Dublin, Ireland, 22 September 2009 - AGI Therapeutics plc (“AGI” or the “Company”) (AIM, IEX: AGI), a speciality pharmaceutical development company, today announced that it has completed the data analysis of ARDIS-1 and-3 , it’s Phase III clinical studies of Rezular™ in diarrhoea-predominant irritable bowel syndrome (IBS-D).
ARDIS 1 study design:
ARDIS-1 was a double-blind, placebo-controlled, parallel-groups, dose-response study of Rezular in IBS-D patients. A total of 708 patients make up the intent-to-treat (ITT) safety population. Patients were treated for 12 weeks following a baseline/run-in period of 2 weeks. Measures of efficacy were typically reported daily by patients. In addition, there were three physician visits during therapy, at weeks 4, 8 and 12. Vital signs and laboratory tests were performed at all visits and ECG measurements taken at weeks 4 and 12. In addition to placebo (P n=174) there were 3 different doses of Rezular treatment, 15mg t.i.d. (45mg/day (R 45mg n=179)), 37.5mg t.i.d (112.5mg/day (R 112.5mg n=177)) and 75mg t.i.d (225mg/day (R 225mg n=178)).
ARDIS 1 efficacy data:
Based on a comprehensive analysis of the data, including a variety of post-hoc analyses, the following are the key conclusions in relation to the efficacy of Rezular in IBS-D:
1. Based on the protocol-defined end-points, the analysis has confirmed the preliminary findings that Rezular at the medium (R 112.5mg) and high dose (R 225mg) showed a clear effect to normalise the loose/watery stool pattern of the IBS-D patients (measured by improvements in stool form using the BSS scale). Furthermore, Rezular improved stool frequency and also showed trends to improve urgency and also quality of life (QOL). However this analysis, based on historically applied end-points, also indicated that Rezular showed no improvement in pain relief or improvement in pain severity compared to placebo, in the broad IBS-D population.
2. In April 2009, at the Endpoints and Outcomes Conference held in Milwaukee, USA and organised by the ROME Foundation to specifically address issues in IBS, the US Food and Drug Administration (FDA) indicated their intent in the future to focus primarily on changes from baseline in symptom severity in both pain and stool function rather than the historical binary global end-point (e.g. adequate relief of IBS symptoms). They also proposed the application of a standardised definition of clinical response (possibly a one point change from baseline on these symptom scales).
3. AGI has analysed the ARDIS data on the basis of these new metrics. This analysis re-confirmed the strong profile of response in stool-related measures, e.g. stool form and frequency, and also suggested an improvement in pain severity in certain post-hoc analyses and in certain sub-populations particularly in those patients with the higher baseline pain severity.
4. Overall, the analysis has confirmed the view of AGI that Rezular offers an effective treatment for chronic diarrhea symptoms, particularly in conditions associated with altered gut motility such as IBS-D. Furthermore, the analysis suggests a possible combined activity on stool function and pain. AGI will seek an opportunity to discuss these findings with the FDA in the coming months.
ARDIS 1 safety data: Overall Rezular was well tolerated and showed a good safety profile. There were no deaths or cardiovascular-related serious adverse events (SAE’s). The incidence of treatment-emergent SAE’s was 1.7% (P), 0.6% (R 45mg), 2.8% (R 112.5mg) and 0.6% (R 225mg) and discontinuations related to AE’s were 9% (P), 8%( R 45mg), 12% (112.5mg) and 11% (R 225mg). The most common AE-related discontinuation was constipation with rates of 1.7% (P), 1.7% (R 45mg), 1.7%(R 112.5mg) and 2.8% (R 225mg). Average changes in cardiovascular function (blood pressure, heart rate and ECG) from baseline were minimal.
ARDIS 3 safety data:
In addition to the safety profile established in ARDIS-1 over 3 months dosing, a long-term, open-label safety study (ARDIS-3) which enrolled 349 patients directly from ARDIS-1 has been completed. Based on an analysis of the data from ARDIS-1 and a preliminary analysis of ARDIS-3, the safety profile of Rezular in ARDIS-3 was similar to that reported for ARDIS-1. In particular there were no deaths or cardiac related SAE’s. There was no case of ischaemic colitis in either ARDIS-1 or ARDIS-3.
Overall, the safety data from both ARDIS-1 and ARDIS-3 confirmed the generally well tolerated and safe profile of Rezular and also confirms the successful disassociation of the previously dominant cardiovascular effects of racemic verapamil from the desired intestinal effects provided by Rezular.
Commenting on the analysis, Dr John Devane, CEO of AGI Therapeutics, said: ’Despite the disappointment of not meeting the pre-defined efficacy end-point (Adequate Relief) in ARDIS-1, our further data analysis leaves us in no doubt that Rezular has demonstrated a profile of desirable efficacy improving diarrhea-related symptoms in IBS-D patients. Furthermore, the ability of Rezular to improve other symptoms (e.g. pain) in certain circumstances is intriguing and merits follow up discussions with the FDA. The safety profile of Rezular and in particular the absence of any clinically meaningful cardiovascular activity validates the use of Rezular as a unique drug with its own profile of therapeutic activity distinct and clearly dissociated from that of racemic verapamil’.
