Six-year pivotal study data reinforce the superiority of Tasigna® over Glivec® in newly-diagnosed patients with Ph+ CML
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Novartis International AG /
Six-year pivotal study data reinforce the superiority of Tasigna® over Glivec®
in newly-diagnosed patients with Ph+ CML
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* Fewer patients on Tasigna vs. Glivec had their leukemia progress to advanced
stage, a key goal of treatment in CML and important clinical benefit[1]
* Patients on Tasigna had higher rates of early, deep and sustained molecular
response, including MR4.5[1], a very low level of the protein that causes
Ph+ CML
* ENESTnd six-year data confirm the favorable risk/benefit profile of Tasigna
vs. Glivec in newly-diagnosed CML patients
Basel, December 8, 2014 - Six-year results from the randomized Phase III ENESTnd
study continue to demonstrate the superiority of Tasigna(®) (nilotinib) compared
to Glivec(®) (imatinib)[*] at achieving higher rates of early, deep and
sustained molecular responses in newly-diagnosed Philadelphia chromosome-
positive chronic myeloid leukemia (Ph+ CML) patients[1]. The six-year update
from the ENESTnd trial was presented at the 56(th) annual meeting of the
American Society of Hematology (ASH) in San Francisco.
"At the ENESTnd six-year follow up, we still see consistent evidence of deeper
molecular response and fewer progressions to advanced disease in patients taking
Tasigna compared to those on Glivec," said Giuseppe Saglio, MD, ENEST studies
investigator, Professor of Internal Medicine and Haematology and Director of the
Department of Molecular Medicine and Targeted Therapy, San Luigi University
Hospital at the University of Turin, Orbassano, Italy. "These data provide
further evidence of the consistent clinical profile of Tasigna as a leading
treatment in newly-diagnosed patients."
The six-year data demonstrated higher rates of early and deeper sustained
molecular response with Tasigna, including MR4.5, and a reduced risk of
progression compared to Glivec[1]. The difference in the rates of MR4.5 showed
continued improvement for both Tasigna 300 mg and 400 mg twice-daily arms
compared to Glivec (MR4.5: 6-10% difference by one year, 22-23% difference by
six years)[1]. MR4.5 represents an extremely low level of detectable BCR-ABL
protein, the cause of Ph+ CML (measured in the blood at 0.0032% or less on a
standardized International Scale). A higher proportion of patients in the
Tasigna arms versus the Glivec arm achieved BCR-ABL(IS) <= 10% at 3 months[1].
Further, there were fewer progressions to accelerated phase/blast crisis (AP/BC)
with Tasigna versus Glivec[1]. Sixteen patients treated with Glivec had CML-
related deaths, compared to 6 and 4 patients on the Tasigna 300 mg and 400 mg
twice-daily arms, respectively[1]. The safety profile of Tasigna remained
consistent with previous reports. The most common adverse events were rash,
headache, ALT increase and nausea, and the cardiovascular events rates were
higher in the Tasigna arms compared to Glivec[1].
"Fifteen years ago at ASH, our first pivotal CML data were presented,
representing the start of a revolutionary shift in the treatment of patients
with this disease. Through our ongoing research, we better understand today the
role that early, deep and sustained molecular responses have on the outcomes of
patients with CML," said Bruno Strigini, President, Novartis Oncology. "We are
now taking this knowledge a step further by exploring deeper molecular response
like MR4.5 and the impact it may have on how we treat CML in the future."
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 and today, the company
continues its long-standing commitment to the global CML community. Two of the
ENEST treatment-free remission (TFR) studies ENESTfreedom and ENESTop, which
will evaluate the feasibility of stopping treatment, and achieving successful
TFR and deep molecular response on Tasigna in patients with CML in the chronic
phase, have completed enrollment.
Stopping treatment is not a clinical recommendation and should only be attempted
in the context of a well-controlled clinical study[2]. A very important part of
these TFR studies is the inclusion of regular molecular monitoring with
International Scale Real-Time Quantitative Polymerase Chain Reaction (IS RT-Q-
PCR) testing. Once treatment is stopped, molecular monitoring is used to
identify if a patient's level of disease remains in deep molecular response or
if the reintroduction of treatment is needed[3].
ENESTnd study details[1]
ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials - Newly
Diagnosed Patients) is a Phase III, randomized, open-label, multicenter trial
comparing the efficacy and safety of Tasigna versus Glivec in adult patients
with newly diagnosed Ph+ CML in chronic phase. It is the largest global
randomized comparison of two oral therapies ever conducted in newly-diagnosed
Ph+ CML patients.
