Back in 2018 I wrote about a deal between Bristol-Myers Squibb and Nektar Therapeutics. I called that one “a steep price” and “a big gamble”, but I wasn’t exactly putting myself out there by writing in those terms. BMS paid way over a billion dollars up front (in cash and stock purchases) for a rather early-stage asset, NKT-214. Of course, it was an early stage asset with a lot of potential. NKT-214, also known by the extremely unsightly generic name of bempegaldesleukin, is a pretty interesting molecule. It’s a modified form of human interleukin-2 (IL-2), which in its original state is an immune system cytokine secreted by T cells to regulate the activity of other T cells and several classes of white blood cells.
Like anything involving immunology, the mechanisms are complex, not least because IL-2’s activity can be mediated by any of three major cellular signaling pathways (JAK/STAT, PI3K, and MAPK/ERK). Calling up a detailed diagram of any of those pathways has even odds of inducing a migraine if you’re not desensitized to that stuff, so hitting all three in some combination is quite a set of chords being played on the Big Multikeyboard Cellular Signaling Harmonitron. But suffice it to say that IL-2 is very important in immune tolerance and in damping down responses to avoid autoimmune disease. It can play both sides of that mechanism, though: it causes formation of more regulatory T cells (T-regs), which keep other immune cells turned down, but it can also stimulate CD*+ T cells, which are on the attack. There’s a vast amount of tightrope-walking stuff like this in immune regulation, and there’s surely more that we haven’t quite grasped yet.
NKT-214 is a modified version of IL-2, with several polyethylene glycol (PEG) chains attached. PEGylation is a widely used method to modify the behavior of proteins – it can change their function, distribution, and half-life depending on how you attach these things. In this case, the PEG groups are designed to gradually fall off, and they’re placed in a region of the protein where they interfere more with IL-2’s T-reg activities. The protein’s half-life is greatly extended (IL-2 normally vanishes pretty quickly), and it starts out so PEGylated that it’s basically inactive. But as time goes on, and the PEG groups start dropping off, it starts picking up activity on the activating-CD8+ side, while still being unable to do much on the T-reg side. Eventually, it loses all its PEG groups and is just back to regular IL-2 function, but (as mentioned above) that doesn’t last long at all before the protein is cleared out. The net effect is a long period of T-cell stimulation, which is a pretty slick mechanism.
BMS was interested in this, as you’d figure, as an addition to the immuno-oncology portfolio. Specifically, they wanted to combine it with Obdivo (nivolumab), their antibody that blocks PD-1 function. PD-1 has the effect of turning away active T cells (it’s a so-called “don’t eat me” signal), and some tumor types are known to take advantage of this to evade immune attack. Blocking PD-1 then can cause these tumors to suddenly start appearing like targets to the immune system, and the hope was that combining this with a T-cell stimulating mechanism like Nektar’s would lead to even greater effects in the clinic. Trials have been underway in melanoma patients with inoperable and/or metastatic disease.
And you know where this is going. To be honest, dark clouds have been slowly gathering for a while now. Phase I results looked like they might be promising, but Phase II melanoma data were not as compelling as people had hoped. And the combination also failed to impress in triple-negative breast cancer. But the companies announced today that adding NKT-214 showed no benefit over treatment with Opdivo alone in Phase III, sadly. This was the first interim analysis of the data, and the combination failed on response rate and failed on progression-free survival: it simply did not work. This also led to the decision to unblind another melanoma trial with the two drugs, but other studies in renal cell carcinoma and bladder cancer are continuing. And quite rightly; you really never know, and those are different varieties of cancer with their own behavior. The combination therapy could still prove to be of benefit somewhere, but that has become an increasingly long shot after the results so far, and after seeing it now fail completely in melanoma. Mechanistically, you’d have ranked that as the most likely place to see an effect, so this is very bad news for BMS, for Nektar, and most of all for cancer patients and their families.
That’s the immune system for you, though. A lot of ideas that have looked like they would work fine have either done nothing or backfired, while some others have worked out better than people could have anticipated. And you can’t be sure until you’ve tried multiple times – Alkermes is another company with an IL-2 therapy that’s looking to add to PD-1/PD-L1 therapy, for example. As we’ve seen through the pandemic, all attempts to modulate the immune system have to be proven eventually in human clinical trials; we have no other way to be sure. Unfortunately, there’s also no way to prove these things in clinical trials other than by spending a great deal of time and money. And we’re seeing that today. . .
