In my reading about cancer (which I do way more of than I would like), I've been seeing some articles about PI3K Inhibitors. Coincidentally, the journal Blood and Lymphatic Cancer: Targets and Therapy just published a review of PI3K inhibitors for CLL and Indolent Lymphomas. As a review article, it isn't offering any new research. It's more of a "here's where we are" article. But it's been a little under a year since the FDA pulled its support for PI3K Inhibitors for Follicular Lymphoma, so it's worth thinking about their possible future.
The article is called "PI3k Inhibitors in NHL and CLL: An Unfulfilled Promise," and I think that's a really great way of describing this class of treatments. One of the things that always struck me about this type of treatment was how excited oncologists got when they discussed it (at least in the videos I have seen, many of which I have posted). In theory, it's an excellent treatment. "Inhibitors" are things that inhibit, or stop something from happening. PI3K inhibitors stop an enzyme called Phosphatidylinositol 3-kinase. This is an important part of a chain of enzymes and proteins that turn switches on and off in a cell that allow the cell to grow and live. When something does wrong with the chain, the cell refuses to die. That's what cancer is, in its simplest form -- a bunch of cells that refuse to die. A PI3K Inhibitor stops that process. That's exciting -- especially since some of them were given as pill that a patient could take every day on their own.
The discovery of that chain of events, and the role of Phosphatidylinositol 3-kinase, was very important for Follicular Lymphoma research, since PI3K was especially important in B cells (the cells that become cancerous in FL). Several PI3K Inhibitors were developed, with slight but important differences between them.
Eventually, four of them were approved for Follicular Lymphoma patients. Because they showed promise in early trials, and were treating cancer in new ways than treatments that were already available, they were given accelerated approval by the FDA. This meant that they could be given to patients based on the results of a small phase 2 clinical trial. However, this approval came with the understanding that a larger phase 3 trial would be necessary for full approval.
And that's where the problems started showing up. You can go back and read what I wrote about the PI3K Inhibitors having problems and then having their temporary approvals taken away by the FDA -- Duvelisib in December 2021, Idelalisib in January 2022, Parsaclisib also in January 2022, and Umbralisib in February 2022. then in March 2022, the FDA discouraged the makers of Zandelisib from seeking Accelerated Approval.
The reason for all of this? Some of the phase 3 trials, which were supposed to confirm the good results from the smaller phase 2 trials, did the opposite -- they showed some new problems with side effects, including an decreased Overall Survival. In other words, instead of keeping people alive longer, there were a greater number of people dying in the trial than had died in the trial that they were comparing themselves to.
The FDA's solution to this was to cancel its temporary approval and insist that full approval would only come with a phase 3 Randomized Control Trial. What does that mean? The trials that had been set up were single-arm trials. A number of patients were given the treatments, and the results were compared to a trial from another treatment (the trial probably took place years before). The makers of the Inhibitor could then say, "See? Our treatment is more effective and/or safer than that other one." A Randomized Control Trial has two arms -- instead of looking back at the trial for another treatment, it's set up so that half the people in the trial get that other treatment directly, and half get the PI3K Inhibitor. This way, there can be more control over which patients are in the trial, and a direct comparison can be made.
But RCTs are expensive, time-consuming, and complicated. They are also the best way to know if a treatment is safe and effective.
However, one by one, the makers of the PI3K inhibitors announced that they were withdrawing their treatments. This was all happening at the height of the Covid-19 pandemic, and they were having trouble getting patients to enroll in their trials. Most decided that the extra expense and time wasn't going to be worth it. It seemed like they had planned on making money and recovering their research costs right away, and they weren't able to. Personally, I think there was too much competition as well, with too many PI3K Inhibitors on the market without enough to distinguish between them.
Business decisions aside, there were still problems with the treatments that needed to be overcome. As this article says, there are still some possible changes to PI3K Inhibitors that could make them safer without being less effective.
One is to change dosage. When they were approved, most had a daily dosing schedule -- the patient took a pill every day. But that constant treatment meant that their immune system was always suppressed. This led to more infections, some of which were fatal. Zandelisib was designed to get around this, with a different dosing schedule, with the patient getting the treatment for a couple of weeks, and then stopping for a couple of weeks. This seemed like it was helping with side effects. But its makers decided that it would be too expensive to continue to develop the treatment, and stopped all of its research (except in Japan).
So that's where we are -- an "unfulfilled promise."
It's too bad. From what I read, this does seem to be a business decision more than a medical decision -- the investment just isn't worth what it would cost to make the treatment safer and more effective (or at least, to find out if it can be made safer and more effective).
But the authors of the article still seem to cling to a small amount of hope that maybe something can come of it. My hope is that a small company will take this on, one that hasn't already spent millions of dollars, and will find ways to improve on this promising treatment.
I also think that failed research is never a failure, and that even if these treatments are never resurrected, researchers will still have learned something that will make some other treatments better.
We'll move forward, one way or another.
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