Goodbye to the Last PI3K Inhibitor

Well, the last of the several PI3K Inhibitors for Follicular Lymphoma is no more. The manufacturer of Copanlisib voluntarily pulled it off of the market yesterday.

It's been a while since I wrote about the sad saga of PI3K inhibitors for FL. They showed lots of promise in early trials. They work by inhibiting, or stopping, an enzyme called PI3K, or Phosphatidylinositol 3-kinase. PI3K is a 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. So when one part of that chain has a problem, the cell refuses to die which is what cancer is -- a bunch of cells that refuse to die. A PI3K inhibitor stops that process so the cell can die as it is supposed to, after doing its job. 

And the PI3K inhibitors that were tested and approved did a pretty good job of stopping the things they were supposed to stop. But they ran into a bunch of other problems, too. One of them was safety. Side effects were more severe than expected, including some related to digestion. (One reason Copanlisib may have lasted as long as it did was because it was intravenous, rather then the once-a-day pill like the others. There was some speculation that helped Copanlisib bypass the stomach issues.) But another trial also found that there was a slightly higher risk of death among patients taking the inhibitor than there was in a comparison group. Not good at all.

I've written a lot about these in the past, so if you want to read more, you can go to this post, and then look for the links to take you to previous posts about the individual inhibitors and the problems they had.)

It seems to me that a lot of the problems with PI3K inhibitors came from the accelerated approvals they got from the FDA. (And as I give you this opinion, I will remind you yet again that I am not an oncologist, or a cancer researcher, or a pharma or FDA employee, or anyone else who is trained to know about these things. I'm just a cancer patient who reads a lot.)

The problem with the accelerated approvals was that, like all accelerated approvals, they were based on small phase 2 clinical trial results. The approval allowed the developers to start marketing the treatment, with the idea that a larger phase 3 trial was necessary for final approval. Those results were mixed. Copanlisib, for example, says that their phase 3 trial did not meet its primary endpoint -- the results did not show what they had hoped to show. No more details than that, but that's the issue.

Another problem, it seems to me, was that there were so many PI3K inhibitors developed at once. They were all slightly different -- different enough that the FDA approved them all.  But in practical terms, they were all competing for patients to join their phase 3 trials.  So a couple of them voluntarily pulled their inhibitor from the market because they couldn't get enough patients. The pandemic was a factor there, too, but having so much competition couldn't have helped.

With Copanlisib being withdrawn, that looks like the end for PI3K inhibitors for Follicular Lymphoma. I suppose it's possible that someone could try to develop a new one, or improve upon those that already exist, or keep trying them in combination with other treatments. But with the amount of time and money that goes into research, testing, and marketing for a new treatment, that doesn't seem likely to me.

Which is a real shame. PI3K inhibitors were one of those treatments that got oncologists really excited, based on early trial results. I always hate to see a treatment option be taken off the table.

I try to take hope in knowing that there are a bunch more treatments in the pipeline. Not all of them will get past stage 1 or stage 2 trials. Some of them might end up like these above, with early promise that's never fulfilled. But maybe a few will be available to us in the next few years.

All the more reason to get to those ASH abstracts.....