Novartis drug Tasigna receives EU approval for inclusion of Treatment-free Remission (TFR) data in product label
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Novartis International AG /
Novartis drug Tasigna receives EU approval for inclusion of Treatment-free
Remission (TFR) data in product label
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* 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)[1]. 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)*[2],[3]. 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[2],[3].
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[2],[3].
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[4].
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.
Please see full Prescribing Information available at www.glivec.com.
*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.
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References
[1] 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.
[2] 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.
[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.
[4] 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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Datum: 06.06.2017 - 07:15 Uhr
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