Glivec To Be Funded For All CML And GIST Patients

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GLIVEC (IMATINIB)* TO BE FUNDED FOR ALL
CML AND GIST PATIENTS IN NEW ZEALAND

Novartis New Zealand is pleased to announce that the Board of the Pharmaceutical Management Agency (PHARMAC) of New Zealand has agreed to fund Glivec® (imatinib)* for the treatment of all phases of Philadelphia-chromosome positive chronic myeloid leukaemia (CML) and for certain forms of gastrointestinal stromal tumour (GIST).

The agency will fund Glivec immediately for patients with Philadelphia chromosome-positive CML in the blast crisis, accelerated phase, or in chronic phase whose treatment with interferon-alpha therapy has been unsuccessful. These indications are already approved by the Ministry of Health in New Zealand. Funding for first-line treatment in newly diagnosed CML patients will begin as soon as the Ministry of Health has approved this indication, which is currently under review.

The agency will also fund Glivec for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours (GISTs), a second indication for the drug that has recently been approved by the Ministry of Health.

Mr Andrew Moore, managing director of Novartis New Zealand, said the funding decision recognizes the outstanding benefits of Glivec when administered to patients as early as possible after diagnosis. “As a result, PHARMAC has taken a forward-looking view and approved Glivec for funding in first-line use in CML – an indication not even approved yet by the Ministry of Health,” Mr Moore said.

“For the New Zealanders with CML and with GIST, this announcement is a major development,” said Moore. “It offers them the prospect of resuming a more normal life with Glivec; something that other treatments have failed to achieve for them. It means that no one who could initially benefit from treatment with Glivec will miss out.”

Mr Moore acknowledged the hard work done by PHARMAC to bring a funding agreement to fruition. “Novartis and PHARMAC both knew that Glivec represented a huge leap forward both in the impact it has on cancer cells as well as in the overall safety and acceptance by patients.”

Data from a large head-to-head study comparing Glivec with a combination of interferon-alpha and cytosine arabinoside (IFN/Ara-C), a traditional treatment for CML, showed that 68% of patients treated with Glivec – given orally at 400 mg per day – achieved a complete cytogenetic response (elimination of the Philadelphia-positive

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chromosome) at 12 months. Patients treated with Glivec were nine times more likely to
achieve a complete cytogenetic response than those treated with the combination. In addition, Glivec significantly delayed the time to progression to the more advanced stages of CML.

Glivec was approved for the treatment of unresectable and/or metastatic GISTs in New Zealand in July. GISTs are relatively rare, with fewer than 30 new cases occurring each year in New Zealand. For patients with metastatic (spread outside the GI tract) or inoperable disease, median survival is approximately 10 to 12 months. Trial results released in May 2002 showed that 60% of patients with GIST achieved confirmed partial response (50% to 99% decrease in tumour size) to Glivec, and an additional 20% attained some degree of tumour shrinkage or stabilization of their disease. The data also revealed that at a median follow-up of 15 months, 73% of patients remained in the study.

Glivec, a signal transduction inhibitor, is one of the first cancer drugs to be developed using rational drug design, based on an understanding of how some cancer cells work. Glivec targets the activity of certain enzymes called tyrosine kinases that play an important role within certain cancer cells. The activity of one of these tyrosine kinases, known as c-kit, is thought to drive the growth and division of most GISTs.

Contraindications and Adverse Events
In the first-line study (IRIS), the safety profile with Glivec was similar to that of previous Phase II studies in other CML patients. Most adverse events were of mild to moderate grade. The most frequently reported drug-related adverse events with Glivec were nausea, vomiting, diarrhoea, oedema and muscle cramps. In the two arms, 2% of Glivec patients compared with 6% of IFN/Ara-C patients discontinued from the study due to adverse events. Additionally, 0.7% of the Glivec patients compared with 23% of the IFN/Ara-C patients crossed over to the control arm due to intolerance to therapy.

The majority of patients treated with Glivec in the Phase II CML clinical trials, upon which the initial approval was based, also experienced adverse events at some time. Most events were of mild to moderate grade, and the drug was discontinued for adverse events in 2% of patients in chronic phase, 3% in accelerated phase and 5% in blast crisis. The most common side effects included nausea, fluid retention, vomiting, diarrhoea, haemorrhage, muscle cramps, skin rash, fatigue, headache, dyspepsia and dyspnoea, as well as neutropaenia and thrombocytopaenia.

Glivec is often associated with oedema and occasionally serious fluid retention, GI irritation and severe hepatotoxicity. Because follow-up of most patients treated with Glivec is relatively short, there are no long-term safety data on Glivec treatment.
In the GIST trial that was the basis for GIST approval, drug was discontinued for adverse events in six patients (8%). In this clinical trial, the most common adverse events were edema, nausea, diarrhea, abdominal pain, muscle cramps, fatigue and rash. In this trial, seven patients (5%) were reported to have gastrointestinal bleeds and/or intratumoural bleeds. Gastrointestinal tumor sites may have been the source of GI bleeds.

