ITCA-650 is an osmotic mini-pump that releases exenatide slowly and continuously over a 3-6 month period. It is placed under the skin in the abdomen via a 5 mm incision. This phase-3 clinical trial shows good outcomes as A1c and body weight were reduced significantly by 1.2% and 6.6 pounds.
Improved medication adherence is a critical aspect of diabetes management. Same principle could be used for insulin delivery in the future.
FREEDOM-1, Phase 3
ITCA-650 (exenatide in osmotic mini-pump) continuously delivers exenatide subcutaneously for 3–6 months. Two doses of ITCA 650 were compared with placebo in patients with uncontrolled type 2 diabetes.
Research Design and Methods
This 39-week, phase 3, double-blind, placebo-controlled trial randomized 460 patients aged 18–80 years with glycated hemoglobin 7.5–10% 1:1:1 to placebo, ITCA-650 40 μg/day, or ITCA-650 60 μg/day. Primary end point was change in HbA1c at 39 weeks.
Least squares (LS) mean change from baseline HbA1c was −1.1% and −1.2% for ITCA 650 40 and 60 μg/day, respectively (P < 0.001 vs. placebo −0.1%). In a prespecified analysis, greater HbA1c reductions occurred in patients NOT receiving sulfonylureas (SUs) versus those receiving SUs (−1.7% vs. −1.2%).
At week 39, HbA1c <7% was attained in 37%, 44%, and 9% of ITCA 650 40 μg/day, ITCA 650 60 μg/day, and placebo groups, respectively (P < 0.001 each dose vs. placebo). LS mean change from baseline body weight was −2.3 kg and −3.0 kg for ITCA 650 40 and 60 μg/day, respectively (P ≤ 0.015 vs. placebo −1.0 kg).
Nausea was the most common adverse event (AE) and subsided over time. Discontinuation for gastrointestinal AEs occurred in 7.2% with ITCA and 1.3% with placebo. Most AEs associated with procedures to place and remove ITCA 650 were mild and transient.
ITCA-650 significantly reduced HbA1c and weight compared with placebo and was well tolerated in patients with uncontrolled type 2 diabetes on oral antidiabetes medications.
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Although numerous drugs are available for individualized management of type 2 diabetes, poor treatment adherence, suboptimal efficacy, inadequate weight control, and unacceptable tolerability remain barriers to glycemic control. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are considered effective therapeutic agents for the treatment of type 2 diabetes that lower glucose, promote weight loss, and have a low risk of hypoglycemia due to their glucose-dependent effect on insulin secretion. However, the need to administer these drugs by injection and low adherence and/or persistence to treatment are major barriers that have impeded the widespread use of the GLP-1 RA class.
Adherence to treatment with antidiabetes drugs is generally low and is reported to range from 38-54% with GLP-1 agonists in the U.S. Qualitatively similar results have been shown in Europe. In addition to the negative impact on achieving effective glycemic control, poor medication adherence results in increased health care costs. Therefore, it stands to reason that in order to reduce the overall burden of diabetes, it is critical to address the issues of poor medication adherence.
ITCA-650 is an investigational combination drug-device product being developed for the treatment of type 2 diabetes. It consists of a small titanium matchstick-sized osmotic mini-pump that delivers a continuous subcutaneous infusion of exenatide for extended periods. Drug administration can be rapidly terminated if necessary by removing the ITCA 650 as exenatide levels fall rapidly within 24 h after removal. Placement and removal of ITCA 650 are performed by trained health care professionals in a brief office procedure. The sterile mini-pump is placed in the subdermis of the abdominal wall using a placement tool and is removed or replaced through a small ∼5 mm incision and closed with Steri-Strips.
In a phase 2, randomized, 24-week, open-label, dose-ranging study, patients with type 2 diabetes inadequately controlled with metformin had significant reductions in HbA1c and body weight at 24 weeks with ITCA 650 that were maintained over 48 weeks of therapy. We report the FREEDOM-1 trial undertaken to investigate the efficacy and tolerability of two doses of ITCA 650 compared with placebo (osmotic mini-pump) over 39 weeks in patients with type 2 diabetes inadequately controlled on oral antidiabetes drugs.
