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

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

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: 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)

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Uppsala, Sweden, 75237
    • Investigational Site Number 7520001

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Antaros Medical

Publications and helpful links

General Publications

• Eriksson O, Velikyan I, Haack T, Bossart M, Laitinen I, Larsen PJ, Berglund JE, Antoni G, Johansson L, Pierrou S, Tillner J, Wagner M. Glucagonlike Peptide-1 Receptor Imaging in Individuals with Type 2 Diabetes. J Nucl Med. 2022 May;63(5):794-800. doi: 10.2967/jnumed.121.262506. Epub 2021 Sep 9.

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2017
• Primary Completion (Actual): June 7, 2018
• Study Completion (Actual): June 7, 2018

Study Registration Dates

• First Submitted: November 16, 2017
• First Submitted That Met QC Criteria: November 20, 2017
• First Posted (Actual): November 22, 2017

Study Record Updates

• Last Update Posted (Actual): April 25, 2022
• Last Update Submitted That Met QC Criteria: April 21, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Overweight; Hypoglycemic Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Obesity Agents; Incretins; Glucagon; Exenatide
• Other Study ID Numbers: PDY15264; 2017-001789-23

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No