Litifilimab significantly reduces disease activity in phase 2 cutaneous lupus erythematosus trial

Q. What are the main limitations of current treatments for cutaneous lupus erythematosus?

Cutaneous lupus erythematosus presents in several forms, including acute cutaneous, subacute cutaneous, discoid and other chronic variants. In practice, treatment approaches are still fairly similar across these subtypes.

Discoid lupus, the most common form of cutaneous lupus, can be especially challenging to manage because it often leads to disfigurement, scarring and dyspigmentation. That makes effective treatment particularly important. Yet treatment options have remained largely unchanged for around 70 years. A major reason for this is that, until recently, we did not have a clinical trial endpoint in cutaneous lupus that was recognized by the US Food and Drug Administration (FDA), and without that, it has been very difficult to gain approval for new therapies.

Some drugs currently approved for systemic lupus can also work well in the skin, but they are often not easily accessible for patients with CLE. At present, treatment usually begins with hydroxychloroquine, with quinacrine sometimes added. If hydroxychloroquine is not effective, we may switch to chloroquine. However, hydroxychloroquine and chloroquine cannot be used together because of the added risk of ocular toxicity. Working out which approach or combination is most effective can take four to five months.

If those treatments are not effective and the patient has significant disease, then, alongside sunscreens, topical steroids, and topical calcineurin inhibitors such as tacrolimus or pimecrolimus, we would usually escalate to systemic therapies such as methotrexate or mycophenolate mofetil. These agents can also be very effective, but they do not work for everyone. Some patients therefore need to move on to other options, such as lenalidomide, which has largely replaced thalidomide as a treatment for severe, refractory cutaneous lupus erythematosus.

All of these treatments have been available for many years, and, to date, no new therapies have been approved specifically for CLE. However, important progress has been made through the work of the Lupus Research Alliance, in collaboration with key opinion leaders, industry partners and the FDA in a public–private partnership. This collaboration has been extremely valuable in supporting recognition of the CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) as an endpoint that can now be used as a primary outcome measure in clinical trials. As a result, we now have a clearer path forward for developing and approving treatments for patients with difficult-to-treat disease.

Q. How is litifilimab thought to work in cutaneous lupus erythematosus?

Litifilimab is thought to target the underlying pathogenesis of CLE by binding to blood dendritic cell antigen 2 (BDCA2) on plasmacytoid dendritic cells (pDCs). This leads to internalisation of the receptor and downregulation of inflammatory cytokines, including type I interferons, tumour necrosis factor-alpha (TNF-α) and other mediators that may be driving disease activity. Rather than depleting pDCs, litifilimab appears to suppress their activity to a level at which disease progression can be halted.

Early studies of litifilimab have shown that even a single dose of litifilimab can rapidly suppress the type I interferon pathway, with improvement in skin disease observed within two to four weeks.

Q. What was the design and eligibility criteria of Part A of the phase 2 AMETHYST study?

AMETHYST Part A was a double-blind, placebo-controlled phase 2 study with a 24-week placebo-controlled treatment period, during which patients were assigned to receive either litifilimab or placebo. This was followed by a 28-week extension period in which all patients received litifilimab. It was the 24-week data that was presented at AAD 2026.

Participants in the study had to be aged 18 years or older, have histologically confirmed CLE, with or without systemic manifestations, and have a CLASI activity score of 10 or higher. They also had to be refractory to or intolerant of antimalarials, and to be receiving stable background lupus standard-of-care therapy before entering the study while still meeting the eligibility criteria.

The primary endpoint was CLA-IGA-R (Cutaneous Lupus Activity Investigator’s Global Assessment-Revised) response with an erythema score of 0 or 1 at week 16, a stringent endpoint designed to reflect clear or almost clear skin.

Secondary endpoints included CLASI-50 and CLASI-70 responses based on the CLASI activity score, achievement of low disease activity defined as a CLASI activity score of 0–3, and changes in CLASI damage (CLASI-D). Other secondary assessments included additional morphological features captured by the CLA-IGA-R, as well as annualized flare rate. Patient-reported outcomes were also included to evaluate quality of life, including CLEQoL (Cutaneous Lupus Erythematosus Quality of Life) and DLQI (Dermatology Life Quality Index) scores. Safety was assessed through the reporting of treatment-emergent adverse events and serious adverse events.

At baseline, 74% of participants enroled in the study were female, 66.7% were White and 24.7% were Hispanic. Notably, the study population had a high degree of cutaneous lupus severity, with a mean CLASI activity score of 20.2 in the litifilimab group and a very similar score in the placebo group, placing patients in the moderate-to-severe disease activity range overall. Background medications were used by around 75% of patients, most commonly hydroxychloroquine. In terms of CLE subtype, the majority of patients had discoid lupus, while approximately 30% had subacute cutaneous lupus.

Q. What did the 24-week results show in terms of efficacy and safety?

The 24-week results showed a statistically significant improvement in the primary endpoint, which was achieving a CLA-IGA-R erythema score of 0–1, consistent with clear or almost clear skin. This endpoint was met by 14.7% of patients in the litifilimab group compared with 2.9% in the placebo group. A separation between the groups was seen as early as week 8, and this difference continued to increase over time, with the benefit maintained through week 24.

For the CLASI-50 endpoint, a statistically significant difference between the litifilimab and placebo groups emerged as early as week 4 and was maintained through week 24. At 24 weeks, 40.8% of patients in the litifilimab group had achieved a CLASI-50 response compared with 21.0% in the placebo group. A similar pattern was observed for the more stringent CLASI-70 endpoint, with a continued separation between the treatment groups, showing that patients in the litifilimab arm consistently performed better than those in the placebo arm (21.7% vs 5.8%).

Another endpoint was the proportion of patients achieving a CLASI-A score of 0–3, which is considered to represent no or minimal disease activity. Here, there was a clear difference between groups at week 24: 16.3% of patients in the litifilimab group achieved this endpoint, compared with 0% in the placebo group.

In terms of safety, there were no real differences reported between litifilimab and placebo. The most common events were nasopharyngitis and headache, which were more prevalent in the placebo group. There were no cases of herpes zoster and really no differences in the numbers of infections. Overall, litifilimab appears to be very well tolerated, with no new adverse events, relative to what was seen in the earlier phase 2 trial.

In summary, litifilimab demonstrated greater improvements versus placebo in skin disease activity in participants with CLE across multiple clinical endpoints through week 24. It also demonstrated rapid improvement in skin disease activity and was generally well tolerated, with no new safety signals. Overall this really was a very positive study and further reinforced litifilimab’s efficacy and safety profile.

Q. What are the next steps towards realizing the potential of litifilimab in cutaneous lupus erythematosus ?

An ongoing phase 3 trial is now under way and will hopefully confirm the positive findings observed in the two phase 2 studies. If the phase 3 data are favourable, it is hoped that this will support FDA approval of litifilimab, potentially making it a new approved treatment option.

Litifilimab has the potential to represent a major advance in our approach to treating patients with isolated CLE, as well as patients who have CLE in the setting of systemic lupus erythematosus.