Novartis drug Tasigna meets primary endpoint in pivotal trial against Gleevec as first-line treatment in chronic myeloid leukemia patients
- Tasigna produced faster and deeper responses compared to Gleevec as first-line treatment in Philadelphia chromosome-positive chronic myeloid leukemia - First registration study using molecular response as key indicator of patient outcomes; Bcr-Abl biomarker test measures very low levels of residual disease (1,2) - Tasigna is a potent and selective inhibitor of the Bcr-Abl protein that causes production of cancer cells (3,4) - Complete results to be submitted for presentation at the American Society of Hematology (ASH) meeting in December
EAST HANOVER, N.J., Oct. 20 /PRNewswire/ -- Novartis announced
today that Tasigna® (nilotinib) 200 mg capsules met its primary
endpoint in the first head-to-head comparison with the company's
groundbreaking drug Gleevec® (imatinib mesylate) tablets*.
Tasigna produced faster and deeper responses than Gleevec when
given as first-line therapy for adult patients with newly diagnosed
Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML)
in chronic phase. Tasigna was well tolerated in the study
(5,6).
The Phase III clinical trial, Evaluating Nilotinib Efficacy and
Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients
(ENESTnd), is the largest global randomized comparison of two oral
therapies ever conducted in newly diagnosed Ph+ CML patients.
Designed to detect a difference in major molecular response (MMR)
between Tasigna and Gleevec after 12 months of treatment, it is
also the first registration study in which molecular traces of a
key biomarker specific to Ph+ CML have been used as a primary
endpoint for regulatory review. The comparison study also met its
secondary endpoint, a difference in complete cytogenetic response
(CCyR) in favor of Tasigna (5,6).
"We developed Tasigna to be a potent and selective inhibitor of
Bcr-Abl, with the goal of eliminating the underlying cause of Ph+
CML. We now know that Tasigna reduces the level of Bcr-Abl faster
and to a lower level than Gleevec, with profound implications for
improving patients' outcomes," said David Epstein, President and
CEO of Novartis Oncology and Novartis Molecular Diagnostics.
"Molecular monitoring enables us to evaluate whether patients have
achieved this deep level of CML residual disease, reducing the
fundamental biomarker of leukemia to nearly undetectable
levels."
The blood test used to determine molecular response can detect a
single cell containing traces of Bcr-Abl in up to one million
normal blood cells (7). In addition to being simpler and less
invasive for patients, the test has a much greater sensitivity than
standard cytogenetic tests (2), which require a sample of bone
marrow to be drawn for visual detection of cells containing the Ph
chromosome (1). Molecular monitoring measures the deepest level of
CML residual disease (12).
Details of the ENESTnd findings will be submitted as a
late-breaking abstract to the 51st annual meeting of the American
Society of Hematology (ASH), to take place in December in New
Orleans, Louisiana, USA.
Ongoing studies of Tasigna as first-line therapy for patients
with newly diagnosed Ph+ CML include the Gruppo Italiano Malattie
Ematologiche dell'Adulto (GIMEMA) study, an open-label,
single-stage, multicenter Phase II clinical trial; and NCT00129740,
an open-label, single-center Phase II clinical trial undertaken at
M.D. Anderson Cancer Center in Houston, Texas, USA. New data from
the GIMEMA study presented earlier this year at the European
Hematology Association (EHA) congress show that at 12 months, 85%
of patients taking Tasigna achieved MMR. These data indicate a more
rapid reduction in disease burden compared to that seen in previous
studies with Gleevec (8).
Study details
ENESTnd is a Phase III randomized, open-label, multicenter study
comparing the efficacy and safety of Tasigna versus Gleevec in
adult patients with newly diagnosed Ph+ CML in chronic phase
(5,6).
ENESTnd is being conducted at 220 global sites, with 846
patients enrolled. Patients were randomized to receive Tasigna 400
mg twice daily (n = 281), Tasigna 300 mg twice daily (n = 282) or
Gleevec 400 mg daily (n = 283). The primary endpoint was MMR at 12
months; the secondary endpoint was complete cytogenetic response
(CCyR) by 12 months. Planned follow-up is for five years
(5,6).
About Ph+ CML
CML is a disease 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
(3). Worldwide, CML is responsible for approximately 10 to 15% of
all adult cases of leukemia (9), with an incidence of one to two
cases per 100,000 people per year (10).
