Activity Transcript

Laura Savage, MBChB, BSc(Hons), MRCP(UK), MRCP, (Dermatology), PhD: Hello and welcome. I'm Dr Laura Savage. I'm a consultant dermatologist and honorary senior lecturer based at the University of Leeds. Welcome to this session entitled "Biologics Targeting the IL-23/IL-17 pathway in Psoriatic Disease: Treating Beyond the Skin". This is a summary of the symposium that was held at the EADV Congress in Milan, alongside professors Andrew Blauvelt and Dennis McGonagle.

So the majority of patients who are destined to develop psoriatic arthritis will have antecedent psoriasis and may therefore be within the care of a dermatologist when they first develop the symptoms of prodromal and then classifiable PSA. Dermatologists are therefore placed at an ideal juncture to intervene and should try to develop an understanding of the treatment landscape for all facets of psoriatic disease.

So traditionally dermatologists have been taught to ask their patients about peripheral joint and back or buttock pain, stiffness which worsens after 30 minutes of inactivity or upon waking, joint swelling, and the presence of heel pain or digital swelling, which may suggest enthesitis or dactylitis. So a range of clinical signs related to the severity or the location of psoriatic lesions may also provide an indication as to which patients are more likely to develop psoriatic arthritis and should be the focus of increased screening and timely referral to rheumatology.

So in recent years, there's been an increased amount of attention on the subclinical and then the transitional phases of psoriatic arthritis in patients with psoriasis. So the process from psoriasis to psoriatic arthritis begins with an aberrant immune activation phase, which may originate from the skin, the intestinal mucosas or enthesis. And that's in those who are genetically predisposed or who are exposed to environmental factors, such as obesity, biomechanical stress, and infections. And this in turn leads to activation of the IL-23 and IL-17 axis with the accompanying production of TNF. Uncontrolled inflammation then leads to silent phase, starting with subclinical enthesitis whereby inflammatory changes can be seen on ultrasound and MRI at the enthesis and subsequently in the adjacent synovial complex in asymptomatic patients with psoriasis.

It's uncertain then if there's a second hit, be it trauma, biomechanical stress, or a microbiome related event that pushes patients into a prodromal phase classified by persistent non-specific musculoskeletal symptoms of arthralgia, fatigue and stiffness, and that's before they develop classifiable PSA, whereby they develop associated synovitis and joint swelling, and where structural damage is detectable on radiographs.

These preclinical phases may provide an opportunity to identify patients at the earliest phases of psoriatic arthritis before they do develop persistent pain and functional limitation. Cohort studies of patients with psoriasis managed with and without biologic therapies have consistently shown that those who are receiving biologics have a lower instance of psoriatic arthritis development over time, compared to those receiving topical treatment, phototherapy, and conventional systemic immunosuppressions. So a handful of studies, including MUSTEK and IVESPA, have also demonstrated a reduction in subclinical inflammation in patients who are managed with a skin directed biologic therapy who are either asymptomatic or have arthralgia. So these data are therefore leading to a paradigm shift around timely intervention to circumvent potential PSA development in patients with psoriasis although we need more data to determine which is the optimal therapeutic target to achieve this.

So let's take a moment now to review the data for inhibitors of IL-23p19 and IL-17 first in psoriasis and then psoriatic arthritis. So over the past decade, four agents targeting IL-17 have been developed. Secukinumab and Ixekizumab targeting I-17a, brodalumab targeting the IL-17 receptor, and bimekizumab targeting both the A and F isoforms of IL-17. And then three agents and guselkumab, tildrakizumab, and risankizumab target the p19 subunit unique to IL-23. These agents all act on the central Th17 pathway in the pathogenesis of psoriasis. So IL-23 is required for the maintenance and expansion of the pathogenic Th17 population, which in turn produces IL-17a and f. And there are other IL-23 independent cellular sources of IL-17, including innate-like lymphoid cells, such as gamma-delta T cells and ILC3 cells.

Agents targeting downstream production of IL-17 have a very rapid onset of action, but as they block all sources of IL-17, they can also lead to an increase in candidiasis that has been observed in a small percentage of patients which is not seen in those receiving IL-23 p19 inhibitors. For psoriasis, there have been a number of active comparative head-to-head trials of agents targeting IL-17 and IL-23, including ustekinumab, which targets the p40 subunit of IL-23 alongside IL-12. However, for the purposes of this session, which is going to focus on only those agents targeting IL-23 p19.

