Glivec is Fraught with Problems

(02.08.2006) Glivec has been a ray of hope for cancer patients as well as a fat and juicy cash cow for its distributor Novartis. Now recent findings indicate that the award-winning anti-cancer drug has multiple hidden drawbacks such as bone loss and heart failure. Should patients be worried? By Winfried Koeppelle

When German cancer researcher Patrick Baeuerle was interviewed about new cancer therapies by Laborjournal one year ago, he was enthusiastic about the healing results of these new generation "wonder drugs". One of Baeuerle's most praised prime examples was Glivec (imatinib mesylate). But recent findings indicate that Glivec has multiple hidden drawbacks such as bone loss and heart failure. Could this be a terminal twist in the success story of this promising, five-year old target cancer therapy, which has been acclaimed as "the magic bullet for cancer"?

The bad news came out in spring 2006 when a study performed by US researchers and reported in the New England Journal of Medicine revealed that Glivec (in USA: Gleevec) could affect bone development (see also Lab Times 2-2006). The scientists found that Novartis' blockbuster against chronic myelogenous leukaemia (CML) and gastrointestinal stromal tumours (GIST) inhibits bone formation and remodelling. As a conceivable side effect cancer patients could therefore contract bone diseases (Berman et al. in: N Engl J Med 2006 May 11;354(19):2006-13).

Even when the public excitement appeared to calm down the next blow struck Glivec. US researchers at the Thomas Jefferson University (Philadelphia) published an online paper about cardio toxic effects related to the leukaemia drug on July 23rd in Nature Medicine (doi:10.1038/nm1446). They described 10 patients with CML who developed severe congestive heart failure (CHF) while being treated with Glivec.

Hitting the bull's eye? Glivec was apparently off-target.

Glivec is administered in tablet form (the recommended dosage is 400 to 600 mg per day). The active ingredient imatinib mesylate (for chemistry aficionados: a white or yellowish crystalline powder with the molecular formula C₂₉H₃₁N_7O * CH₄SO₃ and a molecular weight of 590) turns off the enzyme that allows cancer cells to grow: it inhibits the bcr-abl kinase.

Unfortunately Glivec inhibits similar kinases too: Further studies revealed that Glivec also turns off the Abelson tyrosine kinase protein ("Abl protein"), which has a maintenance function in cardiac-muscle cells and is necessary for their health.

The observed effects are a severe menace not only for Glivec and its users. The authors of the Nature Medicine paper warn that the adverse effect (the heart failure risk) could also be seen with similar drugs. At present dozens of further protein tyrosine kinase (PTK) inhibitors are being checked in clinical studies. Novartis' US rival Pfizer recently launched Sutent, another promising PTK drug with a huge financial capability. Further potent Abl inhibitors such as Tasigna (Novartis) and Sprycel (Bristol-Myers Squibb) are on the way. One can assume that these drugs will also show hitherto unknown adverse effects.

Has the "magic bullet" dream backfired?

But there's still hope for Novartis and its blockbuster which earned $2.2 billion in 2005, representing the Swiss' second largest selling product: The bone-loss finding was based on a small sample of only 16 patients and the cardiovascular study involved only 10 patients, so further studies are necessary to obtain results of greater significance. Nevertheless, the dream to have created the "magic bullet for cancer", capable of terminating it's target only, certainly seems to have backfired for now.