A three-part, double-blind, placebo-controlled, Phase I/Ib study of the safety, tolerability and pharmacokinetics of single and multiple ascending doses of IMU-856 in healthy volunteers and patients with Celiac disease

Exclusion Criteria100

• Part A and Part B: Healthy Volunteers
• History or presence of significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological or psychiatric disease, including any acute illness or surgery within the past three months determined by the PI to be clinically relevant;
• Current infection that requires oral and/or systemic antibiotic, antifungal, anti-parasitic or anti-viral medications, or the use of these medication within 4 weeks of randomization
• Any history of malignant disease in the last 10 years;
• Has clinically relevant immunosuppression from, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia;
• Receives or plans to receive systemic immunosuppressive (e.g. corticosteroids, methotrexate, azathioprine, cyclosporine) or immunomodulating medications (e.g. interferon) during the study or less than or equal to 4 months prior to the first Investigational Product administration;
• Liver function test results (ie, aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma-glutamyl transferase [GGT]) and total bilirubin elevated greater than 1.2 fold above the normal limits at the screening visit;
• Positive testing for active human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies, or Quantiferon tuberculosis (TB) infection (Quantiferon test);
• Any major surgery within 3 months of screening; any previous gastrointestinal surgery or recent (within 3 months) history of gastrointestinal disease that could impact the absorption of the study drug, known malabsorption or short bowel syndrome;
• History of substance abuse or alcohol abuse (defined as more than 10 standard drinks per week or more than 4 standard drinks on any one day; where 1 standard drink is 10 g of pure alcohol and is equivalent to 285 mL beer [4.9% Alc./Vol], 100 mL wine [12% Alc./Vol], 30 mL spirit [40% Alc./Vol]) during less than or equal to 12 months prior to the screening visit;
• Positive urine drug and alcohol breath testing at screening or check-in (Day -1);
• Use of any medication, including multi-vitamin preparations, received within 10 days prior to the drug administration, or within six times the elimination half-life, whichever is longest, except occasional use of paracetamol;
• Volunteers who have demonstrated clinically significant (required intervention, e.g. emergency room visit, epinephrine administration) allergic reactions (e.g. food, drug, atopic reactions, asthmatic episodes) which, in the opinion of the Investigator and Sponsor, interfere with their ability to participate in the trial;
• Any live vaccinations within 30 days prior to study drug administration except for the influenza vaccine;
• Positive serum pregnancy test (for women of childbearing potential [WOCBP]) at the Screening or positive urine pregnancy test with confirmatory serum pregnancy test on Day -1;
• Donation of blood or plasma within 30 days prior to randomization, or loss of whole blood of more than 500 mL within 30 days prior to randomization, or receipt of a blood transfusion within 1 year of the first scheduled dosing in the study;
• Participation in another investigational clinical trial within 60 days prior to the first drug administration;
• Volunteers participating in Part A of this study are excluded from participation in Part B;
• Any other condition or prior therapy, which, in the opinion of the PI, would make the volunteer unsuitable for this study, including unable to cooperate fully with the requirements of the study protocol or likely to be non-compliant with any study requirements;
• Volunteers have legal incapacity or limited legal capacity;
• An employee of an Investigator or Sponsor or an immediate relative of an Investigator;
• Volunteers institutionalized due to judicial or administrative order cannot participate.
• Mental handicaps or disorders leading to inability to give informed consent.
• Clinically diagnosed lactose intolerance;
• Subjects with known or suspected hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltose insufficiency;
• Consumption of grapefruit or grapefruit-containing products within 72 hours prior to study drug administration.
• Part C (Patients with Celiac Disease (CelD))
• Selective IgA deficiency as measured by serum IgA levels being less than 0.07g/L during SV1.
• Wheat or gluten allergy separate from Celiac disease.
• Signs of malabsorption as measured at SV1 by:
• a. Anaemia with a haemoglobin less than 110g/L in women and less than 120g/L in men, and/or
• b. Deficiency of albumin as defined by albumin less than 35 g/L, and/or
• c. Deficiency of folic acid as defined by folic acid < 6.1nmol/L
• History or presence of refractory CelD defined as persistent or recurrent malabsorptive
• symptoms and villous atrophy shown in a most recent biopsy despite strict adherence to a
• GFD for more than 12 months.
• History or presence of severe complications of CelD (e.g., enteropathy associated T cell
• lymphoma (EATL), ulcerative jejunitis, perforation).
• History or presence of skin manifestations of CelD like dermatitis herpetiformis at any
• time.
• History or presence of neurological manifestations of CelD like ataxia or neuropathy at
• any time.
