Alizyme PLC Announces Headline Results from Its European Phase 3 Clinical Trial
Published: Jul 24, 2008
Ulcerative colitis is a chronic relapsing inflammatory disease of the colon for which there is an unmet medical need for a therapy that is both effective and safe. The ‘gold standard’ in terms of efficacy is conventional oral prednisolone. However, this has significant adverse effects that limit its clinical use and restrict the duration for which it can be safely administered. COLAL-PRED® is the combination of Alizyme’s proprietary colonic drug delivery system, COLAL®, and prednisolone metasulfobenzoate sodium (“PMSBS”), a form of prednisolone approved in Europe for the treatment of acute ulcerative colitis.
The European Phase III trial was designed to demonstrate that in individual patients, COLAL-PRED® was both an effective, and a safe and well tolerated treatment for ulcerative colitis, without the debilitating side-effects associated with conventional prednisolone. The study was a double blind comparison of COLAL-PRED® capsules and conventional prednisolone tablets in patients with moderate to severe ulcerative colitis.
COLAL-PRED® (40 mg, 60 mg or 80 mg once daily (“o.d.”)), administered for 8 weeks, was compared with conventional prednisolone. The conventional prednisolone dosing regimen was 40 mg o.d. for 2 weeks, followed by a tapering regimen (to allow recovery from adrenal suppression) that reached 0mg by Week 8.
The study had two co primary endpoints:
• Safety Response Superiority compared to conventional prednisolone in the proportion of patients who were Safety Responders (patients whose early morning plasma cortisol was >150 nmol/l at Week 4 and at Week 8).
• Efficacy Response Non-inferiority compared to conventional prednisolone in the proportion of patients who were Efficacy Responders (patients who showed a reduction of at least 3 points in their Disease Activity Index (“DAI”) score at Week 8 (or time of withdrawal) compared to baseline). The required non-inferiority margin was 15%.
The key secondary endpoint that addressed the Target Product Profile was:
• Treatment Response Superiority compared to conventional prednisolone in the proportion of patients who were Treatment Responders (individual patients who were both Efficacy Responders and Safety Responders). Other efficacy endpoints included change in Simple Clinical Colitis Activity Index (“SCCAI”) score.
Results 799 patients were randomised; approximately 200 per treatment group. Of these, 543 (68%) completed study medication (65% to 67% in the COLAL-PRED® groups and 74% in the prednisolone group). The mean initial DAI score was 8.1. Of the patients randomised, 40% had an initial DAI score of ?9.
The Efficacy Responder rate in the COLAL-PRED® arms (approximately 56%) was about 18% lower than that in the prednisolone arm (74%). Thus non-inferiority of efficacy of COLAL-PRED® to conventional prednisolone was not shown.
The reduction in mean SCCAI in the COLAL-PRED® treatment groups was equivalent to that in the prednisolone treated group at Week 8 (reduction of 2.32 points and 2.42 points respectively in comparison with baseline) and at Week 12 (reduction of 3.06 points and 2.75 points respectively).
Early morning plasma cortisol was unchanged in the COLAL-PRED® treatment groups throughout the study, while there was a clinically significant reduction of 170 nmol/l in the prednisolone group at Week 4.
The incidence of typical steroid-related adverse events was significantly lower in the COLAL-PRED® groups compared to the prednisolone group. Cushingoid syndrome was reported by 5.3% patients in the prednisolone group compared to 0.0% to 1.0% in the COLAL PRED® treated patients, 4.8% of patients in the prednisolone group reported insomnia compared to 1.0% to 1.5% in the COLAL PRED® groups, and 4.8% of prednisolone patients reported acne compared to 0.0% to 1.5% of the COLAL PRED® patients.
Although non-inferiority of efficacy of COLAL-PRED® to conventional prednisolone was not shown, COLAL-PRED® was statistically superior to prednisolone in the proportion of patients who were Treatment Responders, i.e. were both Efficacy and Safety Responders, thereby meeting the key secondary endpoint with respect to addressing the Target Product Profile.
The results of the study support the product profile for COLAL PRED® of safety as well as efficacy in individual patients. The excellent safety profile, particularly the absence of an effect on plasma cortisol, also supports the long term administration of COLAL-PRED® for maintenance of remission.
There was no clinically relevant difference in response in terms of efficacy, safety and tolerability across the three COLAL PRED® treatment groups (40 mg, 60 mg or 80 mg o.d.), supporting a dose recommendation of 40 mg o.d.
Commenting on the results, Prof. CJ Hawkey, Chief Coordinating Investigator, said:
“These results indicate COLAL-PRED® to be a safe treatment for acute ulcerative colitis with fewer adverse effects than conventional prednisolone and support further development of COLAL-PRED® for maintenance of remission.”
Commenting on today’s announcement, Tim McCarthy, Alizyme’s Chief Executive Officer said:
“We are pleased to report that the headline results of this study indicate that COLAL-PRED® is a safe steroid in the treatment of ulcerative colitis. The headline results also indicate that this product has potential for maintenance of remission of ulcerative colitis. We will continue to analyse the results and, in conjunction with our partners and regulatory advisors, establish the optimum way forward in commercialising this product.”