Pushing the Self-Destruct Button

Breakthrough drug Venclexta charged onto the marketplace three months early to battle chronic lymphocytic leukemia. AbbVie’s (North Chicago, IL) and Roche’s (Basel, Switzerland) new therapy gained a quick approval after 80% of patients in the 106-person clinical trial responded to the small molecule inhibitor.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, with approximately 15,000 new cases diagnosed each year according to the National Cancer Institute. Let’s find out why the FDA awarded a Breakthrough Therapy Designation and discover what exactly causes Venclexta to push the self-destruct button.

17p Deletion

The term “leukemia” simply means an overproduction of white blood cells that do little more than continue to divide. CLL ultimately crowds out healthy cells due to the uncontrolled growth and accumulation of B-cells in the bone marrow and blood.

Venclexta is specifically approved for CLL patients who have a deletion in chromosome 17, known as 17p deletion; this deletion typically correlates with a poor prognosis. Today, approximately 10% of newly diagnosed individuals and 20% of those already undergoing treatment have this chromosomal abnormality. This mutation is identified by Abbott’s (North Chicago, IL) companion diagnostic Vysis CLL FISH probe kit, which the FDA approved in 2011.

Mechanism Of Action: Venclexta

Venclexta is a small molecule inhibitor of BCL2, a protein that inhibits apoptosis. Apoptosis is known as “cell suicide,” it is initiated within cells that have incurred a significant amount of DNA or cellular damage. In healthy cells, BCL2 can stop cell suicide from happening inappropriately. But in the 17p deletion type of leukemia, BCL2 is overexpressed, preventing those cells from initiating apoptosis even when damaged. Inhibiting BCL2 enables those apoptotic pathways to be activated, causing the cancer cells to flip the self-destruct switch. Venclexta is the first BCL2 inhibitor to be approved by the FDA.

The Playing Field

Prior to Venclexta’s approval, monoclonal antibodies such as Rituxan (Roche) and Campath (Sanofi; Paris, France) targeted proteins found on the surface of B-cells to fight CLL. Small molecule drugs also on the market included Imbruvica (Janssen Pharmaceuticals; Beerse, Belgium) and Zydelig (Gilead; Foster City, CA)—both are inhibitors of enzymes that drive forward cell division inside of cancer cells.

A Little Too Good

We don’t usually think a highly effective drug can cause a problem. However, sometimes potent cancer drugs cause “tumor lysis syndrome,” wherein tumor cells die at such a high rate that the release of their contents upon lysis (breaking open) can cause changes in blood electrolytes and metabolites. These changes can be dangerous and even fatal. During initial clinical trials, Venclexta was so effective that some patients showed signs of tumor lysis syndrome, which necessitated a lower dose as the trials moved forward.

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