• Any clinically significant concomitant disease of the intestinal tract in addition to CelD
• (e.g., Crohn´s disease, ulcerative colitis, other form of inflammatory bowel disease, severe
• and therapeutically uncontrolled irritable bowel syndrome, microscopic colitis, primary
• sclerosing cholangitis)
• History or presence of significant cardiovascular, pulmonary, hepatic, renal,
• haematological, gastrointestinal (in addition to CelD), endocrine, immunologic,
• dermatologic, neurological or psychiatric disease, including any acute illness or surgery
• within the past 3 months determined by the Investigator to be clinically relevant.
• Known history of diabetes mellitus type 1 or type 2.
• Known history of clinically significant liver disease (including liver cirrhosis, portal
• hypertension), and/or increased ALT and AST (greater than 1.5 x ULN) at SV1.
• Known history of clinically significant kidney disease and/or renal function impairment,
• assessed as Glomerular Filtration Rate less than or equal to 60 mL/min/1.73m2 at SV1.
• Presence of an ileostomy or colostomy or total proctocolectomy, short bowel syndrome, signs of malnutrition following gastrointestinal surgery or other major gastrointestinal surgery.
• Current infection that requires oral and/or systemic antibiotic, antifungal, anti-parasitic or anti-viral medications, the use of oral and/or systemic antibiotic, antifungal, anti-parasitic or anti-viral medications within 4 weeks of randomization;
• or infections that reoccur on a regular basis, if assessed by the Investigator to be
• clinically significant.
• History of chronic systemic infections including but not limited to HIV, hepatitis B or C,
• within 6 months before SV1.
• Positive HBsAg, HBcAb (hepatitis B core antibody), positive HCV and/or HIV-antigen antibody (HIV-Ag/Ab) test at SV1.
• Have or had an infection typical of an immunocompromised host and/or an infection that occurs with increased incidence in an immunocompromised host (including, but not
• limited to, pneumocystis jirovecii pneumonia, histoplasmosis, or coccidioidomycosis); or
• have a known immunodeficiency ongoing.
• Clinically diagnosed small intestinal bacterial overgrowth, other than simple bacterial
• overgrowth present at initial diagnosis of CelD;
• Receive or plan to receive probiotics during the study or less than or equal to 7 days prior to the first IMP administration (foods such as yogurt or kefir are acceptable);
• History of malignant disease within the last 10 years with the following exceptions: a) Curatively treated cervical carcinoma in situ, with no evidence of recurrence within 5 years prior to baseline may
• participate in the study b) Curatively treated non melanoma skin cancer with no evidence of recurrence (i.e. surgically removed basal-cell carcinoma or squamous-cell carcinoma)
• Known, or at SV1 experienced, intolerance to lactulose/mannitol testing.
• Any other condition or prior therapy, which, in the opinion of the Investigator, would
• make the patient unsuitable for this study, including unable to cooperate fully with the
• requirements of the study protocol or likely to be non-compliant with any study
• requirements.
• Intake of corticosteroids or immunomodulators (e.g., oral or systemic glucocorticoids
• including oral budesonide, cyclosporine, methotrexate, anti-tumour necrosis factor-alpha
• therapy, anti-integrin therapy, Janus kinase inhibitors) during the past 3 months before
• screening biopsy sampling at SV2.
• Intake (at least 3 times/week) of non-steroidal anti-inflammatory drugs (NSAIDs; except
• acetylsalicylic acid if daily dose is less than or equal to 350 mg) during the past 2 months before screening biopsy sampling at SV2.
• Patients receiving antiplatelet therapy (i.e. acetylsalicylic acid ± combination with
• thienopyridines [clopidogrel, prasugrel, ticlopidine, or ticagrelor] or oral anticoagulants
• (i.e. warfarin, dabigatran, etexilate, rivaroxaban, apixaban).
• Patients with known bleeding disorder or clinically relevant prolonged bleeding time as
• judged by the Investigator at the SV1.
• Unwillingness to undergo upper endoscopy with biopsy during screening and during the Study.
• Known intolerance/hypersensitivity/resistance to IMP and excipients or drugs of similar chemical structure or pharmacological profile.
• Doubt about the patient’s cooperation, e.g., because of known or suspected addiction to alcohol or drugs (Cannabis excluded).
• Positive urine drug and alcohol breath testing at SV1 or positive alcohol breath test on Day 1, prior to study drug administration.
• Any live vaccinations within 30 days prior to study drug administration (mRNA-based
• vaccinations and adenovirus vector vaccines are not considered live vaccinations);
• Concurrent participation in any other clinical trial using an IMP or medical device, or use
• of any IMP within 60 days or 5 x the respective half-life prior to the first study drug
• administration, whatever is longer.
• Donation of blood or plasma within 30 days prior to randomization, or loss of whole blood of more than 500 mL within 30 days prior to randomization, or receipt of a blood
• transfusion within 1 year of the first scheduled dosing in the study.
• Mental handicaps or disorders leading to inability to give informed consent.
• An employee of an Investigator or Sponsor or an immediate relative of an Investigator.
• Patients institutionalized due to judicial or administrative order.