Description
Insufficient production of pancreatic enzymes (exocrine pancreatic insufficiency, often referred to simply as pancreatic insufficiency) causes malabsorption of fat, protein, and several micronutrients, including the vitamins A, D, E, and K. Malabsorption of fat is exacerbated by bile salt abnormalities if there is concurrent intestinal or liver disease. Pancreatic function tends to decline with age. Across all age groups, about 90% of patients with cystic fibrosis have marked pancreatic insufficiency and 12% require enteral nutrition. Pancreatic insufficiency is a major contributor to nutritional problems in patients with cystic fibrosis (CF).

Guidance to optimize nutrition should be provided to all individuals with cystic fibrosis. Those who do not meet target goals for BMI, whose linear growth is less than expected for their genetic potential, or whose growth rates begin to plateau, require additional attention. These patients should be given intensive counseling to optimize nutrition. They should also be further evaluated to identify reasons for nutritional deficits and potential contributors to malnutrition, including inadequate pancreatic enzyme replacement therapy (PERT) and small bowel bacterial overgrowth. In addition, assessment of psychosocial, economic, and behavioral factors that may contribute to suboptimal nutrition is essential. As soon as a decline in growth parameters is documented, nutritional intervention should begin.

There is little evidence to determine the best way to administer pancreatic enzyme replacement therapy (PERT) in conjunction with enteral nutrition. The mainstay of treatment for pancreatic insufficiency in CF is pancreatic enzyme replacement therapy (PERT). Multiple formulations of pancreatic enzymes exist with different combinations of lipase, protease, and amylase.

The RELiZORB^™ device is the first and only point-of-care accessory for use in adults, designed to fit in series with currently used enteral feeding circuits. RELiZORB^™ is designed to hydrolyze (break down) fats present in enteral formulas from triglycerides into fatty acids and monoglycerides to allow for their absorption and utilization by the body. This breakdown of fats by RELiZORB^™ is intended to mimic the function of the enzyme lipase in patients who do not excrete sufficient levels of pancreatic lipase. RELiZORB^™ exposes the enteral feeding to lipase contained in an in-line cartridge before it is introduced to the patient’s GI tract, thereby enhancing fat absorption.

Policy
Use of a RELiZORB™ is considered MEDICALLY NECESSARY when all of the following criteria are met:

• The patient has an established diagnosis of cystic fibrosis
• The patient is 5 years old or older
• The patient requires enteral feeds despite optimization of pancreatic enzyme therapy (PERT) and oral nutrition support, and the members body mass index (BMI) is not in the target range (BMI at or above the 50th percentile for age,
• Documentation of diagnosis of pancreatic insufficiency with supporting laboratory evidence (fecal elastase or elevated fecal fat) OR Documented strong clinical suspicion of pancreatic insufficiency: Member has two CF transmembrane conductance regulator (CFTR) variants known to be associated with pancreatic insufficiency or member has symptoms of pancreatic insufficiency (growth failure and symptoms of steatorrhea, such as diarrhea, bloating, gassiness, and abdominal pain
• The member’s medication history (within past 6 months) includes at least 30 days of enteral nutrition in conjunction with a trial of PERT with at least two preferred formulary digestive enzyme aids with matching indication OR documented intolerance, FDA labeled contraindication, or hypersensitivity to all preferred formulary digestive enzyme aids with matching indication

Use of a cartridge device (e.g., RELiZORB™ immobilized lipase cartridge) to deliver digestive enzymes to enteral formula is investigational and/or unproven for all other indications and is therefore considered NOT MEDICALLY NECESSARY.

Rationale
Fat malabsorption is a common condition in patients who cannot produce adequate digestive enzymes due to compromised pancreatic function (NIH, 2017). The condition causes a patient’s gastrointestinal (GI) system to function incorrectly (NIH, 2017). Many diseases can cause malabsorption, such as cystic fibrosis (CF), trauma to the pancreas, surgery to remove part of the pancreas, pancreatitis, and pancreatic cancer (BioSpace, 2016). Fat malabsorption affects many aspects of improving the health of critically ill patients, including a patient’s ability to maintain or gain weight, immune system, wound healing, muscle strength, and psychological factors (Stroud, 2003). Patients with conditions that compromise pancreatic function do not produce enough pancreatic lipase necessary for fat hydrolysis (BioSpace, 2016). Individuals who have these conditions and receive enteral tube feeding may be receiving an incomplete breakdown of fats, which can lead to decreased calorie intake, reduced fat digestion (e.g., omega-3 fatty acids), deficiencies of fat-soluble vitamins, and increased GI symptoms (Alcresta Therapeutics, 2017).

Due to the problems posed by fat malabsorption, there is clinical management in place that consists of enteral tube feeding. The enteral tube feeding consists of supplemental nutritional liquids that are delivered to the gastrointestinal tract through a feeding tube into the stomach or small intestines (Stroud, 2003). An enteral feeding in-line cartridge (EFIC) was designed to mimic the normal pancreatic function by breaking down fats in the enteral tube feeding formula (Maki, 1993). Breaking down the fats prior to ingestion will allow the patient who suffers from fat malabsorption to absorb more calories from omega-3 fatty acids, monoglycerides, and fat-soluble vitamins (Maki, 1993).

Currently, Relizorb is the first and only EFIC that has received de novo FDA approval for adult patients who have fat malabsorption (BioSpace, 2016). Relizorb is a novel in-line digestive enzyme cartridge, utilizing proprietary enzyme immobilization technology, designed for use in adult patients who receive enteral tube feeding (BioSpace, 2016). The active ingredient in Relizorb is a type of lipase enzyme (iLipase^™) that breaks down (hydrolysis) triglycerides into absorbable forms during enteral tube feeding (Alcresta Therapeutics, 2017).

