If you’re a member of the Total Pharma Tracker service on Seeking Alpha (which I am an affiliate and contributor for), then you probably got a chance to see the full version of the acute myeloid leukemia (AML) (see the companion page on Invest Against Cancer by clicking here). Buried within the pipeline was AbbVie’s drug venetoclax, which is branded Venclexta.
It was buried not because there wasn’t something exciting there (the drug is a fantastic treatment for relapsed chronic lymphocytic leukemia), but because it hasn’t gone very far in clinical trials.
But here we are, with the announcement that venetoclax has been submitted to the FDA for review in the treatment of first-line AML. And spoiler alert: I think we’ll see the application get accepted in about two weeks, and venetoclax will be approved for AML by February 2019 or so. Today, let’s talk a bit about what venetoclax is (if you don’t already know), and why this movement is very important for the field of AML.
What is venetoclax?
Venetoclax is an inhibitor of an enzyme called Bcl-2, which is a protein that helps to regulate a process called apoptosis. This is where the cell recognizes that something is wrong; rather than let the cell die and spill its guts all over the tissue, possibly causing further damage, the cell will very carefully kill itself and cleanly dispose of its contents as much as possible.
Careful regulation of apoptosis is one of the most important cell functions. One of the hallmarks of cancer is to learn how to circumvent this program. A cancer cell that can avoid dying is a cell that can stay sick and divide.
Bcl-2 plays a critical role in helping to suppress apoptosis. Cancer cells can make larger amounts of Bcl-2 in order to suppress this process and stay alive. In particular, certain chromosomal changes can lead to increased expression of Bcl-2 in diseases like chronic lymphocytic leukemia and other hematologic malignances, as well as solid tumors.
Venetoclax blocks Bcl-2 from making critical connections with other apoptotic machinery, helping to stamp down the cancer cell’s ability to stay alive in the face of stress that is part of being a cancer cell. It has, so far, been approved for management of chronic lymphocytic leukemia that had prior treatment, and earlier this year we saw venetoclax get approved as part of a cocktail for relapsed disease.
Venetoclax continues to be investigated across a wide swathe of malignancies, including multiple myeloma, non-Hodgkin lymphomas, and acute leukemias. The latter is the subject of some recent big news for AbbVie, where they submitted a new drug application for venetoclax as part of treatment for newly diagnosed AML in patients who cannot tolerate standard therapy.
Clinical trial data
Early data first emerged at ASH 2015, where venetoclax was combined with either decitabine or azacitidine in older patients who could not take intensive chemotherapy. This study included 22 patients overall, and between 70% and 75% achieved a response.
This was all well and good, but it was still very preliminary. But they have been updated over time, and with more patients being included in clinical studies. The first big data presentation came out at the 2016 American Society for Hematology Congress. Roche, AbbVie’s partner in development, summarized the data in a corporate presentation.
Reduction in leukemia cells with venetoclax and azacitidine
This also translated into some encouraging overall survival data.
And overall, AbbVie and Roche have demonstrated highly favorable data in the relatively short time that venetoclax has been in development for AML. Here is an abbreviated timeline:
As you can see from the timeline, the updates to the two early-stage clinical trials continually improved over the years since their initiation. They started with modest-to-favorable overall response rates, which upgraded to favorable CR/CRi rates (CR is “complete remission,” and CRi is “complete remission without complete hematologic recovery). Most strikingly, at ASCO 2018 we saw a 40% rate of elimination of minimal residual disease, an endpoint of increasing importance.
Frankly, this alone will probably be a key driver of approval for the FDA.
Timeline from here
For venetoclax in AML, there are now several key catalysts we can anticipate. First and foremost, we will need to see the FDA accept the application, which should come by the end of July. Since the two indications described here have Breakthrough Therapy designation, I expect the application will get priority review status.
From there, it would be at most 6 months before we get a decision. This means that we should see approval for venetoclax in AML by March 2019 at the latest, assuming no major disasters befall the drug.
We should note, however, that this approval will be granted on a conditional basis, as the data are not robust enough to grant full approval. But AbbVie is already on the case, having initiated a pair of phase 3 trials, Viale-A and Viale-C.
- Inititated December 2016
- Targeted enrollment: 400 patients
- Patients ≥60 years old, ineligible for standard induction therapy
- Venetoclax + azacitidine vs placebo + azacitidine
- Initiated May 2017
- Targeted enrollment: 175 patients
- Patients ineligible for standard induction therapy
- Venetoclax + low-dose cytarabine vs placebo + low-dose cytarabine
These trials will likely serve as confirmatory studies for the accelerated approval of venetoclax in AML. This is an important feature for the FDA, who will likely make the approval conditional pending findings from these randomized studies. Of course, we have no way of knowing whether the findings will confirm the benefit of venetoclax. However, these data appear to represent an interesting improvement in overall survival over the low-intensity treatment options alone, which typically yield survival under 10 months.
What does this mean for Venclexta?
AbbVie has a strong chance with this application to finally move the idea of disrupting the anti-aptoptotic machinery in other tumor areas outside of CLL. If approved, it could open the veritable floodgates for venetoclax to be approved in a variety of heme malignancies. We may also see the expansion of this drug into other types of cancer. For example, there is already a trial ongoing incorporating venetoclax into treatment for metastatic breast cancer.
None of it is a slam dunk, of course, but it is a signal that AbbVie is about to take the venetoclax franchise well outside the bounds of dominating CLL treatment. I, for one, can’t wait to see what the result will be.
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