The study 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). The primary
endpoint was major molecular response (MMR) at 12 months; the key secondary
endpoint was durable MMR at 24 months (patients having MMR when evaluated at
both 12 and 24 months). MMR was defined in this study as 0.1% or less of BCR-ABL
as measured by IS RT-Q-PCR. Patients on the Tasigna 300 mg twice-daily arm or on
the Glivec treatment arm who had suboptimal response or treatment failure were
allowed to escalate dose and/or switch to Tasigna 400 mg twice daily in a
separate extension study. These data, presented at ASH, were the six-year
(defined as 72 cycles of 28 days) follow up.
The six-year ENESTnd update found that higher rates of MMR and MR4.5 by six
years were achieved in Tasigna versus Glivec-treated patients. The difference in
the rates of MMR and MR4.5 continued to be higher for both Tasigna 300 mg and
400 mg twice-daily arms compared to Glivec (MMR: 24-28% difference by one year,
16-18% difference by six years; MR4.5: 6-10% difference by one year, 22-23%
difference by six years). Fewer patients progressed to AP/BC on Tasigna versus
Glivec. The estimated rates of patients whose disease did not progress to AP/BC
on study at 72 months in the Glivec, Tasigna 300 mg and Tasigna 400 mg twice-
daily arms were 92.2%, 95.8% and 97.8%, respectively. The estimated rates of
patients on study who are alive (OS) at 72 months in the Glivec, Tasigna 300 mg
and Tasigna 400 mg twice-daily arms were 91.4%, 91.6% and 95.8%, respectively.
The estimated rates of freedom from death due to a CML-related cause at 72
months in the Glivec, Tasigna 300 mg and Tasigna 400 mg twice-daily arms were
93.9%, 97.7% and 98.5%, respectively. More patients in the Tasigna arms (n=234
and 232 for 300mg and 400 mg arms respectively) versus the Glivec arm (n=176)
achieved BCR-ABL(IS) <= 10% at 3 months. The safety profile of Tasigna remained
consistent with previous reports. The most common adverse events were rash,
headache, ALT increase and nausea. Although cardiovascular events rates were
higher in the Tasigna arms compared to Glivec, fewer progressions to AP/BC, or
death from CML were reported in the Tasigna arms compared to Glivec.
About Tasigna (nilotinib)
Tasigna(®) (nilotinib) is approved in more than 110 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 85
countries for the treatment of adult patients with newly diagnosed Ph+ CML in
chronic phase.
Tasigna Important Safety Information
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. Uncommon cases (0.1 to
1%) of sudden death have been reported in clinical studies in patients with
significant risk factors.
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. Women taking Tasigna should not breastfeed.
The most frequent Grade 3 or 4 adverse events are hematological (neutropenia and
thrombocytopenia) which are generally reversible and usually managed by
withholding Tasigna temporarily or dose reduction. Monitor blood counts
regularly. Pancreatitis has been reported. The most frequent non-hematologic
adverse events were rash, pruritus, nausea, fatigue, headache, alopecia,
myalgia, constipation and diarrhea. Most of these adverse events were mild to
moderate in severity.
Please see full Prescribing Information available at www.tasigna.com.
About Glivec (imatinib)
Glivec(®) (imatinib) is approved in more than 110 countries for the treatment of
all phases of Ph+ CML, for the treatment of adult patients with KIT (CD117)-
positive gastrointestinal stromal 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.
Glivec Important Safety Information
Glivec can cause fetal harm in pregnant woman 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.
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.
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by words such as "goal," "ongoing," "exploring," "may," "commitment,"
"continues," "will," "being conducted," 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 and 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 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
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,
eye care, cost-saving generic pharmaceuticals, preventive vaccines, over-the-
counter and animal health products. Novartis is the only global company with
leading positions in these areas. In 2013, the Group achieved net sales of USD
57.9 billion, while R&D throughout the Group amounted to approximately USD 9.9
billion (USD 9.6 billion excluding impairment and amortization charges).
Novartis Group companies employ approximately 133,000 full-time-equivalent
associates and sell products in more than 150 countries around the world. For
more information, please visit http://www.novartis.com.
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[*] Known as Gleevec® (imatinib mesylate) tablets in the US, Canada and Israel.
References
[1] Larson, R, et al. Efficacy and Safety of Nilotinib (NIL) vs Imatinib (IM) in
Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase
(CML-CP): Long-Term Follow-Up (f/u) of ENESTnd. Poster Presentation. Abstract
#4541. 2014 American Society of Hematology Annual Meeting. San Francisco, Calif.
[2] National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines
in Oncology: Chronic Myelogenous Leukemia, V1.2014. Available at:
http://www.nccn.org/patients/guidelines/cml
[3] Kim, D. Recent advances in the path toward the cure for chronic myeloid
leukemia. The Korean Journal of Hematology. 2011; 46(3), 169-174.
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Datum: 08.12.2014 - 19:00 Uhr
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