About Tasigna (4)
Tasigna has been approved in 73 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. 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 WARNING: QT PROLONGATION AND SUDDEN DEATHS
Tasigna prolongs the QT interval. Sudden deaths have been
reported in patients receiving nilotinib. Tasigna should not be
used in patients with hypokalemia, hypomagnesemia, or long QT
syndrome. Hypokalemia or hypomagnesemia must be corrected prior to
Tasigna administration and should be periodically monitored. Drugs
known to prolong the QT interval and strong CYP3A4 inhibitors
should be avoided. Patients should avoid food 2 hours before and 1
hour after taking dose. A dose reduction is recommended in patients
with hepatic impairment. ECGs should be obtained to monitor the QTc
at baseline, seven days after initiation, and periodically
thereafter, as well as following any dose adjustments.
Contraindications
Do not use in patients with hypokalemia, hypomagnesemia, or long
QT syndrome.
Warnings and precautions Myelosuppression
Treatment with Tasigna can cause Grade 3/4 thrombocytopenia,
neutropenia, and anemia. Complete blood counts should be performed
every two weeks for the first 2 months and then monthly thereafter,
or as clinically indicated. Myelosuppression was generally
reversible and usually managed by withholding Tasigna temporarily
or dose reduction.
QT prolongation
Tasigna prolongs the QT interval. ECGs should be performed at
baseline, seven days after initiation, periodically as clinically
indicated, and following dose adjustments. Correct hypokalemia or
hypomagnesemia prior to administration and monitor
periodically.
Significant prolongation of the QT interval may occur when
Tasigna is inappropriately taken with food, and/or strong CYP3A4
inhibitors and/or medicinal products with a known potential to
prolong QT. Therefore, co-administration with food must be avoided
and concomitant use with strong CYP3A4 inhibitors and/or medicinal
products with a known potential to prolong QT should be avoided.
The presence of hypokalemia and hypomagnesemia may further enhance
this effect.
Sudden deaths
There were sudden deaths reported in the safety population and
in the expanded access program. Ventricular repolarization
abnormalities may have contributed to their occurrence.
Elevated serum lipase
Caution is recommended in patients with a history of
pancreatitis. Check serum lipase levels monthly or as clinically
indicated.
Hepatotoxicity Serum bilirubin and hepatic transaminases
The use of Tasigna may result in elevations in bilirubin,
AST/ALT, and alkaline phosphatase. Hepatic function tests should be
checked monthly or as clinically indicated.
Electrolyte abnormalities
Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia,
hypocalcemia, and hyponatremia. Correct electrolyte abnormalities
prior to initiating Tasigna and monitor periodically during
therapy.
Hepatic impairment
Nilotinib exposure is increased in patients with impaired
hepatic function. A lower starting dose is recommended for patients
with mild to severe hepatic impairment and QT interval should be
monitored closely.
Drug interactions
The concomitant use of QT prolonging drugs and strong inhibitors
or inducers of CYP3A4 should be avoided as they may affect serum
concentration of Tasigna.
Concomitant strong CYP3A4 inhibitors
The concomitant use of strong CYP3A4 inhibitors or
anti-arrhythmic drugs (including, but not limited to amiodarone,
disopyramide, procainamide, quinidine, and sotalol) and other drugs
that may prolong QT interval (including, but not limited to
chloroquine, halofantrine, clarithromycin, haloperidol, methadone,
moxifloxacin, bepridil, and pimozide) should be avoided. Should
treatment with any of these agents be required, it is recommended
that therapy with Tasigna be interrupted. If interruption of
treatment with Tasigna is not possible, patients who require
treatment with a drug that prolongs QT or strongly inhibits CYP3A4
should be closely monitored for prolongation of the QT interval,
and a dose reduction to 1/2 the daily dose is recommended (400 mg
once daily). If the strong inhibitor is discontinued, a washout
period should be allowed before Tasigna is adjusted upward to the
indicated dose. Close monitoring for prolongation of the QT
interval is indicated for patients who cannot avoid strong CYP3A4
inhibitors. Grapefruit products and other foods that are known to
inhibit CYP3A4 should also be avoided.