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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.

About Novartis
Novartis AG (NYSE: NVS) is a world leader in healthcare with core businesses in pharmaceuticals, consumer health, generics, eye-care, and animal health. In 2001, the Group's businesses achieved sales of CHF 32.0 billion (USD 19.1 billion) and a net income of CHF 7.0 billion (USD 4.2billion). The Group invested approximately CHF 4.2 billion (USD 2.5 billion) in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ about 74,000 people and operate in over 140 countries around the world. For further information please consult http://www.novartis.com.

ends 4 November 2002

BACKGROUNDER

Chronic Myeloid Leukaemia

Chronic myeloid leukaemia (CML) is one of the four most common types of leukaemia. In New Zealand about 40 new cases of CML are diagnosed every year. Worldwide, CML has an incidence of 1 to 2 cases per 100,000 population per year and is responsible for 15 to 20 per cent of all adult leukaemias. It is usually fatal within five years of diagnosis if left untreated.

What causes CML?

CML is caused by an unknown abnormality in the DNA of the blood stem cells in bone marrow that leads to a cascade of further cellular abnormalities. Next, there is an abnormal transfer of genetic material between chromosomes 9 and 22, forming the so-called "Philadelphia" chromosome. This defective chromosome contains an aberrant gene (Bcr-Abl) which produces an abnormal protein (an enzyme called a tyrosine kinase). This protein drives uncontrolled production of white blood cells in the bone marrow, resulting in an enormous increase in their numbers in the blood. This abnormal condition is known as leukaemia.

Phases of CML

CML progresses through three distinctive phases:
 the chronic phase (typically lasting from five to six years),
 the accelerated phase (typically lasting from six to nine months), and
 the blast crisis (typically lasting from three to six months).
These phases 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 resistant to therapy and therefore more difficult to treat.

What are the current treatment options for CML?

 Bone Marrow, or Stem Cell, Transplant:
An allogeneic bone marrow transplant using healthy stem cells from the bone marrow of a closely matched donor currently offers patients the best hope for a cure. However most CML patients are not eligible for such a transplant because a suitable donor cannot be located. Another option in some patients is an autologous bone marrow transplant using their own blood stem cells after they have undergone intensive chemotherapy and radiation treatment. Although this therapy prolongs survival, almost all patients eventually relapse because, in part, their bodies still harbor malignant CML cells.

 Drug therapy:
A range of drugs is used in the treatment of CML including interferon-alfa, hydroxyurea, cytarabine and busulfan. Interferon (given via injection) is the current standard therapy for most patients who are not candidates for a bone marrow transplant. Interferon is not a cure, however, it may prolong the survival of some CML patients.

What is Glivec?

Glivec is a novel therapy designed to specifically target the cause of certain types of leukaemia.

It is the first, once-daily, orally (capsules taken by mouth) available “Tyrosine kinase inhibitor”. (pronounced tyro-zeen kin- ase)

Glivec directly interferes with the signal of the enzyme, tyrosine kinase, that promotes the growth of cancer cells in chronic myeloid leukaemia.
It is based on the principles of molecular targeting, killing leukaemia cells while leaving normal white blood cells alone, hence the concept of a "targeted therapy"

How does Glivec work?

Glivec selectively blocks the action of the enzyme, tyrosine kinase, so that it stops the proliferation of abnormal leukemia cells without harming normal cells.

Which types of leukemia can be treated with Glivec?

Glivec has been designed to target the abnormal “Philadelphia” chromosome, so it is expected to benefit patients with leukaemias caused by this abnormality.

The Philadelphia chromosome is most commonly present in chronic myeloid leukaemia, but may also less commonly be present in other forms of leukaemia, such as acute lymphocytic leukaemia (ALL) and acute myeloid leukaemia (AML).

How effective is Glivec?

Glivec is most effective when administered in the early stage of CML – known as the chronic phase.

Newly diagnosed patients in chronic phase – comparison of Glivec vs. interferon/cytarabine arabinoside
In May 2002, results of the first major Phase III study - which compared 1st-line use of Glivec and to 1st-line use of interferon – showed that Glivec was three times as effective as interferon in achieving a cytogenetic response in newly diagnosed patients in the chronic phase i.e.the cancer cells disappear from the bone marrow where they are produced. In the study, Interferon was administered in combination with cytarabine arabinoside, a form of chemotherapy. In addition, Glivec significantly delayed the time to progression to the more advanced stages of CML compared to the interferon combination therapy. The median time when data was collected was after 14 months’ treatment.

A major cytogenetic response (i.e. major disappearance of cancer cells ) was achieved in 84 per cent of Glivec patients and a complete cytogenetic response (i.e. complete disappearance of cancer cells) was achieved in 69 per cent. This compared with 30 per cent and 11.5 per cent respectively for the patients on interferon combination therapy.

Blood counts were normal in 96 per cent of Glivec patients in the study compared with 67 per cent on interferon combination therapy. This is called the haematological response.

