Skin in the Game: Advancements in the Pathophysiology of Psoriasis

Disclaimer (00:00 – 00:20)

• This is an educational program sponsored by UCB

• The information contained within this podcast is for your educational purposes only and is not intended to be medical advice

• The guest speakers have been compensated for the presentation of this educational information

• Healthcare providers should exercise their professional judgment when treating their own patient

 

Introduction (00:20 – 01:31)

(music)

Dr Friedman (00:25)

Welcome to the first podcast in the PSOrting It Out Dermatology podcast series, Skin in the Game: Advancements in the Pathophysiology of Psoriasis. I'm your host Dr. Adam Friedman, professor and chair of dermatology at GW School Medicine and Health Sciences. The goals of this podcast are to provide an overview of the key advancements in the understanding of the pathophysiology of psoriasis over the past two decades, discuss the role of interleukin 17 pathways in psoriasis, and introduce bimekizumab and discuss the impact of its dual neutralization of interleukin 17F in addition to interleukin 17A.

In order to do this efficiently and effectively, I welcome Dr. Stevan Shaw, Vice President and Head of Immunology Research at UCB. Dr. Shaw led the bimekizumab clinical program through to phase 2b and led the science and understanding how targeting interleukin 17F and interleukin 17A biology may translate into patient value. As Head of Immunology Research, Dr. Shaw is responsible for driving the strategy of immunology projects from new targets through to candidate selection, alongside continuing to lead the science behind bimekizumab. Welcome, Dr. Shaw.

Dr Shaw (01:29)

It's great to be with you today, Adam.

Evolution of Knowledge on Pathobiology of Psoriasis Over the Past 2 Decades and Unmet Need (01:31 – 06:13)

---

Dr Friedman (01:31)

All right. Let's dive right in. Psoriasis, a relatively common inflammatory skin disease, affects roughly seven to eight million adults in the US. To put that in some context, about the size of New York City. This is a disease that is more than skin deep. Plenty of data out there showing and highlighting the burden of disease, uh, potential for co-morbidities as a systemic inflammatory disease. But something I wanna hone in on as we begin our discussion is that psoriasis really functions as a wonderful tale of translational science and medicine, really a bench-to-bedside and back-to-bench story with respect to our understanding of the pathophysiology, how that understanding has led to the emergence of a fleet of new therapies that are more effective and more targeted. But then even with that development, it has aided in our understanding of that disease, and that's really going back to the bench. Could you kinda walk us through that story over the last 20 years?

Dr Shaw (02:29)

Sure, Adam. When I started out researching the pathological mechanisms in psoriasis over two decades ago, the treatment goal was to develop medicines that will provide a 50% improvement in PASI. And at that stage, Th1 cells were at the heart of the disease. And through nonspecific targeting of T cells, a 50% improvement was achieved but not without side effects.

Then came the next wave of innovation. Through selectively targeting certain pro-inflammatory cytokines that are dysregulated in psoriasis, such as TNF and p40, which is a common sub-unit for the IL-12 and IL-23 cytokines, which led to the possibility that we can achieve a 75% improvement in a significant proportion of patients. And for a few patients, it was even possible to get clear skin.

The most recent wave of innovation has centered around the understanding that the keratinocyte is at the heart of plaque psoriasis and that IL-17 produced from Th17 cells was fundamental to the disease pathogenesis. This led to drugs that targeted the IL-17 and 23 axis, which made durable 90% improvement in PASI a realistic goal for patients. Moreover, skin clearance for some patients was now achievable.

Dr Friedman (03:48)

You know, it's funny. I can think back to my training and residency, and even then, we would look back historically and talk about how psoriasis was looked at as a disease of hyperproliferation. You know, immune dysregulation wasn't originally part of that story. Then it was then we just would drop nuclear weapons on the immune system to kinda wipe everything

out to hopefully reduce that kind of overgrowth of the epidermis and, and all the changes that go with it.

Then we started to funnel in -- I think it really has been a story of funneling down to really attacking and targeting things that are driving what we see clinically. And with each step, we thought we nailed it. You know, we thought, "Oh, if we block this one signal, this will do it." And this is really the driver. And, and it's amazing how, as you mentioned, those drugs that were aiming to achieve higher goals than ever before, we actually learned a great deal about the disease in that process.

