Axcan Goes to FDA Expert Panel With Ursodiol for PBC, Files IND's for New Indications.

MONTREAL--(BUSINESS WIRE)--Sept. 6, 1996--(ME, TSE: AXP ) Axcan Pharma announces that its NDA submission for URSO(TM) (ursodeoxycholic acid) in the treatment of primary biliary cirrhosis (PBC) has been accepted for filing by the FDA. This submission was sent to the agency on March 25, 1996. Axcan will present its data to the FDA's Gastrointestinal Expert Advisory Committee on November 6-7, 1996. While the review process should take several months, it appears that Axcan's submission will be fast tracked considering its orphan drug status, and the fact that no drug is currently approved in the US for this deadly disease. The orphan drug designation was granted by the FDA in 1987 since PBC afflicts a relatively small number of Americans and is a life threatening condition.

URSO(TM) is ursodeoxycholic acid (UDCA), a naturally occurring bile acid found in small quantities in normal human bile and in larger quantities in the bile of certain species of bears. UDCA is used in Japan for the treatment of various liver and gastrointestinal disorders as it was approved in the US in 1987 for the dissolution of gallstones. Oral administration of UDCA in humans leads to a significant change in the relative proportions of the biliary and serum bile acids, such that UDCA becomes the major bile constituent (about 50 percent when a 13-15 mg/kg/day dose is given) and naturally replaces cholic and chenodeoxycholic acids. The degree of bile enrichment with UDCA during chronic ingestion is dose proportional and remains constant over time. UDCA differs from the other bile acids in that it is non-cytotoxic since it has less affinity for cell membranes.

Recent clinical studies also indicated that UDCA is an anti- cholestatic drug effective in the treatment of PBC, which is a chronic, progressive cholestatic liver disease of unknown cause (but probably auto-immune). It afflicts mostly women (9/1 ratio of females to males) of all ages. Clinical symptoms include cholestatis, pruritus, jaundice, hypercholesterolemia, fatigue and osteomalacia. Mean survival after diagnosis is ten years. Liver transplant is the current intervention for end-stage patients with a two-year survival rate of approximately 80 percent. While the exact mechanism of action of UDCA in PBC has not been established, several studies suggest that this drug may have beneficial effects on the immune system and decreases the retention of cholestatic bile acids like cholic and chenodeoxycholic acids. UDCA could then decrease the concentration of bile acids within the hepatocytes and reduce the associated cholestatis.

Tests Show Significant Improvement in Patients

Results of early uncontrolled studies undertaken in the mid-1980's suggested that UDCA improved biochemical, histological and clinical markers of PBC. Double-blind placebo controlled trials have since been conducted to confirm the efficacy of UDCA treatment in PBC. Major clinical trials that have assessed the efficacy and safety of URSO(TM) in the treatment of PBC include Dr. Poupon's double-blind study in which 150 PBC patients were followed for two years. At the end of this period, there was a significant improvement of their condition with 13-15 mg/kg/day of URSO(TM). Because of these benefits, all patients that had completed the study were switched to open-label active treatment and followed for two additional years. Long-term data showed that the needs for transplantation and the occurrence of death were decreased by UDCA. These findings are supported by another published study, the Heathcote et al trial, in which UDCA 14mg/kg/day or placebo was administered to 220 patients in a double-blind portion during a two-year period. Efficacy results at two years showed a statistically significant difference between the two treatments in favour of UDCA for the following parameters:

- a reduction in the proportion of patients exhibiting more than 50 percent increase in serum bilirubin;

- a decrease in serum bilirubin, transaminase and alkaline phosphatase;

- a decreased incidence of treatment failure and an increased time-to-treatment failure.

Furthermore, no major adverse events were reported in any of the studies conducted.

