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LONDON — Sirolimus given in addition to standard therapy for active uncontrolled systemic lupus erythematosus (SLE) significantly improved both clinical and serologic outcomes vs placebo in a randomized, double-blind clinical trial reported at the European Alliance of Associations for Rheumatology (EULAR) 2026 Annual Meeting.

“Our study provides robust evidence that sirolimus is an effective and safe add-on therapy for active SLE and supports its consideration as a valuable treatment option in clinical practice,” Mengtao Li, MD, from Peking Union Medical College Hospital in Beijing, China, said during the late-breaking clinical abstracts session.

Dubbed SIRIUS, the trial was conducted at six centers in China and showed that 52.9% (n = 70) of people with active SLE who were treated with sirolimus vs 22.7% of people treated with placebo had an SLE responder index (SRI)-4 response after 24 weeks of treatment (P = .001).

Moreover, the SRI-4 response was also higher among the sirolimus-treated participants than placebo-treated participants at both 4 weeks (27.1% vs 18.7%; P = .224) and 12 weeks (48.6% vs 20.0%; P < .001).

Commenting for Medscape Medical News, Md Yuzaiful Md Yusof, MBChB, PhD, who was not involved in the study, said that these were “important phase 3 randomized trial results that showed rapid efficacy and a large effect size of 30% between sirolimus and placebo at week 24.”

Md Yusof, an associate professor and honorary consultant rheumatologist within the Leeds Institute of Rheumatic and Musculoskeletal Medicine in Leeds, England, pointed out that there was a low placebo response rate and that other key secondary efficacy endpoints “favored sirolimus too” and that there were no major safety signals.

Secondary endpoints had included the change from baseline to week 24 in the SLE disease activity score (DAS), clinical remission, and Lupus Low DAS (LLDAS).

Md Yusof also observed: “The position of sirolimus in the current and near future pathway of treatment of SLE is unclear with phase 3 results of many targeted therapies with variable mode of actions will be announced in the next 3 years.”

Repurposing an Established Transplant Drug

Sirolimus is an mTOR inhibitor that has been used to prevent transplant rejection for decades. “So the pharmaceutical effect and also the safety profile is well understood,” Li said.

There is evidence that the mTOR signaling pathway is involved “extensively” in the pathogenesis of SLE, Li added. Preliminary findings published in The Lancet in 2018 and from a prospective study and meta-analysis published in 2020 had suggested that sirolimus may have a role to play in the treatment of SLE.

Li and colleagues therefore set out to see if sirolimus added to stable background treatment for active SLE could have a beneficial effect.

For enrolment in their trial, adults with SLE had to have a clinical SLE Disease Activity Index (SLEDAI)-2K score ≥ 4 despite standard treatment, along with serologic activity defined as anti-dsDNA antibody > 10 IU/mL and or complement C3 ≤ 0.90 g/L.

They were then randomly assigned to receive sirolimus 1.5 mg/d or placebo on top of their existing medications or steroids for 24 weeks. After this, patients in the placebo group were crossed over to receive sirolimus 1.5 mg/d for a further 24 weeks.

Stable standard-of-care was defined as receipt of glucocorticoids at a dose of up to 20 mg/d or equivalent for at least 4 weeks; antimalarials or immunosuppressive therapy such as mycophenolate mofetil (MMF) ≤ 1.5 g/d; methotrexate < 15 g/wk for at least 12 weeks; and stable doses of antihypertensives or nonsteroidal anti-inflammatory drugs or other analgesics for at least 2 weeks.

Patient Population and Secondary Results

The mean age of recruited participants was around 35 years, and 94% were women. The mean time from initial SLE diagnosis to randomization into the trial was around 8.5 years.

Despite treatment at baseline with glucocorticoids (83% of participants overall), antimalarials (86%), MMF (56%), and methotrexate (8%), mean SLEDAI-2K scores were 10.0, SLE-DAS was 9.0, and 1 in 5 had at least one British Isles Lupus Assessment Group (BILAG) A score or two BILAG B scores.

Li reported that there were greater mean changes from baseline to week 24 with sirolimus than placebo in the SLEDAI-2K score (-4.7 vs -1.0; P < .001), Physician Global Assessment (-0.38 vs -0.18; P = .009), and BICLA response (60.0% vs 32.2%).

There were also significantly greater mean increases in serologic markers such as complement C3 (0.26 g/L vs 0.02 g/L) and C4 (0.08 g/L vs 0.01 g/L), and a more pronounced reduction in anti-dsDNA antibody titers (-89.3 IU/mL vs 51.1 IU/mL; P < .001 for all).

Response rates for SRI-5 (40.0% vs 17.3%) and SRI-6 (40.0% vs 16.0%) were also significantly higher with sirolimus than with placebo.

Moreover, other significant differences in secondary endpoints that favored the sirolimus group included greater mean reductions in SLE-DAS (-2.84 vs -0.75), proportion of patients who achieved LLDAS (24.3% vs 10.7%), and proportion in clinical remission (14.3% vs 4.0%).

Safety Findings

Adverse events were reported in 97.3% of participants in the sirolimus group and 86.7% of those in the placebo group. Around a quarter in each group had an infection.

The most frequent adverse events associated with sirolimus were high total cholesterol (42.7% vs 9.8% for placebo), hypertriglyceridemia (60.3% vs 26.4%), leukopenia (38.2% vs 20.3%), neutropenia (30.9% vs 8.1%), and menstrual irregularities (17.1% vs 0.0%).

Serious adverse events were rare, occurring in 4.3% of the sirolimus group and 1.3% of the placebo group. There were two deaths — one in each group — and neither was considered to be related to the study treatment allocation.

Implications for Practice

Md Yusof observed: “We need more data from the investigators regarding which SLE features responded best to mTOR pathway inhibition with sirolimus. We also need a global trial to improve generalizability of the results.”

Should these data be reproducible, “I could see that this therapy may be used in patients with active moderate-to-severe nonrenal disease who have failed to respond to one conventional immunosuppressant, that is prior to biologics,” Md Yusof said.

“[Sirolimus] may also be used in patients who have failed to respond to B-cell depleting agents and may be suitable for those with T-cell driven features, including mucocutaneous disease, arthritis, serositis, and cytopenia.”

The drug may also be considered “for patients who prefer oral therapy and in countries where access to biologics is restricted due to cost,” he said.

The study was independently supported by the Beijing Municipal Science & Technology Commission. The study drug and placebo were provided by the North China Pharmaceutical Group Corporation. Li and fellow investigators declared having no conflicts of interest.

Md Yusof reported receiving consulting fees from Aurinia Pharmaceuticals, UCB, and Autolus; advisory board participation for GlaxoSmithKline and Novartis; and receiving speaker fees from Alumis, CSL Vifor, Grifols, Novartis, Roche, and UCB.

Sara Freeman, BSc, MSc, is a freelance medical journalist based in London, England. She has been reporting for specialist healthcare news organizations for more than 20 years.