So first is ECLIPSE. It's a phase three trial of patients with moderate to severe psoriasis, in which guselkumab showed long-term superior efficacy compared to secukinumab for PASI 90 responses a week 48, with 84% of guselkumab and 70% of secukinumab treated patients achieving a 90% improvement in PSI score from baseline. Non-inferiority was established at week 12 and week 48 for PASI 75 responses and the frequency of adverse events was similar in both groups.

For the IMMerge trial, risankizumab was noninferior to secukinumab at week 16 and superior to secukinumab at week 52 for PASI 90 responses with 87% of risankizumab treated patients achieving PASI 90 from baseline compared to 57% of secukinumab treated patients. And the safety profile risankizumab was comparable with secukinumab.

In IXORA-R, the primary endpoint of PASI 100 at week 12 was achieved by 41% of ixekizumab treated patients compared to 25% of patients receiving guselkumab. However, by week 24, there was no difference between the two agents and serious adverse events were the same at 3% for each group.

And then finally, the BE RADIANT study compared the IL-17 A and F inhibitor bimekizumab with secukinumab, which targets only the A isoform of IL-17. The primary endpoint of PASI 100 response at week 16 was achieved by 61.7% of bimekizumab treated patients and that increased to 67% at week 48 and 48.9% and 46.2% of secukinumab treated patients at week 16 and 48 respectively. In terms of rapidity of onset improvements were more rapid for bimekizumab compared with secukinumab at week four and oral candidiasis did occur more often in patients treated with the bimekizumab than secukinumab, but was generally mild, treatable and did not lead to treatment discontinuation.

So if we now first shift our focus over to psoriatic arthritis, here we find far fewer head-to-head studies and no direct comparisons have yet been made between IL-17 and IL-23 p19 inhibitors. So two studies, the SPIRIT head-to-head and EXCEED have compared IL-17 inhibitors to adalimumab, which does remain an effective treatment option for our patients with active PSA. The primary endpoint in the SPIRIT head to head trial was a composite measure of ACR 50 and PASI 100 at week 24, whereas in EXCEED, it was the same end point, but was assessed at week 52.

Superiority was achieved for both ixekizumab and secukinumab in these trials against adalimumab. Now this is in due in the most part due to the skin outcomes. And if you break it down, compare endpoints, it shows superiority for PASI 100, but noninferiority for ACR50 against adalimumab. Secukinumab has also been evaluated in axial psoriatic arthritis in a dedicated trial called MAXIMISE using the ASAS20 criteria at week 12 as a primary endpoint. Secukinumab resulted in rapid and significant improvements in the ASAS20 response at week 12 in patients with psoriatic arthritis and axial manifestations, and the ASAS20 response was sustained through week 52.

Studies such as MAXIMISE, assessing primary outcomes in patients with axial PSA, are also needed for IL-23 inhibitors, but to date only secondary endpoint data has been reported in trials of guselkumab and risankizumab.

So here we can see some pulled data from DISCOVer one and two for guselkumab, for patients with confirmed sacroiliitis and active PSA. So greater logarithmic scale mean changes in overall BASDAI scores, all six BASDAI components and ASDAS scores at week 24 were observed with guselkumab versus placebo. And the treatment event was observed in both guselkumab dosing groups that being every four weeks and every eight weeks, and as early as week eight. Then guselkumab improved axial related symptoms were also maintained out through week 52.

The KEEPsAKE trials investigated risankizumab in patients with psoriatic arthritis. In KEEPsAKE 1, patients were biologic naive with the primary endpoint of ACR20 at week 24. And this was achieved in 57.3% of patients compared to 33.5% of patients receiving placebo. But it is worth noting that a proportion of patients continued their DMARD therapy throughout these trials, which may account for that high placebo response rate.

A proportion of patients in KEEPsAKE 2 also had previous inadequate response or intolerance of up to two biologics and 51.3% of risankizumab treated patients achieved that primary endpoint of ACR20 compared to 26.5 of those receiving placebo. And in both studies risankizumab was generally well tolerated over 24 weeks of treatment.

In the BE OPTIMAL trial, this was a 16-week, double-blind, placebo-controlled, and 36-week treatment-blind trial of bimekizumab in biologic-naive patients with active PSA. We can see that bimekizumab demonstrated superiority of a placebo for the primary endpoint of ACR20 at week 16, and then showed clinically relevant improvements, not only in musculoskeletal outcomes, but also high rates of clearer, almost clear skin. And then near identical outcomes to adalimumab for ACR20 were achieved at both week 16 and week 52. And no new safety signals were observed.

