Gleevec: Improving it utility in exisiting indications; development for extended indications

DailyUpdates - February 10: A devastating disease with a poor prognosis for many patients, until recently CML has had few treatment options and, for the most part, these have succeeded only in delaying disease progression by up to a few years.

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder affecting 1 to 2 people per 100,000 annually. These disorders arise from genetic defects in haematopoietic stem cells, and are associated with an increased production of mature and immature blood cells, which affects one or all cell lineages. CML, like most myeloproliferative disorders progresses through various stages of increasing aggressiveness until the bone marrow is no longer able to produce functional immunocytes. CML is also able to metastasize to other sites in the body.

In adults, CML represents about 15% of all cases of leukaemia and is most often diagnosed in individuals over 45 years of age. Radiation, the first treatment for CML, was introduced in the 1920s with limited results. Chemotherapeutic agents followed in the 1950s and 1960s and increased the survival rate among patients with CML to about 5 years. Bone marrow transplantation arrived in the 1970s, and interferon-alpha appeared in the 1980s.

The approval of Novartis’ Glivec in 2001 represents one of the real success stories in the treatment of CML. In addition this product was one of the first targeted anti-cancer agents to be approved, acting through the inhibition of Bcr-Abl, the oncogene responsible for CML (see Pipeline Insight: Hematological malignancies-Targeted treatments and immunotherapy infuse new blood). Glivec is also able to inhibit c-kit and PDGF protein kinase activity. Inhibition of c-kit led to the approval (2002) of Glivec as a treatment of gastrointestinal stromal cell tumors, a cancer type that overexpresses this oncogene. PDGF is overexpressed in a wide variety of tumors and the development of Glivec for other indication thus continues.

Already generating $2.2 billion in global sales (2005 figures), Glivec is Novartis’ second highest revenue generator and the continued development of this blockbuster seems certain to increase these figures still further.

The February 10^th (2006) edition of DailyUpdates highlights a clinical study evaluating Glivec as a treatment of small cell lung carcinoma (SCLC). This type of cancer commonly express c-kit and its ligand, stem cell factor, suggesting an autocrine loop promoting cell growth. SCLC cells treated with Glivec in vitro undergo cell cycle arrest supporting this proposal. In the January 2006 edition of the journal Cancer, Johnson et al report the results of two Phase I studies that enrolled patients with extensive disease. In both studies patients were treated with Glivec in combination with the cytotoxic agents cisplatin and irinotecan. Although partial responses were observed in nearly all patients, toxicity was considerable and suggested to result from decreased irinotecan clearance in the presence of Glivec treatment.

Of interest c-kit, one of the molecular targets of Glivec, is expressed by interstitial cells of cajal, cells which play an important role in intestinal motility. A recent study by Shimojima et al, reported that Glivec was able to block rhythmic contractions in the small intestine. Since a significant fraction of irinotecan is cleared in the feces it is possible that Glivec reduced this fecal disposal of irinotecan leading to greater exposure to the drug.

A maximum tolerated dose for this combination with granulocyte-colony-stimulating factor support was however identified and further study of this combination is awaited. Recruitment is currently underway for Phase II studies.

The February 10^th (2006) edition of DailyUpdates also highlights a press release from Genzyme announcing the availability of a new diagnostic test able to predict resistance of CML patients to Glivec.

Despite high response rates to Gleevec, approximately 5% of patients who were initially treated successfully will develop resistance during therapy. Genzyme's new BCR-ABL Mutation Analysis test will assist physicians in evaluating resistance to therapy and facilitate appropriate adjustments to treatment.

The development of Genzyme’s new test is in line with their commitment to personalized medicine (this fields is evaluated in Personalized Medicine - scientific & commercial aspects)