A Model-Informed Drug Development (MIDD) Approach for a Low Dose of Empagliflozin in Patients with Type 1 Diabetes

In clinical trials, sodium-glucose co-transporter (SGLT) inhibitor use as adjunct to insulin therapy in type 1 diabetes (T1D) provides glucometabolic benefits while diabetic ketoacidosis risk is increased. The SGLT2 inhibitor empagliflozin was evaluated in two phase III trials: EASE-2 and EASE-3. A low, 2.5-mg dose was included in EASE-3 only. As the efficacy of higher empagliflozin doses (i.e., 10 and 25 mg) in T1D has been established in EASE-2 and EASE-3, a modeling and simulation approach was used to generate additional supportive evidence on efficacy for the 2.5-mg dose. We present the methodology behind the development and validation of two modeling and simulation frameworks: M-EASE-1, a semi-mechanistic model integrating information on insulin, glucose, and glycated hemoglobin; and M-EASE-2, a descriptive model informed by prior information. Both models were developed independently of data from EASE-3. Simulations based on these models assessed efficacy in untested clinical trial scenarios. In this manner, the models provide supportive evidence for efficacy of low-dose empagliflozin 2.5 mg in patients with T1D, illustrating how pharmacometric analyses can support efficacy assessments in the context of limited data.

Download Full-text

Low-Dose Otelixizumab Anti-CD3 Monoclonal Antibody DEFEND-1 Study: Results of the Randomized Phase III Study in Recent-Onset Human Type 1 Diabetes

Diabetes Care ◽

10.2337/dc13-0327 ◽

2014 ◽

Vol 37 (10) ◽

pp. 2746-2754 ◽

Cited By ~ 68

Author(s):

Ronnie Aronson ◽

Peter A. Gottlieb ◽

Jens S. Christiansen ◽

Thomas W. Donner ◽

Emanuele Bosi ◽

...

Keyword(s):

Monoclonal Antibody ◽

Type 1 Diabetes ◽

Low Dose ◽

Phase Iii ◽

Recent Onset ◽

Human Type ◽

Study Results ◽

Phase Iii Study ◽

Human Type 1 Diabetes

Download Full-text

A review of sotagliflozin for use in type 1 diabetes

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/2042018819890527 ◽

2019 ◽

Vol 10 ◽

pp. 204201881989052 ◽

Cited By ~ 2

Author(s):

Wesley Nuffer ◽

Briana Williams ◽

Jennifer M. Trujillo

Keyword(s):

Type 1 Diabetes ◽

Sglt2 Inhibitor ◽

Severe Hypoglycemia ◽

Glucose Variability ◽

Phase Iii ◽

Insulin Dosage ◽

Volume Depletion ◽

Phase Iii Clinical Trials ◽

Lower Glucose

Type 1 diabetes is a challenging disease that is largely managed with the use of insulin. The risk of hypoglycemia, side effects of weight gain, and high glucose variability associated with insulin use have prompted researchers to explore additional therapies to treat this condition. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of medications that lower glucose in type 2 diabetes patients independent of insulin action, and have been studied for use in the type 1 diabetes population. Sotagliflozin is an SGLT2 inhibitor that demonstrates a unique binding affinity for the SGLT1 receptor. A total of three phase III clinical trials (inTandem1, inTandem2, and inTandem3) were conducted to evaluate the safety and efficacy of sotagliflozin in type 1 diabetes. A modest hemoglobin A1C reduction of 0.3–0.4% was observed, with secondary benefits of reduced glucose variability, reduced insulin dosage, and positive weight loss effects. Overall there was a reduction in the risk of severe hypoglycemia with sotagliflozin, but a higher rate of ketone formation and risk of diabetic ketoacidosis was observed, along with increased mycotic infections and volume depletion effects.

Download Full-text

Current State of Type 1 Diabetes Immunotherapy: Incremental Advances, Huge Leaps, or More of the Same?

Clinical and Developmental Immunology ◽

10.1155/2011/432016 ◽

2011 ◽

Vol 2011 ◽

pp. 1-18 ◽

Cited By ~ 16

Author(s):

Brett Phillips ◽

Massimo Trucco ◽

Nick Giannoukakis

Keyword(s):

Type 1 Diabetes ◽

Immune Cells ◽

Phase Iii ◽

Alternative Possibilities ◽

Diabetic Patients ◽

Phase Ii Trials ◽

Safety Issues ◽

Phase Iii Trials ◽

Recent Phase

Thus far, none of the preclinically successful and promising immunomodulatory agents for type 1 diabetes mellitus (T1DM) has conferred stable, long-term insulin independence to diabetic patients. The majority of these immunomodulators are humanised antibodies that target immune cells or cytokines. These as well as fusion proteins and inhibitor proteins all share varying adverse event occurrence and severity. Other approaches have included intact putative autoantigens or autoantigen peptides. Considerable logistical outlays have been deployed to develop and to translate humanised antibodies targeting immune cells, cytokines, and cytokine receptors to the clinic. Very recent phase III trials with the leading agent, a humanised anti-CD3 antibody, call into question whether further development of these biologics represents a step forward or more of the same. Combination therapies of one or more of these humanised antibodies are also being considered, and they face identical, if not more serious, impediments and safety issues. This paper will highlight the preclinical successes and the excitement generated by phase II trials while offering alternative possibilities and new translational avenues that can be explored given the very recent disappointment in leading agents in more advanced clinical trials.

Download Full-text