Concomitant strong CYP3A4 inducers
The concomitant use of strong CYP3A4 inducers should be avoided
(including, but not limited to, dexamethasone, phenytoin,
carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital).
Patients should also refrain from taking St John's Wort. If
patients must be co-administered a strong CYP3A4 inducer, the dose
of Tasigna may need to be increased, depending on patient
tolerability. If the strong inducer is discontinued, the Tasigna
dose should be reduced to the indicated Tasigna dose. Tasigna is a
competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and
UGT1A1. In vitro studies also suggest that nilotinib may induce
CYP2B6, CYP2C8, and CYP2C9, and decrease the concentrations of
drugs which are eliminated by these enzymes. Single-dose
administration of Tasigna to healthy subjects did not change the
pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9
substrate). The ability of Tasigna to induce metabolism has not
been determined in vivo. Caution should be exercised when
co-administering Tasigna with substrates for these enzymes that
have a narrow therapeutic index. Tasigna inhibits human
P-glycoprotein. If Tasigna is administered with drugs that are
substrates of Pgp, increased concentrations of the substrate are
likely and caution should be exercised.
Food effects
Food increases blood levels of Tasigna. Patients should avoid
food 2 hours before and at least 1 hour after the dose is
taken.
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.
Use in pregnancy
There are no adequate and well controlled studies of Tasigna in
pregnant women. However, Tasigna may cause fetal harm when
administered to a pregnant woman. Women of child-bearing potential
should avoid becoming pregnant while taking Tasigna and should be
advised of the potential hazard to the fetus if they do.
Adverse reactions
In chronic phase patients, the most commonly reported adverse
reactions (>10%) were rash (33%), pruritus (29%), nausea (31%),
fatigue (28%), headache (31%), constipation (21%), diarrhea (22%),
and vomiting (21%). The most common (>10%) Grade 3/4 adverse
reactions were thrombocytopenia (28%), neutropenia (28%), elevated
lipase (15%), and hyperglycemia (11%). In accelerated phase
patients, the most commonly reported adverse reactions (>10%)
were rash (28%), pruritus (20%), and constipation (18%). The most
common (>10%) Grade 3/4 adverse reactions were thrombocytopenia
(37%), neutropenia (37%), anemia (23%), and elevated lipase (17%).
Other serious adverse reactions included pneumonia, febrile
neutropenia, leukopenia, intracranial hemorrhage, and pyrexia
(Grade 3/4: 2%).
Dose adjustments or modifications
Tasigna may need to be temporarily withheld and/or dose reduced
for QT prolongation, hematological toxicities that are not related
to underlying leukemia, clinically significant moderate or severe
nonhematologic toxicities, laboratory abnormalities, or concomitant
use of strong CYP3A4 inhibitors. With concomitant use of strong
CYP3A4 inducers, the dose of Tasigna may need to be increased,
depending on patient tolerability.
For Grade 3 to 4 lipase elevations, dosing should be withheld,
and may be resumed at 400 mg once daily. For Grade 3 to 4 bilirubin
elevations, dosing should be withheld, and may be resumed at 400 mg
once daily.
Hepatic impairment
If possible, consider alternative therapies. If Tasigna must be
administered to patients with hepatic impairment, a lower starting
dose is recommended in patients with hepatic impairment and QT
interval should be monitored. The following dose reduction should
be considered:
For patients with mild (Child-Pugh Class A) or moderate
(Child-Pugh Class B) hepatic impairment, an initial dosing regimen
of 400 mg in the morning and 200 mg in the evening (12 hours apart)
per day followed by dose escalation to 400 mg twice daily based on
patient tolerability should be considered. For patients with severe
hepatic impairment (Child-Pugh Class C), a starting dose of 200 mg
twice daily followed by a sequential dose escalation to 400 mg in
the morning and 200 mg in the evening (12 hours apart) per day and
then to 400 mg twice daily based on patient tolerability should be
considered.
Other patients in whom Tasigna should be used with caution
Tasigna should not be used during pregnancy. Sexually active
female patients should use effective contraception during
treatment. Women should not breast feed while taking Tasigna. The
safety and effectiveness of Tasigna in pediatric patients have not
been established.
