Thursday October 19, 7:25 pm ET
Approvals Represent First Time a Regulatory Authority has Simultaneously Approved One Targeted Medicine for Five Disorders
Now Approved for the Solid Tumor Cancer, Dermatofibrosarcoma Protuberans
US Approval Also Granted for Treatment of Four Blood Diseases:
Multiple Approvals in Only Five Years Highlight new Approach of Developing Treatments Based on Common Molecular Pathways
EAST HANOVER, N.J., Oct. 19 /PRNewswire-FirstCall/ — In another important milestone, Gleevec/Glivec® (imatinib mesylate)* tablets has received US regulatory approval to help patients with five distinct and potentially life-threatening disorders, representing the first time that a regulatory authority has ever simultaneously approved one targeted medicine for so many disorders.
With today’s decision, and in only five years, Gleevec has now been approved in the US for seven diseases, including two solid tumors and five blood disorders with molecular targets known to be inhibited by the drug.
All of the diseases covered in the new approval by the US Food and Drug Administration (FDA) are rare and potentially life threatening. For many of the patients who suffer from them, few, if any approved treatments were available prior to Gleevec.
“The effectiveness of Gleevec in these five diseases further underscores how cancers and diseases of different origin and location can share common pathways that often respond to the same targeted treatment,” said Diane Young, MD, Vice President and global head of Clinical Development at Novartis Oncology. “These approvals further build and demonstrate our historical commitment to developing therapies for patients with rare diseases such as acromegaly, carcinoid syndrome and gastrointestinal stromal tumors.”
The FDA approvals are based on data from Novartis-sponsored clinical studies and clinical data from independent medical researchers showing the efficacy of Gleevec in the treatment of these diseases, in which there is a suggested connection between a Gleevec-sensitive pathway and a disease.
Gleevec targets the activity of proteins called tyrosine kinases that appear to play important roles within some cancer cells. Gleevec has been shown to inhibit the function of the tyrosine kinase Bcr-Abl in patients with certain forms of blood cancer — Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) — and the receptor tyrosine kinase Kit in Kit-positive GIST (gastrointestinal stromal tumor).
Researchers have found Gleevec also inhibits other tyrosine kinases, including platelet-derived growth factor receptor (PDGFR), which have been shown to be activated in disease pathways that underlie a number of rare hematologic diseases, as well as some solid tumors.
The new diseases for which Gleevec received approval include one solid tumor and various rare blood disorders. The solid tumor is dermatofibrosarcoma protuberans (DFSP), a type of tumor that begins as a hard lump found in the skin of the chest, abdomen or leg. The four blood diseases include:
- Relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), a rapidly progressive blood cancer characterized by the presence of the Philadelphia chromosome
- Certain forms of myelodysplastic/myeloproliferative diseases (MDS/MPD), which involve certain blood cells made in the bone marrow
- Hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL), which is characterized by the persistent overproduction of eosinophils, a certain type of white blood cell
- Aggressive systemic mastocytosis (ASM), which is marked by the presence of too many mast cells, a certain type of white blood cell.
An approval for newly diagnosed patients is still under review by the FDA. In the European Union (EU), Gleevec was recently approved for treatment of certain patients with Ph+ ALL as well as for adult patients with a form of DFSP. The EU is also reviewing applications for approval of Gleevec as a treatment for the three other diseases MDS/MPD, HES/CEL and ASM.
About Gleevec Tablets
In addition to these new indications, Gleevec (imatinib mesylate) tablets are indicated for the treatment of newly-diagnosed adult and pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase. Follow-up is limited. Gleevec tablets are also indicated for the treatment of patients with Ph+ CML in blast crisis, in accelerated phase, or in chronic phase after failure of interferon-alpha (IFN-a) therapy. Gleevec is also indicated for the treatment of pediatric patients with Ph+ chronic phase CML whose disease has recurred after stem cell transplant or who are resistant to IFN-a treatment. There are no controlled trials in pediatric patients demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.
Gleevec tablets are also indicated for the treatment of patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). The effectiveness of Gleevec 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(1)
For Ph+ CML, severe (NCI Grades 3/4) lab abnormalities-including neutropenia (3%-48%), anemia (< 1%-42%), thrombocytopenia (< 1%-33%), and hepatotoxicity (3%-6%)-and severe adverse experiences (NCI Grades 3/4), including severe fluid retention (eg, pleural effusion, pulmonary edema, and ascites) and superficial edema (1.8%-11%), hemorrhage (1%-19%), and musculoskeletal pain (2%-9%) were reported among adults 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. 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 gastrointestinal (GI) perforation.
The overall safety profile of Ph+ CML pediatric patients treated with Gleevec in 93 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported. Nausea and vomiting were the most commonly reported individual adverse events with an incidence similar to that seen in adult patients.
The adverse reactions and safety profile for Ph+ ALL, MDS/MPD, ASM and HES/CEL were generally similar to Ph+ CML.
