Basel, Switzerland, December 6, 2004 - New data on Glivec (imatinib)[1] demonstrated that newly diagnosed patients with a certain form of leukemia[2] receiving 400 mg daily maintained their response to therapy long term. A separate study found patients receiving 800 mg daily had better outcomes compared to patients receiving 400 mg daily. Patients receiving 800 mg daily were found to be more likely to achieve a major molecular response.
An update to the landmark International Randomized Interferon versus STI571 (IRIS) study was presented on December 5 at the American Society of Hematology (ASH) annual meeting in San Diego. The study results demonstrated a link between rapid, early cytogenetic response and long-term outcome during treatment with Glivec in newly diagnosed patients with chronic-phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML). Patients who achieved cytogenetic responses early in the study had improved rates of progression-free survival compared to those who did not achieve early responses.
In a separate study also presented at ASH, researchers at the M.D. Anderson Cancer Center in Houston, Texas, found that patients with newly diagnosed chronic phase Ph+ CML who took an 800 mg daily dose of Glivec were more likely to achieve a complete cytogenetic response (CCR) than patients taking the approved 400 mg daily starting dose. In addition to a higher rate of CCR, the study found 67% of patients taking 800 mg daily achieved a major molecular response (MMR) at a median follow-up of 19 months compared to 47% of patients taking 400 mg daily at a median follow-up of 36 months. MMR is defined as the near absence of disease at a molecular level. Molecular response may prove a possible new benchmark for evaluating effectiveness of drug therapy and disease prognosis.
"The more data we see on Glivec, the more it appears that patients obtain better long-term outcomes when they reduce their leukemic loads rapidly, which we know can be achieved in more patients with an optimised dose," said Jorge Cortes, MD, Department of Leukemia, M.D. Anderson Cancer Center. "These new data show that patients who have good early responses may have the greatest protection from relapse."
Study details
Abstract # 21: Guilhot F on behalf of the IRIS Study Group. Sustained durability of responses plus high rates of cytogenetic responses result in long-term benefit for newly diagnosed chronic-phase chronic myeloid leukemia treated with imatinib therapy: update from the IRIS study
The study was conducted in 1,106 patients. At the 42-month follow-up, 98% of newly diagnosed patients treated with Glivec had achieved complete hematologic response (CHR), while 91% had achieved a major cytogenetic response (MCR) and 84% had achieved a complete cytogenetic response (CCR).
For patients who had achieved CCR and a thousand-fold (3 log) or greater reduction in Bcr/Abl transcript level - a molecular response - at 12 months, the probability of remaining progression-free was 98% at 42 months compared with 90% for patients with CCR and less than a thousand-fold reduction in Bcr-Abl transcript level and 75% for patients who had not achieved CCR.
Responses to Glivec were found to be durable at the 42-month follow-up, with an estimated 91% of patients maintaining CHR, 91% of patients maintaining MCR and 87% of patients maintaining CCR.
In CML, a molecular response is the disappearance or reduction in the quantity of Bcr-Abl transcripts that produce the abnormal protein responsible for driving the proliferation of white blood cells that occurs in CML patients. CHR refers to the normalization of blood counts, lasting for at least four weeks. However, the cells containing the Philadelphia chromosome (the genetic abnormality that characterizes most cases of CML) may still be present. In MCR, less than 35% of cells containing the Philadelphia chromosome are detected.
The most common adverse events to first-line treatment with Glivec in this study were hemtologic and hepatic toxicities and included severe (NCI Grades 3/4) neutropenia (16.2%), anemia (4.0%), thrombocytopenia (9.3%) and elevated liver enzymes (5.4%). Other drug-related adverse events occurred in 15.8% of patients.
Abstract #999: Cortes J, et al. High-dose imatinib mesylate treatment in patients with previously untreated early chronic phase chronic myeloid leukemia
The second study, conducted by researchers at the M.D. Anderson Cancer Center in Houston, Texas, consisted of three consecutive trials. In these trials, a total of 222 previously untreated early chronic phase CML patients were split into two groups. In one group, patients were treated with the 400 mg daily dose of Glivec, while another group was treated with 800 mg daily. Median follow-up of patients on 400 mg daily was 36 months and median follow-up of patients on 800 mg daily was 19 months.
Patients in the higher dose group had an estimated progression-free survival rate of 99% at 12 months compared with 92% in the standard dose group. Researchers concluded that the 800 mg daily Glivec dose resulted in higher rates of complete cytogenetic and molecular remissions.
