New technology allows freedom from daily manual injections and oral antidiabetics.
Management of type 2 diabetes (T2D) can be complex and pose many barriers. These barriers include poor adherence, efficacy, and weight control. To overcome these barriers, glucagon-like peptide 1 (GLP-1) receptor agonist have been prescribed. The profile of this drug class displays lower glucose levels, promotes weight loss, and has a lower risk of causing hypoglycemia due to glucose-dependency. Although this class overcomes certain barriers, they still have low adherence rates due to the requirement of subcutaneous injections. It has been studied that poor adherence and inadequate glycemic control, leads to increased healthcare-costs. To reduce the burden placed on patients who have diabetes and the healthcare industry, the issue of medication adherence must be addressed and improved. New devices and medications have been developed to do just that. ITCA 650 is the first investigational osmotic mini-pump designed for the treatment of T2D. It provides a continuous subcutaneous infusion of the GLP-1 agonist, exenatide. Healthcare providers can easily install this device into the subdermis of the abdominal wall. It can also be easily removed with drug levels rapidly depleted in 24hrs post-removal. A previous phase-2, open-label, randomized trial compared metformin to ITCA 650. This study showed significant reductions in HbA1c and weight loss over 48 weeks of treatment. The FREEDOM-1 Trial was then designed to test the safety and efficacy of this new device.
The FREEDOM-1 Trial was a phase-3, randomized, double-blind, placebo-controlled study. It was conducted to compare two doses of ITCA 650 to a placebo over 39 weeks in T2D patients whose blood glucose was not properly controlled on oral antidiabetic drugs. The study design consisted of a 4-week screening, a 39-week treatment window, and a 4-week posttreatment follow-up. 460 patients were randomized into one of three groups. 441 out of the 460 were considered the modified intent-to-treat population (mITT). Randomization was done in a 1:1:1 fashion stratified to 40 micrograms/day(mcg/day) for ITCA 650, 60 mcg/day for ITCA 650, or the placebo mini-pump group. Patients in the ITCA 650 groups were initiated on 20 mcg/day. At week 13 of the treatment window, the 20mcg ITCA 650 doses were replaced with either 40mcg or 60mcg.
Patient inclusion criteria were: T2D diagnosis with stable therapy (metformin, sulfonylureas, or pioglitazone) for at least 3 months, 18-80 years of age, HbA1c of 7.5%-10%, fasting plasma glucose of £270 mg/dL, BMI of 25-45 kg/m2, and a serum calcitonin level of <50 mg/L at screening. These patients were required to continue their previous medications throughout the trial. Patient exclusion criteria were: previous therapy with (GLP-1 receptor agonist, DPP-IV inhibitors, alpha-glucosidase inhibitors, meglitinides, SGLT-2 inhibitors or insulin) within 3 months of screening, or an eGFR <60mL/min per 1.72m2. Hypoglycemia and hyperglycemia were monitored throughout the treatment timeline, with rescue therapy available.The primary efficacy endpoint was assessed through a collection of blood samples to determine the change in HbA1c from baseline. Secondary efficacy endpoints were changed in body weight and the percentage of patients who reached a HbA1c <7%. Safety endpoints included adverse events (AE), vital signs, cardiac changes, and clinical labs. The presence of anti-exenatide antibodies and neutralizing antibodies (eurofins) were also examined. A sensitivity analysis was conducted on the population who did not require rescue therapy, also known as the efficacy-evaluable (EE) population. ANCOVA analysis was used to assess all endpoints.
Results showed a significant reduction in HbA1c from baseline to week 39 for each dose of ITCA 650 (P<0.001), with 60mcg showing a 1.2% reduction, 1.1% reduction with 40 mcg and 0.1% reduction with the placebo group. The mean standard deviation was 7.4(1.1), 7.3(1.1), and 8.4(1.3) for 40mcg ITCA 650, 60mcg ITCA 650 and placebo, respectively. The EE population showed a 1.4% reduction of HbA1c in comparison to the placebo group with a 0.4% reduction.
The ITCA 650 groups also had a greater reduction in body weight than the placebo group (60mcg= 3kg average weight loss (P<0.001), 40mcg= 2.3kg average weight loss (P=0.015), placebo= 1kg average weight loss); showing a dose-dependent relationship. Also, a greater proportion of patients in the ITCA groups reached HbA1c levels <7% (44% for the 60 mcg group, 37% for 40mcg and 9% for placebo) (P<0.001). The ITCA 650 device also provided significant reductions in FPG and triglycerides. Due to adverse events, 11.8% of patients in the 40 mcg ITCA 650 group dropped out, as well as 7.8% of the 60 mcg ITCA 650 group and 3.2% of the placebo group. GI disturbances (nausea, vomiting, and diarrhea) were the most common AEs. 24.5% of the patients in the ITCA 650 groups showed positive A1c levels, but this did not affect the primary endpoint.
In conclusion, ITCA 650 is the first injection-free GLP-1 agonist. It showed an overall significant reduction in HbA1c levels and weight in comparison to the placebo. A greater proportion of ITCA 650 patients achieved HbA1c levels <7%. The results were consistent with the previous study on ITCA 650. ITCA 650 continuous infusion was generally well-tolerated with a low rate of discontinuation and non-adherence. Some strengths of this study are the study design, study duration, safety and tolerability. Safety and efficacy can be further studied in future trials.
- HbA1c reduction and weight loss with ITCA 650 is dose related.
- Adherence and glycemic controlled can be improved with this new technology in people who have type 2 diabetes.
- Early addition of ITCA 650 to metformin therapy shows the most optimal therapeutic success.
Rosenstock, Julio, et al. “Efficacy and Safety of ITCA 650, a Novel Drug-Device GLP-1 Receptor Agonist, in Type 2 Diabetes Uncontrolled With Oral Antidiabetes Drugs: The FREEDOM-1 Trial.” Diabetes Care, vol. 41, no. 2, 14 Jan. 2018, pp. 333–340., doi:10.2337/dc17-1306.
Adrianna Jackson, Doctor of Pharmacy Candidate: Class of 2018; LECOM College of Pharmacy