Finally, a major multicentre, randomized, double-blind, placebo controlled trial, was conducted at the Mayo Clinic in Rochester, Minnesota to evaluate the efficacy of URSO(TM) (13-15mg/kg/day) administered as 250 mg tablets in 180 PBC patients. Upon completion of the double-blind portion, all patients followed an open-label active treatment extension phase. Treatment failure was the main efficacy endpoint measured during the study and was defined as either death, liver transplantation, doubling of serum bilirubin, histologic progression, cirrhosis, varices, ascites, or encephalopathy, pruritus, inability to tolerate the drug or voluntary withdrawal. After two years of double-blind treatment, the incidence of treatment failure was significantly reduced in URSO(TM) group (N=89) as compared to the placebo group (N-91). In fact, 23 percent of patients in the URSO(TM) group experienced a treatment failure vs 47 percent in the placebo group (p.01). Time-to-treatment failure was also significantly delayed by several months in the URSO(TM) group as compared to the placebo group, regardless of baseline bilirubin or histologic stage (p=0.0001). Treatment with URSO(TM) also resulted in an improvement in serum hepatic biochemistries when compared to baseline. Furthermore, clear clinical benefits were seen following long-term treatment with URSO(TM) (up to seven-year exposure) which resulted in prolonged transplant-free survival, delayed time-to-treatment failure and a decreased risk of developing varices. Life table analysis of the time-to-death or transplant showed a statistically significant difference in favour of UDCA. Time to treatment failure and time to develop varices was also significantly increased with UDCA. This study is the first clinical study that has been conducted in PBC patients with such a long follow-up, and has clearly demonstrated increased transplant free survival. These data, along with the Poupon and the Heathcote study results, are described in Axcan's New Drug Application for the intended use of URSO(TM) in PBC. Furthermore, Axcan's data will be presented to a Gastrointestinal Expert Advisory Committee at the FDA on November 6-7, 1996. Despite the relatively small number of PBC patients in the US (approximately 50K) the approval of URSO(TM) by the FDA will represent a significant potential market (over US $100M per year) since a one-year treatment costs about US $2,000. Colorectal Cancer Recurrence Study

Axcan also filed an Investigational New Drug submission related to the use of ursodiol 750 mg or 1.5 g/day as URSO(TM) 250 mg tablets to delay the recurrence of metachronous adenomatous colorectal polyps. Colorectal adenomas are well recognized as precursors to malignant lesions, and serve as an appropriate intermediate endpoint in chemoprevention trials. Colorectal cancer is one of the most common malignancies seen in developed nations and is responsible for over 60,000 deaths each year in the United States alone. The prognosis of patients diagnosed with colorectal cancers is related to the stage of the cancer. Almost all cancers arise from premalignant adenomatous polyps, and these growths are usually asymptomatic. Colorectal cancer provides a unique opportunity for intervention among human malignancies because it progresses through clinically recognizable stages from normal mucosa to enlarging and increasingly dysplasic polyps and eventually to carcinoma. It is not well understood what factors contribute to the transformation of a benign adenomatous polyp to malignant neoplasia. However, it has been shown that the removal of polyps does not change the genotoxic milieu responsible for the growth and development.

Bile acids appear to influence the development of adenomatous lesions in the colon and their transformation into malignancies. Ursodiol modifies the fecal bile acid milieu by reducing the proportion of chenodeoxycholic and lithocholic in the colon, which has been linked to the development of colon cancer based on clinical, animal model, and in-vitro studies. Experimental evidence suggests that this drug has anti-neoplastic properties in the large bowel. The data from experimental studies is now significantly mature to suggest that the alteration of colonic bile acids by ursodiol may decrease the development of colonic adenomas and subsequently carcinomas, and justify the clinical development of URSO(TM) as a chemopreventive agent in colorectal cancer.

Phase II Study for 900 Male and Female Patients

The first clinical study that will be conducted on the efficacy and safety of URSO(TM) in the chemoprevention of adenomatous polyps, will be a phase II study in which 900 male and female patients will be randomized to either placebo or URSO(TM) 750mg/day or 1.5g/day. Treatment duration will be one (1) year. All subjects will undergo a one (1) year follow-up colonoscopy which is part of routine clinical practice in these patients. Furthermore, the safety profile of URSO(TM) in this indication will be established by the collection of clinical adverse events and the performance of laboratory tests. The primary objective of this study will be to evaluate the efficacy and safety of URSO(TM) in reducing the incidence of new metachronous colorectal neoplasias at one (1) year. While the recurrence rate for colorectal adenomas has been variably reported, most studies document an adenoma recurrence rate of 22-60 percent by two (2) years. In this trial, most patients will be recruited at the Rochester, Minnesota Mayo Clinic, under the supervision of Dr. Mark V. Larson. Two Mayo Clinic satellites, located in Scottsdale, Arizona and Jacksonville, Florida respectively, will also participate in order to optimize the patient recruiting process. The Mayo Clinic (Rochester, Minnesota) will be the main clinical site involved. It is expected that a maximum of two (2) years will be needed to reach the 900 randomized patients target. Ursodiol in Hypercholesterolemia

