Healthcare Industry News: Ph+ CML
News Release - June 14, 2006
Patients With Treatment-Resistant Leukemia Achieve High Responses to Tasigna(R) (nilotinib) in First Published Clinical Trial ResultsNew England Journal of Medicine publishes first evaluation of Tasigna, a promising next-generation targeted therapy, five years after issuing historic Gleevec(R) Phase I data
Tasigna designed to be a highly selective inhibitor of Bcr-Abl, the definitive cause of Ph+ CML, and its mutations
More than 90% of patients with an unresponsive form of chronic myeloid leukemia (CML) in chronic phase treated with Tasigna achieved normal blood cell counts in less than five months
EAST HANOVER, N.J., June 14 (HSMN NewsFeed) -- The first-ever published clinical trial data about the investigational drug Tasigna® (nilotinib) showed the compound helped more than 90% of patients diagnosed with an unresponsive form of leukemia, a life-threatening disease.
The data were published today in the New England Journal of Medicine.
In less than five months of treatment, 92% of patients with chronic phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) achieved a complete hematologic response with normal white blood cell counts after having shown resistance or intolerance to optimized Gleevec® (imatinib mesylate)* tablets therapy.
In more than a third of these patients, the Ph chromosome, the genetic abnormality that characterizes most cases of CML, was undetectable after treatment with Tasigna, as measured by standard laboratory methods. A total of 106 patients with Ph+ CML participated in this study: 33 patients in blast crisis, 56 patients in accelerated phase, and 17 patients in chronic phase. In addition, 13 patients with Ph+ acute lymphoblastic leukemia were included in the study.
Both Tasigna and Gleevec inhibit Bcr-Abl, the definitive cause of Ph+ CML - in effect, shutting down production of the Ph chromosome. Tasigna was specifically designed to be a highly selective inhibitor of Bcr-Abl and its mutations, which can cause resistance to treatment.
"By selectively inhibiting Bcr-Abl and its common mutations, Tasigna produced dramatic positive responses in patients who had limited treatment options," said Hagop Kantarjian, MD, Professor of Medicine and Internist, Chair, Department of Leukemia, M.D. Anderson Cancer Center. "These extremely encouraging results reinforce the validity of treating this cancer by specifically targeting the one protein known to cause the disease."
Patients in the most advanced phases of CML also responded to Tasigna therapy. The overall rate of hematologic response (normalization of white blood cell counts) for patients in accelerated phase was 72% and the rate of cytogenetic response (reduction or elimination of the Ph+ chromosome) was 48%. Among patients in blast crisis, the response rates were 39% and 27%, respectively.
The study investigators concluded that Tasigna was generally well tolerated. Common adverse events included myelosuppression, transient indirect hyperbilirubinemia and skin rashes. Additionally, the investigators noted that Tasigna was usually not associated with certain toxicities seen with Gleevec (e.g. fluid retention, superficial edema, weight gain), or with rare cases of pleural and pericardial effusions.
Discovered in the biomedical research facilities of Novartis, Tasigna (investigational name AMN107) entered Phase I clinical studies just 21 months after it was first synthesized. It is a next generation tyrosine kinase inhibitor in Ph+ CML with a high affinity and specificity to attach itself to Bcr-Abl and to 32 of 33 mutant forms commonly associated with Ph+ CML. The U.S. Food and Drug Administration (FDA) has granted both fast track designation and orphan drug status to Tasigna. Tasigna also received orphan drug status from the European Medicines Agency (EMEA). Novartis is now planning to submit Tasigna for U.S. and EU regulatory approval in late 2006 compared to earlier estimates for submissions in 2007.
As an investigational compound, the safety and efficacy profile of Tasigna has not yet been established. Access to Tasigna is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the compound's potential benefits and risks and data will be filed with regulatory authorities such as the U.S. FDA and the European Medicines Agency for regulatory approval.
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-a) 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(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 "promising," "extremely encouraging results," "planning," "will be filed," or similar expressions, or by express or implied discussions regarding potential future sales of Gleevec, or regarding the long-term impact of a patient's use of Tasigna or Gleevec. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results with Tasigna and 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 sale in any market. Nor can there be any guarantee regarding potential future sales of Tasigna or Gleevec. Neither can there be any guarantee regarding the long-term impact of a patient's use of Tasigna or Gleevec. In particular, management's expectations regarding Tasigna and Gleevec could be affected by, among other things, unexpected clinical trial results, including new clinical data and 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; and other risks and factors referred to in the Company's current Form 20-F on file with the U.S. 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 96,000 people and operate in over 140 countries around the world. For further information please consult http://www.novartis.com.
(*) Known as Glivec® (imatinib) outside the U.S.
(**) Numbers indicate the range of percentages in 4 studies among adult patients with Ph+ CML in blast crisis, accelerated phase, and chronic phase.
(1) Gleevec® (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2005.
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