PERT – Pancreatic Enzyme Replacement Therapy for Cystic Fibrosis

Last updated Jan. 31, 2023, by Teresa Carvalho, MS

✅ Fact-checked by José Lopes, PhD


What is PERT for CF?

Pancreatic enzyme replacement therapy (PERT) is the current standard of care for exocrine pancreatic insufficiency (EPI) in people with cystic fibrosis (CF). The treatment helps the body digest and absorb nutrients from foods and liquids.

PERT may be given orally or via a feeding tube. Different brands are available, including Creon (marketed by Abbvie), Pertzye (by Digestive Care Inc.), Pancreaze (marketed by Vivus), Relizorb (by Alcresta Therapeutics), as well as Zenpep and Viokace (both marketed by Nestlé Health Science).

How does PERT work?

As a result of CFTR gene mutations, CF patients have a thick mucus in various organs. In the digestive system, this mucus blocks the tubes or ducts within the pancreas, which prevents the release of enzymes needed for digestion, causing EPI. The most effective test to confirm this insufficiency is to measure an enzyme, called fecal elastase, which is low in people with CF.

Enzyme supplements contain a combination of lipase, protease, and amylase that digest fat, protein, and carbohydrates, respectively. The enzymes are released in the small intestine to help with nutrient absorption and with maintaining a healthy weight.

Several current enzyme supplements contain pancrelipase, which is derived from pigs.

Who can use PERT?

Use of pancrelipase has been approved for the treatment of people with EPI due to:

  • CF and other genetic conditions, celiac disease, Crohn’s disease, and autoimmune pancreatitis
  • chronic pancreatitis
  • tumor
  • surgical removal of part or all of the pancreas, stomach, small intestine, and lymph nodes

Who should not use PERT?

Although PERT does not have contraindications, the treatment should be carefully administered for people with certain conditions, such as:

  • diabetes mellitus
  • immunodeficiency
  • kidney damage
  • difficulty swallowing
  • inflammatory bowel disease
  • intestinal obstruction
  • abdominal surgery
  • intestinal obstruction in newborns, called meconium ileus, a CF hallmark
  • porcine (pig-derived) protein sensitivity

Women who are pregnant or breastfeeding should avoid using these supplements unless they are necessary for maternal weight gain or adequate nutrition.

How is PERT administered?

PERT comes in multiple sizes and dosing strengths based on lipase units. This is because fat is the most difficult for the body to digest, so dosing guidelines primarily take into account the amount of lipase in the enzyme.

The maximum recommended dose is 10,000 lipase units per kg of body weight per day (kg/day) orally or less than 4,000 lipase units per gram of dietary fat per day.

Three PERT formulations are available:

  • capsules containing enteric-coated (stomach acid-resisting) small beads
  • non-enteric, most often for people on tube feeding
  • lipase enzyme cartridge (only containing lipase) for patients on continuous tube feeding

Oral formulations may be enteric-coated or not, in which case they should be taken along with a proton pump inhibitor to relieve symptoms of acid reflux. Capsules and tablets should be taken with a meal or immediately before with sufficient fluids. Tablets should not be crushed or chewed. In the case of patients who cannot swallow, enteric-coated micro-spherules can be removed from the capsules and mixed with an acidic food and then administered.

Oral forms should not stay in the mouth for a long time as this may cause irritation of mucosal membranes and inflammation of the mouth.

If patients forget to take PERT at the beginning of a meal, the treatment may be administered during or at the end of it.

For those who cannot take enteric-coated enzymes by mouth, PERT is administered via tube feeding, in which a tube is inserted through the abdomen directly into the stomach or into the small intestine. This type of administration uses non-enteric-coated enzymes, as in Viokace, which is crushed before administration. Patients who are on continuous tube feeding are preferably given Relizorb, a lipase-only cartridge, that is placed in-line with the tube feeding set.

