Oral CDX-7108 in Healthy Adults and EPI Subjects

Study Overview
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Brief Summary
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Phase 1a/1b single and multiple ascending dose study of oral CDX-7108 in healthy adult subjects and a single dose proof-of-concept study of oral CDX-7108 in subjects with exocrine pancreatic insufficiency. No clinical studies have yet been performed with CDX-7108 and its effects in humans are unknown. This is the first-in-human (FIH) study of CDX-7108, which aims to assess the safety, tolerability, pharmacokinetics (PK) of escalating single and multiple oral doses of CDX-7108 in healthy adult subjects and to evaluate the pharmacodynamics of a single dose of oral CDX-7108 in a proof-of-concept (POC) study in subjects with exocrine pancreatic insufficiency (EPI).

Detailed Description
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This is an integrated 3-part study to investigate the safety, tolerability, PK, and PD of CDX-7108. The Parts A and B are randomized, double-blind, placebo-controlled dose escalation parts to investigate the safety, tolerability, immunogenicity, and PK of CDX-7108 after single and multiple oral dose administration in healthy adult subjects. Part C is a randomized, double-blind, placebo-controlled, single-dose, 2-way crossover part to assess POC of CDX-7108 in terms of PD as well as its safety, tolerability, and immunogenicity in subjects with EPI. The study will commence with Part A (single ascending dose [SAD] study) and will progress to Part B (multiple ascending dose [MAD] study), and Part C (POC study)

Official Title
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A 3-part, Phase 1a/1b, First-in-human, Randomized, Double-blind, Placebo-controlled Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of Oral CDX-7108 in Healthy Adult Subjects and to Evaluate Proof-of-concept Via Pharmacodynamics of a Single Dose of Oral CDX-7108 in Subjects With Exocrine Pancreatic Insufficiency

Conditions
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Exocrine Pancreatic Insufficiency

Intervention / Treatment
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* Drug: Part A
* Drug: Part B
* Drug: Part C


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects: Capable of giving signed informed consent prior to initiation of any protocol-specific procedures, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Body mass index (BMI) between 18.0 and 30.0 kg/m2. Nonsterilized male subjects are eligible to participate if they agree to ONE of the following starting at Screening and continuing throughout the clinical study period, and for 90 days after IP administration: Must agree to stay abstinent (where abstinence is the preferred and usual lifestyle of the subject), OR Male subjects with a female partner of childbearing potential must agree to use highly effective contraception consisting of 2 forms of birth control. Male subjects 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 do not apply to subjects in a same sex relationship. Male subjects must agree not to donate sperm starting at Screening and continuing throughout the clinical study period, and for 90 days after IP administration. Female subjects of childbearing potential are eligible to participate if they meet the following criteria: Must agree not to become pregnant during the clinical study period and for 30 days after IP administration. Must have a negative serum pregnancy test at Screening and Day -1. If heterosexually active, must agree to consistently use a form of highly effective birth control, in combination with a barrier method (as defined in Appendix 3) starting at Screening (signing the ICF) and continuing throughout the clinical study period, and for 30 days after IP administration, OR Must agree to stay abstinent (where abstinence is the preferred and usual lifestyle of the subject), starting at Screening (signing the ICF) and continuing throughout the clinical study period, and for 30 days after IP administration. These requirements do not apply to subjects in a same sex relationship. Female subjects of non-childbearing potential are eligible to participate if 1 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 subject'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 subjects 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 (Appendix 3) from Screening (signing the ICF) until at and continuing throughout the clinical study period, and for 30 days after IP administration if they wish to continue their HRT during the study. Female subjects must agree not to donate ova starting at Screening (signing the ICF) and continuing throughout the clinical study period, and for 30 days after IP administration. Subject agrees not to participate in another interventional study while participating in the present clinical study. Parts A (Single Ascending Dose Study) and B (Multiple Ascending Dose Study) Healthy male and female, non-smoking, subjects between the ages of 18 and 55 years, inclusive, at the time of Screening. In each cohort, at least 2 male