**5.4 Safety concerns, side effect and treatment failure**

Enzyme replacement therapy using pancrelipase (pancreatin) delayed-release capsules (i.e. Creon®, Solvay Pharmaceuticals, Inc., Marietta, GA, USA) have been available in the United States of America for more than 20 years with very few observed side effects (Krishnamurty et al., 2009). Meanwhile, allergic reactions to the porcine proteins and some others side effects may occur: Pancreatin extracts are prone to form insoluble complexes with folic acid resulting in folate deficiency (Russell & al., 1980). One serious adverse effect has been reported by Smyth et al. (1994, 1995). The authors described five children with cystic fibrosis in which a colonic obstruction developed due to fibrosing colonopathy (FC) after using very high doses of the enteric-coated micro- minisphere preparations (i.e. more than 20000 lipase units/capsule). Fortunately, the cases of reported FC have decreased considerably since the Medicine Control Agency (MCA) recommended in 1994 that the dose of pancreatic enzymes should not exceed 10,000 IU lipase/kg/day in patients with CF (Taylor , 2002 as cited in Medicine Control Agency, 1994).

Recently, Axcan Pharma Inc. and its subsidiaries received safety update reports describing a total of 46 adverse events observed in a clinical study carried out between 01 November 2008 and 31 May 2009 and involving three pancreatic enzyme preparations: ULTRASE®, VIOKASE® and PANZYTRAT® (Table 5). Fifty-three patients were enrolled, 40 of these patients completed the study.

In most cases, adverse effects were single occurrences. Drug ineffectiveness was the most frequently reported adverse effect for ULTRASE® (Table 5). A lack of therapeutic effect was also reported for some other preparations (Kraisinger et al., 1994). In fact, among marketed PEPs, great variability in the amount of enzymes included in each capsule has been noted (Case & al., 2005; US Food and Drug Administration, 2006; Wooldridge & al., 2009) due in part to the manufacturer practice of overfilling capsules to account for enzyme degradation that occurs over the course of the product's shelf life (US Food and Drug Administration, 2004). While instability of the enzymes results in delivery medications that contain less than the packaged amount of enzyme, the practice of "overfilling" in an effort to address enzyme degradation may result in excess enzyme content, resulting in formulations that deliver inadequate or excess amounts of enzyme.

The possible safety risk posed by high-dose enzyme therapy, particularly fibrosing colonopathy , in combination with the issue of enzyme overfill, recently prompted the FDA to require the manufacturers of PEPs to demonstrate drug efficacy and safety in randomized, placebo-controlled trials before approval (Trapnell & al., 2009). The FDA ruled that manufacturers of pancreatic enzyme supplements must file new drug applications

The most surprising fact regarding efficacy assessment of this therapy is that few investigations are made considering nutritional status and quality of life improvements as well as weight gain (Czako et al., 2003; Trolli et al., 2001; Dominguez-Munoz, 2007). Reduction in stool fat achieved by pancreatic enzyme replacement therapy has not been proven by robust research to be correlated with a complete correction of nutritional deficiency in patients with pancreatic insufficiency. Accordingly, an overall assessment of this therapy efficacy is yet dependent on future demonstration of long-term interesting

Enzyme replacement therapy using pancrelipase (pancreatin) delayed-release capsules (i.e. Creon®, Solvay Pharmaceuticals, Inc., Marietta, GA, USA) have been available in the United States of America for more than 20 years with very few observed side effects (Krishnamurty et al., 2009). Meanwhile, allergic reactions to the porcine proteins and some others side effects may occur: Pancreatin extracts are prone to form insoluble complexes with folic acid resulting in folate deficiency (Russell & al., 1980). One serious adverse effect has been reported by Smyth et al. (1994, 1995). The authors described five children with cystic fibrosis in which a colonic obstruction developed due to fibrosing colonopathy (FC) after using very high doses of the enteric-coated micro- minisphere preparations (i.e. more than 20000 lipase units/capsule). Fortunately, the cases of reported FC have decreased considerably since the Medicine Control Agency (MCA) recommended in 1994 that the dose of pancreatic enzymes should not exceed 10,000 IU lipase/kg/day in patients with CF (Taylor , 2002 as cited in

Recently, Axcan Pharma Inc. and its subsidiaries received safety update reports describing a total of 46 adverse events observed in a clinical study carried out between 01 November 2008 and 31 May 2009 and involving three pancreatic enzyme preparations: ULTRASE®, VIOKASE® and PANZYTRAT® (Table 5). Fifty-three patients were enrolled, 40 of these

In most cases, adverse effects were single occurrences. Drug ineffectiveness was the most frequently reported adverse effect for ULTRASE® (Table 5). A lack of therapeutic effect was also reported for some other preparations (Kraisinger et al., 1994). In fact, among marketed PEPs, great variability in the amount of enzymes included in each capsule has been noted (Case & al., 2005; US Food and Drug Administration, 2006; Wooldridge & al., 2009) due in part to the manufacturer practice of overfilling capsules to account for enzyme degradation that occurs over the course of the product's shelf life (US Food and Drug Administration, 2004). While instability of the enzymes results in delivery medications that contain less than the packaged amount of enzyme, the practice of "overfilling" in an effort to address enzyme degradation may result in excess enzyme content, resulting in formulations that deliver

The possible safety risk posed by high-dose enzyme therapy, particularly fibrosing colonopathy , in combination with the issue of enzyme overfill, recently prompted the FDA to require the manufacturers of PEPs to demonstrate drug efficacy and safety in randomized, placebo-controlled trials before approval (Trapnell & al., 2009). The FDA ruled that manufacturers of pancreatic enzyme supplements must file new drug applications

**5.4 Safety concerns, side effect and treatment failure** 

Medicine Control Agency, 1994).

patients completed the study.

inadequate or excess amounts of enzyme.

outcomes.