If patients eat or drink for longer than 30 minutes, another PERT dose should be given as the treatment lasts only half an hour in the small intestine.

Each person needs a different amount of enzymes, so these levels must be checked and determined by a healthcare practitioner.

Since enzymes deteriorate if left in hot or humid places, they should be stored in the fridge with the lid tightly closed. When patients leave the house, a cooler bag containing an ice brick can be used. Enzymes that are past their expiry date or have changed color and appearance should be discarded.

PERT in clinical trials

PERT has been available for several decades in the U.S., which means these therapeutic enzymes had not gone through the current formal requirements for approval. However, in 2004, the U.S. Food and Drug Administration determined that PERT products did not meet the requirements of over-the-counter preparations, so they had to undergo clinical trials and complete a new drug application.

Trial of Pertzye

The short-term safety and efficacy of Pertzye was evaluated in a study involving 24 CF patients with EPI, ages 8 to 43. Patients were randomly assigned to receive Pertzye at individually adjusted doses (up to 2,500 lipase units/kg per meal) or a placebo, for six to eight days, followed by a switch to the other group for the same period of time. Results showed that patients treated with Pertzye had a higher mean coefficient of fat absorption (CFA), a measure of how much fat is absorbed, compared to those on placebo (83% vs. 46%). Patients on Pertzye also showed a significantly higher mean coefficient of nitrogen absorption (CNA), a marker of protein absorption, than those on placebo (79% vs. 47%).

Trials of Creon

The short-term efficacy of Creon was evaluated in three studies conducted in 103 patients with EPI. Of those studies, two involved 49 CF patients, ages 7 to 43. In each study, patients were randomly assigned to receive Creon at a dose of 4,000 lipase units/g of fat ingested per day or a placebo, for five to six days, followed by a group switch for the same period of time. Mean CFA and CNA were determined.

In study 1, patients treated with Creon had significantly higher CFA compared to those on placebo (89% vs. 49%). Mean CNA was 86% with Creon, higher than the 49% with placebo. In study 2, mean CFA was also higher at 83% with Creon treatment compared with 47% with the placebo. A significantly higher CNA was found in Creon-treated patients in both studies.

Trials of Zenpep

The short-term safety and efficacy of Zenpep was assessed in two studies conducted in 53 CF patients with EPI, ages 1 to 23. Study 1 included 34 patients who were randomized to receive Zenpep or a placebo for six to seven days and switched to the other group for the same period of time. Treatment dose ranged from 3,900 lipase units/kg/day to 5,700 lipase units/kg/day. The primary efficacy measure was the mean CFA  difference between the groups. The study showed greater mean CFA in patients treated with Zenpep than in participants on placebo (88% vs. 63%).

Study 2 involved 19 children and compared fat malabsorption (difficulty in absorption) before and after treatment with Zenpep. All participants were on other enzyme supplement before starting Zenpep. Patients were given the treatment at titrated doses ranging between 2,300 and 10,000 lipase units/kg/day for 14 days. When switched to Zenpep, patients had a similar control of fat malabsorption.

Trials of Pancreaze

Two studies evaluated the safety and efficacy of Pancreaze in a total of 57 CF patients with EPI. Study 1 involved 40 patients, ages 8 to 57, who were given Pancreaze at titrated doses (up to 2,500 lipase units/kg/meal) for 14 days (open-label phase). Patients with a CFA of 80% or higher were then randomly assigned to receive Pancreaze, at a mean dose of 6,400 lipase units/kg/day or a placebo, for a week.

The primary efficacy measure was the change in CFA from the open-label period until the end of the randomization phase. The study found a lower reduction in CFA in patients treated with Pancreaze compared to the placebo (2% vs. 34%).

Study 2 was conducted in 17 children previously receiving another enzyme supplement who were switched to 375 lipase units/kg/meal of Pancreaze for six days (run-in period). After that period, the participants were randomly assigned to receive one of four doses of Pancreaze (375, 750, 1,125, and 1,500 lipase units/kg/meal) for five days. The study found no differences in CFA, either at the end of the run-in period or at the end of the randomization phase, across all treatment doses.