The most frequently reported drug-related adverse events reported in the Ph+ ALL studies were mild nausea, vomiting, diarrhea, myalgia, muscle cramps and rash, which were easily manageable. Superficial edemas were 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 events 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 event at some time. The most frequently reported adverse events were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritis, rash and lower respiratory tract infection.
All HES/CEL patients experienced at least one adverse event, the most common being gastrointestinal, cutaneous and musculoskeletal disorders. Hematological abnormalities were also frequent, with instances of Grade 3 leukopenia, neutropenia, lymphopenia and anemia.
In patients with HES and cardiac involvement, cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of Gleevec therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Gleevec. MDS/MPD and ASM may be associated with high eosinophil levels. Monitoring should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels.
For GIST, severe (NCI Grades 3/4) lab abnormalities-including neutropenia (3%-48%), anemia (< 1%-42%), thrombocytopenia (< 1%-33%), and hepatotoxicity (3%-6%)-and severe adverse experiences (NCI Grades 3/4), including severe fluid retention (eg, pleural effusion, pulmonary edema, and ascites) and superficial edema (1.8%-11%), hemorrhage (1%-19%), and musculoskeletal pain (2%-9%) were reported among Gleevec patients. 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. 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 gastrointestinal (GI) perforation.
Frequently reported adverse events in the 12 DFSP patients assessed include 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).
Important Safety Information for all Indications(1)
Severe congestive heart failure and left ventricular dysfunction have occasionally been reported in patients taking Gleevec. Most of the patients with reported cardiac events have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. In an international randomized phase 3 study of 1,106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Gleevec compared to 0.9% of patients taking IFN + Ara-C. 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.
Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have been reported. In some cases, the reaction recurred upon rechallenge. Several post-marketing reports described cases in which patients tolerated reintroduction of Gleevec after resolution or improvement of the bullous reaction. In these instances, Gleevec was resumed at a lower dose with or without supportive care.
Some patients (5%) were reported to have severe GI bleeds or intratumoral bleeds. GI tumor sites may have been the source of GI bleeds.
Dose adjustments may be necessary due to hepatotoxicity, other non-hematologic adverse events, or hematologic adverse events.
Therapy with Gleevec was discontinued for adverse events in 3% to 5% of adult patients with Ph+ CML or Kit+ GIST. None of the 5 patients in the ASM study discontinued Gleevec due to drug-related adverse events or abnormal laboratory values.
Gleevec is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of Gleevec tablets should increase by at least 50% and clinical response should be carefully monitored in patients receiving Gleevec tablets with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with Gleevec include acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full prescribing information for other potential drug interactions).
For daily dosing of 800mg and above, dosing should be accomplished using the 400mg tablets to reduce exposure to iron. Use of Gleevec tablets is contraindicated in patients with hypersensitivity to imatinib or to any other component of Gleevec tablets.
Patients with severe hepatic impairment should be treated at a starting dose of 300 mg/day and should be closely monitored.
Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec tablets. Because of the potential for serious adverse reactions in nursing infants, women should be advised to avoid breast-feeding while taking Gleevec tablets.
Common Side Effects of Gleevec Tablets(1)
The majority of the approximately 1700 adult patients who received Gleevec in clinical studies experienced adverse events at some time, but most were mild to moderate in severity. The most frequently reported adverse events were superficial edema (58%-81%), nausea (47%-74%), diarrhea (39%-70%), muscle cramps (28%-62%), vomiting (21%-58%), rash (36%-53%), fatigue (30%-53%), musculoskeletal pain (30%-49%), and abdominal pain (30%-40%).
The adverse reactions and safety profile for Ph+ ALL, MDS/MPD, ASM and HES/CEL were generally similar to Ph+ CML.
Supportive care may help management of most mild to moderate adverse events so that prescribed dose can be maintained whenever possible
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.
The foregoing release contains forward-looking statements that can be identified by terminology such as “commitment,” “potentially,” or similar expressions, or by express or implied discussions regarding potential new indications for Gleevec or potential future sales of Gleevec, or regarding the long-term impact of a patient’s use of Gleevec. Such forward-looking statements 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 in any market. Nor can there be any guarantee regarding potential future sales of Gleevec. Neither can there be any guarantee regarding the long-term impact of a patient’s use of Gleevec. In particular, management’s expectations regarding Gleevec could be affected by, among other things, unexpected clinical trial results, including additional analysis of existing Gleevec clinical data and new clinical data; unexpected regulatory actions or delays or government regulation generally; competition in general; the company’s ability to obtain or maintain patent or other proprietary intellectual property protection; government, industry, and general public pricing pressures; and other risks and factors referred to in the Company’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 this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.
Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets leading innovative prescription drugs used to treat a number of diseases and conditions, including central nervous system disorders, organ transplantation, cardiovascular diseases, dermatological diseases, respiratory disorders, cancer and arthritis. 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 – News) – a world leader in pharmaceuticals and consumer health. In 2005, the Group’s businesses achieved sales of USD 32.2 billion and pro forma net income of USD 6.1 billion. The Group invested approximately USD 4.8 billion in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 99,000 people and operate in over 140 countries around the world. For further information please consult http://www.novartis.com.