4SC AG, has announced the final data from the ENTRANCE Phase IIa trial in inflammatory bowel disease (IBD) with vidofludimus, an oral inhibitor of interleukin-17 (IL-17) release and DHODH, including the secondary endpoints comprising the analysis of CDAI (Crohn’s disease, CD) and CAI (ulcerative colitis, UC) disease scores, change of prednisolone intake and threshold doses, safety, pharmacokinetics and biomarkers.
The data support the previously reported top-line primary endpoint result, which was achieved with a total response rate of 88.5%. These were presented last week at the 6th ECCO IBD Conference in Dublin, Ireland.
• Primary objective of the ENTRANCE study in 26 CD and UC patients was to assess vidofludimus’ remission maintenance potential in steroid-dependant IBD patients upon steroid weaning.
• Primary endpoint was met with an 88.5% total response rate (complete and partial responders), supported by secondary endpoint results demonstrating a clear clinical benefit for treated IBD patients.
• Required relapse-free prednisolone doses at the end of vidofludimus therapy were significantly lower than average doses needed prior to study entry.
• Average prednisolone consumption dramatically dropped over the course of the treatment period.
• Prednisolone threshold doses of partial responders at the end of the treatment were significantly reduced compared to documented threshold doses prior to study entry.
• Vidofludimus was safe and well tolerated by all patients.
Entrance Trial Final Data
The top-line results from the exploratory, open-label, single-arm ENTRANCE Phase IIa study, announced in November 2010, demonstrated a 88.5% total response rate with vidofludimus versus an average placebo response rate of approximately 20% across published benchmark clinical trials, in steroid-dependant IBD patients.
53.9% (14 out of 26) of patients were complete responders, 34.6% (9 out of 26) of patients were partial responders (34.6%), and 11.5% (3 out of 26) of patients were evaluated as non-responders. No variation in response rates across the sub-disease populations of Crohn’s disease (85.7%) and ulcerative colitis (91.7%) over the 12 week treatment period was observed.
CDAI/CAI disease score development was in-line with the assignment of patients to the categories complete, partial, and non-responders. All 26 evaluable patients, excluding the three non-responders, reached a relapse-free prednisolone dose which was significantly (p<0.001) lower than their individual threshold doses at which they experienced relapses prior to entering into the study.
In addition, the decrease of prednisolone intake over the 12 week treatment period indicates a strong steroid-sparing effect from vidofludimus. Mean prednisolone consumption was significantly (p<0.001) lowered from 26.5 mg/day (± 8.0) at treatment start to 1.0 mg/day (± 2.7) at week 12.
In addition to complete responders who by definition were in steroid-free remission at the end of the study, also partial responders experienced a significant clinical benefit. The mean prednisolone threshold dose of partial responders significantly (p<0.001) dropped from 12.5 mg/day (± 3.1) before study start to 1.4 mg/day (± 2.5) at the end of the study.
As expected, due to the inclusion of patients in remission and on concomitant treatment with prednisolone, biomarker data (IL-17, C-reactive protein CRP, erythrocyte sedimentation rate ESR, and calprotectin) revealed poor or no correlation with patients’ disease activity. However, these biomarkers are expected to be valuable parameters to characterize the disease status and to potentially stratify patient populations in future IBD trials with vidofludimus.
Vidofludimus was safe and well tolerated by all patients. No clinically relevant changes of pulse rate, blood pressure, electrocardiography, body temperature, hematology and biochemistry were recorded. A total of 75 adverse events (AEs) were reported (53 mild, 18 moderate, 4 severe) of which 19 AEs were judged by investigators as “possibly” or “probably” drug-related. These included isolated cases of nasopharyngitis, abdominal pain, fatigue, insomnia, glucosuria, leucocyturia, microhematuria, musculoskeletal pain, myalgia, tachycardia, and dyspepsia. No drug-related serious adverse events (SAEs) were reported.
Dr Bernd Hentsch, Chief Development Officer of 4SC, commented, “The ENTRANCE study has produced encouraging data with vidofludimus in inflammatory bowel disease, an indication that is underserved for patients and is lacking effective and safe drugs especially in long-term remission maintenance therapy. These data provide early evidence that our oral therapy vidofludimus could provide such an alternative and we look forward to assessing the potential of this compound in further IBD trials.”