Furthermore, Axcan Pharma will also embark in a clinical research program on the efficacy and safety of URSO(TM) in the treatment of hypercholesterolemia. Preliminary data have been obtained from a placebo controlled, double-blind study conducted by Dr. Lindor et al in 177 PBC patients, which suggested that serum TOTAL-Cholesterol and LDL-Cholesterol levels could be decreased with ursodiol treatment at a 13-15 mg/kg/day dose. After one and two years of therapy, TOTAL-Cholesterol was decreased by 20 and 28 percent respectively, versus baseline. No significant change was noted in triglyceride levels or high density lipoprotein cholesterol (HDL-C). The results of this study suggested that the cholesterol lowering effect of ursodiol may be due to either an improvement of the underlying liver disease or a direct alteration of the metabolism of cholesterol. Previous pre-clinical and clinical studies have shown that ursodiol may decrease serum cholesterol levels by several mechanisms. The first one is inhibition of hydroxymethylglutaryl-coenzymeA reductase (HMG-CoA reductase), a key enzyme in the intra cellular synthesis of cholesterol. Studies have shown that the activity of this enzyme could be reduced by a factor of 1.5-2 after one to five months of therapy. A second mechanism by which ursodiol could decrease serum cholesterol levels is by reducing the absorption of cholesterol from the gastrointestinal tract. Scientists estimate that the cholesterol load (biliary + dietary) to the intestine can be reduced by ursodiol from an average of 1600-1800 mg/day to 1200-1300 mg/day. Considering a decreased fractional cholesterol absorption, total absorption could be reduced from 800-1100 mg/day to 400-500 mg/day (the equivalent of the cholesterol contents of two eggs). Some others found that after a 20 day treatment with ursodiol, the mean cholesterol absorption decreased by 48 percent. A third mechanism that could explain the reported cholesterol lowering properties of ursodiol is an increased conversion of cholesterol to bile acids. Some studies have suggested that the mean total bile acid synthesis can be increased by about 50 percent when ursodiol is administered for at least one month at a 15 mg/kg/day dose. Lastly, ursodiol may have an effect on the expression of hepatic LDL receptors. In experimental studies, ursodiol has been shown to increase the receptor dependent uptake of LDL-Cholesterol in isolated hamster hepatocytes. In light of these findings, ursodiol appears to be a potentially promising new cholesterol lowering agent. A double-blind, placebo controlled phase II dose ranging study will soon be initiated at the Rochester Mayo Clinic, under the supervision of Dr. Frank Kennedy. The role of this study will be to confirm the cholesterol lowering efficacy of URSO(TM) and to determine an effective dose level. A second study will also be conducted for evaluating the effects of a combined therapy consisting of ursodiol and a HMG-CoA reductase inhibitor (like Lovastatin or Pravastatin). If this combination proves to be more effective than the use of an HMG-CoA reductase inhibitor alone, it could be very useful in the primary or secondary prevention of myocardial infection. It is now well established that MI patients are at risk of a recurrence and that a significant reduction of their LDL-Cholesterol can lead to atherosclerosis regression. The first lipid study with ursodiol is expected to start this fall. U.S. launch in 1997?

Axcan Pharma hopes to launch URSO(TM) for the therapy of PBC in the United States towards the end of 1997. A total of 15 clinical trials--13 at the Mayo Clinic and 2 others at the Fred Hutchinson Cancer Research Center--are underway and Axcan hopes to expand the indications for ursodiol during the coming years.

Axcan is involved in discussions with several U.S. pharmaceutical companies that are interested in marketing or co- marketing URSO(TM) in the U.S.A. A decision will be made after the FDA's expert advisory committee meeting in November when Axcan firms up its plans to enter the U.S. market.

Axcan Pharma specializes in the field of gastroenterology and is also active in contraception, the prevention of sexually transmitted diseases and hemodialysis. Founded in 1983, its head office is located in Mont-St-Hilaire, (Quebec), and it has other offices and subsidiaries in Laval (Quebec), Calgary, (Alberta), and Plattsburgh, (New York).

CONTACT: Axcan Pharma Inc.

Leon F. Gosselin, 514/467-5138