Trials of Relizorb

Relizorb was assessed in the multicenter 497 Study. The study enrolled 34 CF patients with EPI, ages 5 to 34, who were receiving supplemental enteral nutrition (via tube feeding). The trial’s main goals included assessing changes in blood plasma concentrations of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), two omega-3 fatty acids that are measures of overall fat absorption.

The study found that Relizorb increased the concentrations of these fatty acids by 2.8 times, normalizing these values to those found in the healthy population. The therapy also reduced the frequency of gastrointestinal symptoms in more than 50% of patients.

Another multicenter study, called ASSURE, assessed the effect of long-term use of Relizorb, during overnight enteral feeding, in red blood cell uptake of DHA and EPA as well as in easing of gastrointestinal symptoms. A total 36 participants completed the study (mean age 13.8 years).

Results showed a 2.1 times increase in red blood cells containing EPA and DHA, and a normalization of plasma omega-3 levels that was maintained over at least 90 days. These results suggest an improvement in fat malabsorption. The study also found an improvement in weight scores in 61% of the patients, as well as fewer participants reporting gastrointestinal symptoms from day 30 to day 90.

Trials of adrulipase

A Phase 2 clinical trial called OPTION 2 (NCT04375878) compared the safety, efficacy, and tolerability of enteric capsules of adrulipase — a yeast-derived lipase — with a traditional PERT. Results showed that the therapy (formerly MS1819), developed by First Wave BioPharma, was safe and well-tolerated, but it was not as effective as standard PERT at improving fat absorption in most CF patients.

Another Phase 2 trial (NCT04302662) assessed adrulipase in combination with porcine PERT in 20 CF patients with severe EPI. The trial’s main goal was the improvement of fat absorption. The study found that combining both therapies, for 15 days, improved fat absorption, increased body weight, and reduced stool weight.

A new formulation that packs the adrulipase enzyme in micro-granules to safely get to the small intestine — traversing the acidic environment of the stomach — will be tested in a Phase 2 clinical trial. The primary efficacy measure is CFA, with secondary measures of stool weight, signs and symptoms of malabsorption, and CNA. According to First Wave, this new formulation may reduce the daily pill burden associated with currently available treatments for EPI associated with CF.

What are common side effects of PERT?

The most common side effects of oral pancrelipase include:

  • blurred vision
  • dry mouth
  • dry skin
  • fruit-like breath odor
  • headache
  • increased appetite
  • excessive thirst
  • frequent urination
  • sweating
  • unexplained weight loss
  • vomiting

Intestinal fibrosis (scarring)

In CF, a condition called fibrosing colonopathy occurs as a complication from taking PERT at very high doses. Although the exact cause of this complication remains unknown, PERT is thought to break down the lining of the colon (large intestine), leading to a repair process that results in scarring. PERT labels warn of caution when doses exceed 2,500 lipase units/kg/meal (or higher than 10,000 lipase units/kg/day). Patients should talk with their healthcare providers if they think they or their child may be experiencing this issue.

Irritation of the mouth

Patients may experience irritation of the mucous membrane lining the inside of the mouth. To avoid that, PERT capsules should not be chewed or retained in the mouth.

Increase in blood uric acid levels

Pig-derived enzymes may increase blood uric acid levels, so PERT should be cautiously used by patients with gout (a painful form of arthritis), kidney damage, and elevated uric acid level in the blood.

Allergic reactions

Patients may have a known allergy to proteins of porcine origin. If experiencing severe allergy, they should discuss with their healthcare team the risks and benefits of continued treatment.

Risk of viral infection

Pig-derived enzymes are sourced from the pancreas of animals. Although it has never been reported, patients may get an infection from porcine viruses by taking these treatments.

 


Cystic Fibrosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

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