Amiselimod exhibits favourable safety in healthy individuals

Amiselimod, an oral selective sphingosine 1-phosphate (S1P) receptor modulator, demonstrated a favourable safety profile among healthy individuals, according to a phase I study presented at Crohn’s and Colitis 2021.

“S1P receptor-1 modulators are a class of compounds currently under development for various autoimmune diseases, such as multiple sclerosis, systemic lupus erythematosus, and inflammatory bowel disease,” said the researchers. These compounds reduce the emigration of lymphocytes from secondary lymphoid organs to the periphery. [Int Immunopharmacol 2011;11:366-372; Br J Clin Pharmacol 2017;83:1011-1027]

Evidence shows that amiselimod regulates lymphocyte trafficking and induces immunomodulatory effects by reducing the number of circulating peripheral lymphocytes. [PLoS One 2019;14:e0226154; Br J Pharmacol 2017;174:15-27] Moreover, studies have reflected the favourable safety profile of amiselimod, with no clinically significant cardiac effects. [Br J Clin Pharmacol 2017;83:1011-1027; Mult Scler 2018;24:1605-1616; Lupus 2020;29:1902-1913]

“Amiselimod [has] a long half-life and slow accumulation to steady state that limits effects on some measures of cardiac safety, including heart rate and atrioventricular conduction,” said the researchers.

To ascertain the safety profile of amiselimod, the team ran a 28-day treatment period in 190 healthy* volunteers (mean age 39 years, 40 percent female). While the study primarily evaluated the probable QT interval prolongation with amiselimod, the current analysis looked into its overall safety.

Participants were randomized 2:1:1 to receive either a single dose of placebo (day 1) followed by amiselimod (days 1–26), a single dose of oral moxifloxacin 400 mg (day 1) followed by placebo (days 1–26), or placebo (days 1–26) followed by a single dose of moxifloxacin 400 mg (day 27). To achieve a 0.4-mg and 0.8-mg steady-state exposure, amiselimod doses were upwardly titrated from 0.4 to 1.6 mg. [Crohn’s and Colitis 2021, abstract P049]

Discontinuation rates were relatively low in both the amiselimod and the moxifloxacin/placebo arms (8 percent vs 4 percent). Among those who discontinued amiselimod, three were due to meeting the protocol-defined discontinuation criteria for low lymphocyte counts, while two withdrew owing to adverse events, one of which was deemed serious (ie, atrial fibrillation).

The most common treatment-emergent AEs (TEAEs) associated with amiselimod use were reduced white blood cell (WBC) count, constipation, and dizziness. Most TEAEs were mild (83 percent), while the rest were moderate in severity. There were no deaths reported.

Although the mean WBC counts among amiselimod recipients fell (ranging from 3.49 to 3.85 thou/uL) below the reference range (3.9–10.7 thou/uL) on days 14, 27, 28, and 29, these returned to normal, without sequelae, after discontinuation.

Moreover, the reductions in neutrophils, lymphocytes and haemoglobin, and increases in creatine kinase, alanine aminotransferase, and aspartate aminotransferase, all resolved without sequelae.

“[These findings suggest that] upwardly titrated doses of amiselimod … were generally well-tolerated in healthy subjects. The amiselimod therapeutic dose of 0.4 mg and the supratherapeutic dose of 0.8 mg steady-state exposure was determined to be safe,” said the researchers.

“Amiselimod may provide a safe alternative to currently available nonselective S1P receptor modulators,” concluded the researchers, who called for further investigation to ascertain the findings.