A review of the IL-23 inhibitors and their long-term and safety data.
Peter L. Salgo, MD: All right, let’s talk about some of the newer biologics.
Steven Feldman, MD, PhD: Bringing up newer biologics, to your point, these new drugs are the easiest and maybe the safest option. If there is an associated cardiovascular burden from even having that little bit of psoriasis, that it’s a sign of inflammation in your body, giving 1 of these fancy new medicines in theory might be reducing the cardiovascular risk. And the safety of them is so good that if it weren’t for the cost, it might be a very reasonable treatment.
Joel Gelfand, MD, MSCE, FAAD: That would be a great hypothesis to test, right? One would want to do a big trial, randomizing people who have limited disease to 1 of these biologics versus usual care, and see if it could change the natural history of what’s going on.
Peter Dehnel, MD: But wouldn’t you have to track those patients over the next 30 years?
Joel Gelfand, MD, MSCE, FAAD: Maybe not 30 but 5 years or so. As we talked earlier in the program, we don’t know who’s going to go on to have severe devastating disease. But we know who we potentially could prevent that in: people who show up in our office with psoriasis.
Peter L. Salgo, MD: Well, the problem is that if you’re going to do the study over 10 years, and they change insurance every 2 years, that’s 5 different insurance plans. Let’s back up for a second, we’ll go over the mechanism of action in the IL-23 [interleukin-23] inhibitors, which is what? Tildrakizumab, guselkumab, and risankizumab.
Joel Gelfand, MD, MSCE, FAAD: Well done.
Peter L. Salgo, MD: Thank you so much. You just bought the answer.
Joel Gelfand, MD, MSCE, FAAD: IL-23 is an inflammatory cytokine; it helps differentiate T-cells into Th-17 [T-helper 17] type cells. And their effector cytokine is IL-17, and they’re sort of a downstream effect that causes epidermal hyper perforation, and what we physically see, or clinically see as the psoriasis. And so the IL-23’s are really nice agents because they tend to promote high clearance rates of psoriasis. They tend to work over the long term, at least the older versions of it like ustekinumab. If you look at the odds of staying on that drug long term it’s higher with that class of drug than say the TNFs [tumor necrosis factor inhibitors], for example. And so those are some big advantages.
Some new things we need to figure out are how well will they do for the joints. Those studies are ongoing. None are currently FDA approved for psoriatic arthritis, and we’ll find out. We know that ustekinumab is approved now for Crohn’s disease. It may get approved for ulcerative colitis. That’s a big advantage for some of our patients, and we’ll find out if IL-23s play the same role there.
Steven Feldman, MD, PhD: I think one of the things we should point out is that 3 of the genes associated with psoriasis are interleukin-23 genes. Interleukin-23 consists of 2 subunits. The gene for each of those subunits is a link to psoriasis. The gene for the receptor is linked to psoriasis. In some ways, arguably probably for a lot of patients, treating this pathway is getting to the route cause of their disease, or at least I like to think that. Another way to think about it is if these genes are linked to the disease, the other alleles are linked to not having the disease, and so this is nature’s way of preventing psoriasis.
Peter L. Salgo, MD: So you’re telling me you’re a naturopath.
Steven Feldman, MD, PhD: It’s what my patients want.
Joel Gelfand, MD, MSCE, FAAD: But I think it’s a really important point that Steve brings up. In the 1960s and 1970s it was thought to be an epidermal disease. In the 1980s they started recognizing it was probably an inflammatory disease. In the early 2000s it was thought to be a Th-1 disease. It wasn’t until we understood the Th-17 arm in the immune system that it became clear that psoriasis was probably fundamentally a Th-17 disease. And that’s why the disease has such enormous response rates.
With some of our newer drugs, roughly 85% of patients are almost clear. You’ve never seen that with any other chronic inflammatory disease, right? If someone has Crohn’s disease or RA [rheumatoid arthritis], none of the biologics achieve remission rates in that percentage of patients. If it’s 20% or 30% you’re happy. And so, to Steve’s point, I think many of us feel like it’s probably the secret magic bullet, if you will.
Peter L. Salgo, MD: I know that you addressed this before, but just do it again. The long-term safety data, or do we just have short-term safety data of these drugs in this approach?
Steven Feldman, MD, PhD: Yes, we have several years with the IL-23. In the IL-12/23 we have data, it’s been used for over 10 years.
Joel Gelfand, MD, MSCE, FAAD: At least 10 years now, yes. I think ustekinumab, which blocks IL-12 and 23, has been around since 2009. It has a very strong long-term safety track record when it comes down to it. And then with the IL-23s, they are newer drugs, so we don’t have a decade of experience. We don’t have experience in people who may have higher rates of problems, like a history of cancer. But based on our mechanism, and then more targeted, we predict they should be as safe or safer than what we have with ustekinumab.
Steven Feldman, MD, PhD: You say based on the mechanism of action, we have people who have genetic deficiencies in the interleukin-23 pathway. You don’t even discover them in the United States. I think in countries where they give BCG [bacillus Calmette-Guerin] vaccinations they may get some atypical BCG vaccination. But at least in the United States, I think they walk around happy and healthy and we never even detect that they have it. You’re given the drug every 2 or 3 months, and so there’s some drug in your body. And then you go out 4 half-lives or so, there’s probably almost nothing there, and yet the disease stays quiescent.
Joel Gelfand, MD, MSCE, FAAD: There’s a clear pharmacodynamic effect of the drug where you put people in remission, they can remain in remission for many months without having any drug onboard. So they may be the first drugs that are truly disease modifying. In rheumatoid arthritis they talk about it’s a disease modifying drug, it’s going to lower risk of progression to joint damage. The sense is that IL-23s are probably disease modifying in a way.
In my clinical experience I have patients I’ve treated with those classes of drugs. And when they do well, they may come back years later off the drug and then psoriasis comes back, they may not be as bad as they ever were. They still have fairly mild disease.
Peter L. Salgo, MD: Can I take these 3 drugs, the tildrakizumab, guselkumab, and risankizumab, put them in a bucket and say that, in your experience, their risk profile is about the same? Or is there a difference among them?
Joel Gelfand, MD, MSCE, FAAD: What would you say Steve?
Steven Feldman, MD, PhD: From personal experience they all seem very safe. And I couldn’t say there was a lick of difference between them in terms of safety. I don’t have, it’s not like a clinical trial. I don’t have 1000 patients on each 1 carefully monitoring adverse event rates. Even if you look at the studies, which you see for serious infections, the rate is basically the same as the placebo.
Joel Gelfand, MD, MSCE, FAAD: Yes. I think within class we tend to think of the drugs as having more or less the same safety profile. Expect maybe in the IL-17 there’s a drug called brodalumab that carries a black box warning for suicidal thoughts. It’s part of a clinical conundrum, and we have to manage that for our patients. But within the class for the most part, the drugs have fairly similar safety profiles.
Steven Feldman, MD, PhD: Do you think that’s true with TNF inhibitors?
Joel Gelfand, MD, MSCE, FAAD: Well, infliximab probably has higher rates of serious infections, but clinically speaking, you have to treat thousands of patients to notice the difference between the 2.