In this 39-week, phase 3 study, statistically and clinically meaningful improvements in HbA1c, body weight, and the proportion of patients achieving goal HbA1c <7% were demonstrated with two doses of ITCA 650 versus placebo. These results are consistent with an open-label phase 2 study of ITCA 650 that demonstrated significant efficacy of these two doses over 24 weeks and are comparable to those reported with exenatide and other GLP-1 agonists. Significantly fewer patients in the ITCA 650 groups (11–16%) required rescue therapy for hyperglycemia compared with patients in the placebo group (∼40%). Rescue in the ITCA 650 groups occurred later (primarily at weeks 27–33) compared with placebo (at weeks 18–22 for majority of patients), driven largely by the rescue requirement for HbA1c to be ≤8% by week 26.
While the reduction in HbA1c was similar between the two doses of ITCA 650, the 60 μg/day dose demonstrated greater overall efficacy (aggregate of HbA1c reduction, weight loss, goal attainment of HbA1c <7% and ≤6.5%, need for rescue) without a dose-dependent increase in AEs compared with the 40 μg/day dose. These results are consistent with the findings of a previous study comparing exenatide 0.8 and 2 mg once weekly and support the observation that HbA1c and weight reductions may be optimized at different doses with GLP-1 agonists.
Treatment with ITCA 650 was generally well tolerated. Nausea was the most common AE, usually occurring at the time of treatment initiation and dose escalation and returning to baseline in subsequent weeks. Discontinuation due to nausea was low and not dose dependent. The incidence reported in this study was comparable to the incidence reported with other GLP-1 RAs.
The procedures to administer ITCA 650 are simple and performed during an outpatient office visit by trained medical personnel that include physician assistants and nurse practitioners. Procedures were well tolerated by patients. AEs reported at the site of administration were generally mild in severity and self-limited. A small number of removal procedures required referral to specialty health care providers and resulted in successful removals. Enhanced training and the introduction in latter ITCA 650 studies of a depth guide that limits the depth of placement to the subdermis has significantly reduced the likelihood of placement in the subcutaneous fat.
The study population had long-standing poorly controlled diabetes despite a majority (∼90%) being on stable treatment with oral antidiabetes medications. Intensification of treatment for patients with type 2 diabetes is often delayed for years despite poor glycemic control on one or more oral antidiabetes drugs. Clinical inertia and/or poor treatment adherence delay the appropriate advancement of effective therapy and result in frequent treatment discontinuations or nonpersistence. Evidence from controlled trials demonstrates that earlier intensification is superior to sequential add-on therapy for achieving glycemic control.
GLP-1 RAs are broadly recommended as add-on to monotherapy with metformin or in combination with multiple oral agents and insulin for patients with poorly controlled diabetes. In this study, greater efficacy was observed in the subgroup of patients who were not receiving an SU. These patients were predominantly receiving drug treatment with metformin. Since effectiveness with exenatide is not expected to wane over time and adherence to treatment is expected while ITCA 650 is in situ, early addition to metformin monotherapy is considered the optimal treatment scenario with ITCA 650.
The strengths of this study include the use of a double-blind, randomized, placebo-controlled design with all patients undergoing the procedures to place and remove the mini-pump and the comprehensive analysis of safety and tolerability. Once ITCA 650 is placed, no action is required on the part of the patient beyond standard attention to lifestyle management in order to ensure therapeutic adherence for the 3- or 6-month dosing period. The 39-week duration is longer than many studies in a type 2 diabetes population, but owing to the chronic nature of the disease, longer duration studies will address the durability of effect with ITCA 650.
ITCA 650 is the first injection-free GLP-1 RA. This integrated drug-device combination maintains long-term effective blood concentrations of exenatide and has the ability to ensure medication adherence and lead to sustained glycemic control and weight loss. This report provides the first results from a large controlled study that demonstrates the efficacy and tolerability of ITCA 650 in patients with long-standing type 2 diabetes on a variety of background antidiabetes medications.