All EFICs are considered to be experimental and investigational to assist with fat hydrolysis (breakdown), fat absorption, and any other indications. Even with Relizorb’s de novo FDA approval, there is insufficient evidence to support the safety, effectiveness, and impact on health outcomes resulting from the use of an EFIC (BioSpace, 2016). There are a small number of clinical trials and evidence-based health technology assessments that have evaluated Relizorb. Hayes (2016) determined that there is insufficient evidence that assesses the patient’s safety, impact on health outcomes, and patient management for the use of the Relizorb device.

Although a 33-patient clinical trial was conducted across several locations in the United States, there is a lack of human subjects on a large scale (ClinicalTrials.gov, 2016). According to Hayes (2016), the current published clinical data for Relizorb is very small and consists of only six conference abstracts containing all pig models.

References

1. Alcresta Therapeutics. Relizorb: (Immobilized Lipase) Cartridge, 2017. Accessed on April 5, 2017 and available at: http://relizorb.com/.
2. BioSpace, October 28, 2016. PRNewswire: Alcresta’ Relizorb Increases Fat Absorption in Adult and Pediatric Patients with Cystic Fibrosis Receiving Enteral Nutrition. Newton, Massachusetts. Accessed on April 14, 2017 and available at: http://www.biospace.com/news_story.aspx?StoryID=437369.
3. Centers for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD) for Medical Nutrition Therapy (180.1), October 1, 2002. Accessed at: https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=252&ncdver=1&DocID=180.1&SearchType=Advanced&bc=IAAAAAgAAAAAAA%3d%3d&.
4. ClinicalTrials.gov. Safety, Tolerability and Fat Absorption Using Enteral Feeding In-line Enzyme Cartridge (Relizorb), ClinicalTrials.gov Identifier: NCT02598128. Last updated: June 2016. Accessed on April 7, 2017 and available at: https://clinicaltrials.gov/ct2/show/NCT02598128.
5. Hayes, Inc. Relizorb (Alcresta Pharmaceuticals), February 4, 2016. Accessed on April 14, 2017 and available at: https://www.hayesinc.com/subscribers/displaySubscriberArticle.do?articleId=37626&searchStore=%24search_type%3Dall%24icd%3D%24keywords%3DRELIZORB%24status%3Dall%24page%3D1%24from_date%3D%24to_date%3D%24report_type_options%3D%24technology_type_options%3D%24organ_system_options%3D%24specialty_options%3D%24order%3DasearchRelevance.
6. Maki, J., Neelagiri, M., Olshaw, B., Devarakonda, S., Loring, G. ePS05.2 Novel point of care immobilized lipase device (EFIC™) is compatible with a range of nutritional formulas and can simplify delivery of hydrolyzed fat during tube feeding, 1993. Journal of Cystic Fibrosis. Accessed on April 10, 2017 and available at: http://www.cysticfibrosisjournal.com/article/S1569-1993(15)30161-2/pdf.
7. National Institutes of Health (NIH): U.S. National Library of Medicine, 2017. MedlinePlus: Malabsorption. Bethesda, Maryland. Accessed on April 14, 2017 and available at: https://medlineplus.gov/ency/article/000299.htm.
8. Stroud, M., Duncan, H., Nightingale, J. Guidelines for enteral feeding in adult hospital patients: Institute of Human Nutrition, 2003. Accessed on April 7, 2017 and available at: http://www.bsg.org.uk/pdf_word_docs/enteral.pdf. 
9. Alcresta Therapeutics. Relizorb: (Immobilized Lipase) Cartridge, 2017. Accessed on June 5, 2017 and available at: relizorb.com/.
10. Alcresta Therapeutics. Absorption and Safety With Sustained Use of Relizorb Evaluation (ASSURE) Study in Patients With Cystic Fibrosis Receiving Enteral Feeding. Accessed on August 1, 2017. www.cff.org/Trials/Finder/details/470/ASSURE-Study-of-Relizorb-in-people-with-CF-who-receive-enteral-tube-feeding.
11. ClinicalTrials.gov. Safety, Tolerability and Fat Absorption Using Enteral Feeding In-line Enzyme Cartridge (Relizorb), ClinicalTrials.gov Identifier: NCT02598128. Last updated: June 2016. Accessed on June 7, 2017 and available at: clinicaltrials.gov/ct2/show/NCT02598128.
12. Freedman S., Orenstein D et al. Increased fat absorption from enteral formula through an in-line digestive cartridge in patients with Cystic Fibrosis. www.ncbi.nlm.nih.gov/pubmed/?term=relizorb
13. Hayes, Inc. Search and summary, Relizorb (Alcresta Pharmaceuticals). February 4, 2016. www.hayesinc.com/hayes/publications/search-summary/hss-relizorb3607/ Accessed June 2017.
14. Medscape, LLC. FDA clears Relizorb for use with enteral tube feedings. Medscape, LLC. New York, NY. December 03, 2015.Available at: www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/denovo.cfm?ID=DEN150001 Accessed June 2017.
15. Stevens T., Conwell D.L. Exocrine pancreatic insufficiency www.uptodate.com/contents/cystic-fibrosis-nutritional-issues?source=search_result&search=digestive%20enzymes%20cystic&selectedTitle=1~150

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.  

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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