Systemic lupus erythematosus (SLE), the most common type of lupus, is an autoimmune disease that causes the body to attack its own tissues. With a variable standard of care (SOC) and unpredictable disease progression, SLE is a notoriously tough indication for designing sensitive clinical trials with the right treatment candidates.

Nevertheless, four major drug trials in SLE have results expected in the remainder of 2022 or the first half of 2023, according to GlobalData’s clinical trials database. These include AbbVie’s small molecule combination ABBV-509 and three biologics: Eli Lilly’s LY-3471851, Merck KGaA’s M-5049, and Swedish Orphan Bio’s emapalumab. GlobalData is the parent company of Clinical Trials Arena.

The current SLE treatment paradigm revolves around hydroxychloroquine and corticosteroids, with monoclonal antibodies (mAbs) playing a limited role. While this creates an untapped opportunity for these new biologics in development, it also presents a host of clinical trial design challenges.

“Lupus patients who might benefit from novel, targeted biologics are often too unstable to be abruptly removed from their variegated background medications,” explains Dr Joan Merrill, a rheumatologist at University of Oklahoma Health Sciences Center. “It’s challenging to design a clinical trial where apples are not being compared to oranges.”

AbbVie tests Rinvoq with BTK inhibitor

AbbVie is testing ABBV-509—a combination of elsubrutinib and Rinvoq (upadacitinib)—in a Phase II trial with results expected by the end of 2022. The SLEek trial (NCT03978520) tests the signs and symptoms of SLE in 341 patients with moderate to severe SLE.

Elsubrutinib is a Bruton's tyrosine kinase (BTK) inhibitor, and Rinvoq is a Janus Kinase 1 (JAK1) inhibitor—both of which act as immunosuppressive agents. On its own, Rinvoq has approval in several autoimmune disorders, including psoriatic arthritis, atopic dermatitis, ulcerative colitis, and rheumatoid arthritis.

As a primary endpoint, the Phase II study is testing achievement of SLE Responder Index (SRI)-4 after 24 weeks with less than 10mg per day of steroid use. SLE-4 is defined as at least a four-point reduction in the SLE Disease Activity Index 2000 (SLEDAI-2K) without worsening of the overall condition.

Eli Lilly investigates IL-2 receptor agonist

Eli Lilly is testing LY-3471851 in a 280-patient Phase II ISLAND-SLE trial (NCT04433585) with results expected in H1 2023. LY-3471851, also known as rezpegaldesleukin, targets the interleukin 2 receptor, rebalancing the immune system through an increase in T regulatory cells.

As a primary endpoint, the Phase II study measures the percentage of participants with at least a four-point reduction in SLEDAI-2K after 24 weeks. Secondary endpoints include percentage of patients achieving SRI-4 at week 24, as well as other lupus severity scales and pharmacokinetic measures.

Nektar Therapeutics, which first developed LY-3471851, is listed as a study collaborator on the trial’s listing. The mAB LY-3471851 is also in development for atopic dermatitis, ulcerative colitis, and plaque psoriasis.

Merck KGaA’s M-5049 takes on SLE and CLE

Merck KGaA’s M-5049 is in an investigator-sponsored Phase II trial with results also expected in the 1H of 2023. The WILLOW study (NCT05162586) is testing multiple doses of M-5049 and placebo in 440 patients with SLE or cutaneous lupus erythematosus (CLE)—an acute form of lupus where the immune system attacks the skin.

WILLOW is recruiting out of 86 sites, including in the US, Argentina, Australia, Bulgaria, China, Japan, and South Africa. Massachusetts-based EMD Serono Research & Development Institute is the study sponsor.

In the Phase II study, M-5409 is orally administered over the course of 24 weeks with coprimary endpoints: percentage change in Lupus Erythematosus Disease Area and Severity Index (CLASI-A) at week 16, and British Isles Lupus Assessment Group (BILAG)-Based Composite Lupus Assessment (BICLA) Response at week 24. CLASI-A is a validated measure of disease activity and disease-induced damage in SLE, and BILAG is a validated assessment of SLE disease activity.

Swedish Orphan Bio’s Gamifant targets severe SLE complication

Swedish Orphan Bio is studying Gamifant(emapalumab) in a Phase II/III trial for macrophage activation syndrome (MAS) in SLE or in Still’ disease. The 41-patient EMERALD trial (NCT05001737) has results expected in H1 2023.

MAS is a severe, potentially fatal complication of rheumatic diseases including SLE, characterised by high fever, cytopenia, liver complications, and coagulopathy. Gamifant, which has approval for the rare white blood cell disease hemophagocytic lymphohistiocytosis, is a mAb that inhibits interferon gamma (INFG) to generate immunosuppression.

EMERALD consists of two cohorts: one enrolling patients with MAS in the context of systemic juvenile idiopathic arthritis and adult-onset Still's disease, and one with MAS in the context of SLE. The primary endpoint is complete response (CR) at eight weeks, with secondary endpoints focusing on PK/PD values.

Where SLE is headed

Given the heterogeneity of lupus progression, it is often difficult to obtain interpretable scoring of disease activity, Merrill explains. However, improved success in recent studies has been built on close scrutiny by experts, better disease activity scoring, and tapering background medications, she says.

Overall, SLE trials are beginning to represent a greater percentage of drug trials in autoimmune disorders, according to GlobalData’s database. In 2022, Phase I–III trials in SLE trials accounted for 19.4 % of autoimmune disorder trials that year, up from just 8.5% in 2013. During that ten-year stretch, Phase I and Phase III trials saw the greatest percentage increase.

An estimated 1.5 million Americans and 5 million people worldwide have lupus, many of which also suffer from SLE. As more sponsors aim at developing new pills and biologics beyond steroids and hydroxychloroquine, patients and clinicians anxiously await new therapeutic options.