Oral treatment with cenerimod shows promising safety and efficacy in people with mild to moderate systemic lupus erythematosus (SLE), including reduced disease activity and lower levels of immune cells in the blood, according to data from a Phase 2 trial.
The research, “First Use of Cenerimod, a Selective sphingosine-1-phosphate 1 (S1P1) Receptor Modulator, for the Treatment of Systemic Lupus Erythematosus: A Double-Blind, Randomised, Placebo-Controlled, Phase II, Proof-of-Concept Study,” was presented at the 2019 American College of Rheumatology (ACR) / Association for Rheumatology Professionals (ARP) Annual Meeting, held in Atlanta.
Cenerimod, developed by Idorsia Pharmaceuticals, is a selective sphingosine-1-phosphate 1 receptor modulator given as oral tablets. By blocking the activity of these receptors on the surface of immune cells, cenerimod is intended to prevent immune cells from leaving lymph nodes and enter other tissues and organs to cause inflammation.
The Phase 2 study (NCT02472795, sponsored by Idorsia) assessed the effects of cenerimod on disease activity (measured by the modified SLE Disease Activity Index-2000, mSLEDAI-2K) and on the total levels of circulating lymphocytes in people with mild to moderate SLE.
Additional goals included assessing the safety and pharmacokinetic properties of cenerimod. Of note, pharmacokinetics refers to how a medication is absorbed, distributed, metabolized, and eliminated from the body.
The study was divided into two parts. In part A, 49 participants were randomly assigned to receive one of three daily doses of cenerimod (0.5, 1, or 2 mg) or a placebo over 12 weeks. Part B recruited 18 additional patients. Thirteen received 4 mg of cerenimod; five, a placebo.
Results revealed that, compared to baseline values, treatment with cenerimod reduced the total levels of circulating immune cells in a dose-dependent manner at the end of the 12-week period. With the exception of the lowest dose (0.5 mg/day), all other doses led to a significant reduction in circulating lymphocytes compared to the placebo.
Early analyses also indicated that the highest dose (4 mg/day) lowered disease activity, as well as the blood levels of anti-double stranded (ds) DNA autoantibodies, a standard parameter of SLE disease activity.
The incidence of treatment-emergent adverse events was similar across cenerimod groups and was consistently lower than seen with placebo.
After the first dose, cenerimod led to small, temporary and dose-dependent reductions in heart rate. A small decline in respiratory function was also seen.
Pharmacokinetic analyses also revealed that blood levels of cenerimod stabilized after four to eight weeks of treatment, in a dose-proportional manner.
“This was the first study to investigate cenerimod in patients with SLE and confirmed its lymphocyte-lowering effects in this patient population. Considering this was a small, 12-week study in patients with mild to moderate SLE, we were encouraged by the early signs of reduced disease activity,” Guy Braunstein, MD, head of Idorsia’s global clinical development, said in a press release.
“We are now investigating whether this translates into clinical efficacy in the ongoing longer-term efficacy and safety study,” he added.
A double-blind Phase 2b study (NCT03742037) is currently evaluating the safety and efficacy of the same four doses of cenerimod in a similar group of people with SLE.
Participants will receive cenerimod in addition to standard therapy for up to one year. The trial is still recruiting patients at 105 sites across the United States, Europe, and elsewhere. Idorsia is anticipating to enroll around 500 patients and conclude the trial in May 2021.
At the meeting, Idorsia also presented findings of other clinical and preclinical studies of cenerimod.
The research, “Cenerimod, a Potent and Selective Sphingosine-1-Phosphate Receptor 1 Modulator, Controls Systemic Autoimmunity and Organ Pathology in Mouse Models of Systemic Lupus Erythematosus and Sjögren’s Syndrome,” showed that 10-week treatment with cenerimod lowered inflammation, eased autoimmunity and helped preserve organ function in mice with SLE or Sjögren’s syndrome, another autoimmune disease characterized by lymphocyte activation.
In turn, the study, “In Vitro Characterization of the Effect of Cenerimod, a Potent and Selective Sphingosine 1-Phosphate Receptor 1 (S1P1) Modulator, on S1P1 Receptor Expression, Receptor Internalization, and Migration of Primary Human T Cells in the Presence or Absence of Glucocorticoids,” assessed the effects of cenerimod in immune cells collected from healthy donors and cultured in a lab dish.
The findings revealed that cenerimod led to the entry of S1P1 receptor in immune T cells, preventing these lymphocytes from migrating toward S1P. This was “in line with the retention of lymphocytes in the lymph node and the reduction of circulating lymphocytes observed in the clinical setting,” the researchers said.
Adding glucocorticoids — commonly used by people with SLE to reduce inflammation — also reduced levels of S1P1 receptor at the cell surface and did not affect the activity of cenerimod. This suggests that the two medications can be used together, the team said.
The study, “Cenerimod, a Potent, Selective and Orally Active Sphingosine 1-phosphate Receptor 1 Modulator, Reduced Blood Antibody-secreting Cells in Patients with SLE,” further indicated that treatment with cenerimod reduces levels of S1P1 receptors on the surface of immune cells in vitro, as shown in B- and T-lymphocytes from SLE patients and healthy donors.
Among participants in the Phase 2 trial, cenerimod not only reduced the levels of immune T and B cells by 90–95%, but also the number of autoantibody-producing B-cells by 85%.
“I am very encouraged by the excellent data presented with cenerimod, the result of 20 years of research in our labs. As expected, we saw a dose-dependent reduction in lymphocyte counts in patients with lupus. Perhaps more importantly, we saw that the antibody-producing B-cells, which are elevated in patients with lupus and critical to the disease processes, were markedly reduced,” said Martine Clozel, MD, chief scientific officer of Idorsia.
Clozel added, “In the limited current treatment landscape, I believe that the properties of cenerimod and the mechanism of S1P1 receptor modulation provides significant potential to address the pathophysiology of lupus, reducing circulating autoreactive T and B cells thereby stopping the production of pathogenic autoantibodies.”
The development of cenerimod in SLE is under a Fast Track program by the U.S. Food and Drug Administration.