A Study to Assess the Safety and Tolerability of Different Doses of AG019 Administered Alone or in Combination With Teplizumab in Participants With Recent-onset Diagnosed Type 1 Diabetes (T1D)

This Phase 1b/2a, multi-center study will be conducted in participants with clinical recent-onset type 1 diabetes (T1D).

The primary objective of this study is to assess the safety and tolerability of different doses of AG019 alone as well as AG019 in combination with teplizumab. The secondary objectives of this study are: to obtain pharmacodynamic (PD) data of AG019 alone as well as AG019 in combination with teplizumab; and to determine the potential presence of AG019 in systemic circulation (safety - systemic exposure) and the presence of L. lactis bacteria in fecal excretion (local exposure): Pharmacokinetic (PK) profile.

This study consists of 2 phases:

Phase 1b: this open-label part of the study will investigate the safety and tolerability of 2 different doses of AG019 in 2 age groups (18-40 years of age and 12-17 years of age).

Phase 2a: this randomized, double-blind part of the study will investigate the safety and tolerability of AG019, in combination with teplizumab, in 2 age groups (18-40 years of age and 12-17 years of age).

• AG019 - Low Dose (Biological): Solid, orally administered capsule - 2 capsules per day for 1 day (single dose) or 8 weeks (repeat dose)
• Teplizumab (Drug): Daily IV infusions of Teplizumab during the first 12 days of AG019 treatment. Total cumulative dose is approximately 17mg (dose calculation based on body surface area).
• Placebo-AG019 (Drug): Formulated identically to AG019 with the active ingredient removed.
• Placebo-Teplizumab (Drug): Formulated identically to teplizumab with the active ingredient removed.
• AG019 - High Dose (Biological): Solid, orally administered capsule - 6 capsules per day for 1 day (single dose) or 8 weeks
• AG019 - High Dose (Biological): Solid, orally administered capsule - 6 capsules per day for 8 weeks.

Primary outcomes

• Incidence of Treatment-emergent Adverse Events (TEAE) [up to 6 months]: Treatment-emergent adverse events assessed by the investigator, review of lab reports and information provided by the participant during site visits and/or participant diary with AG019 alone or with teplizumab

Secondary outcomes

• AG019 in Systemic Circulation [Up to 3 months after initiation of the treatment]: The presence of live L. lactis bacteria in blood will be assessed by plating
• L. Lactis-secreted hPINS or hIL-10 in Systemic Circulation [Up to 3 months after initiation of the treatment]: The presence of L. lactis-secreted hPINS or hIL-10 in the blood will be assessed by ELISA (enzyme-linked immunosorbent assay)
• AG019 in Feces [Up to 8 days after completion of the treatment]: The presence of L. lactis (live or dead) in feces will be assessed by Q-PCR (quantitative real-time polymerase chain reaction)
• C-peptide Area Under the Concentration-time Curve (AUC) Calculated From a 2 Hour Mixed Meal Tolerance Test (MMTT) at 12 Months [up to 12 months]: MMTT-stimulated 2-hour C-peptide AUC was defined as the mean area under the C-peptide level time curve over the 2-hour period divided by the duration after a mixed-meal tolerance test.

Other outcomes

• Incidence of Treatment Emergent Adverse Events up to 12 Months [Up to 12 months from screening]: Incidence of all reported TEAE up to the 12-month follow-up visit. The TEAE are counted once within each patient on the preferred term level.

Sex: All, ages: 12 Years to 40 Years

Inclusion Criteria:

* Male or non-pregnant, non-lactating females, 18 - 40 years of age (both inclusive) or 12-17 years of age (both inclusive)
* Diagnosis of diabetes according to the American Diabetes Association (ADA) recommended criteria
* Evidence of auto-antibodies to at least 1 β-cell autoantigen
* Stimulated C-peptide measured during 4h Mixed Meal tolerance Test (MMTT) > 0.2 nmol/L
* The first administration of AG019 should occur no later than 150 days post diagnosis of diabetes
* Body weight ≥ 33kg
* Written informed consent obtained and documented (participant, parent, guardian as applicable)

Exclusion Criteria:

* Previous history of serious cytokine release syndrome to teplizumab or other humanized anti-CD3 monoclonal antibodies with no or minimal capacity to bind Fc receptors. (Participants enrolled in the second phase of the trial in either Combination Cohort 1 or Combination Cohort 2, only)
* Use of immunosuppressive or immunomodulatory therapies, including systemic steroids within 1 month prior to randomization
* Participation in another investigational drug trial within 12 weeks prior to the first study drug intake and during participation in this study
* History of recurrent infections, other autoimmune diseases, cardiac disease, malignancy, or any other (chronic) medical condition which, in the investigator's opinion, could compromise participant safety
* Documented history of human immunodeficiency virus (HIV), Hepatitis Virus Type C (HCV), Hepatitis Virus Type B (HBV) infection
* Evidence of active infection with Epstein-Barr Virus (EBV) or cytomegalovirus (CMV)
* Evidence of active or latent tuberculosis (TB)
* Administration of anti-CD3 antibody in past year
* Current therapy with any other anti-diabetic agents other than insulin (MDI, CSII or analogue). Current or planned therapy with experimental (i.e., unapproved) insulin. Patients on therapy for type 2 diabetes (e.g. metformin) should stop their therapy in order to be eligible for study participation.
* Use of medications known to influence glucose tolerance
* Daily use of non-steroidal anti-inflammatory agents
* Compromised GI mucosal integrity or motility, not attributable to T1D (i.e., recent diarrhea, gluten sensitive enteropathy, inflammatory bowel disease, irritable bowel syndrome), or current use of medications known to influence GI motility
* Positive result of SARS-Cov2 PCR test at screening or within 3 days before randomization

