Molecular Differentiation of Dermatologic Therapeutics With Christopher Bunick, MD, PhD

At the 25th World Congress of Dermatology meeting in Singapore, Christopher Bunick, MD, PhD, an associate professor of dermatology and physician-scientist at the Yale University School of Medicine, was selected to present 3 in-depth sessions, all exploring the common theme of molecular differentiation of dermatologic therapeutics. Bunick, a Dermatology Times® editorial advisory board member, presented:

1. Unique molecular features of the Cutibacterium acnes 70S ribosome and its implications for antibiotic therapy in acne vulgaris

Key highlights include the way tetracycline antibiotics are binding to the ribosome of Cutibacterium acnes and how the discovery from Bunick’s lab that there's a second active site for sarecycline within the ribosome, impacts the reduction of antibiotic resistance risk for the use of the narrow-spectrum antibiotic, sarecycline.

2. Enhancing precision medicine: the structure of IL-23 inhibitor epitopes correlates with short-term clinical efficacy in plaque psoriasis

Key highlights include the differences between the p19-specific IL-23 inhibitors risankizumab, guselkumab, and tildrakizumab, and specifically the differences in the way their mechanisms of action work.

3. Clinically relevant differences in the chemical and structural mechanism of action of cAMP phosphodiesterase-IV inhibitors used in dermatologic therapy

Key highlights include the differences in how the 3 PDE4 inhibitors roflumilast, apremilast, and crisaborole bind to the PDE4 enzyme itself.

Transcript

Bunick: Hi, I'm Christopher Bunick, associate professor of dermatology from Yale University. I'm here live from Singapore at the World Congress of Dermatology 2023. It's an exciting meeting. I've given 3 talks here, and I wanted to highlight some of the key points that I educated the dermatologists about. The main theme that I had in all of the talks was really molecular differentiation of dermatologic therapeutics. I think it's really important that we understand well the medicines that we're prescribing for our patients, and what is it about their mechanism of action that really is driving efficacy and safety?

The first talk really focused on acne therapies and antibiotic resistance. So I talked about the differences between minocycline and doxycycline and sarecycline, the concept of broad-spectrum vs narrow-spectrum antibiotics, and how some of the new research out of my laboratory into Cutibacterium acnes and the way the antibiotics, tetracycline antibiotics in particular, are binding to the ribosome of Cutibacterium acnes and how the discovery our lab made that there's a second active site for sarecycline within the ribosomes, how that impacts reduction of antibiotic resistance risk for use of the narrow spectrum antibiotic, sarecycline. And so we're really emphasizing the concepts of antibiotic stewardship and lowering antibiotic resistance by really understanding and improving the targeting of our tetracycline as well as other antibiotics to incorporate both active sites that we've discovered are really relevant in the ribosome to antibacterial therapy. I also emphasize the role of the anti-inflammatory properties of tetracycline antibiotics, which is I think is a sometimes misunderstood area in dermatology because our patients often scared sometimes to take oral antibiotics because of the risk of antibiotic resistance, but they don't always realize that some of the purpose behind using antibiotics like tetracyclines in dermatology, not just in acne, but beyond, is because they have potent anti-inflammatory properties. And so I discussed that as well.

In the second talk, I really focused on psoriasis. I think that there's a lot of confusion among dermatologists about the differences between the p19-specific IL-23 inhibitors. And what I wanted to do in my talk was I wanted to show how risankizumab, guselkumab, and tildrakizumab were very different in terms of the way their mechanism work. Yes, they all target p19, but they target very different epitopes on p19. And this has real clinical consequence for how the drugs work in terms of binding affinity, dissociation rate constants, as well as we showed that the epitope’s surface area actually statistically significantly correlates with some of these kinetic parameters of the of the drugs. And so this was, I think, a really important topic and it was really nice to be able to show the audience the real difference on how these p19-specific biologics work, particularly the areas of the epitopes that are different, and risankizumab in particular, showing how it targets a specific loop in p19 that the other p19 specific biologics don't target. I think this is a major differentiator between those particular biologics.

Lastly, I just got done talking about PDE4 inhibitors, and what I really wanted to accomplish here was to explain from a biochemical point of view, why all three of these PDE4 inhibitors available in dermatology today, which are roflumilast, apremilast, and crisaborole, how they're very different, and they're all very different medicines, even though the goal is to accomplish the same thing which is PDE4 inhibition and lowering inflammation in our skin. What I showed for these three PDE4 inhibitors is that the way they bind the PDE4 enzyme itself is very different. Roflumilast has three major points of stability in its binding mechanism. Apremilast has a kink, or an almost 90-degree bend in the molecule that I think actually decreases some of the potential binding affinity of that particular medicine. And crisaborole, on the other hand only has one particular anchor point, not three like roflumilast. So there's actually a wide range of ways in which the chemistry is happening in terms of the binding of the PDE4 enzyme. And this has major consequences for the affinity and I believe the efficacy of these therapies in dermatology patients. So, it was really good to get up there and tell my fellow dermatologists about how the chemistry and mechanism of action of these drugs are not only different, but why it means that from a clinical perspective, you can't just assume that because all the medicines are in one class, that they're all the same. In fact, I think whether it's anti-TNF inhibitors, whether it's tetracycline antibiotics, whether it's p19-specific biologics, or whether it's PDE4 inhibitors, what we're showing through the research in my laboratory is that these medicines are very different, and we as dermatologists have to understand the nuances of these differences because it matters to our patients.

Lastly, I'd like to tell everyone that the 2027 World Congress of Dermatology is going to be in Guadalajara, Mexico. So get ready and hope to see you in four years in Guadalajara.

[Transcript edited for clarity]