touchDERMATOLOGY coverage from EADV 2025:

Dermatomyositis (DM) is a rare systemic autoimmune disease characterised by skin and muscle involvement, typically presenting with proximal muscle weakness and persistent cutaneous eruptions, along with symptoms such as joint pain, dysphagia, fatigue and calcinosis. Current treatments are often ineffective and carry significant risks, particularly with long-term use.

Brepocitinib is an oral TYK2/JAK1 inhibitor that blocks pro-inflammatory cytokine pathways (IFN-α/β, IL-12, IL-23, IFNγ) implicated in DM pathogenesis. We spoke with Dr Aaron Mangold (Mayo Clinic, Phoenix, AZ, USA) to better understand the need for new therapies in this indication, the rationale for investigating brepocitinib, and the findings from his study presented at EADV 2025.

The abstract “Rapid Improvement of Cutaneous Dermatomyositis with Brepocitinib: A 12-Week Open-Label Trial” was presented at EADV 2025, 17-20 September, Paris, France.

Could you tell us a little about dermatomyositis and the unmet needs in its treatment?

Dermatomyositis is a systemic autoimmune disorder that primarily affects the skin and muscle. Both the skin and muscle are associated with significant morbidity. Patients who have significant muscle disease will have impairments in their activities of daily living and, for example, may need a mobility aid like a wheelchair. Interestingly, although the skin disease is often chronic and persistent, it typically affects exposed areas and patients will get red, itchy rashes, as well as skin ulcers that cause significant morbidity, affecting patient quality-of-life. Currently, there are no modern therapies for dermatomyositis and the mainstay is often chronic steroids or using non-steroidal immunosuppressants like mycophenolate or methotrexate. There are approved therapies that have a bit less toxicity than those prior; those are rituximab, which is known for having a slow onset of activity, as well as having a high risk of infection. IVIg is also approved, and that seems to be mild to moderately effective, but there is difficulty in the administration, where patients have to get infusions two to five times per month. The harmful impacts of dermatomyositis include long-term muscular disability or skin disease affecting quality-of-life, and that’s an accumulative effect over time. So the longer the disease is untreated, the more irreversible damage occurs, and it’s really important that we can access targeted therapies with rapid onset and convenient administration.

What is the rationale for investigating brepocitinib for dermatomyositis?

Brepocitinib is a first-in-class, dual specific JAK inhibitor, targeting TYK2 and JAK1. Unlike other drugs that target one or the other, brepocitinib is able to combine efficacy by inhibiting type-1 and type-2 interferons as well as cytokines that are implicated in dermatomyositis. These include IL-6, which affects B-cell activation and antibody production, as well as IL-12 and IL-23, which potentiate the polarisation of disease causing Th1 and Th17 cells. The drug has generated positive phase II data across multiple autoimmune diseases already. It’s currently being looked at in a global phase III trial called VALOR for dermatomyositis, which is the largest trial ever conducted in this space. This particular phase II trial complements the VALOR study, where we evaluated patients in a smaller number (only 5 versus over 240) looking at those with recalcitrant skin disease. Compared to the larger trial, which was looking at skin and muscle, we were able to focus on not just the outcomes in that population, but also the biological changes that happen at the cellular level. We were able to do integrated single-cell and spatial sequencing on the patients using transcriptomics of both the legional and non-legional skin samples obtained at baseline and in week four, which provide granular mechanistic insights into what drives the disease and what’s associated with treatment response. That data won’t be presented now, but complements the data that I’ll be presenting a little bit later today. What we’re able to show with that is that we can actually implicate the specific cytokines and chemokines of disease and show how those are disruptive of cell-cell interactions that drive the disease, even in a small study that should extrapolate to a larger trial. Those mechanistic results we’ll present later in October.

Could you outline the aims, design and inclusion criteria of the 12-week open-label trial?

The 12-week open label study was conducted at Mayo Clinic in Scottsdale, Arizona. The aim of the study was to evaluate the effects of brepocitinib 30 mg once daily in patients with dermatomyositis severe recalcitrant skin disease. The primary endpoint efficacy was cutaneous dermatomyositis disease area and severity index activity, which is CDASI-A score. The patients were assessed using this particular endpoint because it is a gold standard for having inter-rater reliability and reliability over time. This endpoint correlates well with patient-reported outcomes and minimizes placebo effects, allowing us to identify the minimal clinically important difference, which is the smallest change that is meaningful to patients. In context, the minimal clinically important difference, that’s that lowest level of impact and that’s about a 4 point improvement or 40% reduction in CDASI-A.

For the patients in this study, we wanted to look at two things. The first was the rapidity of onset of response with a 12-week, short-term treatment and secondly, what happens to patients when they are off therapy. So we were able to see on-treatment and off-treatment differences, which provided insights into the actual benefit of the drug for those patients.

The patients themselves were required to have active skin disease with a CDASI-A score of over 14, indicating moderate disease, and minimal muscle disease, so a MMT8 score of greater than 142, which is near normal muscle function. They were also required to have at least one unsuccessful prior systemic or standard of care treatment. When we think about those criteria, the CDASI-A was 14 for moderate disease and when we look at the participants in this trial, the average CDASI-A  score was 40.2 – so it was much, much higher. When we think of severe disease, that’s a CDASI-A score of 27, so it’s a very high disease burden for every patient enrolled. Furthermore, when we think about the other trials in this space, for example the phase II dazukibart data and the phase III ProDERM IVIg trial, those patients respectively had a 32 and 29 of CDASI-A, so this is almost 10 points higher than that, indicating severe skin disease in these patients.

What were the key outcomes observed?

Between August and November of last year, we enrolled five patients with severe recalcitrant dermatomyositis. All the patients enrolled in the study had actually failed two systemic standard of care therapies, including antimalarials, systemic corticosteroids, and conventional immunosuppressants. All patients demonstrated a rapid improvement in CDASI-A score; the mean change from baseline in CDASI-A was a 21 point improvement, with a mean percentage change of 52% reduction within just 4 weeks. They had continued benefit through week 12 and, as a reminder, the minimal improvement score is a 4 point improvement and these patients had a 21 point improvement, so a dramatic effect on the disease. Two of the patients had functional remission of disease at 12 weeks, and we saw similar improvements across patient reported outcomes, as well as physician global assessments.

A couple of things I’d like to emphasize beyond just the clinical response was the response with the patient reported quality-of-life metrics, specifically the Skindex-16, which correlates with overall quality-of-life across multiple domains. We know patients who have dermatomyositis tend to have much higher scores on par with other chronic inflammatory diseases. We noted the patients had a mean improvement of 37 points and if we think about this in context, a 10 point improvement has seen a significant and dramatic improvement in  patient quality-of-life.

The last point that I would like to make is that patients who came off the study had rebound. Three of the five patients on the study were maintained on stable systemics throughout the trial and all of them had rebound of disease off of treatment, indicating that we can attribute that effect to the trial drug itself.

What are the next steps towards realising the potential of brepocitinib in this indication?

In parallel with the open-label study that we’re discussing, the concurring global phase III double-blind, placebo-controlled, 52-week, VALOR trial was conducted. The study investigated brepocitinib in adults with dermatomyositis with active muscle and skin disease. This study represents the largest placebo-controlled trial to date with 241 patients enrolled. That study was successful and the topline results will be shared at an upcoming medical conference. The approval of brepocitinib for the treatment of dermatomyositis may be a possibility in the near future, and this would constitute a paradigm shift from our current approach of nonspecific to more targeted therapies, and really move the field of dermatomyitis forward.