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A Therapeutic Breakthrough in Treatment Through the Inhibition of IL-17A/IL-17F

A Therapeutic Breakthrough in Treatment Through the Inhibition of IL-17A/IL-17F

Significant clinical trial data and results wowed digital attendees at the recent American Academy of Dermatology Virtual Meeting Experience (AAD VMX) 2020, which took place from June 12 to June 14, 2020. Among the more than 900 ePosters were 157 in the “psoriasis & other papulosquamous disorders” category alone, not including a number of abstracts selected as late-breaking research for presentation at AAD VMX 2020.

Two late-breaking research abstracts highlighted the results of phase 3 clinical trials (BE VIVID1 and BE READY2) on bimekizumab, a novel biologic therapy that selectively binds to and neutralizes both IL-17A and IL-17F, cytokines thought to influence the immunopathogenesis of psoriasis. In short, bimekizumab demonstrated superior efficacy to ustekinumab and placebo,1 showed a long duration of maintenance of response,2 and was generally well-tolerated with a similar safety profile.

Kristian Reich, MD, PhD, was an investigator on both phase 3 studies of bimekizumab. Prof Reich is a professor for translational research and inflammatory skin diseases at the Center for Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, at University Medical Center Hamburg-Eppendorf and the Skinflammation Center in Germany. He spoke with The Dermatologist regarding bimekizumab, the efficacy and safety data, and the implications of this new biologic for dermatology.  

Q. What differentiates bimekizumab from currently available biologic therapies?
A.
Bimekizumab has a new mode of action, but a mode of action that overlaps with targeted therapies we are already using in our daily practice. These other targeted therapies are called IL-17 inhibitors, but they should really be called IL-17A inhibitors, because that is what these therapies block. In contrast, bimekizumab is an IL-17A and IL-17F inhibitor. So, I think it makes some sense to briefly explain where this is all coming from. IL-17 is not one cytokine, but rather a family of cytokines, and the two members of this family that really seem to play a role in psoriasis are IL-17A and IL-17F, and they probably both come from T cells and they both activate keratinocytes to create this rapid phenotype, and that keratinocytes make some other cytokines that then further perpetuate and enhance the immune response. Now, IL-17A and IL-17F do not work on their own, but they form dimers. If you have two molecules, you can form three kinds of dimers: two IL-17A together, one IL-17A and one IL-17F, and two IL-17Fs. So, if you really think this through, the currently used IL-17 inhibitors only block out IL-17A/A and IL-17A/F, but they will not touch IL-17F/F. Bimekizumab, in addition to what the existing IL-17A inhibitors do, will block the IL-17F/F homodimer. That’s the important difference in the mode of action.

Q. How may the additional mode of action of bimekizumab play a role in the efficacy of this therapeutic agent?
A.
It’s interesting to see that there is good scientific evidence that IL-17F plays a certain independent role in driving the disease process in psoriasis and also psoriatic arthritis. The main on-switch of inflammation is IL-17A, but IL-17F, let’s say has a 20% to 30% independent role in driving the disease. So, the hope would be that if you block IL-17F in addition to IL-17A, you can push your efficacy—the levels of response, maybe the onset of response—even beyond what we see with the IL-17A inhibitors. 

How will this compare to IL-23 inhibitors? The answer is “we have to see.” It’s hard to say from the mode of action to make any predictions on how this additional blocking IL-17F compare to what the IL-23 inhibitors can do because they are upstream in the disease process. IL-23 has a different role as a cytokine that activates T cells to make IL-17, but we do not specifically understand if IL-23 drives more IL-17A production vs more IL-17F production or both equally. So, I think this last part of the question has to be decided based on the clinical data.


Watch Prof Reich discuss the results of BE VIVID and BE READY and what the data could mean for your patients with psoriatic disease in an exclusive interview from our AAD VMX 2020 Insights Page.


Q. The recently shared late-breaking research abstracts presented at the AAD VMX 2020 had primary end points of Psoriasis Area and Severity Index (PASI) 90 and Investigator’s Global Assessment (IGA) 0/1 at week 16, but BE VIVID showed a rapid response at week 4. To the best of your knowledge, how does this compare with currently available biologic therapies?
A.
BE VIVID1 and BE READY2 had a little bit of a different design, with BE VIVID having a real head-to-head design to compare with ustekinumab vs BE READY just having a placebo response but then having this randomized withdraw. The numbers in general were very similar, which again is reassuring, so one study validates the results of the other. The BE READY numbers were even a little bit higher than the BE VIVID numbers, and we can start to speculate why this is—is it because you only have super good response and no response, so you do not have ustekinumab in the middle?