Participant flow

Outcome results

• Incidence of Treatment-emergent Adverse Events (TEAE) (Primary), Number, Events: AG019 Cohort 1 - Low (Single) Dose/Adults 1; AG019 Cohort 1 - Low (Repeat) Dose/Adults 6; AG019 Cohort 2 - High (Single) Dose/Adults 1; AG019 Cohort 2 - High (Repeat) Dose/Adults 19; AG019 Cohort 3 - Low (Single) Dose/Adolescents 1; AG019 Cohort 3 - Low (Repeat) Dose/Adolescents 28; AG019 Cohort 4 - High (Single) Dose/Adolescents 1; AG019 Cohort 4 - High (Repeat) Dose/Adolescents 19; Combination Cohort 1 - Active AG019/Teplizumab - Adults 91; Combination Cohort 1 - AG019-placebo/Teplizumab-placebo - Adults 25; Combination Cohort 2 - Active AG019/Teplizumab - Adolescents 22; Combination Cohort 2 - AG019-placebo/Teplizumab-placebo - Adolescents 1
• AG019 in Systemic Circulation (Secondary), Count of participants, Participants: AG019 Cohort 1 - Low (Repeat) Dose/Adults 0; AG019 Cohort 2 - High (Repeat) Dose/Adults 0; AG019 Cohort 3 - Low (Repeat) Dose/Adolescents 0; AG019 Cohort 4 - High (Repeat) Dose/Adolescents 0; Combination Cohort 1 - Active AG019/Teplizumab - Adults 0; Combination Cohort 1 - AG019-placebo/Teplizumab-placebo - Adults 0; Combination Cohort 2 - Active AG019/Teplizumab - Adolescents 0; Combination Cohort 2 - AG019-placebo/Teplizumab-placebo - Adolescents 0
• L. Lactis-secreted hPINS or hIL-10 in Systemic Circulation (Secondary), Count of participants, Participants: AG019 Cohort 1 - Low (Repeat) Dose/Adults 0; AG019 Cohort 2 - High (Repeat) Dose/Adults 0; AG019 Cohort 3 - Low (Repeat) Dose/Adolescents 0; AG019 Cohort 4 - High (Repeat) Dose/Adolescents 0; Combination Cohort 1 - Active AG019/Teplizumab - Adults 0; Combination Cohort 1 - AG019-placebo/Teplizumab-placebo - Adults 0; Combination Cohort 2 - Active AG019/Teplizumab - Adolescents 0; Combination Cohort 2 - AG019-placebo/Teplizumab-placebo - Adolescents 0
• AG019 in Feces (Secondary), Count of participants, Participants: AG019 Cohort 2 - High (Repeat) Dose/Adults 3; AG019 Cohort 4 - High (Repeat) Dose/Adolescents 3; Combination Cohort 1 - Active AG019/Teplizumab - Adults 9; Combination Cohort 1 - AG019-placebo/Teplizumab-placebo - Adults 0; Combination Cohort 2 - Active AG019/Teplizumab - Adolescents 3; Combination Cohort 2 - AG019-placebo/Teplizumab-placebo - Adolescents 0
• C-peptide Area Under the Concentration-time Curve (AUC) Calculated From a 2 Hour Mixed Meal Tolerance Test (MMTT) at 12 Months (Secondary), Mean, nmol/L: AG019 Cohort 2 - High (Repeat) Dose/Adults 0.89 +/- 0.61; AG019 Cohort 4 - High (Repeat) Dose/Adolescents 0.57 +/- 0.13; Combination Cohort 1 - Active AG019/Teplizumab - Adults 0.48 +/- 0.19; Combination Cohort 1 - AG019-placebo/Teplizumab-placebo - Adults 0.73 +/- 0.01; Combination Cohort 2 - Active AG019/Teplizumab - Adolescents 0.57 +/- 0.21; Combination Cohort 2 - AG019-placebo/Teplizumab-placebo - Adolescents 0.25 +/- 0; AG019 Cohort 1 - Low (Repeat)-Dose/Adults 0.62 +/- 0.48; AG019 Cohort 3 - Low (Repeat) Dose/Adolescents 0.78 +/- 0.35
• Incidence of Treatment Emergent Adverse Events up to 12 Months (Other pre specified), Number, events: AG019 Cohort 1 - Low (Single) Dose/Adults 1; AG019 Cohort 1 - Low (Repeat) Dose/Adults 8; AG019 Cohort 2 - High (Single) Dose/Adults 1; AG019 Cohort 2 - High (Repeat) Dose/Adults 26; AG019 Cohort 3 - Low (Single) Dose/Adolescents 1; AG019 Cohort 3 - Low (Repeat) Dose/Adolescents 33; AG019 Cohort 4 - High (Single) Dose/Adolescents 1; AG019 Cohort 4 - High (Repeat) Dose/Adolescents 26; Combination Cohort 1 - Active AG019/Teplizumab - Adults 97; Combination Cohort 1 - AG019-placebo/Teplizumab-placebo - Adults 26; Combination Cohort 2 - Active AG019/Teplizumab - Adolescents 23; Combination Cohort 2 - AG019-placebo/Teplizumab-placebo - Adolescents 2

Adverse events

Time frame: Adverse events were collected from signature of informed consent until completion of the study (or premature withdrawal), an average of 13 months (1 month of screening plus 12 months of study participation).

Other adverse events by term

91 more terms not shown.

• Results publication: Mathieu C, Wiedeman A, Cerosaletti K, Long SA, Serti E, Cooney L, Vermeiren J, Caluwaerts S, Van Huynegem K, Steidler L, Blomme S, Rottiers P, Nepom GT, Herold KC; AG019-T1D-101 Trial Investigators. A first-in-human, open-label Phase 1b and a randomised, double-blind Phase 2a clinical trial in recent-onset type 1 diabetes with AG019 as monotherapy and in combination with teplizumab. Diabetologia. 2024 Jan;67(1):27-41. doi: 10.1007/s00125-023-06014-2. Epub 2023 Oct 2. PMID 37782353
• Results publication: Alexander LM, van Pijkeren JP. Modes of therapeutic delivery in synthetic microbiology. Trends Microbiol. 2023 Feb;31(2):197-211. doi: 10.1016/j.tim.2022.09.003. Epub 2022 Oct 8. PMID 36220750

• Study Protocol (PDF, 2020-06-11)
• Statistical Analysis Plan (PDF, 2021-05-28)

• Chantal Mathieu, MD, Principal investigator, University Hospital of Leuven, Clinical and Experimental Endocrinology
• Kevan Herold, MD, Principal investigator, Yale Center for Clinical Investigation; Yale University

NIH grants: 2017