New lipase NHS7108 safety and potential efficacy in adults with exocrine pancreatic insufficiency

Inclusion Criteria: Participants are eligible to be included in the study only if all of the following criteria apply:

1. Participant is a male or female between 18 to 85 years of age, inclusive, at the time of signing the informed consent.
2. Participants with clinically confirmed\* chronic established (not due to a transient clinical diagnosis, i.e., acute pancreatitis) EPI and with a clinical indication for PERT.
3. CFA off PERT of \<80% at screening
4. Normal body mass index (BMI) by age and sex to ensure participant's EPI is adequately controlled in the opinion of the investigator (BMI of at least 17.0 and no greater than 35.0 kg/m²)
5. Standard-of-care medications are allowed (antibiotics, mucolytic agents, aerosols, antacids), if on stable doses for at least 1 month prior to baseline CFA and CNA assessments and must not be altered in dose or stopped during the study.
6. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators are allowed if on stable doses for at least 3 months prior to randomization. Participants should not start taking CFTR modulators during the duration of the study.
7. Contraceptive use by men and women must be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

   Male Participants:
   * Non-sterilized male participants are eligible to participate if they agree to one of the following starting at screening and continuing throughout the clinical study period, and until the end-of-study safety follow-up: Must agree to stay abstinent (where abstinence is the preferred and usual lifestyle of the participant), OR male participants with a female partner of childbearing potential must agree to use highly effective contraception consisting of 2 forms of birth control (1 of which must be a barrier method). Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration. These requirements also apply to participants in a same sex relationship.
   * Male participants must agree not to donate sperm starting at screening and continuing throughout the clinical study period, and until the end-of-study safety follow-up.

   Female Participants:
   * Female participants of childbearing potential (as defined in Appendix 4) are eligible to participate if they meet the following criteria: Agree not to become pregnant during the clinical study period and until the end-of-study safety follow-up. Have a negative serum pregnancy test at screening and a negative urine pregnancy test at Day 1. If heterosexually active, must agree to consistently use a form of highly effective birth control, in combination with a barrier method starting at screening and continuing throughout the clinical study period, and until the end-of-study safety follow-up, OR agree to stay abstinent (where abstinence is the preferred and usual lifestyle of the participant), starting at screening and continuing throughout the clinical study period, and until the end-of-study safety follow-up. These requirements do not apply to participants in a same sex relationship.
   * Female participants of nonchildbearing potential are eligible to participate if one of the following conditions apply: Must have a confirmed clinical history of sterility (documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy, as confirmed by review of the participant's medical records, medical examination, or medical history interview). Must be postmenopausal as defined as: amenorrhea for at least 1 year prior to screening and a laboratory confirmed serum follicle-stimulating hormone (FSH) level ≥ 40 mIU/mL. Female participants on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use 1 of the non-estrogen hormonal highly effective contraception methods from screening until at and continuing throughout the clinical study period, and until the end-of-study safety follow-up if they wish to continue their HRT during the study.
   * Female participants must agree not to donate ova starting at screening and continuing throughout the clinical study period, and until the end-of-study safety follow-up.
   * For WOCBP only, serum pregnancy test will be performed at screening and urine pregnancy tests will be performed at the timepoints outlined in the SoA.
   * The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
8. Participants are capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
9. Participants agree not to participate in another interventional study while participating in the study.

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

1. Female participants who are breastfeeding at the time of screening.
2. Previous GI surgery, except for non-invasive neonatal or early childhood procedures such as correction of hypertrophic pyloric stenosis, surgical correction of Meckel's diverticulum, volvulus, or intestinal intussusception. Hernia repair, appendectomy, cesarean section, tubal ligation, hysterectomy, polypectomy, hemorrhoidectomy, or cholecystectomy are allowed if performed at least 2 years before randomization and have no impact on intestinal transit or absorption.
3. Participants on enteral feeding.
4. Participants with celiac disease.
5. Known allergy or adverse reaction history to any component of NHS7108, Zenpep®, omega-3 oil, and/or to any other product administered during the study, including the blue dye.
6. Concurrent clinically significant, at the discretion of the Investigator, hematological, renal, endocrine, pulmonary, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, and seasonal allergies and childhood asthma) or any other disorder that in the opinion of the Investigator may put the participant at greater safety risk, influence response to study intervention, or interfere with study assessments.
7. Concurrent conditions having a clinically significant impact on GI motility function, with the exception of pancreatic insufficiency due to pancreatectomy or CP.
8. Any significant clinical/laboratory/radiological sign of unstable or unexpectedly deteriorating respiratory disease during the study duration, at the discretion of the Investigator.
9. Omega-3 supplements are prohibited during all the study periods and should be stopped at least 7 days prior to the baseline off-treatment fat absorption assessments.
10. Participants starting new medications or changing dose within 1 month before baseline off-treatment screening assessments.
11. Acute use of oral or intravenous antibiotics within 2 weeks prior to the first dose of study intervention.
12. Treatment with any investigational drug or device/treatment within the 30 days or 5 half-lives of the drug (whichever is longer) prior to first dose of study intervention.
13. Participant has any clinically significant abnormalities in hematology, coagulation, clinical chemistry, or urinalysis at screening as judged by the Investigator OR as detailed below:

    * Estimated glomerular filtration rate \< 60 mL/min at screening visit.
    * Total bilirubin \> 1.5 × upper limit of normal (ULN) at screening visit.
    * Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2 × ULN at screening visit.
14. Positive human immunodeficiency virus (HIV) antibody test.
15. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) at screening or within 3 months prior to first dose of study intervention.
16. Positive hepatitis C virus (HCV) antibody test result at screening or within 3 months prior to first dose of study intervention AND positive on reflex to hepatitis C RNA test.
17. Concurrent drug or alcohol addiction that in the opinion of the Investigator would preclude participation and compliance with the study procedures.