mTOR inhibition may be an ‘attractive therapeutic option’ for SLE
medwireNews: Results of an open-label phase I/II trial suggest that the mammalian target of rapamycin (mTOR) inhibitor sirolimus has a favorable safety profile and may reduce disease activity in patients with systemic lupus erythematosus (SLE).
As reported in The Lancet, 40 patients with active SLE and an inadequate response or intolerance to conventional treatment were given oral sirolimus at a starting dose of 2 mg daily, with dose adjustment based on tolerability to maintain a therapeutic range of 6–15 ng/mL. All but two patients were women, and the vast majority (92.5%) of participants were of White ethnicity.
A total of 29 patients completed 1 year of sirolimus treatment; two discontinued the drug due to intolerance, while the remaining nine did not adhere to the treatment protocol.
Andras Perl (SUNY Upstate Medical University New York, Syracuse, USA) and co-investigators found that patients experienced a significant improvement in average Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores over the study period, from 10.2 points at baseline to 4.8 points after 1 year of sirolimus treatment. Similarly, mean British Isles Lupus Assessment Group index scores decreased from 28.4 to 17.4 points.
At 1 year, 66% of patients achieved an SLE Responder Index response, a “similar” rate to that previously observed for belimumab, “which is the only medication that has been approved for systemic lupus erythematosus by the US Food and Drug Administration since the 1960s,” remark Perl and team.
Participants also experienced a significant reduction in the mean daily dose of prednisone that was required to control disease activity, from 23.7 mg at baseline to 7.2 mg at the 1-year follow-up.
When specific lymphocyte subsets were analyzed, the researchers demonstrated that CD4+ and CD8+ memory T-cell counts increased only in the 11 patients who achieved at least a 4-point improvement in SLEDAI score from baseline to 1 year. Of the different cell types studied, depletion of a specific subset of CD8+ effector–memory T cells expressing CD26L and CD197 was the strongest predictor of response to sirolimus treatment.
In the safety analysis, high-density lipoprotein cholesterol, neutrophil counts, and hemoglobin were “moderately reduced” with sirolimus treatment, but the investigators note that “values remained within a range that was considered to be safe.” One patient experienced extensive oral ulcers after 12 weeks of receiving sirolimus, which resolved after the drug was discontinued.
David Fernandez and Mary Crow (both from the Hospital for Special Surgery in New York, USA) note in an accompanying commentary: “Although the study was not powered to assess safety endpoints, the absence of safety signals such as thrombosis or pneumonitis is encouraging.”
They add, however, that the generalizability of the results may be “limited” given that almost all participants were White women.
The study authors agree, emphasizing that “[f]ollow-up placebo-controlled clinical trials in diverse patient populations are warranted to further define the role of mTOR blockade in treatment of systemic lupus erythematosus.”
And the commentators conclude: “Inhibition of the mTOR pathway with sirolimus – a therapy approved by the US Food and Drug Administration for prevention of organ transplant rejection – could be a novel and attractive therapeutic option” for SLE patients.
medwireNews is an independent medical news service provided by Springer Healthcare. © 2018 Springer Healthcare part of the Springer Nature group