Extramedullary toxicity (toxicity outside the bone marrow) was similar in the two groups, but myelosuppression was more common with high dose. Severe (NCI Grades 3/4) anemia, neutropenia and thrombocytopenia occurred in 7%, 39% and 27% of patients receiving the high dose, respectively, and 4%, 20% and 12% of patients receiving the standard dose, respectively. At 12 months, the median actual dose for the high-dose group was still 800 mg daily, with 40 of 112 (36%) evaluable patients having required dose reduction. This compared with 7 of 43 (14%) of those treated with the standard dose.
About Glivec
Glivec is indicated in the EU for the treatment of patients with newly diagnosed Ph+ CML for whom bone marrow transplantation is not considered as the first line of treatment. Glivec is approved in the U.S. for newly diagnosed adult patients with Ph+ chronic phase CML and pediatric patients with Ph+ chronic phase CML whose disease has recurred after stem cell (an unspecialized cell that gives rise to differentiated cells) transplant or who are resistant to interferon-alpha treatment. In Japan, Glivec is approved for adult patients in all phases of Ph+ CML. In addition, Glivec is already approved for the treatment of adult patients with Ph+ CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha treatment in more than 80 countries worldwide.
Glivec is approved in the EU, US and other countries for the treatment of patients with Kit (CD117) positive gastrointestinal tumors (GISTs), which cannot be surgically removed and/or have already spread to other parts of the body (metastasized). In Japan, Glivec is approved for the treatment of patients with Kit (CD117) positive GISTs.
The effectiveness of Glivec is based on overall hematologic and cytogenetic response rates and progression-free survival in CML and objective response rates in GIST. There are no controlled trials demonstrating increased survival.
Contraindications, warnings and adverse events[3]
In the first-line study (IRIS), the safety profile with Glivec was similar to that of previous Phase II studies in other CML patients. The majority of patients treated with Glivec experienced adverse events at some time. Most events were of mild to moderate grade and treatment was discontinued for adverse events only in 2% of patients in chronic phase, 3% in accelerated phase and 5% in blast crisis. The most common side effects included nausea, superficial edema, muscle cramps, skin rash, vomiting, diarrhea, hemorrhage, fatigue, headache, joint pain, cough, dizziness, dyspepsia and dyspnea, as well as neutropenia and thrombocytopenia.
The most common undesirable effects experienced during Glivec treatment in GIST are: headache, nausea, vomiting, diarrhea, dyspepsia, myalgia, muscle spasm and cramps, joint swelling, dermatitis, eczema, rash, edema, fluid retention, neutropenia, thrombocytopenia or anemia.
Glivec is contraindicated in patients with known hypersensitivity to imatinib or any of its excipients. Women of childbearing potential should be advised to avoid becoming pregnant while taking Glivec.
The foregoing release contains forward-looking statements that can be identified by terminology such as "long-term," "prolonged efficacy," "potential for improved response," "remarkable overall survival," "progression-free survival," "greater response," "better outcomes," "more likely to achieve," "improved rates," "it appears", "possible new benchmark," "greatest protection," "found to be durable," "estimated", or similar expressions, or by express or implied discussions regarding potential new indications for Glivec or potential future sales of Glivec, or regarding the long-term impact of a patient's use of Glivec. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results with Glivec to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Glivec will be approved for any additional indications in any market. Nor can there be any guarantee regarding potential future sales of Glivec. Neither can there be any guarantee regarding the long-term impact of a patient's use of Glivec. In particular, management's expectations regarding commercialization of Glivec could be affected by, among other things, additional analysis of Glivec 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.
For more information
Information about Glivec is available at www.Glivec.com. Reporters interested in more information regarding Glivec or Novartis Oncology can visit the Novartis Oncology Virtual Press Office at www.novartisoncologyVPO.com. The site features background information on Novartis Oncology products.
About Novartis
Novartis Oncology is a business unit within Novartis AG (NYSE: NVS), a world leader in pharmaceuticals and consumer health. In 2003, the Group's businesses achieved sales of USD 24.9 billion and a net income of USD 5.0 billion. The Group invested approximately USD 3.8 billion in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ about 80,000 people and operate in over 140 countries around the world. For further information please consult http://www.novartis.com.
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[1] Known as Gleevec in the US
[2] The studies were conducted in patients with newly diagnosed chronic phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML)
[3] Numbers indicate the range in percentages in four studies among patients with CML in blast crisis, accelerated phase and chronic phase.
