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AbbVie Venclexta, Abbott CDx Approval Provide Docs Opportunity to Individualize CLL Treatment


NEW YORK (GenomeWeb) – The US Food and Drug Administration this week approved a new personalized, oral drug for a molecularly defined subset of chronic lymphocytic leukemia (CLL) patients who have relapsed or are refractory to chemotherapy.

Venclexta (venetoclax), which AbbVie developed and markets with Genentech in the US, targets B-cell lymphoma 2, a commonly overexpressed protein known to drive cancer in CLL patients. The agency approved the drug for patients who have received prior therapy and have a 17p deletion as detected by Abbott Molecular's Vysis CLL FISH probe kit.

"In initial studies with patients who had been previously treated for CLL with multiple lines of therapy, the usual predictors of who was and wasn't going to respond didn't seem to be holding," Gary Gordon, AbbVie's VP of oncology development, told GenomeWeb. 

The National Cancer Institute estimates there are 15,000 newly diagnosed CLL patients each year, making it one of the most common types of adult leukemias. The 17p deletion leads to the loss of the TP53 tumor suppressor gene. Approximately 10 percent of treatment naïve CLL patients have the 17p deletion, but as patients get treatment and become resistant, around 30 percent of patients acquire the deletion.

According to published literature, those with 17p deletions have the shortest median survival among CLL patients. "This is a group of patients who we know don't have a really good option," Gordon said. "And it is a population that can be identified with a diagnostic test."

In order to garner FDA accelerated approval for Venclexta, AbbVie conducted a single-arm study of around 100 CLL patients who all had the 17p deletion and had received prior treatment. The study participants took the drug every day for five weeks, starting with a 20 mg dose and increasing to 400 mg. In the study, 80 percent of the patients had a complete or partial remission. 

Common side effects due to the drug included low white blood cell count, diarrhea, and nausea, and serious adverse events included pneumonia and low white blood cell count with fever. The FDA noted that patients taking Venclexta should not receive live attenuated vaccines.

Venclexta is the first approved drug targeting BCL2. In lymphocytes, high levels of this protein throw off the normal process by which cells die and regenerate, which allows cancer cells to thrive. Gordon likened BCL2 to a sponge that holds on to other proteins that allow cells to die. Venclexta interacts with BCL2 in a way that "pushes out these pro-death signals," he said. Specifically, the drug causes the cells' energy-making factories, the mitochondria, to leak, which in turn kills cells. 

"Different cancers can have high levels of BCL2 … or high levels of the pro-death proteins," Gordon said. "And understanding the distributions and ratios will be really important in understanding which tumors are going to respond to which drug."

Meanwhile, studies to date suggest that CLL patients regardless of 17p deletion status respond well to Venclexta. In the journal Blood this week, researchers led by Mary Ann Anderson from the Walter and Eliza Hall Institute of Medical Research in Australia reported data from a study in which they explored Venclexta's mechanism of action and found that in in vitro experiments cancer cells died regardless of 17p status, TP53 mutation, or TP53 function.

Although, historically, CLL patients with 17p deletions didn't have good treatment options, Venclexta is part of a new wave of targeted agents that's starting to improve the standard of care, Matthew Davids, a physician at Dana-Farber Cancer Institute and a senior author on the Blood paper, told GenomeWeb. In recent years, the FDA has approved new agents, such as Gilead's Zydelig (idelalisib) and Janssen/Pharmacyclics Imbruvica (ibrutinib), which seem to be useful options for this subset of patients.

Although Zydelig and Imbruvica did not come with their own companion diagnostic, Venclexta's CDx will be beneficial to doctors trying to carve out individualized treatment strategies, Davids believes. He noted ongoing studies that suggest that Venclexta and Imbruvica, for example, might impart comparable response rates in CLL patients with 17p deletions, but they might experience longer progression-free survival on Venclexta. Moreover, this subset of patients doesn't seem to achieve complete remission with these other drugs like they do with Venclexta, he noted.

"If you run the test, and the patient does not have the 17p deletion, you may think about other options besides Venclexta, whereas if you see the 17p deletion, then you might choose Venclexta," he said. "So, if [the test] is positive, it makes it more likely you'll use this therapy."

The FDA has indicated Venclexta for CLL patients with 17p deletions as determined by an FDA-approved CDx. The agency defines a CDx as an "in vitro diagnostic device … that provides information that is essential for the safe and effective use of a corresponding therapeutic product."

But the available and evolving efficacy data on Venclexta suggests that doctors may not use the CDx as strictly as that. "It's not like a traditional [CDx for] like an EGFR mutation," where a positive result means physicians prescribe an EGFR inhibitor in lung cancer and if it's negative they don't, Davids said. "If you don't have a 17p deletion, you can still use Venclexta and it's expected to be just as effective."

Venclexta has orphan drug status and the FDA granted the drug application breakthrough therapy designation because it is for a population that lacks treatment options. Since the agency approved the drug under an accelerated timeline, based on its impact on overall response rate, the sponsor will need to submit additional data on the safety and efficacy of the drug in order to garner full approval.

According to the FDA's approval letter to AbbVie, the sponsor has to submit by 2019 data from a Phase III study comparing Venclexta in combination with Rituxan (rituximab) versus bendamustine and Rituxan in relapsed or refractory CLL patients with 17p deletions.

Based on published reports, AbbVie has priced Venclexta at $109,500 for a year's supply. The company, of course, would want to make this drug — estimated to eventually bring in $2 billion a year — a frontline option in CLL.

There are studies exploring how patients with early-stage CLL and 17p deletions will respond to Venclexta in combination with other drugs. In the frontline setting, the goal is to "drive patients to have very deep responses," so they are ultimately negative for minimal residual disease, Gordon said.