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BOSTON—The rapid advance of Novartis’ CDK4/6 inhibitor LEE011 indicates that the company’s development program has moved into high gear. In October at the AACR meeting here, Novartis reported promising results in drug-resistant melanoma and drug-resistant breast cancer when tested in combination with other targeted therapies, and based on these preclinical results, several Phase I clinical trials were launched recently, according to results presented here at the AACR-NCI- EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 19–23. Since then, Novartis has disclosed that LEE011 would soon move into Phase III testing.
A total of 500 women are expected to be enrolled into the Phase III study of LEE011 and the trial is due to be completed in November 2016, according to NIH’s ClinicalTrials.gov website.
In many cancers, a tumor suppressor protein called retinoblastoma is deactivated because of an increase in the activity of the proteins CDK 4 and 6. This results in unchecked cell proliferation. The activity of CDK4/6 is regulated by cyclin D, whose expression is increased by activation of BRAF and PIK3CA, which are implicated in some melanomas and breast cancers, respectively. Drugs targeting BRAF and PIK3CA have had success, but most treated cancers subsequently develop resistance to these drugs.
“Chemistry optimization has led to the discovery of LEE011, which to our knowledge is the most selective CDK4/6 inhibitor to date,” said William Sellers, M.D., vice president and global head of oncology at the Novartis Institutes for Biomedical Research in Cambridge, Mass. “Utilizing the latest cancer genomics data and our knowledge of the role of CDK4/6 activity in the growth of tumor cells, we have identified unique indications and combinations of drugs with LEE011, in which LEE011 demonstrates a robust antitumor activity.”
Cyclin dependent kinases 4 and 6 (CDK4/6) control the entry into cell cycle progression by regulating the activity of Retinoblastoma protein (Rb). Upon mitogen stimulation, activation of the major signal transduction pathways (including MAPK and PI3K pathways) leads to increase of the abundance of D-cyclins, which activate CDK4/6 kinase activity, resulting in Rb phosphorylation and activation of E2F transcription factors. This series of events then allows cells to undergo DNA replication and proliferate.
The Rb pathway is universally inactivated in cancer to favor cell proliferation. Approximately, 80% of human neoplasms maintain functional Rb and have aberrations that increase the CDK4/6 activity (e.g., translocation and amplification of D-cyclins, amplification of CDK4/6 and inactivation of p16). In addition, Rb positive cancers driven by activated oncogenes that are upstream regulators of D-cyclins, including KRAS mutation and PTEN deletion, are expected to be dependent on CDK4/6 activity for growth.
Pfizer's rival drug palbociclib, which was granted a "breakthrough therapy" designation by the FDA in April, is already in Phase 3 trials, but Novartis' rapid progress means palbociclib could face competition sooner than expected. Like palbociclib, LEE011 will be tested in combination with a standard drug, letrozole, in postmenopausal women undergoing treatment for advanced or metastatic breast cancer.
Also like Pfizer, Novartis is hoping to use its drug beyond breast cancer. The website reveals a total of 11 clinical trials for LEE011 at various development stages, four of which are in breast cancer. Other earlier-stage studies with LEE011 are looking at melanoma, lymphoma and pediatric cancers.
Eli Lilly also has a CDK 4/6 inhibitor in development but it is further behind the other two drug companies.
Cancer drugs are expected to be the top-selling therapy area in the coming years, with sales in developed markets forecast to reach between $74 billion and $84 billion by 2017, according to pharmaceutical information firm IMS Health. Analysts currently expect annual palbociclib sales of about $2 billion by 2019, according to consensus estimates compiled by Thomson Reuters Pharma, and some think it could eventually reach $5 billion in annual sales if it is approved for multiple cancer indications.