Anti–Interleukin-17–Receptor Antibody for Psoriasis

Published - Written by Daniela Lamas

The 45-year old woman in your office is discouraged.

For years now, she’s suffered from psoriasis; thick, red skin with flaky silver patches leaving her self-conscious and, often, in pain. She feels like she’s tried everything. First it was topical treatments, then phototherapy, salt-water baths and now systemic therapy with immune suppression. She’s considered newer biologic agents such as anti-TNF drugs, but is wary of the side effect profile.  Her skin continues to itch and scale.

She asks you: “Isn’t there anything else we can try?”

According to two phase 2 clinical trials published in this week’s NEJM, the answer could soon be “yes.”

Both studies – one led by Kim A. Papp, the other by Craig Leonardi— test new drugs whose action is based on the immunopathogenesis of this chronic inflammatory skin disorder. For years, it’s been understood that psoriasis is a T-cell mediated autoimmune disease. This knowledge has driven the use of immune suppressant meds and, more recently, the dawn of biologic agents.

Newer research has identified a specific subset of T cells, type 17 helper T (TH17), which produce interleukin-17, as key pro-inflammatory players in psoriasis. Levels of interleukin-17 are higher in skin with psoriatic skin lesions, for instance, and correlate with disease severity. Furthermore, in a drug-induced model of psoriasis, mice without a particular interleukin-17 receptor don’t develop psoriatic lesions while those with the receptor do. With this background, researchers set out to determine if blocking interleukin-17 in humans can help treat psoriasis.

To this end, Papp et al enrolled nearly 200 patients in a trial of brodalumab (AMG 827), a monoclonal antibody against the interleukin-17 receptor. (The other, similar, study also published in this week’s NEJM, investigates a humanized anti- interleukin-17 monoclonal antibody). The Papp study enrolled adults with moderate-to -severe plaque psoriasis, meaning that at least 10 percent of their skin surface was affected. All met a predetermined minimum score on a psoriasis severity index. Those receiving systemic therapy, phototherapy or biologic agents were entered in the study after a period of drug “washout.”

Participants from 23 sites were randomly assigned to receive placebo or brodalumab – in a range of doses and different dosing frequencies—over 12 weeks. Of the nearly 200 participants, 66% were men, mean age was 43 and, on average, the participants had psoriatic lesions covering a quarter of their skin.

As early as the first follow-up visit, which took place 2 weeks after starting the study drug, those receiving brodalumab were clinically improved compared to patients getting placebo. And the effect persisted throughout the duration of the trial.  At week 12, patients taking study drug showed a significant improvement in their psoriasis severity score, compared to their placebo counterparts. In fact, those on a mid-level dose of the study drug improved their score by 96% compared to nearly 12% in the placebo group. More patients in the study drug group were found to be clear of psoriasis at the end of follow-up.

Adverse events occurred more frequently in the brodalumab group than in the placebo group – most commonly upper respiratory tract infections, arthralgia and erythema at the injection site. There were two cases of asymptomatic neutropenia. The authors note that the trial was neither long enough, nor large enough, to assess infection or cardiovascular outcomes, so safety really remains an unknown.

In an accompanying editorial addressing both studies on IL17 and psoriasis, Ari Waisman, PhD, discusses the potential advantages of targeting interleukin-17 versus current biologic treatments. Waisman remarks that more specific targeted therapy can yield clinical benefit while potentially avoiding the side-effects associated with the relatively blunter current tools: “Treatment with antibodies targeting interleukin-17 or its receptor should be more specific and may be expected to result in fewer side effects and therefore holds promise for patients with psoriasis.”