In January, based on a review of the outstanding six-month results for Glivec in the study, an Independent Data Monitoring Board requested a change in the study protocol that enabled patients receiving interferon combination therapy to switch to Glivec if they had not achieved a major cytogenetic response after one year. At the time of this analysis, 39 per cent of interferon combination patients had crossed over to Glivec due to insufficient efficacy or intolerance.

Second line treatment of patients in chronic phase after failure or intolerance of interferon
Results from an international Phase II trial announced in March 2002 – which looked at the safety and efficacy of the drug in patients who had already failed treatment with interferon – showed blood counts were normal in 95 per cent of the 454 patients in the trial. (Only 60 – 70% of patients achieve normal blood counts when interferon is used first-line). There was a major cytogenetic response in 60 per cent of patients. Forty-one per cent of patients had a complete cytogenetic response at 18 months. The study investigators concluded that the leukaemia had either regressed or not progressed in 89% of patients in the trial.

Patients in accelerated phase
In the accelerated phase, the haematological response with Glivec treatment is 78 per cent and the major cytogenetic response is 26 per cent.

Patients in blast crisis
In the blast crisis phase, the haematological response with Glivec treatment is 29 per cent and the major cytogenetic response is 16 per cent.

Quality of life study
In June 2002, results of a Quality of Life study of 1049 patients showed that newly diagnosed patients with CML in the chronic phase had a significantly better quality of life than patients on interferon and standard chemotherapy. The data were derived from an analysis of the major Phase III study. Patients in the Glivec group were able to maintain their quality of life, whereas those in the interferon group experienced a decline in quality of life that was evident within the first month of treatment.

BACKGROUNDER

Understanding Gastrointestinal Stromal Tumours (GISTs)

Gastrointestinal stromal tumours (GISTs) are life-threatening soft tissue tumours located generally in the upper gastrointestinal tract. These tumour cells are derived from cells in the wall of the GI tract (interstitial cells or stroma). Approximately 60% of GIST cases occur in the stomach, 30% in the small intestine and 10% in other locations along the gastrointestinal tract. GISTs can metastasise (spread) to other organs, including the liver, as well as spread throughout the abdomen.

Incidence
GISTs are the most common malignant form of sarcoma (tumours arising from cells that form blood, bone, muscle and connective tissue) of the gastrointestinal tract, but are still relatively rare. Worldwide, there are approximately 12,000 new cases each year. There are about 10 new cases occurring in New Zealand each year. The incidence is highest in people aged 30 to 60 years.

Pathology and Diagnosis
GISTs are separate and distinct from other sarcomas of the GI tract. Some normal cells express a protein on their surface called Kit (CD117), the product of a proto-oncogene—c-kit. Kit is a growth factor receptor spanning the cell membrane. Its intracellular part is an enzyme called a tyrosine kinase. In the normally functioning gastrointestinal tract, cells that express Kit do not have this enzyme activity “turned on” all the time; whereas in GISTs, all are driven by a continuously activated enzyme, and in many GISTs, this is due to mutations in the c-kit gene.

Historically, the diagnosis of GIST has been based on careful morphological examination of the tumour cells and correlation with the behaviour of the tumour, yet GISTs remained difficult to distinguish from other GI sarcomas. Recent findings, including the description of Kit expression in all GISTs, co-expression of other receptors and cellular proteins, and more refined morphologic and clinical criteria, have provided additional guidance for physicians in accurately making this diagnosis.

Treatment Options
Until now, if surgery was not curative (removal of entire tumour with no residual disease), other options for treating GIST were limited and offered little hope for recovery. As opposed to some other sarcomas, GISTs are highly resistant to treatment with chemotherapy and radiation. Thus for patients with metastatic or unresectable disease, GISTs represent an incurable malignancy with a median survival of approximately ten to twelve months. However, since July 2002, Glivec® (imatinib)* has been available for the treatment of patients, in New Zealand, with Kit (CD117) positive unresectable (inoperable) and/or metastatic malignant GISTs.

The Ministry of Health approval for the GIST indication for Glivec is supported by data from an open-label, multinational study conducted in 147 patients with inoperable or metastatic malignant GISTs.

The effectiveness of Glivec in GIST is based on induced tumour shrinkage. The impact on patient survival has not been formally assessed in a randomised trial – i.e. comparing Glivec to no treatment - as such a trial design is not considered ethical in this situation.

Data which were presented at the 38th meeting of the American Society of Clinical Oncology in May 2002 showed that 60 per cent of patients with GIST achieved confirmed partial response (50 – 99 per cent decrease in tumour size) to Glivec, and an additional 20 per cent attained some degree of tumour shrinkage or stabilisation of their disease. The data also revealed that at a median follow-up of 15 months, 73 per cent of patients remained on the study.

Glivec is one of the first cancer drugs to be developed using rational drug design, based on an understanding of how some cancer cells develop and grow. Glivec inhibits the activity of selected tyrosine kinases, including the one associated with the Kit receptor, which drives the growth and division of GISTs.

ENDS

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