Psoriasis - head-to-head comparison with clear winner

Psoriasis therapy has made great progress in recent years. This is due on the one hand to immunological research into the pathogenesis and the recognition of the systemic nature of psoriasis, and on the other hand to the associated development of drugs with increased selectivity. Biologics and small molecules offer many possibilities, but also make the therapeutic field more complex. Head-to-head comparisons on the numerous new substances are therefore highly welcome. There was an update on this at the AAD convention in Orlando. There are also promising innovative approaches in the topical treatment of psoriasis and atopic dermatitis.

Developments in the field of psoriasis therapy are enormous. Nevertheless – or perhaps precisely because of this – whenever another substance enters the market, the additional benefit of the new therapy compared with the previous one must be carefully weighed up. Scientifically adequate, this is done with randomized head-to-head studies. IXORA-S (Phase III), the results of which were presented at the congress, is one such trial. This compared the safety and efficacy of ixekizumab and ustekinumab in patients with moderate to severe plaque psoriasis. Both substances are approved in Switzerland for this indication.

Ustekinumab is a fully humanized IL-12/23 blocker that binds the common subunit of the cytokines IL-12 and -23, which are important in local immune responses. Although indispensable for the development of psoriatic skin lesions, cytokines do not appear to be essential for normal immunity. IL-17A, which is targeted by ixekizumab, is also a messenger substance that is very specifically responsible for local inflammation. Due to this selective inhibition of the immune response, side effects are limited.

Half achieve complete clearance

After ixekizumab had already proven superior to ustekinumab after twelve weeks (according to the conclusion of a presentation at the EADV congress last October), the study authors now wanted to investigate whether the effect lasted up to 24 weeks. The study population consisted of 136 patients randomized to ixekizumab and 166 patients receiving ustekinumab. Both drugs are administered subcutaneously. The average age of the participants was about 43 years, and two-thirds were men.

The primary endpoint was the number of patients with a Psoriasis Area and Severity Index (PASI) improvement of at least 90%, i.e., a PASI-90. At baseline, the PASI averaged 20, which improved by 90% after 24 weeks of observation in 83.1% (ixekizumab) vs. 59% (ustekinumab). Almost half of the patients in the ixekizumab group achieved even better results, namely completely symptom-free skin or complete clinical remission (PASI-100) – this compared to just over a quarter in the comparison group (49.3% vs. 23.5%). An improvement of at least 75% (PASI-75) was found in 91.2% vs. 81.9% in the above order. All differences between arms were significant.

The latter value may serve as an illustration of the progress that has been made in recent years, as a PASI-75 response was and is already considered the primary efficacy endpoint in many other studies.

A score of 0 on the static Physician’s Global Assessment (sPGA), secondary endpoint of IXORA-S, and thus remission in another key clinical trial measurement, was achieved by 53.7% vs. 24.1% at 24 weeks in the above order (p<0.001). A score of 0 or 1 with an improvement of at least two points since baseline was achieved by 86.6% vs. 69.3%; this difference was also significant.

Do not forget the patient side

The PASI does not reflect the patient’s subjective assessment; it is a one-sided physician-centered severity assessment. Using a scale of 0 to 4, redness, thickness and scaling are rated, weighted by body surface area and skin involved. The sPGA is also, as its name implies, a physician’s assessment, and a global assessment of disease severity at a given point in time.

Supplementing these results with the patient perspective, e.g. with the Dermatology Life Quality Index (DLQI), is therefore useful. Finally, a PASI-50 response for one patient may already provide more subjective improvement than, for example, a PASI-75 response in another person. It should be noted, however, that the DLQI only covers the last seven days and may therefore only provide an inadequate snapshot. In total, there are ten questions that can yield values between 0 and 30, with lower ones representing a better quality of life.

In IXORA-S, a higher number of patients with DLQI 0 or 1, i.e., no effect on quality of life, was found in the ixekizumab group than in the ustekinumab group, 66.2% vs. 53% (p=0.03). Itching was also significantly more strongly reduced here after an observation period of 24 weeks (this had not yet been the case after twelve weeks).

And the side effects?

Overall, the superiority of the anti-IL-17A antibody also persisted for a further 12 weeks, the study leaders said – this compared with ustekinumab, which is established in psoriasis treatment and itself already shows high efficacy.

