Healthcare Industry News: Ph+ CML
News Release - June 3, 2006
Gleevec(R) Sets New Treatment Standard in Chronic Myeloid Leukemia With High Overall Survival, Increasing Response and Decreasing ProgressionNearly 90% of patients with Philadelphia chromosome-positive CML alive at 5 years with new analysis showing less than 5% mortality due to CML
Response rate to Gleevec increases substantially over five years in landmark IRIS study, the largest ever conducted in CML patients
Yearly rate of progression to more advanced disease continues to drop the longer patients take Gleevec, falling to 0.6% in fifth year
EAST HANOVER, N.J., June 3 (HSMN NewsFeed) -- Response rates to GleevecŪ (imatinib mesylate)* tablets continue to increase substantially over time while the yearly risk of progression to advanced disease continues to decline the longer patients take the medicine, according to five-year data from a landmark study in patients with a form of life-threatening chronic myeloid leukemia.
Results of the International Randomized Interferon versus STI571 (IRIS) study were presented today at the 2006 Annual Meeting of the American Society of Clinical Oncology.
Data from the IRIS study, the largest clinical trial to date for newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase, showed the overall survival rate at five years to be 89.4% (range 86% to 92%) for patients receiving Gleevec. This considers deaths from all causes, but only 4.6% of the patients died from causes related to their leukemia. Before Gleevec was available, about 50% of patients progressed to the more advanced stages of Ph+ CML after only three to five years, and survival was generally short for those patients.
The results of this Phase III trial, which was started in June 2000, also showed that the number of patients with a complete cytogenetic response increased from 69% to 87% between the first and fifth years of treatment. Moreover, the yearly risk of progressing to advanced disease continued to decline -- to 0.6% in the fifth year.
"Very few oncology medicines offer patients the opportunity to achieve better outcomes the longer they take the therapy," said David Epstein, President of Novartis Oncology. "That Gleevec demonstrates these significant improvements with long-term use is a good sign science will provide the path to turn lethal cancers into potentially manageable conditions with durable, well-tolerated targeted therapies."
An estimated 93% of Gleevec patients in the early, chronic phase of CML did not progress to the rapidly lethal advanced stages of the disease, and an estimated 83% survived with no evidence of disease progression at all at the five-year follow-up.
IRIS study details
The International Randomized Interferon versus STI571 (IRIS) study is an open-label Phase III clinical trial enrolling 1,106 newly diagnosed patients with Ph+ CML in chronic phase in 177 centers across 16 countries. There are two arms to the study: one group of patients receiving Gleevec 400 mg per day and another receiving a target dose of interferon (IFN) of 5 MIU/m2/day in combination with Ara-C 20 mg/m2/day for 10 days each month. Because of tolerability reasons or lack or loss of response to treatment, 69% of patients in the IFN/Ara-C arm crossed over to the Gleevec arm, whereas only 3% of patients in the Gleevec arm crossed over to the IFN/Ara-C arm.
Cumulative best responses to Gleevec treatment improved significantly between the first and fifth years of treatment. Over the period, complete hematologic responses rose from 96% to 98%, major cytogenetic responses rose from 85% to 92% and complete cytogenetic responses rose from 69% to 87%.
In a complete hematologic response, the patient's blood cell counts return to normal. Cytogenetic response refers to the disappearance or reduction of the number of Ph+ cells detectable by standard lab methods.
Gleevec continued to be generally well tolerated as initial drug therapy for Ph+ CML at the five-year follow-up. See "Gleevec contraindications, warnings and adverse events" for details.
About Gleevec Tablets
Gleevec (imatinib mesylate) tablets are indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (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-alpha) therapy.
Important Safety Information(1)
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 600mg/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, and papilledema and gastrointestinal 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 cases note a resolution or improvement of bullous reaction following dose reduction with or without supportive care.
Dose adjustments may be necessary due to hepatotoxicity, other nonhematologic adverse events, or hematologic adverse events. Therapy with Gleevec was discontinued for adverse events in 3% to 5% of patients.
Patients with severe hepatic impairment should be treated at a starting dose of 300 mg/day and should be closely monitored.
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.
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 adult patients who received Gleevec in clinical studies experienced adverse events at some time. Most adverse events were mild to moderate in severity. The most frequently reported adverse events (all Grades) were superficial edema (58%-74%), nausea (47%-73%), muscle cramps (28%-62%), vomiting (21%-58%), diarrhea (39%-57%), musculoskeletal pain (38%-49%), and rash with related terms (26%-47%).**
Supportive care may help the management of most mild to moderate adverse events so that the prescribed dose can be maintained whenever possible.
Gleevec tablets should be taken with food and a large glass of water to minimize gastrointestinal (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 "increases substantially over five years," "yearly rate of progression," "increase substantially over time," "yearly risk of progression to advanced disease," "long-term use," "will," 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 commercialization of Gleevec could be affected by, among other things, additional analysis of Gleevec clinical data; new clinical data; unexpected clinical trial results; 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; 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 ) - 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 91,000 people and operate in over 140 countries around the world. For further information please consult http://www.novartis.com.
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* Known as GlivecŪ (imatinib) outside the US
** Numbers indicate the range of percentages in 4 studies among adult patients with Ph+ CML in blast crisis, accelerated phase, and chronic phase.
(1) GleevecŪ (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2005.
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