Bimekizumab Therapy and Beyond for Ankylosing Spondylitis

In an interview with Autoimmune Learning Network, Lianne Gensler, MD, rheumatologist and director of the University of California, San Francisco, Spondyloarthritis Clinic, discussed the role of IL-17 in ankylosing spondylitis (AS) and the use of bimekizumab in treating this disease. Currently, bimekizumab is currently under investigation rather than an approved product.

How does IL-17 induce inflammation in rheumatic disease?
IL-17 is a downstream cytokine that promotes inflammation in the joints and in the skin as well. It induces inflammation in both arthritis in the small joints as well as the axial skeleton (which involves the spine and sacroiliac joints).

How does targeting the IL-17F cytokine in addition to the more traditional IL-17A affect disease outcomes?
At a translational level, there is greater suppression of inflammation when inhibiting both IL17A and F compared to A alone. If that translates into patients, then one would expect there to also be greater efficacy.

Could you share some of the data from the American College of Radiology (ACR) Annual Meeting regarding the use of bimekizumab therapy for AS?¹
At the ACR Annual Meeting, I presented data from the long-term extension of a phase 2b study of AS. We looked at 152 weeks of follow-up in patients who had been given bimekizumab or placebo in a double-blind portion of the study, and then exposed to 2 different doses of bimekizumab during the dose-blind period, before continuing on open label bimekizumab over time.

I think that these data clearly show that the drug works in AS, when compared with placebo. The nice part of that phase 2b study is that you see that dose effect; it is clear, at least in the extension of the phase 2, study, that the effect is sustained. Ultimately, efficacy is going to be best shown in phase 3 data, but those haven't been presented yet.

As we introduce novel mechanisms on to the market, it is important that we feel good about their safety. That's especially true with the latest post-marketing data in some other drug mechanisms. What we were presenting in our oral presentation is that there is sustained safety over 3 years.

The question that came up a lot with bimekizumab and IL-17s in general was, “What is the candidal risk?” I'm not a dermatologist, but as a rheumatologist, I've had scares in the past with fungal infections with tumor necrosis factor inhibitors.

The main point of the presentation was the safety over 3 years, and the data look good. There were no severe adverse events (eg, major adverse cardiac events, malignancies) that we would attribute to the drug.

There is no question that there is a candidal risk. We have already evidence with the data comparing bimekizumab with secukinumab that were published in July.² However, reassuringly, these are not systemic or severe candidal infections. All events were mild to moderate, localized, and largely oral candidal infections. For our female patients, we worry about vaginal candidiasis, but that was not the case in the presented data; there was only 1 instance of vaginal candidiasis, and we can treat through that.

At the end of the day, this was a study looking at the long-term safety of bimekizumab, and I feel very reassured by the data.

In efficacy studies of bimekizumab for psoriasis, dermatologists are seeing Psoriasis Area and Severity Index (PASI) scores of 100 posttreatment. Is a similar effect being observed in AS?
I wish that we could get close to PASI 100 in AS (complete remission)—that is the dream. Psoriasis is very objective, and you can measure it in a quantitative way. In AS, we don't get close to those remission numbers, in part because AS results in damage. Psoriasis results in inflammatory change, but this clears with treatment. In arthritis, the inflammation and subsequent damage is much harder to treat and to reverse.

The other part of it is that in arthritis, we have a lot of patient-reported outcomes (PROs), and those can be driven by a multitude of factors. Even if a therapy is working, it does not mean that all of the patient’s symptoms, such as fatigue or pain, are going to go away.

We do have cutoffs, and remission states or inactive disease states; the most robust one is the Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP) < 1.3. This score is reflective of PROs, including the patient global, axial, back, and hip pain as well as morning stiffness and the C reactive protein. ASDAS-CRP is the most robust measure for disease activity.

Are there any other thoughts that you would like to share with your peers?
Across all inflammatory diseases, our goals for treatment have changed. Twenty years ago, we just hoped for a little bit of efficacy, but we’re now reaching for the stars and for remission states. It's important that we continue to push the boundaries, using novel mechanisms such as targeting IL-17A and IL-17F together, that may work across disease states to reduce inflammation.

References

1. Gensler L, Deodhar A, van der Heijde D, et al. Bimekizumab long-term safety and efficacy in patients with ankylosing spondylitis: interim results after 3 years of treatment in an ongoing phase 2b study. Abstract presented at: American College of Rheumatology Convergence 2021; November 5-9, 2021; virtual.
2. Reich K, Warren RB, Lebwohl M, et al. Bimekizumab versus secukinumab in plaque psoriasis. N Engl J Med. 2021;385(2):142-152. doi:10.1056/NEJMoa2102383