But let’s focus on the BE VIVID numbers now and with a more conservative approach. The PASI 90 response at week 16 was 85% compared to roughly 50% with ustekinumab. Ustekinumab is a good therapy; it’s one of our previous champions. This PASI 90 response in BE VIVID was already 40% at week 4, so this is really very early, a lot earlier than with other therapies. Take ixekizumab, an IL-17A inhibitor, as an example. The PASI 75 at week 4 with this therapy would be around 50%. The same outcome level of PASI 75 was 75% with bimekizumab. So, I think we can say without doing any unfair comparisons here that the onset of response of bimekizumab is the best we have seen with any other biologic. Its PASI 90, IGA scores of clear or almost clear, and PASI 100 response levels at week 16 are among the highest. If I take some of the well-working IL-17A inhibitors, such as secukinumab and ixekizumab, as well as guselkumab, and risankizumab, the well-working IL-23 inhibitors, I wouldn’t say you can expect to see the same data that was shown in bimekizumab’s comparison to ustekinumab, but still the bimekizumab numbers are among the highest.

Q. Thoughts on the progression of therapies for the treatment of psoriatic disease?
A. I’m an immunologist by training, and I’m already old, so I have been in dermatology for more than 25 years now. Looking at a study like these bimekizumab studies and seeing that six and seven of 10 patients over time are fully cleared, PASI 100, is astounding for me. We are so used to looking at these results and may think “oh yeah, that is a high number,” but it is a revolution in the care of our patients with psoriatic disease. Twenty-five years ago, we had methotrexate, phototherapy, and some corticosteroid creams, and we were happy if a patient would have a PASI 75 response and we were happy if 50% or 60% of patients developed PASI 75. Now we almost have these numbers for PASI 100! 

So, if I look back, I say it’s fantastic to be in dermatology. It’s fantastic to see how well we understand the pathophysiology of an important disease such as psoriasis. It’s even more exciting to see that we can use this knowledge and come up with therapies like bimekizumab that actually translate this knowledge into something relevant for the patient: very high level of response, very safe therapies, very nice maintenance of response. Recently, I saw 25 patients, half of them were on a biologic for their psoriasis. They’re doing fine. We’re no longer talking about psoriasis; we’re talking about how they’re doing in COVID-19 and if they still have plans for summer vacation. Bimekizumab is pushing this element in what dermatologists can do even further. We haven’t even mentioned psoriatic arthritis yet, but the phase 2 data for bimekizumab in psoriatic arthritis have already been published.3 If these results can be replicated in phase 3 trials, bimekizumab may be a game changer, because for the first time, also in psoriatic arthritis, we see levels of response we have not seen before.

So, I continue to be excited. I think it’s a fantastic time to be a dermatologist. By using therapies such as bimekizumab, we can really achieve more for our patients, and that’s what is most important.


References
1. Reich K, Papp KA, Blauvelt A, et al. Efficacy and safety of bimekizumab in patients with moderate-to-severe plaque psoriasis: results from BE VIVID, a 52-week phase 3, randomized, double-blinded, ustekinumab- and placebo-controlled study. Presented at: American Academy of Dermatology Virtual Meeting Experience 2020; June 12-14, 2020.

2. Gordon K, Foley P, Krueger J, et al. Efficacy and safety of bimekizumab in patients with moderate-to-severe plaque psoriasis: results from BE READY, a 56-week phase 3, randomized, double-blinded, placebo-controlled study with randomized withdrawal. Presented at: American Academy of Dermatology Virtual Meeting Experience 2020; June 12-14, 2020.

3. Ritchlin CT, Kavanaugh A, Merola JF, et al. Bimekizumab in patients with active psoriatic arthritis: results from a 48-week, randomised, double-blind, placebo-controlled, dose-ranging phase 2b trial. Lancet. 2020;395(10222):8-14. doi:10.1016/S0140-6736(19)33161-7

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