Gleevec Receives FDA Priority Review as First Therapy to Reduce Recurrence of Gastrointestinal...

Gleevec Receives FDA Priority Review as First Therapy to Reduce Recurrence of
Gastrointestinal Stromal Tumors After Surgery
- Clinical data showing unprecedented 89% reduction in risk of GIST relapse
with use of Gleevec after surgery are basis for FDA, EMEA, Swissmedic filings

EAST HANOVER, N.J., Aug. 27 /PRNewswire/ -- Novartis announced today that
Gleevec(R) (imatinib mesylate) tablets* has been granted priority review
status by the US Food and Drug Administration (FDA) as the first therapy to be
reviewed for use after surgery in kit-positive gastrointestinal stromal tumors
(GIST). FDA priority review status is granted to therapies that could
potentially fill a currently unmet medical need and accelerates the standard
review timing from ten to six months(1). Similar regulatory submissions have
been filed in the European Union and Switzerland and will be filed in other
countries shortly.
* Known as Glivec(R) (imatinib) outside the US, Canada and Israel.
The Gleevec submissions are based on data from a Phase III, double-blind,
randomized, multicenter, international study of more than 700 GIST patients
who had surgery to remove their tumors. The results showed a dramatic 89%
reduction in risk of kit-positive GIST returning after surgery (adjuvant
setting) in patients treated with Gleevec versus placebo(2).
In early 2007, the study met its primary efficacy endpoint, showing an
advantage for Gleevec in recurrence-free survival. At that time, following the
recommendation of the independent study data monitoring committee to stop the
trial accrual early, the study investigators made public the interim results
and offered Gleevec to patients receiving placebo(3).
Approximately half of all patients with newly diagnosed GIST are
considered candidates for surgical resection, or removal of their tumors. Of
those who have the surgery, about half will suffer a recurrence(4). If
approved for this indication, Gleevec will be the first treatment option
available to GIST patients after surgery to reduce the risk of disease
recurrence or to possibly prevent the disease from returning.
"The dramatic clinical results from this study of Gleevec in the adjuvant
GIST setting are especially encouraging when we consider the incremental
benefit we typically see with other adjuvant therapies for solid tumors," said
Rainer Boehm, MD, Executive Vice President, North American Region Head,
Novartis Oncology. "The adjuvant use of Gleevec, if approved, would represent
an important advance in the ongoing post-surgery management of GIST."
Gleevec is currently indicated in both the US and EU for the first-line
treatment of metastatic or unresectable (inoperable) kit-positive GIST. If
approved, the use of Gleevec for the treatment of GIST in the adjuvant setting
would add to its eight current indications, which include Philadelphia
chromosome-positive chronic myelogenous leukemia (Ph+ CML) and five other rare
diseases. Novartis also has a therapy for the treatment of carcinoid tumors
and acromegaly and multiple treatments in the pipeline targeting rare
diseases.
Filing data
The study on which the regulatory filing is based compared the
recurrence-free survival of GIST patients taking Gleevec 400 mg/day versus
placebo for one year immediately following surgery. The results showed that
98% of patients receiving Gleevec remained recurrence free at one year
following surgery compared to approximately 82% of those receiving placebo(3).
This shows that as a result of adjuvant therapy with Gleevec, there was an 89%
reduction in risk of GIST returning(2).
The study, known as ACOSOG Z90001, was conducted at multiple cancer
centers throughout the US and Canada, under a Cooperative Research and
Development Agreement between Novartis and the National Cancer Institute
(NCI). The study was led by the American College of Surgeons Oncology Group
(ACOSOG).
The investigators reported that Gleevec therapy was well tolerated by most
patients, with side effects similar to those observed in previous clinical
trials with Gleevec. These include nausea, diarrhea and swelling (edema)(3).