Table 5. Adverse Events (Preferred Term) Recorded for Pancreatic Enzyme Preparations in the Axcan Pharma Safety Database Classified by System Organ Class from November 1, 2008, to May 31, 2009 (Reproduced from Page 8 of the Safety Update for NDA 22-222 dated August 4, 2009).

Emerging Approaches for the Treatment of

**6.3 Microbial and plant derived lipases** 

this recombinant lipase (Fickers & al., 2011).

Fat Malabsorption due to Exocrine Pancreatic Insufficiency 285

Exinalda for cystic fibrosis patients. A phase I clinical trial showed that addition of recombinant bile salt-stimulated lipase to standard pancrelipase (Creon) enabled a dose reduction of pancrelipase. The treatment had the advantage of restoring a normal level and pattern of plasma chylomicron secretion (Fieker & al., 2011, as cited by Strandvik et al., 2004). The combined results from two Phase II studies evaluating Kiobrina in preterm infants demonstrated an increase in growth velocity and uptake of long chain polyunsaturated fatty acids such as docosahexanoic acid and arachidonic acid. The safety and tolerability profile of rhBSSL added to formula was similar compared to placebo (Maggio et al., 2010). Based on these encouraging results, Swedish Orphan Biovitrum enrolls in August 2011 the first patient in Kiorbina phase III clinical trial. An open-label exploratory phase II study on Exinalda (rhBSSL) in patients with cystic fibrosis and pancreatic insufficiency has been completed. The aim was to study the effect of Exinalda on fat absorption as well as safety in this patient population. The results showed that Exinalda is safe and tolerable at a dose level of 170 mg three times a day. In terms of efficacy (coefficient of fat absorption CFA) the primary endpoint was not met. Swedish Orphan Biovitrum is now assessing options to continue the

With the aim of developing porcine-free enzyme supplements and in order to avoid the short-life of lipolytic enzymes of pancreatic origin, microbial lipases of fungal or bacterial origin were suggested for replacement therapy. Therefore, potential efficacy of many fungal Lipases derived from *Aspergillus niger* (Griffin & al., 1989), *Rhizopus arrhizus* (Iliano & Lodewijk, 1990), *Rhizopus delemar* (Galle & al., 2004 ), *Candida cylindracea* (Schuler & Schuler, 2008) and *Yarrowia lipolytica* (Turki & al., 2010a) was investigated. The *Yarrowia lipolytica* lipase seemed to be of potential interest because of its acid and protease-stable properties and its resistance to the detergent action of bile salts as shown *in vitro* (Turki & al., 2010a). Supporting its use as a pharmaceutical, safety assessment of the enzyme in rats showed that there were no toxicologically severe changes in clinical signs, growth, hematology, clinical chemistry, organ weight and pathology related to oral administration of *Yarrowia lipolytica* lipase in animals (Turki & al., 2010b). Actually, a substitute for EPI treatment based on Lip2p is under investigation by Laboratoire Mayoly Spindler, a French pharmaceutical company specialized in gastroenterology therapeutics (Fickers & al., 2011, as cited in http://www.mayoly-spindler.com/). The process development in cGMP conditions for the production of the *Yarrowia lipolytica* MS1819 lipase was completed in 2009 with the Swiss biotech company DSM Nutritional Product Ltd (Fickers & al., 2011, as cited in http://www.dsm.com, press release, December 22th, 2009). In 2010, a drug development partnership was established with Protea Biosciences to initiate phase I/IIA clinical trials in France with the aim of demonstrating safety and proof-of-concept of the therapeutic use of

A pipeline preparation Liprotamase (formerly known as ALTU 135 and Trizytek) containing bacterial lipase, fungal protease and amylase was developed by Eli Lilly company (Eli Lilly, IN, USA, www. Lilly.com). An open-label Phase III safety study was carried out in order to evaluate 214 patients, of which 145 CF patients, ages 7 and above, completed 12 months of treatment with Liprotamase. Investigators found that 96 percent of all CF patients who received liprotamase for 12 months maintained or gained weight. Based on key nutritional parameters, the study showed that patients who completed 12 months of treatment with

development (Swedish Orphan Biovitrum website www. sobi.com).

 (NDA) to ensure consistent efficacy, safety, and quality of these agents (US Food and Drug Administration, 2006). Therefore, in order to comply with the FDA 2004 mandate, several studies have been recently conducted to ensure safety and effectiveness of some new reformulated pancreatic enzyme supplements such as Creon® 24,000 and EUR-1008 (Zenpep™) (Wooldridge & al., 2009; Trapnell & al., 2009). Nevertheless, these products of animal origin present yet a risk of viral transmission. Accordingly, there remains a need for new alternatives to treat correctly exocrine pancreatic insufficiency.
