A Clinical Study to Investigate if SAR425899 Binds to the Liver and Pancreas in Overweight to Obese Type 2 Diabetes Mellitus Patients

Study Overview
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Brief Summary
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Primary Objectives: To assess in overweight to obese T2DM patients: The glucagon receptor occupancy of SAR425899 at two dose levels in the human liver with positron-emission tomography (PET) imaging using [68Ga]Ga-DO3A-VS-Cys40-Tuna-2 as a tracer compound. The GLP-1 receptor occupancy of SAR425899 at two dose levels in the human pancreas with PET imaging using [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 as a tracer compound. Pharmacodynamic effects on fasting plasma glucose and biomarkers of lipid metabolism. Pharmacokinetic parameters for SAR425899 after repeated subcutaneous (SC) doses in plasma. Safety and tolerability of SAR425899.

Detailed Description
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Study duration is approximately 7 weeks with a 20 days treatment period.

Official Title
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A PET/CT Study to Assess the Receptor Occupancy by SAR425899 After Repeat Dosing Using Radiolabelled Tracers for the Glucagon and GLP-1 Receptor in Overweight to Obese T2DM Patients

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: SAR425899
* Drug: [68Ga] Ga-DO3A-VS-Cys40-Tuna-2 (glucagon receptor tracer)
* Drug: [68Ga] Ga-DO3A-VS-Cys40-Exendin-4 (GLP-1 receptor tracer)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Male and female patients, between 18 and 75 years of age, inclusive. Body weight between 60.0 and 120.0 kg, inclusive, body mass index between 28.0 and 38.0 kg/m2, inclusive. Diagnosis of type 2 diabetes mellitus for at least 1 year at the time of inclusion with stable metformin treatment prior to inclusion, with or without comorbidities related to type 2 diabetes mellitus. Fasting plasma glucose ≥ 90 mg/dL at screening. Glycosylated hemoglobin (HbA1c) ≥6.5% and ≤9 % at screening. Exclusion criteria: Any history or presence of clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, hematological, neurological, osteomuscular, articular, psychiatric, systemic, ocular, gynecologic (if female), urologic or infectious disease, hormonal active tumors (e.g. pheochromocytoma or insulinoma), or signs of acute illness that is not related to the metabolic status of the patient. Presence or history of drug hypersensitivity (including known allergic reactions associated with glucagon like peptide-1 (GLP-1) agonist treatment [exenatide, liraglutide, lixisenatide]), or allergic disease diagnosed and treated by a physician. Any intake of menopausal hormone replacement therapy, systemic corticosteroids, growth hormones, weight-loss drugs, antihyperlipidemic treatment, antihyperglycemic treatment [e.g., GLP-1 agonists, insulin, thiazolidinediones, dipeptidylpeptidase (DPP-IV) inhibitors, sodium/glucose cotransporter-2 (SGLT-2) inhibitors etc.]) during the treatment period and within 21 days before first dosing or within 5 times the elimination half-life or pharmacodynamic half-life of the medication (if known), with the exception of metformin, sulphonylureas (SU), standard antihypertensive treatment, statins and acetyl salicylic acid. Any condition possibly affecting gastric emptying or absorption from gastro-intestinal tract (e.g., gastric surgery, gastrectomy, bariatric surgery, malabsorption syndromes, gastroparesis, abdominal surgery other than appendectomy, hysterectomy, cholecystectomy and herniaplasty). Surgically treated obesity, bariatric surgery. Severe dyslipidemia with fasting triglycerides >450 mg/dL at screening. Severe hypoglycemia resulting in seizure/unconsciousness/coma or hospitalization for diabetic ketoacidosis in the last 3 months before screening. Persistent hyperglycemia not adequately controlled by metformin, SUs