European Commission approves Novartis drug Tasigna® for treatment of patients with newly diagnosed Ph+ chronic myeloid leukemia
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European Commission approves Novartis drug Tasigna® for treatment of patients
with newly diagnosed Ph+ chronic myeloid leukemia
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* Pivotal Phase III data show superiority over standard of care Glivec® in
achieving molecular and cytogenetic response, delaying cancer progression
* Tasigna approval gives newly diagnosed patients new medical option; European
Union joins US, Switzerland and Japan, other submissions under review
Basel, December 23, 2010 - Novartis received approval today from the European
Commission for Tasigna® (nilotinib) as a treatment for adult patients with newly
diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in
chronic phase.
The approval from the European Commission followed a positive opinion from the
Committee for Medicinal Products for Human Use (CHMP). It is based on findings
from a pivotal Phase III trial demonstrating superiority to the standard of care
Glivec® (imatinib)* in achieving molecular and cytogenetic response and delaying
cancer progression. These data were first published in the June 17 issue of The
New England Journal of Medicine[1] and were confirmed by 18-month median follow-
up data presented at the 46th American Society of Clinical Oncology (ASCO)
annual meeting held in June[2].
The US Food and Drug Administration (FDA), Swissmedic and Japan's Ministry of
Health, Labour and Welfare have also approved Tasigna in this first-line
indication. Regulatory submissions are under review in other countries
worldwide.
"We are pleased that Tasigna is now approved for newly diagnosed Ph+ CML
patients in chronic phase in the member states of the European Union," said
Hervé Hoppenot, President, Novartis Oncology. "With this expanded indication,
newly diagnosed patients can benefit from a Bcr-Abl tyrosine kinase inhibitor
that, according to pivotal data, surpassed the standard of care Glivec, in key
measures of efficacy, including delaying disease progression at 12 months."
In laboratory studies, Tasigna has been shown to be a potent and selective
inhibitor of the Bcr-Abl protein that causes production of cancer cells in Ph+
CML[3],[4]. It has also been shown to be active against a broad spectrum of Bcr-
Abl mutations associated with resistance to Glivec[5].
In its pivotal head-to-head trial, Tasigna surpassed Glivec in key measures of
treatment efficacy, as has been reported. Tasigna eliminated Bcr-Abl faster and
more deeply than Glivec and resulted in lower rates of cancer progression after
12 months of therapy[1]. Major molecular response (MMR), a measure of deep
reduction in Bcr-Abl, is considered to be a critical therapeutic milestone
associated with good long-term outcomes for patients with Ph+ CML in chronic
phase[6]-[8]. Treatment with Tasigna led to higher rates of both MMR and
complete cytogenetic response (CCyR) (undetectable levels of the Philadelphia
chromosome that is the hallmark of this cancer) compared with Glivec[1].
After a median of 18 months of follow-up treatment, two patients on the Tasigna
300 mg twice daily arm progressed to either accelerated phase or blast crisis
while 17 patients on the Glivec arm progressed to either accelerated phase or
blast crisis. In the study, Tasigna and Glivec were generally well tolerated.
Fewer patients discontinued due to adverse events from the Tasigna 300 mg twice
daily arm of the study compared to the Glivec 400 mg once daily arm.
The randomized, open-label, multicenter trial, called ENESTnd (Evaluating
Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML
Patients), compared the efficacy and safety of Tasigna versus Glivec in adult
patients with newly diagnosed Ph+ CML in chronic phase[1]. It is the largest
global randomized comparison of two oral therapies ever conducted in newly
diagnosed Ph+ CML patients in chronic phase.
This year, Novartis also began a collaboration with molecular diagnostics
company Cepheid to develop a new FDA cleared/approved Bcr-Abl test, which
adheres to the International Scale. The goal of the collaboration is to help
doctors more reliably monitor Ph+ CML patients. Cepheid and Novartis also will
develop a next generation test, which is expected to enable even more sensitive
testing, indicating the depth of a patient's response to tyrosine kinase
inhibitors, including Tasigna and Glivec. Currently, there are no FDA
cleared/approved tests to monitor for Bcr-Abl.
About Tasigna[3]
Tasigna is indicated for the treatment of adult patients with newly diagnosed
Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in the
chronic phase.
Tasigna has also been approved in over 90 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 Glivec. The effectiveness of Tasigna for
this indication is based on confirmed hematologic and unconfirmed cytogenetic
response rates. There are no controlled trials demonstrating a clinical benefit,
such as improvement in disease-related symptoms or increased survival.
