On March 13, 2017, the use of Novartis cell cycle inhibitor Kisqali® (ribociclib, LEE011) in combination with an aromatase inhibitor was approved by the U.S. Food and Drug Administration as a first-line treatment for postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

Kisqali is a selective inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 which are master regulators of the G1-to-S-phase transition of the cell cycle. The dysregulation of CDK4/6 in various cancers (including breast cancers) drives uncontrolled cellular proliferation, making them attractive targets for chemotherapeutic agents. Anticancer drugs with diverse mechanisms of action are often employed in tandem to circumvent tumor drug resistance. Aromatase catalyzes the final step estrogen synthesis and thereby promotes the development and progression of breast cancers. Aromatase inhibitors have been shown to be useful in such combination therapy regimens

The FDA approval of Kisqali was based off of data derived from the Phase III MONALEESA-2 trial, which compared Kisqali plus aromatase inhibitor letrozole versus letrozole alone. According to a Novartis press release, “[kisqali] plus letrozole reduced the risk of disease progression or death by 44 percent over letrozole alone, and more than half of patients (53%) with measurable disease taking [kisqali] plus letrozole experienced a tumor burden reduction of at least 30 percent.” Novartis further states that its ongoing MONALEESA clinical trial program is evaluating the use of Kisqali in other patient populations and in combination with other agents.

Kisqali arose out of a research collaboration between Novartis and Astex Pharmaceuticals. Astex scientists solved the crystal structure of human CDK4 in complex with a D-type cyclin, which was published in PNAS. According to an Astex press release, it “then applied its structure-based drug discovery technology, part of its Pyramid™ platform, in the collaboration that led to the discovery of LEE011, (now known as Kisqali).” Astex also announced that the FDA marketing approval triggers a milestone payment to the company, with royalty payments based on the sales of the drug also forthcoming.

The approval of Kisqali ends the two year monopoly that Pfizer’s breast cancer therapeutic Ibrance has enjoyed as the only marketed inhibitor of CDK4/6. According to Reuters, Novartis plans on pricing Kisqali at an 18-20 percent markdown relative to Pfizer’s competing therapeutic.