When AbbVie was first moving through testing for its newly approved chronic lymphocytic leukemia (CLL) drug Venclexta, its researchers made a key observation. Patients who had a certain chromosomal abnormality that makes treatment of CLL more difficult were responding equally as well to the drug as other patients.
CLL tends to be a slow-progressing cancer in most adults. But people with this abnormality, known as 17p deletion, face a particularly grim prognosis and often die within two to three years. At the same time, this chromosomal defect renders other treatment options, such as chemotherapy or the drug rituximab, less effective.
Venclexta, however, seemed to work just as well in people with 17p deletion as in those with regular CLL. That observation shaped AbbVie’s approach to bring Venclexta to market.
“We made the observation and said this is a place we can make a difference for patients. It also gave us a relatively, we hoped, quick path to an approval,” said Dr. Gary Gordon, vice president of Oncology Development at AbbVie.
That bet paid off, with the Food and Drug Administration granting the drug a breakthrough designation in May 2015, and then approving it for treatment of relapsed, refractory CLL in patients with 17p deletion earlier this month.
AbbVie hopes this approval will be just the start, aiming to widen Venclexta’s indication to include treatment of other blood cancers, and possibly solid tumors as well. Forecasts have pegged the drug to hit nearly $1.5 billion in annual sales by 2020, potentially giving AbbVie a cornerstone oncology treatment, as its best-selling drug Humira faces generic competition.
A new mechanism of action
Venclexta is the first drug approved by the FDA to target the so-called B-cell lymphoma 2, or BCL-2, protein. Targeting this protein is a new approach to treatment and stems from research first done in the 1990s studying a cellular process called apoptosis, or programmed cell death.
The human body has many trillions of cells and every day billions of them die. The programmed cell death process helps manage this in an orderly way, allowing the body to replace damaged cells and grow new ones.
Cancer, however, can subvert this process, switching off apoptosis and preserving mutated cells from being destroyed. The BCL-2 protein helps cells do this by acting as a kind of sponge holding back other proteins which prompt cell death.
“What ABT-119 [AbbVie’s ID for Venclexta] and what the family of drugs that Abbvie and others have been working on do is they essentially come over and squeeze the sponge,” explained Gordon. “They force the pro-apoptotic family members out of the sponge.”
“When they get forced out of the sponge, they allow the cell to go ahead and die,” he said.
Venclexta proved effective in inhibiting the BCL-2 protein, thereby restoring apoptosis. This was true even among those 17p patients who usually responded poorly to treatment. In a trial of 106 previously-treated CLL patients with 17p deletion, the overall response rate—a percentage of patients whose cancer shrinks or disappears—was 80%, leading the FDA to grant accelerated approval.
Scope for wider indications
17p deletion only occurs in 3% to 10% of previously untreated CLL patients, and up to 30%-50% of relapsed/refractory cases, limiting Venclexta’s initial use. But AbbVie appears set to follow up with applications for further indications.
Gordon gave a hint of just how broad these plans are: “For us, it is an exciting program because this first indication in this kind of heavily pretreated difficult-to-treat CLL setting is what we hope will be the first of a whole series of indications for this drug, not only in CLL but in other hematologic malignancies like non-Hodgkins lymphoma, multiple myeloma, Waldenstrom macroglobulinemia, multiple myeloma, AML, and potentially even solid tumors.”
All told, AbbVie and its development partner Roche have 16 programs in clinical development across CLL, non-Hodgkins lymphoma, multiple myeloma, and acute myeloid leukemia, many of which are in combination with Rituxan (rituximab) and Roche’s drug Gazyva. In the U.S., AbbVie and Roche are jointly commercializing the drug, while AbbVie has sole responsibility outside the U.S.
According to earnings documents from Roche, the companies plan to submit a Venclexta/Rituxan combo for treatment of relapsed/refractory CLL to the FDA in 2017. Three others are set for 2019 and beyond.
One of the challenges AbbVie had to overcome in Venclexta’s development was the possibility of tumor lysis syndrome.
When drugs are very active—like Venclexta is—they can cause cancer cells to die very quickly. Rapid and widespread cell death spills cellular contents out into the bloodstream and can lead to a number of serious problems, like high levels of potassium or uric acid.
AbbVie needed to find a way to minimize this risk while maintaining the drug’s effectiveness at killing cancer cells, just in a more organized fashion.
“We have a very rational approach to how to dose patients where we gradually increase the dose of the drug one week at a time over a period of about five weeks,” Gordon explained.
With this escalating dose schedule, AbbVie was better able to counteract the effect of tumor lysis. But adverse effects, including tumor lysis, were still an issue during clinical trials. In earlier stage trials of 240 patients, serious adverse reactions were reported in 43.8% patients. However, in 66 CLL patients who received escalating doses, 6% experienced tumor lysis. Other serious adverse events reported in the earlier trials included pneumonia, low white and red blood cell counts, and fever.
A 2016 Drugs to Watch report from Thomson Reuters Cortellis pegged Venclexta for $1.477 billion in annual sales by 2020, which would make the drug a significant contributor to AbbVie sales. For comparison purposes, the biggest seller in 2015 after Humira (which took in over $14 billion) was AbbVie’s hepatitis C treatment Viekira Pak with $1.64 billion in revenue.
The Thomson Reuters’ forecast predicts relatively steady growth for Venclexta from year to year, with a predicted $168 million for 2016 sales. As the FDA only approved the drug on April 11, Venclexta probably will not show up in earnings reports until the second quarter. With only three quarters of the year to rack up sales, a strong launch will be important to meet that forecast.
Some of the stiffest competition for Venclexta might come at first from Imbruvica, a drug AbbVie comarkets with Janssen. AbbVie acquired the drug when it bought Pharmacyclics in May 2015 for $21 billion.
Imbruvica is currently approved for CLL, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia and pulled in $754 million for AbbVie last year. It also has a long tail of potential indications. Adding Venclexta though should give AbbVie a more robust presence in oncology.
AbbVie also has announced new investments in preclinical oncology development, signing collaboration deals with Argenx and CytomX this week for several immune-oncology assets. With increased competition for Humira set to enter the market over the next several years, it will be important for AbbVie to offset that with new growth products.