About gastrointestinal stromal tumors (GIST)
Gastrointestinal stromal tumors (GIST) belong to a group of cancers known
as soft tissue sarcomas. They are the most common sarcomas and can be found
most often in the stomach and small intestine. The incidence of GIST is
estimated to be 4,500 - 6,000 new cases per year in the US (15-20 cases per
million population)(5), of which more than 90% are kit-positive(6). Kit --
also known as CD117 -- is a protein that, when mutated, has been identified as
one of the major causes of GIST.
About Gleevec
Gleevec(R) (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. Follow-up is limited to 5
years. Gleevec is also indicated for the treatment of patients with Ph+ CML in
blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) after
failure of interferon-alpha (IFN-alpha) therapy; adult patients with relapsed
or refractory Ph+ acute lymphoblastic leukemia (Ph+ ALL); adult patients with
myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR
(platelet-derived growth factor receptor) gene rearrangements; adult patients
with aggressive systemic mastocytosis (ASM) without the D816V c-KIT mutation
or with c-KIT mutational status unknown; adult patients with hypereosinophilic
syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-
PDGFR alpha fusion kinase (mutational analysis or FISH demonstration of CHIC2
allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFR
alpha fusion kinase-negative or unknown; adult patients with unresectable,
recurrent, and/or metastatic dermatofibrosarcoma protuberans (DFSP); patients
with KIT (CD117)-positive unresectable and/or metastatic malignant
gastrointestinal stromal tumors (GIST). The effectiveness of Gleevec in GIST
is based on objective response rate. There are no controlled trials
demonstrating a clinical benefit, such as improvement in disease-related
symptoms or increased survival.
Important safety information(7)
Fetal harm can occur when Gleevec is 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.
In adult Ph+ CML patients, 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 experiences (NCI Grades
3/4), including severe fluid retention (e.g., pleural effusion, pulmonary
edema, and ascites) and superficial edema (1.3%-11%), hemorrhage (1.8%-19%),
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.
* Numbers indicate the range of percentages in 4 studies among adult
patients with Ph+ CML in blast crisis, accelerated phase, and chronic phase.
In HES/CEL patients, instances of Grade 3 leukopenia, neutropenia,
lymphopenia, and anemia were reported.
For DFSP, severe (NCI Grades 3/4) lab abnormalities included anemia (17%),
thrombocytopenia (17%), neutropenia (8%) and increased creatinine (8%).
In GIST, severe (NCI Grades 3/4) lab abnormalities (400 mg/day; 600
mg/day) -- including neutropenia (10%; 11%), anemia (3%; 9%), thrombocytopenia
(0%; 1%) and hepatotoxicity (6%; 8%) -- and severe adverse experiences (NCI
Grades 3/4), including severe fluid retention (e.g., pleural effusion or
ascites; 3%; 8%) and superficial edema (6%; 5%), hemorrhage (6%; 11%),
abdominal pain (11%; 4%), nausea (6%; 4%), diarrhea (3%; 7%) and
musculoskeletal pain (6%; 1%) were reported among patients receiving Gleevec.
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.
Dose adjustments may be necessary due to hepatotoxicity, other
nonhematologic adverse reactions, or hematologic adverse reactions. Therapy
with Gleevec was discontinued for drug-related adverse reactions in 2.4% to 5%
of adult patients with Ph+ CML and for adverse reactions in 5% of KIT+ GIST
patients. None of the 5 patients in the ASM study discontinued Gleevec due to
drug-related events or abnormal laboratory values. 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).
A 25% decrease in the recommended dose should be used for patients with
severe hepatic impairment.
Some GIST patients (5%) were reported to have severe gastrointestinal (GI)
bleeds and/or intratumoral bleeds. GI tumor sites may have been the source of
GI bleeds.
Patients should be weighed and monitored regularly for signs and symptoms
of edema, which can be serious or life-threatening. There have also been
reports, including fatalities, of cardiac tamponade, cerebral edema, increased
intracranial pressure, papilledema, and GI perforation.