subjects and 2 female subjects should be enrolled. Appropriate general health, as determined by an experienced physician based on a medical evaluation including detailed medical history, clinical laboratory tests, vital signs, 12-lead ECG, and full physical examination (and neurological assessment). Part C (Proof-of-Concept Study) Male and female subjects between the ages of 18 and 75 years (inclusive) who have undergone total or partial pancreatectomy or have an established diagnosis of CP, as confirmed by fecal pancreatic elastase-1 <100 μg/g in formed stools within 12 months of the Screening visit. Subjects with clinically well controlled EPI under the regular use of PERT (remission or adequate improvement of steatorrhea on PERT), as determined by an experienced physician based on a medical evaluation including detailed medical history, clinical laboratory tests, vital signs, 12-lead ECG, and full physical examination (and neurological assessment). 150min percentage 13CO2 excretion rate <4.4% dose/h using the Pancreo-Lip breath test at Screening. Exclusion Criteria: All subjects Female subject who has been pregnant within the 6 months prior to Screening or breastfeeding within the 3 months prior to Screening. Treatment with any antiplatelet and/or anticoagulant medication, except low-dose aspirin. Evidence or history of specific food intolerance. Examples include gluten intolerance, lactose intolerance, or dairy food intolerance or any food/ingredient included in the standard breakfast provided at the study site. A positive result, on Screening, for serum hepatitis B surface antigen, hepatitis A virus antibodies, hepatitis C virus antibodies or antibodies to human immunodeficiency virus type 1 and/or type 2. Known active infection with COVID-19, or a suspected infection with severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2]). Chronic alcoholic intoxication that would preclude compliance with the study procedures. Habitual use of nicotine products or smoking within 3 months (>10 cigarettes per day) prior to Screening, and/or unwilling to refrain from smoking during the confinement period. Nicotine replacement therapy is allowed during the study. Drug addiction that would preclude participation and compliance with study procedures. Subject has a pulse rate <40 or >100 bpm; mean systolic blood pressure (SBP) >150 mmHg; mean diastolic blood pressure (DBP) >95 mmHg at Screening. Repeat measurements are allowed at the discretion of the Investigator. Subject has any clinically significant abnormalities at Screening in rhythm, conduction or morphology of the resting ECG and any clinically significant abnormalities in the 12-lead ECG, as considered by the Investigator, that may interfere with the interpretation of QTc interval changes including abnormal ST-T wave morphology. Subject has prolonged QTcF >450 msec for male subjects or >470 msec for female subjects or a family history of prolonged QT syndrome, at Screening. Plasma donation within the 14 days prior to the first dose of IP or any whole blood donation/significant blood loss >500 mL during the 3 months prior to the first dose of IP. Treatment with any investigational drug or device/treatment within the 30 days or 5 half-lives of the drug (whichever is longer) prior to the administration of IP. Known allergy or adverse reaction history to any component of the CDX-7108 oral dose formulation. Part A (Single Ascending Dose Study) and Part B (Multiple Ascending Dose Study) Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies and childhood asthma) at time of Screening or IP administration, that in the opinion of the Investigator may put the subject at greater safety risk, influence response to study drug, or interfere with study assessments. Current or chronic history of GI disorders or conditions interfering with normal GI anatomy or function. Examples include GI bypass surgery, partial or total gastrectomy, gastric band surgery, major (>1 m) small bowel resection, vagotomy, malabsorption, Crohn's disease, ulcerative colitis, irritable bowel syndrome, celiac sprue, and small intestinal bacterial overgrowth. A positive Screening test for use of drugs (amphetamines, cocaine, marijuana, opiates, barbiturates, benzodiazepines, methadone, and methamphetamines) and alcohol (breath test). However, there is the option to re-screen once during the Screening period at the discretion of the Investigator or delegate in the case of a positive result at Screening for a prescribed medication, eg, codeine. Subject has any clinically significant abnormalities in hematology, coagulation, clinical chemistry, or urinalysis at Screening as judged by the Investigator, including aspartate aminotransferase (AST) or ALT >1.5 times above the ULN. Repeat measurements are allowed at the discretion of the Investigator. Use of any prescribed or nonprescribed medication in the 2 weeks preceding the first dose of IP. EXCEPTION: Subjects who have received approved vaccines (including approved COVID-19 vaccines) may be allowed if these vaccines are taken no less than 72 hours prior to the IP dose at the discretion of