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Alizyme plc today announces headline results of its European Phase III clinical trial of COLAL-PRED(R) in patients with moderate to severe ulcerative colitis
Cambridge UK | July 24, 2008 | Alizyme plc (LSE: AZM) ('Alizyme') today announces headline results of its European Phase III clinical trial of COLAL-PRED(R) in patients with moderate to severe ulcerative colitis.
Highlights
* Results indicate safe treatment for acute ulcerative colitis
* COLAL-PRED(R) showed significantly improved risk-benefit profile compared to conventional prednisolone
* Non-inferiority of efficacy of COLAL-PRED(R) to conventional prednisolone in terms of DAI at 8 weeks was not shown
* COLAL-PRED(R) showed equivalent efficacy in terms of SCCAI compared to conventional prednisolone after 8 weeks' dosing, and at the 12 week follow-up visit
* Optimal dose shown to be 40 mg of COLAL-PRED(R)
* Results indicate further potential for COLAL-PRED(R) in the maintenance of remission of ulcerative colitis
* Delay to submission of MAA pending discussions with partners and regulatory advisors
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(R) is the combination of Alizyme's proprietary colonic drug delivery system, COLAL(R), 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(R) 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(R) capsules and conventional prednisolone tablets in patients with moderate to severe ulcerative colitis.
COLAL-PRED(R) (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(R) 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(R) arms (approximately 56%) was about 18% lower than that in the prednisolone arm (74%). Thus non-inferiority of efficacy of COLAL-PRED(R) to conventional prednisolone was not shown.
The reduction in mean SCCAI in the COLAL-PRED(R) 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(R) 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(R) 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(R) treated patients, 4.8% of patients in the prednisolone group reported insomnia compared to 1.0% to 1.5% in the COLALߛPRED(R) groups, and 4.8% of prednisolone patients reported acne compared to 0.0% to 1.5% of the COLALߛPRED(R) patients.
Although non-inferiority of efficacy of COLAL-PRED(R) to conventional prednisolone was not shown, COLAL-PRED(R) 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 COLALߛPRED(R) 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(R) for maintenance of remission.
There was no clinically relevant difference in response in terms of efficacy, safety and tolerability across the three COLALߛ-RED(R) 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(R) to be a safe treatment for acute ulcerative colitis with fewer adverse effects than conventional prednisolone and support further development of COLAL-PRED(R) 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(R) 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.'
Alizyme plc
Alizyme is a speciality biopharmaceutical development company, focused on the therapeutic areas of metabolic disorders, gastrointestinal disorders and cancer supportive care. In addition to COLAL-PRED(R) it is developing cetilistat for the treatment and management of obesity and related diseases, such as type 2 diabetes and ATL-104 for mucositis, a side effect of cancer therapy.
Ulcerative colitis
Ulcerative colitis is an inflammatory disease of the colon that causes symptoms such as abdominal pain, bleeding, cramping, fatigue and diarrhoea. These conditions are characterised by episodes of acute flare of the inflammation, followed by periods of remission. In severe cases, surgery may be required to remove the diseased tissue.
The ulcerative colitis market is currently dominated by anti-inflammatory steroids and 5-ASA products, which have safety and/or efficacy issues. Currently around 2 million people in the major pharmaceutical territories around the world suffer from ulcerative colitis with projected sales of COLAL-PRED(R) in these territories in excess of US$250 million per annum.
COLAL-PRED(R)
COLAL-PRED(R) is a proprietary gastrointestinal product developed by Alizyme for the treatment of ulcerative colitis. It is the combination of Alizyme's proprietary colonic drug delivery system, COLAL(R), and a prednisolone ester, prednisolone metasulfobenzoate sodium ('PMSBS'), a steroid approved in Europe.
COLAL-PRED(R) has a coating that is broken down only in the colon, by locally occurring bacteria. This leads to topical delivery of PMSBS to the colon, rather than systemic delivery.
COLAL-PRED(R) partnerships
In November 2007, Alizyme granted Prometheus Laboratories Inc ('Prometheus') an exclusive licence to develop and market COLAL-PRED(R) in North America. Prometheus will be primarily responsible for clinical development costs in North America and has commenced Phase II development.
In December 2007, Alizyme entered into an agreement with TSD Japan Inc ('TSD') for the co-development and commercialisation of COLAL-PRED(R) in Japan. TSD is scheduled to commence Phase I development of COLAL-PRED(R) later in 2008.
In June 2008, Alizyme granted Norgine BV ('Norgine') an exclusive licence to develop and market COLAL-PRED(R) in Europe, South Africa, New Zealand and Australia. Norgine will be responsible for commercialisation.
COLAL(R)
COLAL(R) is a drug delivery technology that enables drugs to be taken orally and then be specifically released when the preparation reaches the colon. Achieving colonic release with conventional oral dosage forms has proved difficult because of the variation between individuals in transit times and conditions within the gastrointestinal tract. COLAL(R) overcomes this difficulty by covering small pellets containing the drug with a coating of ethylcellulose and a specific form of amylose (derived from starch). This coating prevents drug release in the stomach and small intestine. When the pellets reach the colon the amylose in the coating is broken down by bacterial enzymes and the drug is released.
The identification of compounds for successful research, their progress through development and the obtaining of regulatory approvals or authorisations before marketing, manufacture and/or distribution of products is not certain or a formality.
SOURCE: Alizyme plc |