and/or diet/exercise. Diagnosed diabetic neuropathy, retinopathy, nephropathy or renal impairment (GFR <60 mL/min; estimate after Cockcroft-Gault) at screening. Unstable hypo- or hyperthyroidism (as assessed by TSH) at screening. History of pancreatitis or pancreatectomy. Amylase and/or lipase > 2 upper limit of normal (ULN) at screening. Personal history or family history of medullary thyroid cancer or a genetic condition that predisposes to medullary thyroid cancer. Elevated basal calcitonin (≥20 pg/mL / 5.9 pmol/L) at screening. Known past or present diseases or disorders of any target organ (liver, pancreas, spleen). Medical positron emitting tomography (PET), single photon emission computer tomography (SPECT), abdominal or thoracic computer tomography (CT) examination during the previous 12 months' time period. Claustrophobia. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR425899 high dose<br>Repeated once daily subcutaneous (SC) doses of SAR425899 administered over 20 days | Drug: SAR425899<br>* Pharmaceutical form: Solution for injection Route of administration: Subcutaneous<br>Drug: [68Ga] Ga-DO3A-VS-Cys40-Tuna-2 (glucagon receptor tracer)<br>* Pharmaceutical form: Solution for injection Route of administration: Subcutaneous<br>Drug: [68Ga] Ga-DO3A-VS-Cys40-Exendin-4 (GLP-1 receptor tracer)<br>* Pharmaceutical form: Solution for injection Route of administration: Subcutaneous<br>|
| Experimental: SAR425899 low dose<br>Repeated once daily SC doses of SAR425899 administered over 20 days | Drug: SAR425899<br>* Pharmaceutical form: Solution for injection Route of administration: Subcutaneous<br>Drug: [68Ga] Ga-DO3A-VS-Cys40-Tuna-2 (glucagon receptor tracer)<br>* Pharmaceutical form: Solution for injection Route of administration: Subcutaneous<br>Drug: [68Ga] Ga-DO3A-VS-Cys40-Exendin-4 (GLP-1 receptor tracer)<br>* Pharmaceutical form: Solution for injection Route of administration: Subcutaneous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucagon receptor occupancy | Change of glucagon receptor tracer binding in the liver with SAR425899 between Day 1 and Day 20 | Day 1 and Day 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GLP-1 receptor occupancy | Change of GLP-1 receptor tracer binding in the pancreas with SAR425899 between Day 1 and Day 17 | Day 1 and Day 17 | 
| Adverse events | Number of adverse events in patients under treatment with SAR425899 | Up to 27 days | 
| Pharmacokinetics | Assessment of SAR425899 maximum plasma concentration (Cmax) | Day 20 | 
| Change in fasting plasma glucose (FPG) | Absolute change in FPG from baseline to Day 20 | Day 1 to Day 20 | 
| Change in ketone bodies | Absolute change in ketone bodies from baseline to Day 20 | Day 1 to Day 20 | 
| Change lipid biomarkers | Absolute change cholesterol from baseline to Day 20 | Day 1 to Day 20 | 
| Change in volume of distribution (Vt) in the liver | Change of glucagon receptor tracer Vt in the liver with SAR425899 between Day 1 and Day 20 | Day 1 and Day 20 | 
| Change in Vt in the pancreas | Change of GLP-1 receptor tracer Vt in the pancreas with SAR425899 between Day 1 and Day 17 | Day 1 and Day 17 | 
| Average standard uptake values (SUVs) of PET tracers in the liver and pancreas | Average SUVs for glucagon and GLP-1 tracer in liver and pancreas | Day 1, Day 17 and Day 20 | 
| Pharmacokinetics | Assessment of SAR425899 time to reach Cmax ( tmax) | Day 20 | 
| Pharmacokinetics | Assessment of SAR425899 area under the concentration versus time curve (AUC) | Day 20 | 
| Pharmacokinetics | Assessment of SAR425899 terminal elimination half-life ( t1/2) | Day 20 | 
| Pharmacokinetics | Assessment of SAR425899 total body clearance from the plasma (CL) | Day 20 | 
| Change lipid biomarkers | Absolute change in free fatty acids from baseline to Day 20 | Day 1 to Day 20 | 
| Change lipid biomarkers | Absolute change in triglycerides from baseline to Day 20 | Day 1 to Day 20 |