A specialist in the treatment of plaque psoriasis reviews the mechanism of action for IL-23 inhibitors and examines the dosing and administration of tildrakizumab, guselkumab, and risankizumab.
Brad Glick, DO, MPH: Hearing this conversation about newer therapies, specifically biologic therapies, prompts me to ask George to tell us about the landscape for treating patients. Over the last 3 or 4 years, these new interleukin-23 blockers have come to market, and the whole Th17 cytokine pathway, including 17 blockers and 23 blockers, have revolutionized our treatment of patients with psoriasis. Talk to us a little about that, then reiterate the mechanism of action of interleukin-23 blockers. Then talk about what’s in that particular class of agent-switch therapies.
George Han, MD, PhD: The IL-23 inhibitors are, as a whole, the newest class of medicines. They’re differentiated from IL-12/23 inhibition in that—well, ustekinumab blocked the P40 subunit, and these all block the P19 subunit that should make the IL-23. Back in the mid-2000s, when ustekinumab was developed, it was thought that both those IL-12/23 inhibitors worked together, but it was thought that L-12 was the predominant cytokine of the 2. Since then, we’ve come around and realized that that doesn’t seem to be the case. When you analyze mRNA [messenger RNA] from lesional tissue—nonlesional psoriatic skin vs healthy controls, for example—we see that the levels of IL-12 are consistent among all 3, and what we see is that in lesional psoriasis skin, IL-23 is much higher, so that’s 1 piece of evidence that supports that.
There were some interesting studies done. There was a Nature Communications paper published in 2016 that looked at IL-12 inhibition—wild type vs inhibiting IL-12—and the title of the paper was “IL-12 Protects From Psoriatic-Formed Skin Inflammation.” The suggestion was that it’s better not to touch IL-12. On the side, there are some functions of IL-12 that are protected. It’s effective against certain infections—salmonella and microbacterial infections are among them—and it does seem to have a regulatory role in tumor modulations, so it’s basically preventing invasion. When you think of it, there are some reasons. There’s a rational decision to block IL-23, aside from the fact that, with more specific inflammation, you can perhaps get a higher blockade with less trade-off. In that sense, it’s been a great boon that we’ve had access to these IL-23 inhibitors.
The other nice thing is that, as a class, they generally have longer dosing regimens, so there’s a longer time between doses. Patients like fewer injections, and they offer an effective, clean safety profile. It looks like IL-23 inhibition, just like IL-12/23 inhibition, may be a promising treatment for inflammatory bowel disease as well. There are a lot of interesting, subtle differences that set this apart from previous available treatments.
Brad Glick, DO, MPH: Because I have you, why don’t you go over the 3 representative agents in the class of interleukin-23 blockers and quickly tell us their dosing regimens and frequency?
George Han, MD, PhD: What’s nice about IL-23 inhibitors is that they all work the same way. We don’t have different targets, receptive blockers, or cell blockers. They’re all the same thing: P19 subunit inhibitors. There’s tildrakizumab, guselkumab, and risankizumab. Of the 3, the first 1 approved was guselkumab. That 1 has a dosing, first at week 0, then 1 month later, 4 weeks later, and then every 2 months. Some of the differentiators are that it comes as a prefilled syringe, but it also comes with an auto-injector device. The intent is so patients—instead of with the click-pen devices, where there is a 6/10 rate of infusion—control the rate by the pressure from their palm a little. Supposedly, that’s designed to be a little more ergonomic. When you look at the next 1 that came out, tildrakizumab, the differentiator is that dosing is at week 0, week 4, and then every 3 months after that, instead of every 2 months. That 1 is indicated for health care practitioner administration, meaning that it’s not intended for patients to self-administer.
Sometimes, we have patients who are health care proficient, have a medical assistant, or have a nurse in the house. They can technically do it that way, but it’s indicated for HCP [health care professional] administration. There’s no real scientific reason for this. My understanding is it’s just the way that the trials are set up, but that’s 1 differentiator. Finally, there’s risankizumab, which is dosed at weeks 0, 4, and then every 12 weeks, or every 3 months thereafter. Risankizumab is available as a prefilled syringe. They’re going to be out with an auto-injector, but previously, it was 2 syringes for each injection. These are very similar medicines, and they’re quite effective. What I like about the IL-23 class is it seems to have good longevity in terms of treatment efficacy and in lasting durability.
Brad Glick, DO, MPH: That’s very helpful.
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Transcript edited for clarity.