Discussing Risankizumb, Differences in IL-23 Inhibitor Epitopes with Christopher Bunick, MD, PhD

The importance of interleukin (IL)-23 to the pathogenesis of plaque psoriasis and psoriatic disease in general has become increasingly apparent in the past few years within the sphere of dermatology research.

This area of research was explored recently in a study titled ‘Structural Basis for p19 Targeting by Anti–IL-23 Biologics: Correlations with Short- and Long-Term Efficacy in Psoriasis,’ with one of the study’s authors being Yale School of Medicine associate professor Christopher Bunick, MD, PhD. Bunick spoke to HCPLive about his team’s findings and their implications.

“What we've realized is that as there's been an evolution in generations of IL-23-targeting biologics, that's a progression from targeting the p40 subunit, ustekinumab to the p19-specific subunits of IL-23, which are risankizumab, tildrakizumab, and guselkumab,” Bunick explained. “So this evolution, how we target interleukin-23 has really become clinically-apparent as these IL-23-targeting biologics have come to really dominate the clinical realm of psoriasis treatment.”

Bunick noted that his team sought to better understand the differences in these IL-23 biologic inhibitors and their relationship to psoriasis pathogenesis. He was asked how the structural differences in IL-23–binding epitopes among these inhibitors impact their clinical efficacy, particularly in terms of binding affinity, kinetic values, and long-term outcomes.

The team used epitope data that had been derived from hydrogen-deuterium exchange or crystallographic experiments, correlating the molecular properties of the inhibitor epitopes to their kinetic values, binding affinity, and clinical effectiveness scores for psoriasis.

The investigators had found that there were substantial correlations between the epitopes' surface areas, an inhibitor's dissociation rate constant (k_off), dissociation equilibrium constant (K_D) but not association rate constant (k_on). They also found that epitope surface area, K_D, and k_off each had been linked to both shorter-term and longer-term Psoriasis Area Severity Index (PASI)-90 response efficacy.

“What was really fascinating is that, when we looked at the different IL-23 biologics, there was certainly a difference in surface area among the epitopes,” Bunick said. “Risankizumab had the largest followed by guselkumab rather closely and then much lower down you had ustekinumab and then tildrakizumab.”

Bunick was later asked about some of the specific factors which could contribute to this superior efficacy with some of these drugs over others, and how they compare to the efficacy of the other IL-23 inhibitors.

“In the clinic, we know that risankizumab has been a very strong performer, if not the best performer, of the p19-specific biologics in treating plaque psoriasis,” Bunick said. “We feel that our paper and our analysis has done this to shed molecular insights into what really makes risankizumab different as a p19-targeted biologic, and I think there's a few key factors.”

Bunicke explained that the first factor is that the drug is binding a key loop region that no other biologic is targeting. The second factor is that it has the largest epitopes surface area, and he noted that this is significant because it has the lowest k_off rate.

“That means risankizumab is forming the strongest biologic complex with the IL-23,” Bunick said. “And that has clinical impact because if you're soaking up IL-23 with risankizumab and that complex is not coming apart easily, that IL-23 can't signal and can’t perpetuate the signal that's driving psoriasis.”

For additional information on the team’s results, view the full interview posted above.

The quotes contained in this interview were edited for the purposes of clarity. Bunick has served as a consultant for AbbVie, Almirall, Amgen, Eli Lilly, Janssen, Novartis, and UCB, though the other authors state no conflict of interest.