of a Phase 2 GIMEMA CML WP Clinical Trial. 52nd Annual Meeting of the American Society of Hematology. Abstract no. 359. December 6, 2010. 3. National Cancer Institute. General Information About Chronic Myelogenous Leukemia (PDQ). cancer.gov/cancertopics/pdq/treatment/CML/patient/. Accessed March 2009. 4. American Cancer Society. Detailed Guide: CML. what are the key statistics about CML? (Sept 2008 revision) Available at: cancer.org/cancer/leukemia- chronicmyeloidcml/detailedguide/leukemia-chronic-myeloid-myelogenous-key- statistics. Accessed April 2009. 5. Central European Leukemia Study Group. About CML. [Cited 2009 Jan 13] Available from: cml-info.com/de/healthcare-professionals/about- cml.html. 6. Tasigna (nilotinib) European Summary of Characteristics. Novartis AG. tasigna.com/en/tasigna-product-information.jsp#. 7. Glivec® (imatinib) prescribing information. Basel, Switzerland: Novartis International AG; March 2009.
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