the Investigator. Part C (Proof-of-Concept Study) Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies and childhood asthma) at time of Screening or IP administration, that in the opinion of the Investigator may put the subject at greater safety risk, influence response to study drug, or interfere with study assessments. NOTE: Subjects with treated diabetes secondary to CP or pancreatectomy are allowed. Subject has any clinically significant abnormalities in hematology, coagulation, clinical chemistry, or urinalysis at Screening as judged by the Investigator, including AST or ALT >1.5 times above the ULN, or cholesterol or triglycerides >400 mg/dL. Repeat measurements are allowed at the discretion of the Investigator. Current or chronic history of GI disorders or conditions interfering with normal GI anatomy or motility, with the exception of pancreatic insufficiency due to pancreatectomy, including pancreaticoduodenectomy, or CP Use of any prescribed or nonprescribed medication potentially interfering with gastric pH, intestinal motility, or fat absorption, including herbal and dietary supplements and antacids; these medications shall be stopped for a minimum of 5 times their half-life before IP administration if, in the opinion of the Investigator, this does not represent a risk for the subject's wellbeing. EXCEPTIONS: Histamine H2 receptor antagonists, PPI, insulin, analgesics, and chronic pain medications. Oral contraceptives, paracetamol, or multivitamins. Subjects who have received approved vaccines (including approved COVID-19 vaccines) may be allowed if these vaccines are taken no less than 72 hours prior to the IP dose at the discretion of the Investigator. Use of antibiotics within 8 days before the Pancreo-Lip breath test at Screening or Day 1.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 3-part study Parts A and B are randomized, double-blind, placebo-controlled dose escalation parts to investigate the safety, tolerability, immunogenicity, and PK of CDX-7108 after single and multiple oral dose administration in healthy adult subjects. Part C is a randomized, double-blind, placebo-controlled, single-dose, 2-way crossover part to assess POC of CDX-7108 in terms of PD as well as its safety, tolerability, and immunogenicity in subjects with EPI.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CDX-7108<br>CDX-7108, an oral recombinant lipase. It is a modified version of a triacylglycerol lipase enzyme derived from the bacteria Bacillus thermoamylovans (btLIP) and produced by fermentation of recombinant Escherichia coli.7 | Drug: Part A<br>* Randomized, double-blind, placebo-controlled dose escalation part to investigate the safety, tolerability, immunogenicity, and PK of CDX-7108 after single oral dose administration in healthy adult subjects. Single-dose administration of CDX-7108 at the following anticipated dose levels. 10 000, 50 000, 150 000, 250 000, and 500 000 lipase units will be evaluated in 5 sequential cohorts of 6 subjects each.<br>* Other names: Single Ascending Dose Study;Drug: Part B<br>* Randomized, double-blind, placebo-controlled dose escalation parts to investigate the safety, tolerability, immunogenicity, and PK of CDX-7108 after multiple oral dose administration in healthy adult subjects. It will evaluate multiple dose administration of CDX-7108 at an appropriate low (50 000 lipase units), mid (150 000 lipase units), and high dose (250 000 lipase units) 4 times a day (QID) for 6 consecutive days in 3 sequential cohorts of 6 subjects each.<br>* Other names: Multiple Ascending Dose Study;Drug: Part C<br>* Randomized, double-blind, placebo-controlled, single-dose, 2-way crossover part to assess POC of CDX-7108 in terms of PD as well as its safety, tolerability, and immunogenicity in subjects with EPI. Approximately 10 subjects with severe EPI from partial/total pancreatectomy or chronic pancreatitis will be enrolled. It is anticipated that Part C (POC study) will commence after completion of the third single-dose cohort from Part A (SAD study) and following SRC review of the data from this cohort.<br>* Other names: Proof-of-Concept Study;|
| Placebo Comparator: Placebo<br>Excipients only | Drug: Part A<br>* Randomized, double-blind, placebo-controlled dose escalation part to investigate the safety, tolerability, immunogenicity, and PK of CDX-7108 after single oral dose administration in healthy adult subjects. Single-dose administration of CDX-7108 at the following anticipated dose levels. 10 000, 50 000, 150 000, 250 000, and 500 000 lipase units will be evaluated in 5 sequential cohorts of 6 subjects each.<br>* Other names: Single Ascending Dose Study;Drug: Part B<br>* Randomized, double-blind, placebo-controlled dose escalation parts to investigate the safety, tolerability, immunogenicity, and PK of CDX-7108 after multiple oral dose administration in healthy adult subjects. It will evaluate multiple dose administration of CDX-7108 at an appropriate low (50 000 lipase units), mid (150 000 lipase units), and high dose (250 000 lipase units) 4 times a day (QID) for 6 consecutive days in 3 sequential cohorts of 6 subjects each.<br>* Other names: Multiple Ascending Dose Study;Drug: Part C<br>* Randomized, double-blind, placebo-controlled, single-dose, 2-way crossover part to assess POC of CDX-7108 in terms of PD as well as its safety, tolerability, and immunogenicity in subjects with EPI. Approximately 10 subjects with severe EPI from partial/total pancreatectomy or chronic pancreatitis will be enrolled. It is anticipated that Part C (POC study) will commence after completion of the third single-dose cohort from Part A (SAD study) and following SRC review of the data from this cohort.<br>* Other names: Proof-of-Concept Study;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Number and severity of adverse events | Up to 9 weeks | 
