A New Pancreatic Enzyme Therapy (ANG003)

Anagram Therapeutics, Inc is developing a non-porcine Pancreatic Enzyme Replacement Therapy (PERT)- ANG003.  For people with Cystic Fibrosis (PwCF) with exocrine pancreatic insufficiency (EPI), the currently approved PERTs are porcine (pig) derived and require enteric (plastic) coating to allow the capsules to survive the acidic stomach. About 3-6 PERT capsules are taken with each meal and snack.

While the CF community and providers had hoped that highly-effective modulator therapy (HEMT) like elexacaftor/tezecaftor/ivacaftor (E/T/I) may have restored some pancreatic function, that has not been the case. Besides anecdotal reports in very young children and infants, PwCF and EPI taking HEMT still need PERT to digest food as demonstrated in the PROMIS study. This study evaluated stool elastase (measure of pancreatic function) before and after 30 months of taking E/T/I; approximately 80% of people had undetectable stool elastase (<15 µg/g) before and after treatment. Additionally, a 2024 community survey of PwCF found that the majority (85%) reported gastrointestinal (GI) symptoms as the most bothersome despite HEMT. Also, despite treatment with current PERT, PwCF remain deficient of essential fatty acids and fat-soluble vitamins even if one’s weight and body-mass index (BMI) are at goal.

With the above plus the treatment burden of multiple capsules per meal/snack, the reliance on a pig population with a variable supply and associated animal viruses, and the enteric (plastic) coating, there is potential to improve upon the challenges of approved PERT.

ANG003 contains three enzymes to digest/breakdown fats, proteins, and carbohydrates- lipase, protease, and amylase, respectively. Each enzyme is made from a microbial source (non-porcine/non-pig) and in tablets that do not require enteric (plastic) coating. The ratio of the three enzymes is closer to that of a human pancreas instead of the ratio of a pig pancreas. They begin working in the stomach and continue to work in the upper small intestine before naturally breaking down.

ANG003 is currently being investigated in a large, international Phase 2 study in PwCF and EPI ages 12 years and older. ANG003 will be compared alongside a current standard of care PERT. Along with safety, changes in fat & nutrient absorption, changes in stool, and changes in GI symptoms will be evaluated. This Phase 2 study uses individual tablets of each enzyme in ANG003 with a single tablet containing all three enzymes in development for Phase 3 trials and beyond.

Potential participants need to meet certain criteria to enter the study.

Key inclusion criteria:

• CF diagnosis aged 12 years and older
• Exocrine pancreatic insufficiency with fecal elastase-1 ≤50ug/g
• Stable PERT dose for 90 days

Key exclusion criteria:

• FEV1 (measure of lung function) <30% predicted
• Unable to go 6 hours without taking short-acting insulin
• Recent pulmonary exacerbation requiring IV antibiotics, oxygen support or hospitalization

Like the current FDA-approved PERTs, ANG003 will be studied using a test where people have their stool collected over several days to see how much fat is absorbed (coefficient of fat absorption, CFA). Blood tests are also drawn to see how well fats, proteins & carbohydrates are absorbed in the body. While stool is being collected, participants eat a variety of standard meals so the exact amounts of fat, protein, & carbohydrates eaten are known. There are a few parts to the study: 

• If eligible to participate, everyone starts with the acclimation period, taking the same currently approved porcine PERT (pPERT). Next, in Period A, standard meals are eaten and stool is collected for a few days. This includes a day in the research center when blood tests are drawn over several hours.
• Participants are then randomly assigned to receive one of two doses of ANG003 or to continue on the pPERT. At the end of this time is Period B, with the same procedures as Period A. A small number of people at a few clinics who agree to, may receive no pPERT or ANG003 during Period B.
• At the end of Period B, participants re-start their prior home PERT with one more study visit about 5 days later.

By comparing the results from the two study periods, we will see how similar ANG003 is to the currently approved PERT in how PwCF and EPI digest and absorb nutrients from food while also determining which dose(s) of ANG003 to use in potential Phase 3 studies. To learn more about the study, please go to clinicaltrials.gov (NCT07450547) or the Cystic Fibrosis Foundation’s Trial Finder.

All of us at Anagram want to thank the entire CF community for their continued support and participation in clinical trials.