Tasigna important safety information
Tasigna should be taken twice daily at an interval of approximately 12 hours
apart and must not be taken with food. No food should be consumed for two hours
before the dose and for at least one hour after the dose. Avoid grapefruit juice
and other foods that are known to inhibit CYP3A4.
Tasigna should not be used in patients who are hypersensitive to nilotinib or
any of the excipients.
Treatment with Tasigna has been associated with hematological side effects such
as thrombocytopenia, neutropenia and anemia, which was generally reversible and
usually managed by withholding Tasigna temporarily or dose reduction. Complete
blood counts should be performed every two weeks for the first two months and
then monthly thereafter as clinically indicated.
Tasigna should be used with caution in patients with uncontrolled or significant
cardiac disease (e.g., recent heart attack, congestive heart failure, unstable
angina or clinically significant bradycardia), as well as in patients who have
or may develop prolongation of QTc. These include patients with abnormally low
potassium or magnesium levels, patients with congenital long QT syndrome,
patients taking anti-arrhythmic medicines or other drugs that may lead to QT
prolongation. Low levels of potassium or magnesium must be corrected prior to
Tasigna administration. Close monitoring for an effect on the QTc interval is
advisable and a baseline electrocardiography is recommended prior to initiating
therapy with Tasigna 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.
Tasigna should be used with caution in patients with liver impairment, in
patients with a history of pancreatitis and in patients with total gastrectomy.
Patients with rare hereditary problems of galactose intolerance, severe lactase
deficiency or glucose-galactose malabsorption should not use Tasigna. Tasigna
should not be used during pregnancy unless clearly necessary and breast feeding
is not recommended during treatment.
The most frequent Grade 3 or 4 adverse events for Tasigna were primarily
hematological in nature and included neutropenia and thrombocytopenia.
Elevations seen in bilirubin, liver function tests, lipase enzymes and blood
sugar were mostly transient and resolved over time. These cases were easily
managed and rarely led to discontinuation of treatment. Pancreatitis was
reported 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 to
moderate in severity.
About Glivec[9]
Glivec is approved in more than 110 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)-positive
gastrointestinal tumors (GIST), which cannot be surgically removed and/or have
already spread to other parts of the body (metastasized). In the US and EU,
Glivec is now approved for the post-surgery treatment of adult patients
following complete surgical removal of Kit (CD117)-positive gastrointestinal
stromal tumors. In the EU, Glivec is also approved for the treatment of adult
patients with newly diagnosed Ph+ acute lymphoblastic leukemia (Ph+ ALL) in
combination with chemotherapy and as a single agent for patients with relapsed
or refractory Ph+ ALL. Glivec is also approved for the treatment of adult
patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma
protuberans (DFSP) who are not eligible for surgery. Glivec is also approved for
the treatment of patients with myelodysplastic/myeloproliferative diseases
(MDS/MPD). Glivec is also approved for hypereosinophilic syndrome and/or chronic
eosinophilic leukemia (HES/CEL).
The effectiveness of Glivec is based on overall hematological and cytogenetic
response rates and progression-free survival in CML, on hematological and
cytogenetic response rates in Ph+ ALL, MDS/MPD, on hematological response rates
in systemic mastocytosis (SM), HES/CEL, on objective response rates and
progression-free survival in unresectable and/or metastatic GIST, on recurrence
free survival in adjuvant GIST and on objective response rates in DFSP.
Increased survival in controlled trials has been demonstrated only in newly
diagnosed chronic phase CML and GIST.
Not all indications are available in every country.
Glivec important safety information
The majority of patients treated with Glivec in clinical trials experienced
adverse events at some time. Most events were of mild to moderate grade and
treatment discontinuation was not necessary in the majority of cases.
The safety profile of Glivec was similar in all indications. The most common
side 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 of
a transient liver toxicity in the form of transaminase elevation and
hyperbilirubinemia observed when Glivec was combined with high dose
chemotherapy.
Rare/serious adverse reactions include: sepsis, pneumonia, depression,
convulsions, cardiac failure, thrombosis/embolism, ileus, pancreatitis, hepatic
failure, exfoliative dermatitis, angioedema, Stevens-Johnson syndrome, renal
failure, fluid retention, edema (including brain, eye, pericardium, abdomen and
lung), hemorrhage (including brain, eye, kidney and gastrointestinal tract),
diverticulitis, gastrointestinal perforation, tumor hemorrhage/necrosis and hip
osteonecrosis/avascular necrosis.