About Gleevec (11)
Gleevec® (imatinib mesylate) tablets are indicated for the
treatment of 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 is often associated with edema and occasionally severe
fluid retention. Patients should be weighed and monitored regularly
for signs and symptoms of fluid retention, which can be serious or
life-threatening.
Cytopenias have been reported. Complete blood counts should be
performed weekly for the first month, biweekly for the second
month, and periodically thereafter as clinically indicated (for
example, every 2-3 months).
Dose adjustments may be necessary due to hepatotoxicity, other
nonhematologic adverse reactions, or hematologic adverse
reactions.
In Ph+ CML trials,** severe (NCI Grades 3/4) lab abnormalities -
including neutropenia (3.6%-48%), anemia (1%-42%), thrombocytopenia
(<1%-33%), and hepatotoxicity (approx 5%) - and severe adverse
reactions (NCI Grades 3/4), including hemorrhage (1.8%-19%), fluid
retention (eg, pleural effusion, pulmonary edema, and ascites)
(2.5%-11%) and superficial edema (1.5%-6%), and musculoskeletal
pain (2%-9%) were reported among patients receiving Gleevec. Severe
fluid retention appears to be dose-related, was more common in the
advanced phase studies (where the dosage was 600 mg/day), and is
more common in the elderly.
Severe congestive heart failure and left ventricular dysfunction
have occasionally been reported. Most of the patients with reported
cardiac events have had other comorbidities and risk factors,
including advanced age and previous medical history of cardiac
disease. 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.
Hepatotoxicity, occasionally severe, may occur. Assess liver
function before initiation of treatment and monthly thereafter or
as clinically indicated. Monitor liver function when combined with
chemotherapy known to be associated with liver dysfunction. A 25%
decrease in the recommended dose should be used for patients with
severe hepatic impairment.
Patients with moderate renal impairment (CrCL = 20-39 mL/min)
should receive a 50% decrease in the recommended starting dose, and
future doses can be increased as tolerated. Doses greater than 600
mg/day are not recommended in patients with mild renal impairment
(CrCL = 40-59 mL/min). For patients with moderate renal impairment,
doses greater than 400 mg/day are not recommended. Gleevec should
be used with caution in patients with severe renal
impairment.
In the newly diagnosed CML trial, 2% of patients had (NCI Grades
3/4) hemorrhage.
There have also been reports, including fatalities, of cardiac
tamponade, cerebral edema, acute respiratory failure, and
gastrointestinal (GI) perforation.
Bullous dermatologic reactions (eg, erythema multiforme and
Stevens-Johnson syndrome) have also been reported. In some cases,
the reaction recurred upon rechallenge. Several postmarketing
reports describe patients able to tolerate the reintroduction of
Gleevec at a lower dose with or without concomitant corticosteroids
or antihistamines following resolution or improvement of the
bullous reaction.
Clinical cases of hypothyroidism have been reported in
thyroidectomy patients undergoing levothyroxine replacement during
treatment with Gleevec. TSH levels should be closely monitored in
such patients.
Consider potential toxicities - specifically liver, kidney, and
cardiac toxicity, and immunosuppression from long-term use.
Fetal harm can occur when administered to a pregnant woman;
therefore, women of childbearing potential should be advised to not
become pregnant while taking Gleevec tablets and to avoid
breast-feeding while taking Gleevec tablets because of the
potential for serious adverse reactions in nursing infants.
Sexually active female patients taking Gleevec should use adequate
contraception. If the patient does become pregnant while taking
Gleevec, the patient should be advised of the potential hazard to
the fetus.
Gleevec is metabolized by the CYP3A4 isoenzyme and is an
inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of Gleevec should
increase by at least 50%, and clinical response should be carefully
monitored, in patients receiving Gleevec with a potent CYP3A4
inducer such as rifampin or phenytoin. Examples of commonly used
drugs that may significantly interact with Gleevec include
ketoconazole, acetaminophen, warfarin, erythromycin, and phenytoin.
(Please see full Prescribing Information for other potential drug
interactions.)
For daily dosing of 800 mg and above, dosing should be
accomplished using the 400-mg tablet to reduce exposure to
iron.