And then finally in BE COMPLETE, this was a 16-week, double-blind, placebo-controlled trial of bimekizumab in psoriatic arthritis patients with prior inadequate response to TNF inhibitors. 43.4% of the bimekizumab treated patients achieved the primary endpoint of ACR50 at week 16 compared to just 6.8% of those receiving placebo.

And so to briefly summarize these data in PSA, IL-17 inhibitors appear comparable to TNF blockers, with both classes performing slightly better than IL-23 blockers. However, as there are no head-to-head psoriatic arthritis studies for IL-23 versus IL-17, a direct comparison cannot be made.

In psoriasis, we can make these direct comparisons thanks to a larger number of head-to-head actual comparative studies. All IL-17/IL-23 inhibitors do appear to be more efficacious and better tolerated than TNF blockers, but still no clear distinction can be made between IL-17 and IL-23 classes as a whole with some IL-17 classes outperforming the IL-23 inhibitors and then vice versa.

So whatever treatment we choose, early intervention is encouraged with the aim of minimizing physical and psychological harm, preventing damage associated inflammation and reducing the development of comorbidities. An observed phenomenon in psoriasis is that once psoriatic plaques have resolved, the skin appears healthy, although in flare, the lesions can tend to occur at the same location. So this is now thought to be as a result of a subpopulation of circulating affected T cells infiltrating the dermis during active disease. And these turn into long lived CD69 and CD103 positive tissue resident memory T cells, which establish site specific disease memory as psoriatic inflammation resolve. And then upon reintroduction of an antigen trigger, these TRMs drive recurrent inflammation at the same cutaneous locations through downstream production of IL-17. And this is described as a molecular scar, whereby gene expression differences are found in healed and versus unaffected skin.

IL-23 is involved in the differentiation and survival of pathogenic TRM cells. So it's therefore proposed that inhibition of the IL-23 pathway could result in long term clearance of psoriatic plaques and this has formed the basis of the GUIDE study, which is a phase 3B randomized double blind trial to investigate if early intervention with the IL-23 inhibitor guselkumab could lead to better clinical responses and more durable maintenance of response after drug withdrawal. And as part of this as a mechanistic subsidy, looking at changes in gene expression and immune cell populations to understand if IL-23 leads to clearance of these TRMs. The primary objective of GUIDE was to demonstrate that super responders maintain controlled disease beyond week 68 with a prolonged guselkumab dosing interval of 16 weeks and super responders were those who had psoriasis who received on-label guselkumab treatment until week 20 and then who responded with complete skin clearance PASI 0 at both week 20 and week 28.

So a further trial that was treating patients with moderate to severe psoriasis early with an effective systemic therapy to identify if it could alter clinical outcomes in the natural course of the disease is called STEPin. This time it's evaluating the IL-17a inhibitor secukinumab. So there were two groups. The first was those with onset psoriasis who had had the appearance of psoriatic plaques within the last 12 months and who were naive to systemic treatment or phototherapy. And then the second group was those with the appearance of first psoriatic plaques, five years or longer, and intolerance or inadequate response to phototherapy or any systemic treatment, including biologics with the exception of IL-17a inhibitors.

In the patients randomized to receive secukinumab or nb-UVB for 52 weeks after which time they then entered a treatment free follow-up phase. Those were the response of a PASI 50 or more, but less than PASI 90 were observed up to week 104 or until they relapsed. And then those who had a PASI 90 response continued to be observed out to week 208, or until they relapsed. The primary endpoint was PASI 90 response at week 52 and secondary endpoints were PASI 90 response at week 104, an investigative global assessment of 01 at week 52. And then there's a mechanistic substudy looking to collect skin biopsies at baseline week 16, 52, 104, and 208, to see if they can assess the immune markers, including the number of inflammatory tissue resident memory T cells to see if treatment with secukinumab can make any clinical impact on disease flare.

So it's going to be interesting to see if in due course, if early introduction of biologic therapy may play a disease modifying role, particularly as we already see sustained efficacy in clinical trials of guselkumab, secukinumab and other drugs out to five years in patients in clinical trials. And they are often recruited with a much longer duration of disease.

And so that concludes this session. Thank you very much for your attention.

This transcript has not been copyedited.