Abstract
Background
Sphingosine 1-phosphate (S1P) receptor modulators are being developed to treat autoimmune-mediated diseases, including ulcerative colitis (UC) and Crohn’s disease (CD). Amiselimod (AMS), a second-generation S1P receptor modulator, was developed to reduce bradycardia associated with other S1P receptor modulators, including fingolimod.
Methods
This multicenter, randomized, double-blind, parallel group, placebo (PBO)-controlled (DBPC) phase 2a clinical trial in adults with moderate to severe active CD evaluated the safety and efficacy of oral AMS 0.4 mg/d for 14 wks, followed by open-label extension (OLE) of AMS for ≤36 wks. Patients were required to have used corticosteroids, immunosuppressants, or anti-TNF-α agents for CD treatment. The primary efficacy endpoint was a 100-point drop at wk 12 in the Crohn’s Disease Activity Index.
Results
Of the 78 patients randomized 1:1 to receive AMS (n=40) or PBO (n=38), 78% [n=61] completed the DBPC phase. Of those continuing into the OLE, 26 (AMS/AMS [n=14]; PBO/AMS [n=12]) completed it. AMS 0.4 mg for 12 wks did not have a significant effect on clinical disease activity (CDA) in CD. At least 1 treatment-related adverse event (TRAE) was reported by 31% receiving AMS and 24% receiving PBO; the most frequently reported TREAs for AMS were skin and subcutaneous tissue disorders (10%), infections and infestations, musculoskeletal and connective tissue disorders, nervous system disorders, and cardiac disorders (all 8%). Five serious AEs (SAEs) led to treatment discontinuation (1 in the PBO group; 4 in the AMS group). In the OLE, more PBO/AMS patients (40%) vs AMS/AMS (33%) reported TRAEs; most frequent TRAEs for AMS/AMS were blood and lymphatic system disorders (14%) and investigations (14%). Of 13 SAEs reported by 9 patients, 2 treatment-related SAEs (1 in the PBO/AMS group) led to treatment discontinuation. In the DBPC study, cardiac disorders, all mild, were reported in 3 in the AMS group vs 1 in the PBO group; in the OLE, cardiac disorders were reported by 1 in the AMS group and 1 in the PBO group. There were no clinically significant reports of bradycardia, ventricular tachycardia, or atrioventricular block in the AMS group in either study. In the DBPC study, macular edema (ME) was confirmed in 1 AMS patient (mild/nonserious); none were reported in the OLE. There were no deaths, opportunistic infections, clinically significant negative laboratory or abnormal ECG findings after AMS treatment.
Conclusions
Oral AMS 0.4 mg was generally well tolerated, with no new safety concerns identified. Other than 1 patient with mild ME, there were no other findings related to the known AMS risk profile. While AMS did not have an effect on CDA in previously treated CD, this favorable safety profile, including no clinically significant reports of bradycardia, is promising for treatment of other autoimmune-mediated diseases, including UC.
DOP48 Amiselimod, a selective S1P receptor modulator in Crohn’s disease patients: a proof-of-concept study