In patients with HES and cardiac involvement, cases of cardiogenic
shock/left ventricular dysfunction have been associated with the initiation of
imatinib therapy. The condition was reported to be reversible with the
administration of systemic steroids, circulatory support measures, and
temporarily withholding imatinib. MDS/MPD disease and systemic mastocytosis
may be associated with high eosinophil levels. Performance of an
echocardiogram and determination of serum troponin should therefore be
considered in patients with HES/CEL, and in patients with MDS/MPD or ASM
associated with high eosinophil levels. If either is abnormal, the
prophylactic use of systemic steroids (1-2 mg/kg) for 1-2 weeks concomitantly
with imatinib should be considered at the initiation of therapy.
Bullous dermatologic reactions (eg, erythema multiforme and Stevens-
Johnson syndrome) have also been reported. In some cases, the reaction
recurred upon re-challenge. 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.
Consider potential toxicities-specifically liver, kidney and cardiac
toxicity, and immunosuppression from long-term use.
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 tablets to reduce exposure to iron.
Common side effects of Gleevec tablets
The majority of adult Ph+ CML patients 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%), muscle cramps
(28%-62%), vomiting (23%-58%), diarrhea (43%-57%), musculoskeletal pain (38%-
49%) and rash and related terms (36%-47%).*+
* Numbers indicate the range of percentages in 4 studies among adult
patients with Ph+ CML in blast crisis, accelerated phase, and chronic phase.
+ For more detailed study information, please see full Prescribing
Information.
The adverse reactions and safety profile for Ph+ ALL, MDS/MPD, ASM and
HES/CEL were generally similar to the safety profile for Ph+ CML.
The most frequently reported drug-related adverse reactions reported in
the Ph+ ALL studies were mild nausea, vomiting, diarrhea, myalgia, muscle
cramps and rash, which were easily manageable. Superficial edemas were also a
common finding in all studies and were described primarily as periorbital or
lower-limb edemas. However, these edemas were rarely severe and may be managed
with diuretics, other supportive measures, or, in some patients, by reducing
the dose of Gleevec.
Frequently reported adverse reactions (all Grades) in the seven MDS/MPD
patients assessed were nausea (57%); diarrhea and muscle cramps (43% each);
anemia, fatigue, arthralgia and periorbital edema (29% each).
All ASM patients experienced at least one adverse reaction at some time.
The most frequently reported adverse reactions were diarrhea, nausea, ascites,
muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash and
lower respiratory tract infection.
All HES/CEL patients experienced at least one adverse reaction, the most
common being gastrointestinal, cutaneous and musculoskeletal disorders.
Hematologic abnormalities were also frequent, with instances of Grade 3
leukopenia, neutropenia, lymphopenia and anemia.
Frequently reported adverse reactions (all Grades) in the 12 DFSP patients
assessed included nausea and fatigue (42% each); periorbital, peripheral and
eye edema (33% each); diarrhea, vomiting, rash, lacrimation increased and
anemia (25% each); face edema, pyrexia, exertional dyspnea, rhinitis, and
anorexia (17% each).
The majority of patients who received Gleevec in the GIST study
experienced adverse reactions at some time. Most adverse reactions were mild
to moderate in severity. The most frequently reported adverse reactions (400
mg/day; 600 mg/day) (all Grades) were superficial edema (81%; 77%), nausea
(63%; 74%), muscle cramps (47%; 58%), diarrhea (59%; 70%), fatigue (48%; 53%),
abdominal pain (40%; 37%), rash and related terms (38%; 53%), vomiting (38%;
35%), musculoskeletal pain (37%; 30%) and hemorrhage (26%; 34%).*
* For more detailed study information, please see full Prescribing
Information.
Supportive care may help management of some mild-to-moderate adverse
reactions so that the prescribed dose can be maintained whenever possible.
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.