Moreover, the improved efficacy was not associated with an increased rate of treatment-emergent adverse events, the vast majority of which were mild to moderate. No fatalities occurred. There were two subjects in the ixekizumab arm and one in the ustekinumab arm who stopped treatment with their respective assigned agent due to adverse events.

The promising results will now be followed up in an extension study. Ixekizumab is also being investigated in active psoriatic arthritis, with data from a corresponding phase III trial expected later this year. Studies are also underway in axial spondyloarthritis.

Mild to moderate plaque psoriasis – news here too

The field of topical psoriasis treatment is far less in flux compared to systemic therapy, and new active ingredients are found much less frequently here. Benvitimod is one of these new approaches. In a phase III trial, the NSAID, whose mechanisms of action are not yet fully understood (these include cytokine, phosphotransferase and T-lymphocyte inhibition), has now been shown to be safe and effective. The study involved 686 patients with mild to moderate plaque psoriasis for at least six months, a PGA score of 2 or higher, and a body surface area (BSA) score of less than 10%. They were randomized to receive either 1% benvitimod cream (n=344), 0.005% calcipotriol ointment (vitamin D analogs, n=169), or placebo (n=173) twice daily for 12 weeks. Primary endpoints were a PASI-75 response and a PGA score of 0 (“clear skin”) to 1 (“almost clear skin”) at the end of treatment.

The new compound was significantly superior to both the comparator and placebo with respect to PASI-75 (in this order): 51.2% vs. 37.9% (p<0.05) vs. 14.5% (p<0.001). With the test substance, more subjects also achieved a significant improvement in skin appearance of 90% (PASI-90). In PGA, both active compounds performed significantly better than placebo: 66.3% and 63.9% vs. 33.5%, respectively (p<0.001).

Clinically relevant systemic abnormalities were not found with topical application, and most side effects were local and transient. These included erythema, stinging, or warm sensation. Mainly, they were classified as mild to moderate. Overall, such adverse events occurred in 44.5% of patients on benvitimod therapy, compared with 19.5% on calcipotriol and 20.2% on placebo.

New option for severe courses of atopic dermatitis?

Severe forms of atopic dermatitis in adults are particularly difficult to manage. In persistent severe eczema, systemic therapy (mainly ciclosporin) is currently recommended in addition to the usual topical measures. It goes without saying that immunosuppressants bring about numerous undesirable effects due to their broad action on the immune system, and more targeted approaches are therefore urgently desired.

A new variant is the blockade of the IL-4 receptor-α. The corresponding antibody Dupilumab thereby blocks the signaling pathway of IL-4 and IL-13, two cytokines that are important for atopic and allergic diseases. Dupilumab has been generating positive feedback for some time (most recently, two phase III studies were published [1]) and is considered one of the most promising future options in the field of atopic dermatitis. In the USA, a corresponding approval process has just been completed.

At the AAD, results on the long-term use of the biologic were now available for the first time. The antibody was administered subcutaneously either every week or every other week (alternating with placebo). In a third arm, participants received placebo only. All (adult) patients suffered from moderate to severe atopic dermatitis with insufficient response to topical corticosteroids. They continued to receive the latter in low to moderate potency, as well as calcineurin inhibitors in sites where corticosteroids are not recommended. Phasing out or stopping this topical therapy was possible.

The first coprimary endpoint, a “clear” (0) or “almost clear” (1) skin appearance on the Investigator’s Global Assessment and an improvement of at least two points since baseline, was achieved by 40% with verum (weekly) and 36% (biweekly) vs. 12.5% with placebo after almost one year. In the second co-primary endpoint, the Eczema Area and Severity Index (EASI), a score similar to the PASI, 64.1% and 65.2% versus 21.6% achieved 75% improvement, respectively. Pruritus also decreased. All of these efficacy endpoints were highly significantly improved.

The good adverse event profile seen in previous studies was maintained over 52 weeks: The same number of (serious) adverse events occurred in the treatment groups, and no abnormalities were seen in the laboratory. More common were local reactions to the injection and conjunctivitis, a side effect that has been seen for some time under the antibody.

Source: American Academy of Dermatology (AAD) Annual Meeting, March 3-7, 2017, Orlando.

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