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The history of Glivec^® (imatinib) is one of challenges, innovation, perseverance, and success.

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The Glivec story begins in 1960 with an important breakthrough in cancer biology by Peter Nowell, MD, of the University of Pennsylvania School of Medicine, and David Hungerford, MD, of the Institute for Cancer Research, both in Philadelphia, Pennsylvania, USA. They identified an abnormally short chromosome in patients with chronic myeloid leukaemia (CML), which they named the "Philadelphia chromosome" (Ph chromosome) after the city in which they worked⁶. The Ph chromosome could be detected in approximately 95% of cells of patients with CML. Drs Nowell and Hungerford provided the first clear evidence that a population of identical cells could result from a genetic abnormality in a single chromosome and proliferate into a deadly malignancy.

It took some 13 years after the discovery of the Ph chromosome for researchers to shed light on the nature of the genetic mutation that produced this abnormality. Janet Rowley, MD, of the Franklin McLean Memorial Research Institute, University of Chicago, Chicago, Illinois, USA, discovered that the Ph chromosome results from a reciprocal translocation between chromosome 9 and chromosome 22⁷.

More than a decade later, researchers demonstrated that the translocation resulted in the juxtaposition of the ABL proto-oncogene, normally found on chromosome 9, with a previously unidentified gene on chromosome 22, later dubbed BCR for breakpoint cluster region⁸. In 1986, Yinon Ben-Neriah, MD, and colleagues at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, USA, reported results of in vitro studies demonstrating that the product of the fusion gene BCR-ABL is a 210-kD phosphoprotein (p^210BCR-ABL) associated with CML⁹. The fusion protein BCR-ABL is a tyrosine kinase with constitutive activity due to the abnormal juxtaposition of ABL with BCR. This aberrant activity results in the overproduction of white blood cells in the body. While blood from a healthy person contains 4000 to 10,000 white blood cells per cubic millimetre, the blood from a patient with CML contains 10 to 25 times this amount. The massive increase in the number of white blood cells characterises CML.

With the groundbreaking discovery establishing BCR-ABL expression as the molecular cause of the development of CML, medical researchers faced a rare opportunity. Unlike previous efforts with oncologic targets that were not well defined, BCR-ABL was a clear genetic target. This allowed the process of drug development to proceed rationally, with the goal of producing an agent to block the constitutive tyrosine kinase activity of BCR-ABL. Work began in early 1990 on the discovery of BCR-ABL inhibitors by researchers at Novartis (then Ciba-Geigy). The 2 lead researchers, Nicholas B. Lydon, PhD, and Alex Matter, MD, PhD, were particularly optimistic about one promising compound from a pool of several potential agents. The compound—a phenylaminopyrimidine derivative-had "lead—like" properties and good potential for diversity, allowing simple chemistry to be applied to increase activity and selectivity^10-12.

The task of improving this compound was assigned to 4 Novartis scientists: Dr Juerg Zimmermann (Medicinal Chemistry), Dr Elisabeth Buchdunger (Cell Biology), Dr Helmut Mett (Screening and Enzymology), and Dr Thomas Meyer (Enzymology). They soon began changing, adding, and deleting certain molecules to alter the original compound's activity against BCR-ABL.

After 2 years of painstaking experimentation, the team finally transformed the original compound —a weak, nonspecific inhibitor —into a potent, specific inhibitor of BCR-ABL. This agent effectively blocked the enzyme that leads to the proliferation of white blood cells in patients with CML. Their pioneering work led to a class of compounds with optimised activity against BCR-ABL and other kinases¹³. The result of this monumental achievement was the filing of the basic patent application covering this class of inhibitors in 1993 and 1995.

Building on the achievement of the development team, in 1994 Novartis began a collaboration with Brian J. Druker, MD, a haematologist-oncologist at the Oregon Health and Science University in Portland, Oregon, USA. Pursuing his interest in tyrosine kinases and CML, Dr Druker and members of the Novartis team profiled the activity of the compound that would eventually be called Glivec in cellular models of CML¹⁴.

The compound Dr Druker and other scientists studied showed selective in vitro activity against the BCR-ABL protein, and it suppressed the proliferation of BCR-ABL-expressing cells in vitro and in vivo. Of equal significance, unlike traditional cancer treatments, the compound did not demonstrate significant activity against normal cells¹⁴. The findings from this work were subsequently confirmed by other researchers^{15, 16}.

Over the next several years, Novartis conducted the additional research needed to start clinical trials, including elaboration of the chemical synthesis, studies of drug formulation, studies of pharmacokinetics, and toxicology screenings.

These studies led to the original reports on this class of inhibitor that were published by Novartis scientists in 1996¹⁷. While the results from initial oral bioavailability and toxicology studies showed promise, additional refinements were needed. Therefore, preclinical development of Glivec soon began, with Dr Lydon directing a multidisciplinary team of scientists. Drs Matter, Lydon, and Druker, together with David Baltimore, PhD, and Owen N. Witte, MD, would eventually be awarded the 2000 Warren Alpert Foundation Prize for their work with BCR-ABL. The Warren Alpert Foundation Prize recognises significant discoveries in the prevention, treatment, or curing of disease.

Glivec Clinical Development in CML

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