New drug shows dramatic Leukaemia results

MEDIA RELEASE

December 4, 2000

New drug shows dramatic results against common type of Leukaemia

Novartis Oncology today announced that data on Glivec®, formerly STI571, will be featured in more than 50 abstracts this week at the annual meeting of The American Society of Haematology (ASH) in San Francisco. Glivec® is an investigational treatment for certain forms of leukaemia. The data offer new and updated information regarding the agent’s potential activity in treating certain forms of leukaemia that are characterised by the presence of the Philadelphia chromosome, including chronic myeloid leukaemia (CML) and, to a lesser extent, acute lymphocytic leukaemia (ALL) and acute myeloid leukaemia (AML).

Glivec® is one of the first molecularly targeted drugs in clinical trials and is based on the fact that the Philadelphia (Ph) chromosome is present in 95% of patients with Chronic myeloid leukaemia (CML). STI571 works by blocking the action of the Ph chromosome as it produces a unique fusion tyrosine kinase that is linked to malignant transformation.

Peter Browett, Associate Professor of Haematology Auckland University, is New Zealand’s investigator involved with trials of Glivec® in New Zealand and says the results are very exciting and encouraging: “This is the first time an understanding of the biology and molecular basis of the leukaemia has led to a specific, targeted approach to cancer therapy and the response of patients so far in clinical trials is extremely good both in those patients in the chronic phase and those patients in the more advanced accelerated phase,” he says.

Says Peter Browett: “This is a very good response rate in a group of patients who have already failed traditional frontline therapy. The next step will be to compare the new treatment Glivec® head to head with interferon to see if it as good or possibly even better. This study is currently being done at a number of centres including Auckland.”

Sean Evans, Medical Director Novartis (NZ) Ltd believes the results are very encouraging: "Glivec® is expected to be available commercially towards the end of 2001. Currently Glivec is only available for newly diagnosed patients participating in a clinical trial.

"Novartis is committed to the ongoing study of Glivec® as a vital treatment option for physicians and patients in the battle against this disease," he adds.

Clinical Data

On Monday and Tuesday, December 4th and 5th, of more than 50 presentations taking place, 14 will be oral. Data will be presented from the four largest multicentre Phase II studies ever conducted in CML to date, including the effectiveness of Glivec® in patients with each phase of CML (chronic phase, accelerated phase and blast crisis) and each phase of Philadelphia chromosome-positive acute lymphoblastic leukaemia.

1. Chronic Phase Study
A Phase II Study of STI571, A Tyrosine Kinase Inhibitor, in Patients with Resistant or Refractory Philadelphia Chromosome-Positive Chronic Myeloid Leukaemia Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Resta D, Capdeville R, Druker B

This Phase II, open-label study evaluated STI571 in patients with Philadelphia chromosome-positive (Ph+) CML who had failed interferon. Of the 532 patients enrolled, preliminary bone marrow cytogenetic results are available for 388 patients at three months. The findings demonstrated an overall cytogenetic response rate of 37 percent. Of the responses, 13 percent were complete (0 Ph+ cells) and 23 percent were major (<35 percent Ph+ cells). In 290 patients who had completed six months of therapy at the time of the analysis, preliminary data suggest an overall response rate of 56 percent. Haematologic results, not currently available, will also be presented at the meeting.

2. Accelerated Phase Study
A Phase II Study of STI571 in Adult Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Accelerated Phase
Talpaz M, Silver RT, Druker B, Paquette R, Goldman JM, Reese SF, Capdeville R

This Phase II study includes 234 patients with CML in the accelerated phase. The preliminary response data, as assessed by the investigators, includes 154 patients who
have been treated with STI571 for at least 4 weeks. The overall hematological response rate at 4 weeks is 78 percent, including 22 patients who have achieved a complete response.

3. Blast Crisis Phase Study
A Phase II Study to Determine the Safety and Anti-Leukemic Effects of STI571 in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Myeloid Blast Crisis
Sawyers C, Hochhaus A, Feldman E, Goldman JM, Miller C, Ben-Am M, Capdeville R,
Druker B

This Phase II, open-label trial includes 262 CML patients in the blast crisis phase. Preliminary data is based on 94 patients, 44 of whom received prior treatment for blast crisis and 50 of whom were untreated. In the previously untreated patients, the overall response rates were 48 percent and 47 percent at 4 and 8 weeks of therapy with STI571, respectively. In those who had received prior therapy for blast crisis, the response rates were 38 percent and 33 percent, respectively.

About Glivec® (Formerly STI571)
Glivec® belongs to a new class of antiproliferative agents called signal transduction inhibitors (STIs), which have been shown to have the potential to interfere with intracellular signalling pathways that have been implicated in tumour development. Glivec® is molecularly targeted to the specific chromosomal abnormality, called the Philadelphia chromosome, in chronic myeloid leukaemia. The abnormal protein and chromosome may also be present, to a lesser extent, in AML and ALL. Some patients with these rare forms of leukaemia have been included in the Glivec clinical trials.

Researchers are also investigating the role of Glivec® in solid tumours. Novartis recently began a program of small-scale proof of concept studies in selected solid tumours with its agent Glivec, where the biological mechanisms suggest potential activity. These small-scale pilot studies are intended to establish the basis for further studies in clinical trials.

As Glivec® is still in clinical development, its safety and efficacy have not yet been established, and clinical trial participants are being closely monitored. In terms of side effects, preliminary results indicate that the agent has been well tolerated to date. Side effects including nausea, muscle cramps, edemas, skin rash, diarrhoea, heartburn and headache have been largely mild or moderate in intensity. Fewer than three percent of patients have experienced occurrence of rare but serious side effects such as the potential for liver toxicity, fluid retention syndrome and haemorrhages.

Chronic Myeloid Leukemia
Chronic myeloid leukemia (CML) is one of the four most common types of leukemia. Approximately 280 New Zealanders are affected and the peak age incidence is around the late 50s to 60s.

CML is a haematologic stem cell disorder caused by an acquired abnormality in the DNA of the stem cells in bone marrow. The abnormality results in a gene that produces an abnormal protein.

Although researchers do not fully understand what causes this DNA change, they do know that the abnormal protein that results disrupts the bone marrow’s normally well-controlled production of white blood cells. This “deregulated” production of white blood cells leads to a massive increase in their concentration in the blood.

CML progresses through three distinct phases: the chronic phase (typically lasting from three to four years), the accelerated phase (typically lasting from three to nine months), and blast crisis (typically lasting from three to six months), which are marked by a progressive increase in the number of white blood cells. As a patient moves through these stages, the disease usually becomes increasingly refractory to therapy and, therefore, more difficult to treat.

Novartis (NYSE: NVS) is a world leader in healthcare with core businesses in pharmaceuticals, consumer health, generics, eye-care, and animal health. In 1999, the Group achieved sales of CHF 25.4 billion (NZ$35.4 billion) and invested approximately CHF 3.6 billion (NZ$5 billion) in R&D. Headquartered in Basel, Switzerland, Novartis employs about 66 000 people and operates in over 140 countries around the world. For further information please contact http://www.novartis.com.

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For further information please contact:
Sean Evans
Medical Director
Novartis New Zealand Limited
Tel +9 828 3149
fax +9 820 3776
sean.evans@pharma.novartis.com

Peter Browett
Associate Professor of Haematology Auckland University
Tel 025 738 173

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