And you mentioned interleukin 17, and it's a love-hate relationship with the epidermis, and the keratinocyte being a central force in driving disease and being probably a pivotal force at that. Could you go into a little bit more about interleukin 17? What is it -- what is its biology? And then we can maybe go into how it really plays a role in the underpinnings of psoriasis.

Dr Shaw (05:07)

Yeah. So, so it's really interesting around IL-17 because when we say IL-17, everybody talks and means IL-17A. But actually, that's not the whole story. There is a further twist on this story. And actually, the IL-17 family has six members. It's got IL-17A, B, C, D, E, also known as IL-25, and IL- 17F. And this is the real interesting bit, is that IL-17F is actually very similar in sequence homology to IL-17A. And more importantly, it actually signals through the same receptor complex, so they actually have overlapping biology. Additionally, both cytokines are co- expressed at inflammation and, actually, at the heart of driving, uh, IL-17-mediated diseases.

So, together, this creates a scientific hypothesis that IL-17F in addition to A is a pivotal driver of this pathological mechanism. And that targeting of IL-17A and IL-17F, may be better than inhibition of IL-17A alone.

IL-17 Biology & Psoriasis (06:13 – 08:33)

---

Dr Friedman (06:13)

So now that we know more about the IL-17 family members, can you go into a little about what exactly does IL-17 do with respect to the immune-mediated inflammatory cascade in psoriasis?

Dr Shaw (06:25)

Sure. IL-17 binds to the IL-17 receptor on keratinocytes, and that causes aberrant keratinocyte biology. You get proliferation of the keratinocytes. You also get release of pro-inflammatory cytokines, and particularly chemokines, that cause the recruitment of other important cell types, such as neutrophils, which cause a sort of damage within the psoriatic plaque.

Dr Friedman (06:48)

Now, you mentioned something interesting before, how there's such a focus on interleukin 17A. And, as you mentioned, there are multiple members, one of which, F, hasn't really received the right attention where its due in the past. Why is it? Why has interleukin 17F been overlooked in the past?

Dr Shaw (07:06)

This is an interesting question. It's one of the questions I'm most asked when we're talking about, uh, the pathobiology in psoriasis. And it comes from the fact that over a decade ago, most of the mechanisms within immunology were elaborated in mice. And when you do experiments in mice, IL-17F is pretty much impotent. It's 10,000 times less potent than IL-17A. Whereas when you do with the, uh, human equivalent experiment, IL-17F is 100 times less potent than IL-17A but can reach the same sort of maximum pharmacology. Of course, that isn't the whole story because when we zoom into the psoriatic plaque and sample the psoriatic plaque, we now understand how 17F is more abundant than IL-17A. And from recent single-cell studies, we've now been able to show that IL-17F exclusively producing cells exist within that psoriatic plaque, highlighting the need to inhibit both IL-17A and IL-17F.

Dr Friedman (08:00)

And I believe there is actually clinical data highlighting that there is greater interleukin 17F expression in lesional skin with patients with psoriasis. Is that correct?

Dr Shaw (08:10)

That's correct. There was a paper published a few years ago where they did micro-perfusion right into the psoriatic plaque in a number of patients with moderate-to-severe psoriasis. And they were able to real-time quantify the concentrations of IL-17A and IL-17F. And that's where we realized that IL-17F is probably 30 times more abundant than IL-17A in the lesional tissue.

Varying Cellular Sources of IL-17A and IL-17F (08:33 – 10:08)

Dr Friedman (08:33)

So let's switch gears a little bit. And I'm gonna take a note from the old adage, "In order to know where you're going, you need to know where you came from." And with that in mind, you know, there have been some studies demonstrating both interleukin 23-dependent and independent sources of interleukin 17A and F. Can you go a little bit into that?

Dr Shaw (08:51)

Sure. It's well-described that IL-23 is a critical survival factor and for the function of Th17 cells. However, this linear view of biology doesn't explain the fact that if you inhibit IL-23 in diseases such as ankylosing spondylitis, it doesn't work, which sets up the hypothesis that there must be other cellular sources of IL-17. And in fact, when you dig into the literature, uh, you start to understand that, actually, not only Th17 cells but cells called innate lymphoid cells - these are

ILC3s-, MAIT cells, gamma delta T cells - are all capable of producing IL-17A. And actually, and most interestingly, they produce a lot of IL-17F, completely independent of IL-23, suggesting that these cells contribute to the pathobiology of IL-17-mediated diseases.

