Potential New Target in Chronic Spontaneous Urticaria

Discussions at the American Academy of Dermatology annual meeting about chronic spontaneous urticaria (CSU) highlighted evolving skin-directed and immune-targeted therapies, but new research is challenging the view of CSU as a primarily immunoglobulin E (IgE)-driven condition.

In this exclusive MedPage Today video, Nicole Chase, MD, of St. Paul Allergy & Asthma in Minnesota, discusses the potential role of the Mas-related G protein-coupled receptor X2 (MRGPRX2) pathway in CSU, including early data on targeted inhibitors and what this evolving science could mean for patients who remain symptomatic despite current therapies.

Following is a transcript of her remarks:

Something that’s been really hot lately is this MRGPRX2. So this is basically, if you look at mast cells, mast cells are just really messy. They have a lot of receptors. They have a lot of ways to be activated. You can directly activate mast cells, you can indirectly activate mast cells.

We’ve always thought about mast cells in CSU as being IgE, and high-affinity IgE receptor, and antibodies against this or that or the other thing in that pathway. MRGPRX2 is a totally different way to activate mast cells. And so Septerna is one company — there are a couple now that have these MRGPRX2 inhibitors — and the Septerna story is fascinating. It’s an allosteric inhibitor. So if you were actually trying to block this receptor, it’s not like actually just putting gum in the lock. It’s actually like taking the door and folding it in half so you can’t even see the lock anymore. So it’s a really, really interesting mechanism.

They showed data on a really cool study, which was looking to see if patients that had wheals in response to icatibant (Firazyr), which is very, very strange to me, but using icatibant to induce wheals, which we know it can do, can you actually block that with this oral small molecule MRGPRX2 antagonist? And the answer is absolutely.

And so I think that it’s a whole different approach to CSU than we’ve ever seen before. Number one, is this what the majority of patients with CSU suffer from? Is it MRGPRX2 activation or is it IgE and Fc epsilon receptor one, high-affinity IgE receptor activation? Or is MRGPRX2 the reason why things like [omalizumab (Xolair)] and even [barzolvolimab] cannot actually, cannot fully block some of these pathways? I don’t know.

I think also that the Septerna data is cool in that you’re seeing this completely different approach with blocking the pocket of where the drug needs to bind to block where the agonist would bind by totally changing the conformation of the target molecule. It’s just really, really mind-blowing.

I have a lot of concerns about this. I don’t think about patients with hives as being the same as hives that you can induce with a drug. And the fact that they’re using icatibant, yes, there’s data to support doing this, but also it’s really weird to me that that was what their phase I looked at as opposed to actually looking at… I guess that maybe for phase I it makes sense, but I think for a phase II, they’re going to have to use real patients with real hives. Because the hives that you see in patients with CSU, I always like to say that it’s not the same kind of itching and hives as you get with a mosquito bite. I don’t have allergies, so I get a mosquito bite and I’m like, oh my gosh, this is so itchy. Patients with hives, I think that their intensity and just their quality of itch and of misery is way, way worse.

So I’m curious to see, is MRGPRX2 an actual pathway that needs a drug for CSU or is it just there and also true, true, unrelated, or is this actually a primary pathway that we’ve been missing out on by only targeting IgE? And then as well, this concern about, is this proof of concept? It makes sense for icatibant MRGPRX2 in a phase I. Is this actually going to work in phase II? I don’t know.

I’m super excited to see though because I think that this could be a really cool way to actually help some of those patients that, let’s say are omalizumab almost better, but not fully better. So could you actually use an anti-IgE type mechanism or maybe even a dupilumab (Dupixent)-type mechanism with an MRGPRX2 inhibitor? Maybe.