PANCREAZE (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed with pancrelipase.

14 CLINICAL STUDIES

The short-term safety and efficacy of PANCREAZE were evaluated in two studies conducted in 57 patients with exocrine pancreatic insufficiency (EPI) associated with cystic fibrosis (CF).

Study 1 was a randomized, double-blind, placebo-controlled study of 40 patients, ages 8 to 57 years, with EPI due to CF. In this study, patients received PANCREAZE at individually titrated doses (not to exceed 2,500 lipase units per kilogram per meal) for 14 days (open-label period) followed by randomization to PANCREAZE or matching placebo for 7 days of treatment (double-blind withdrawal period). Only patients with coefficient of fat absorption (CFA) ≥80% in the open-label period were randomized to the double-blind withdrawal period. The mean dose during the controlled treatment period was 6,400 lipase units per kilogram per day. All patients consumed a high-fat diet (greater than or equal to 100 grams of fat per day) during the treatment period.

The primary efficacy endpoint was the change in CFA from the open label period to the end of the double-blind withdrawal period. The CFA was determined by a 72-hour stool collection period during both treatment periods, when both fat excretion and fat ingestion were measured (Table 2).

Table 2. Change in CFA in Study 1 (Open-Label Period to End of Double-Blind Withdrawal Period)

	PANCREAZE n=20	Placebo n=20
* Minimum of 72 hours from start of open label period. † Double-blind withdrawal period ranged from 4 to 7 days. ‡ p<0.001
CFA [%]
Open-Label Period * (Mean, SD)	88 (5)	91 (5)
End of Double-Blind Withdrawal Period † (Mean, SD)	87 (8)	56 (25)
Change in CFA ‡ [%]
Open-Label Period to End of Double-Blind Withdrawal Period (Mean, SD)	-2 (6)	-34 (23)
Treatment Difference Point Estimate (95% CI)	33 (25, 40)

At the end of the double-blind withdrawal period, the mean change in CFA from the open-label period to the end of the double-blind withdrawal period was -2% with PANCREAZE treatment compared to -34% with placebo treatment. There were similar responses to PANCREAZE by age and gender.

Study 2 was a randomized, investigator-blinded, dose-ranging study of 17 patients, ages 6 months to 30 months (mean 18 months) with EPI due to CF. The final analysis population was limited to 16 patients; 1 patient was excluded due to withdrawal of consent. All patients were transitioned from their usual PEP treatment to PANCREAZE at 375 lipase units per kilogram body weight per meal for a 6-day run-in period. Patients were then randomized to receive PANCREAZE at one of four doses (375, 750, 1,125, and 1,500 lipase units per kilogram body weight per meal) for 5 days. The CFA was measured at the end of the run-in period and at the end of the randomized period (Table 3).

Table 3. Change in CFA in Study 2 (End of Run-in Period to End of Study)

	375 units lipase/kg/meal n=4	750 units lipase/kg/meal n=4	1,125 units lipase/kg/meal n=4	1,500 units lipase/kg/meal n=4
* End of Run-in Period; † End of Study
CFA (%)
Day 6 * (Mean, SD)	93 (2)	90 (5)	81 (11)	93 (3)
Day 11 † (Mean, SD)	92 (3)	91 (4)	80 (13)	91 (2)
Change in CFA (%)
Day 6 to Day 11 (Mean, SD)	-2 (3)	1 (3)	-1 (3)	-2 (3)

Overall, patients showed similar CFA at the end of the run-in period (mean PANCREAZE dose of 1,600 lipase units per kilogram body weight per day) as at the end of the study across the four treatment arms.

15 REFERENCES

1. Borowitz DS, Grand RJ, Durie PR, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Journal of Pediatrics. 1995; 127: 681-684.
2. Borowitz DS, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. Journal of Pediatric Gastroenterology Nutrition. 2002 Sep; 35: 246-259.
3. Stallings VA, Start LJ, Robinson KA, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. Journal of the American Dietetic Association. 2008; 108: 832-839.
4. Smyth RL, Ashby D, O’Hea U, et al. Fibrosing colonopathy in cystic fibrosis: results of a case-control study. Lancet. 1995; 346: 1247-1251.
5. FitzSimmons SC, Burkhart GA, Borowitz DS, et al. High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis. New England Journal of Medicine. 1997; 336: 1283-1289.