| Changes in haematology from baseline | Number of participants with changes in haematology measurements (erythrocyte count, thrombocyte count, haemoglobin, haematocrit, mean cell hemoglobin concertation) using immunoassays. | Up to 5 weeks | 
| Changes in coagulation tests from baseline | Number of participants with changes in coagulation factors (INR, prothrombin time, fibrogen, red blood cell indices and leukocyte count) using immunoassays. | Up to 5 weeks | 
| Changes in clinical chemistry from baseline | Number of participants with changes in clinical chemistry (bicarbonate, albumin, total protein, blood glucose, sodium, potassium, phosphate, calcium, urea creatine, chloride, creatine kinase, urate, AST, ALT, ALP, GGT, triglycerides, total cholesterol, lactate dehydrogenase, c-reactive protein, total bilirubin) using immunoassays. | Up to 5 weeks | 
| Changes in urinalysis from baseline | Number of participants with changes in leucocyte esterase, protein, urobilinogen, ketones, bilirubin, microscopy, blood, pH, nitrate, specific gravity, urobilinogen and glucose) using immunoassays. | Up to 5 weeks | 
| Changes in Systolic Blood Pressure from baseline | Changes in Systolic Blood Pressure from baseline | Up to 5 weeks | 
| Changes in Diastolic Blood Pressure from baseline | Changes in Diastolic Blood Pressure from baseline | Up to 5 weeks | 
| Changes in Pulse Rate vital signs from baseline | Changes in pulse rate from baseline | Up to 5 weeks | 
| Changes in Respiratory Rate vital signs from baseline | Changes in respiratory rate from baseline | Up to 5 weeks | 
| Changes in Body Temperature vital signs from baseline | Changes in body temperature from baseline | Up to 5 weeks | 
| Changes in 12-lead electrocardiogram (ECG) Heart Rate from baseline | Changes in ECG Heart rate from baseline | Up to 5 weeks | 
| Changes in 12-lead electrocardiogram (ECG) PR Interval from baseline | Changes in ECG PR interval from baseline | Up to 5 weeks | 
| Changes in 12-lead electrocardiogram (ECG) QRS duration from baseline | Changes in electrocardiogram QRS duration interval from baseline | Up to 5 weeks | 
| Changes in 12-lead electrocardiogram (ECG) QT Interval from baseline | Changes in ECG QT interval from baseline | Up to 5 weeks | 
| Changes in 12-lead electrocardiogram (ECG) QTcF Interval from baseline | Changes in ECG QTcF interval from baseline | Up to 5 weeks | 
| Changes in physical examination from baseline: Head | Changes in general appearance of the head from baseline | Up to 5 weeks | 
| Changes in physical examination from baseline: Ears | Changes in general appearance of the ears from baseline | Up to 5 weeks | 
| Changes in physical examination from baseline: Eyes | Changes in general appearance of the eyes from baseline | Up to 5 weeks | 
| Changes in physical examination from baseline: Nose | Changes in general appearance of the nose from baseline | Up to 5 weeks | 
| Changes in physical examination from baseline: Throat | Changes in general appearance of the throat from baseline | Up to 5 weeks | 
| Changes in physical examination from baseline: Neck | Changes in general appearance of the neck (including thyroid) from baseline | Up to 5 weeks | 
| Changes in physical examination from baseline: General Appearance | Changes in general appearance of the skin from baseline | Up to 5 weeks | 
| Changes in physical examination from baseline: Cardiovascular system | Changes in cardiovascular system from baseline | Up to 5 weeks | 
| Changes in physical examination from baseline: Respiratory system | Changes in respiratory system from baseline | Up to 5 weeks | 
| Changes in physical examination from baseline: GI system | Changes in GI system from baseline | Up to 5 weeks | 
| Changes in physical examination from baseline: Musculoskeletal system | Changes in musculoskeletal system from baseline | Up to 5 weeks | 
| Changes in physical examination from baseline: Lymph nodes | Changes in lymph nodes from baseline | Up to 5 weeks | 
| Changes in physical examination from baseline: Nervous system | Changes in nervous system from baseline | Up to 5 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration-time profile of CDX-7108 | Serum concentration-time profile of CDX-7108 | Up to 7 days | 
| Lipase activity | Serum Lipase activity | Day 1 | 
| CO2 excretion rate | CO2 excretion rate (% dose/h), | Up to 43 days |