Common side effects of Gleevec tablets
The majority of adult patients with Ph+ CML who received Gleevec
in clinical studies experienced adverse reactions at some time, but
most were mild to moderate in severity. The most frequently
reported adverse reactions (all Grades) were superficial edema
(60%-74%), nausea (50%-73%), diarrhea (43%-57%), musculoskeletal
pain (38%-49%), rash and related terms (36%-47%), muscle cramps
(28%-62%), and vomiting (23%-58%).**+
Supportive care may help management of some mild-to-moderate
adverse reactions. However, in some cases, either a dose reduction
or interruption of treatment with Gleevec may be necessary.
Gleevec tablets should be taken with food and a large glass of
water to minimize GI irritation. Gleevec tablets should not be
taken with grapefruit juice and other foods known to inhibit
CYP3A4.
Patients should be informed to take Gleevec exactly as
prescribed, not to change their dose or stop taking Gleevec unless
they are told to do so by their doctor. If patients miss a dose,
they should be advised to take their dose as soon as possible
unless it is almost time for their next dose, in which case the
missed dose should not be taken. A double dose should not be taken
to make up for any missed dose.
**Numbers indicate the range of percentages in 4 studies among
adult patients with newly diagnosed Ph+ CML and patients in BC, AP,
and CP after failure of interferon-alpha therapy.
+For more detailed study information, please see full
Prescribing Information.
Disclaimer
The foregoing release contains forward-looking statements that
can be identified by terminology such as "to be submitted,"
"implications," "predictive," "will," "to take place," 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 Gleevec. 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 or Gleevec
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 Gleevec will achieve any particular
levels of revenue in the future. In particular, management's
expectations regarding Tasigna and Gleevec could be affected by,
among other things, unexpected clinical trial results, including
unexpected new clinical data and unexpected additional analysis of
existing clinical data; unexpected regulatory actions or delays or
government regulation generally; the company's ability to obtain or
maintain patent or other proprietary intellectual property
protection; competition in general; government, industry and
general public pricing pressures; 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
Located in East Hanover, New Jersey, Novartis Pharmaceuticals
Corporation is an affiliate of Novartis AG, which provides
healthcare solutions that address the evolving needs of patients
and societies. Focused solely on healthcare, the Novartis Group
offers a diversified portfolio to best meet these needs: innovative
medicines, preventive vaccines, diagnostic tools, cost-saving
generic pharmaceuticals and consumer health products. The Novartis
Group is the only company with leading positions in each of these
areas. In 2008, the Group's continuing operations achieved net
sales of USD 41.5 billion and net income of USD 8.2 billion.
Approximately USD 7.2 billion was invested in R&D activities
throughout the Group. Headquartered in Basel, Switzerland, Novartis
Group companies employ approximately 99,000 full-time-equivalent
associates and operate in more than 140 countries around the world.
For more information, please visit http://www.us.novartis.com/.
*Known as Glivec® (imatinib) outside the US, Canada and Israel.
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3. National Cancer Institute. General Information About Chronic
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March 2009.
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USA: Novartis Pharma.
http://www.pharma.us.novartis.com/product/pi/pdf/tasigna.pdf.
5. Novartis data on file
6. A Study of Imatinib Versus Nilotinib in Adult Patients With Newly
Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous
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09-07-232595v1
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statistics about CML? (Sept 2008 revision) Available at:
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April 2009.
10. Central European Leukemia Study Group. About CML. [Cited 2009 Jan 13]
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http://www.cml-info.com/de/healthcare-professionals/about-cml.html.
11. Gleevec® (imatinib mesylate) tablets prescribing information. East
Hanover, NJ: Novartis Pharmaceuticals Corporation; November 2008.
12. Jabbour E, Cortes J, Kantarjian H, et al. Molecular Monitoring in
Chronic Myeloid Leukemia Response to Tyrosine Kinase Inhibitors and
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Media Contacts
Media only: Investors only:
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Novartis Oncology Novartis Corporation
P: +1 862 778 6387 P: +1 212 830 2433
Dana Kahn Cooper
P: +1 732 817 1800
C: +1 732 239 6664
Source: Novartis
CONTACT: Sabrina Oei, Novartis Oncology, +1-862-778-6387; or
Richard
Jarvis, Novartis Corporation, +1-212-830-2433; or Dana Kahn Cooper,
P:
+1-732-817-1800, C: +1-732-239-6664
Web Site: http://www.us.novartis.com/
Posted: October 2009