Patients with cardiac disease or risk factors for cardiac failure should be
monitored carefully and any patient with signs or symptoms consistent with
cardiac failure should be evaluated and treated. Cardiac screening should be
considered in patients with HES/CEL, and patients with MDS/MPD with high level
of eosinophils (echocardiogram, serum troponin level).
Glivec is contraindicated in patients with known hypersensitivity to imatinib or
any of its excipients. Women of childbearing potential should be advised to
avoid becoming pregnant while taking Glivec.
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by terminology such as "under review," "to develop," "goal," or similar
expressions, or by express or implied discussions regarding potential new
indications or labeling for Tasigna or regarding potential future revenues from
Tasigna or Glivec. You should not place undue reliance on these statements. Such
forward-looking statements reflect the current views of management regarding
future events, and involve known and unknown risks, uncertainties and other
factors that may cause actual results with Tasigna and Glivec to be materially
different from any future results, performance or achievements expressed or
implied by such statements. There can be no guarantee that Tasigna will be
approved for any additional indications or labeling in any market. Nor can there
be any guarantee that Tasigna or Glivec will achieve any particular levels of
revenue in the future. In particular, management's expectations regarding
Tasigna and Glivec could be affected by, among other things, unexpected
regulatory actions or delays or government regulation generally; unexpected
clinical trial results, including unexpected new clinical data and unexpected
additional analysis of existing clinical data; competition in general;
government, industry and general public pricing pressures; the company's ability
to obtain or maintain patent or other proprietary intellectual property
protection; the impact that the foregoing factors could have on the values
attributed to the Novartis Group's assets and liabilities as recorded in the
Group's consolidated balance sheet, and other risks and factors referred to in
Novartis AG's current Form 20-F on file with the US Securities and Exchange
Commission. Should one or more of these risks or uncertainties materialize, or
should underlying assumptions prove incorrect, actual results may vary
materially from those anticipated, believed, estimated or expected. 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 healthcare solutions that address the evolving needs of
patients and societies. Focused solely on healthcare, Novartis offers a
diversified portfolio to best meet these needs: innovative medicines, cost-
saving generic pharmaceuticals, preventive vaccines, diagnostic tools and
consumer health products. Novartis is the only company with leading positions in
these areas. In 2009, the Group's continuing operations achieved net sales of
USD 44.3 billion, while approximately USD 7.5 billion was invested in R&D
activities throughout the Group. Headquartered in Basel, Switzerland, Novartis
Group companies employ approximately 100,000 full-time-equivalent associates and
operate in more than 140 countries around the world. For more information,
please visithttp://www.novartis.com.
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References
[1] Saglio G, Kim D-W, Surapol Issaragrisil S, et al. Nilotinib versus
imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med.
2010 Jun 17;362(24):2251-9.
[2] Larson R, Philipp le Coutre, Reiffers J, Hughes T. et al. Nilotinib
is Superior to Imatinib in Patients (pts) with Newly Diagnosed
Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd Beyond
One Year. Abstract # CRA6501. American Society of Clinical Oncology
2010 Annual Meeting.
[3] Novartis data on file.
[4] le Coutre P, Ottmann OG, Giles F, et al. Nilotinib (formerly AMN107),
a highly selective BCR-ABL tyrosine kinase inhibitor, is active in
patients with imatinib-resistant or-intolerant accelerated-phase
chronic myelogenous leukemia. Blood. 2008 Feb 15;111(4):1834-9.
[5] Swords R, Mahalingam D, Padmanabhan S, et al. Nilotinib: optimal
therapy for patients with chronic myeloid leukemia and resistance or
intolerance to imatinib. Drug Des Devel Ther. 2009 Sep 21;3:89-101.
[6] Hochhaus A, O'Brien SG, Guilhot F,et al. IRIS Investigators. Six-year
follow-up of patients receiving imatinib for the first-line treatment
of chronic myeloid leukemia. Leukemia. 2009 Jun;23(6):1054-61.
[7] Müller MC, Hanfstein B, Erben P, et al. Molecular response to first
line imatinib therapy is predictive for long term event free survival
in patients with chronic phase chronic myelogenous leukemia - an
interim analysis of the randomized German CML Study IV. Blood (ASH
Annual Meeting Abstracts) 2008, 112: Abstract 333.
[8] Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an
update of concepts and management recommendations of European
LeukemiaNet. J Clin Oncol. 2009 Dec 10;27(35):6041-51.
[9] Glivec® (imatinib) prescribing information. Basel, Switzerland:
Novartis International AG; March 2009.
* Known as Gleevec(®) (imatinib mesylate) tablets in the US, Canada and
Israel.
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