Dr Friedman (09:45)

So what's the take-home message for the practicing dermatologist here, now knowing that there are both interleukin 23-dependent and independent sources for interleukin 17?

Dr Shaw (09:57)

If you neutralize IL-23, there will be cellular sources of IL-17A and F in the lesional tissue that will still be able to drive the inflammatory process.

Overview of Bimekizumab and its Molecular Structure (10:08 – 11:16)

Dr Friedman (10:08)

Okay. Let's get translational. Enter bimekizumab, which is approved for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Dr. Shaw, could you go into its origin story and features of this monoclonal antibody?

Dr Shaw (10:24)

Behind every great medicine, there's always scientific innovation. And with bimekizumab, it's no different. We started out with an antibody that bound IL-17A with high affinity. It also bound IL-17F but with affinity that wouldn't make a medicine. Through proprietary antibody technology - today it'd be known as artificial intelligence - we were able to dial in IL-17F affinity while retaining IL-17A affinity. And this created an antibody with balanced affinities for IL-17A, IL-17F, and the heterodimer AF. Bimekizumab is a humanized IgG1 monoclonal antibody that was rationally designed to inhibit the biological function of IL-17A, IL-17AF heterodimer, and IL- 17FF homodimer. And it's the FF homodimer which is the distinguishing feature compared to IL- 17A therapeutics.

The Impact of Dual Neutralization of IL-17F in addition to IL-17A (in human in vitro and in vivo studies) (11:16 – 13:02)

---

Dr Friedman (11:16)

Okay. So for my next question, I'm going to harness my inner Austin Powers and ask you, what does it all mean? And what I mean by this is, what should we take away and understand about how dual neutralization of interleukin 17F in addition to interleukin 17A with bimekizumab affects the psoriatic patient? What does this mean for psoriasis?

Dr Shaw (11:39)

We also generated some exciting data with bimekizumab in a skin biopsy surgery in moderate- to-severe psoriasis patients. Indeed, two doses of bimekizumab were sufficient to normalize the psoriatic transcriptome to levels that were indistinguishable to nonlesional skin, highlighting the concept of molecular remission. If we look a little deeper into the data, treatment with bimekizumab normalizes keratinocyte-associated biology, such as antimicrobial peptides, chemokines, pro-inflammatory cytokines, which are released from the keratinocyte along with keratinocyte proliferation markers. And also, the downstream IL-17-responsive genes to levels that were seen in nonlesional skin. Most interestingly, cytokines that are considered to be upstream in the psoriasis pathobiology, such as IL-36 and particularly IL-23 were normalized to levels seen in nonlesional skin, too. And as a consequence, both IL-17A and IL-17F was also normalized. Together, the data suggests that the psoriatic process isn't linear as the waterfall hypothesis described, rather a complex network of amplification loops that drives the chronicity of the disease and that dual inhibition of IL-17A and IL-17F completely switches off the psoriatic transcriptome.

Conclusion (12:58 – 14:09)

---

Dr Friedman (12:58)

Okay. So to wrap up, Dr. Shaw, what are the key take-home messages you hope our audience walks away with from this podcast?

Dr Shaw (13:05)

Yeah. Key take-home messages here are IL-17F has overlapping biology to IL-17A. Both are expressed in lesional tissue and are pivotal drivers of psoriasis. From the human in vitro experiments, we've shown that dual inhibition of A plus F gives you a greater level of inhibition than inhibition of IL-17A alone. And that dual neutralization of A and F with bimekizumab translates into a rapid, deep, and durable clinical response of patients with psoriasis.

Dr Friedman (13:38)

Well, thank you so much, Dr. Shaw, for a great and extremely enthusiastic discussion on the advancements and the understanding of psoriasis pathophysiology, especially when it comes to the science of interleukin 17 pathway, a pathway you are intimately involved and knowledgeable on. So we really appreciate you sharing your experience with us today.

Dr Shaw (13:57)

It's been an absolute pleasure to be with you all today.

Dr Friedman (14:04)

And thanks to all our listeners. Stay tuned for future editions of this podcast.