Disclaimer
The foregoing release contains forward-looking statements that can be
identified by terminology such as "priority review", "risk", "commitment",
"potentially", "will", "if approved", "possibly", "encouraging", "would", or
similar expressions, or by express or implied discussions regarding potential
new indications or labelling for Gleevec or regarding potential future
revenues from Gleevec. Such forward-looking statements reflect the current
views of the Company regarding future events, and involve known and unknown
risks, uncertainties and other factors that may cause actual results with
Gleevec to be materially different from any future results, performance or
achievements expressed or implied by such statements. There can be no
guarantee that Gleevec will be approved for any additional indications or
labelling in any market. Nor can there be any guarantee that Gleevec will
achieve any particular levels of revenue in the future. In particular,
management's expectations regarding Gleevec 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;
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, 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 Pharmaceuticals Corporation researches, develops, manufactures
and markets leading innovative prescription drugs used to treat a number of
diseases and conditions, including those in the cardiovascular, metabolic,
cancer, organ transplantation, central nervous system, dermatological, GI and
respiratory areas. The company's mission is to improve people's lives by
pioneering novel healthcare solutions.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation
is an affiliate of Novartis AG (NYSE: NVS), which provides healthcare
solutions that address the evolving needs of patients and societies. Focused
on growth areas in healthcare, Novartis offers a diversified portfolio to best
meet these needs: innovative medicines, cost-saving generic pharmaceuticals,
preventive vaccines and diagnostic tools, and consumer health products.
Novartis is the only company with leading positions in these areas. In 2007,
the Group's continuing operations (excluding divestments in 2007) achieved net
sales of USD 38.1 billion and net income of USD 6.5 billion. Approximately USD
6.4 billion was invested in R&D activities throughout the Group. Headquartered
in Basel, Switzerland, Novartis Group companies employ approximately 98,200
full-time associates and operate in over 140 countries around the world. For
more information, please visit http://www.novartis.com.
For more information
Additional information regarding Gleevec and Novartis Oncology can be
found on the websites www.novartisoncologyvpo.com, www.gleevec.com,
www.us.tasigna.com and www.novartisoncology.us.
References
1. Fast Track, Priority Review and Accelerated Approval. US Food and Drug
Administration - Center for Drug Evaluation and Research.
http://www.accessdata.fda.gov/scripts/cder/onctools/Accel.cfm. Accessed 31
July 2008.
2. Internal data.
3. Z9001: A Phase III Randomized Double-blind Study of Adjuvant STI571
(Gleevec(R)) Versus Placebo in Patients Following the Resection of Primary
Gastrointestinal Stromal Tumor (GIST).
http://www.cancer.gov/clinicaltrials/ACOSOG-Z9001. Accessed June 2008.
4. Van den Abbeele A., Benjamin R., Blanke C, et al. Clinical Management
of GIST. Recurrence patterns and prognostic factors for survival. 2003;1-24.
5. American Cancer Society. Cancer Reference Information. Detailed Guide
for Gastrointestinal Stromal Tumors. Key Statistics.
http://www.cancer.org/docroot/CRI/content/CRI_2_4_1x_What_Are_the_Key_Statisti
cs_About_Gastrointestinal_Stromal_Tumors.asp?rnav=cri. Accessed 22 February
2008.
6. US Department of Health and Human Services. Agency for Healthcare
Research and Quality (AHRQ). Technology Assessment: Report on the Relative
Efficacy of Oral Cancer Therapy for Medicare Beneficiaries Versus Currently
Covered Therapy, Part 2. Imatinib for Gastrointestinal Stromal Tumors (GISTs).
Available at: http://www.ahrq.gov/clinic/ta/gist/gist1.htm
7. Gleevec(R) (imatinib mesylate) tablets prescribing information. East
Hanover, NJ: Novartis Pharmaceuticals Corporation; Nov 2007.

Media Contacts
Media only: Kim Fox, Novartis Oncology, P: +1 862 778 7692
Dana Kahn Cooper, P: +1 732 817 1800, C: +1 732 239 6664

Investors only: Jill Pozarek, Novartis Corporation, +1-212-830-2445

SOURCE Novartis

Media, Kim Fox, Novartis Oncology, +1-862-778-7692, or P: +1 212 830 2445, or
Dana Kahn Cooper, +1-732-817-1800, C, +1-732-239-6664; or Investors, Jill
Pozarek of Novartis Corporation, +1-212-830-2445