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A Once-A-Year Continuous Exenatide Therapy Shows 100% Compliance

Posted: Sunday, October 10, 2010

Implantable device promises diabetes patients continuous exenatide therapy with 100% compliance. Tolerability and weight loss was better with ITCA 650 20 μg/day than with exenatide injections.

The results of a 24-week phase 2 clinical trial presented at the European Association for the Study of Diabetes 46th Annual Meeting show that continuous subcutaneous delivery of exenatide resulted in a reduction in HbA1clevels and body weight with 100% compliance.

Exenatide, a glucagon-like peptide-1 (GLP-1) mimetic, was delivered with an implantable drug-dispensing 4 × 45 mm cylindrical osmotic pump, using DUROS (DURECT Corp, Cupertino, California) technology. As subcutaneous tissue fluid flows into the device through a semipermeable membrane, it expands an osmotic "engine," pumping the drug out at a constant rate. The device can be inserted into the skin in just a few minutes.

According to lead investigator Robert Henry, MD, chief of the section of diabetes, endocrinology, and metabolism at the University of California, San Diego, a key aspect of the technology is a formulation that maintains the stability of proteins and peptides at body temperature for an extended period of time. The complete drug-delivery system, now in clinical development, is called ITCA 650.

The multicenter clinical trial randomized 155 Type 2 diabetic patients who were inadequately controlled on metformin therapy to 3 initial treatment groups (51 to 53 patients per group) for 12 weeks, and then re-randomized each group in a 1:1 manner for another 12 weeks. ITCA 650 dose increases were achieved by removing the delivery device and replacing it with one providing a higher dose. Patients were on a background of metformin monotherapy.

Baseline HbA1c levels were 7% to 10%. The 3 groups were well matched for age (53 to 54 years), HbA1c levels (7.9% to 8%), weight (91.5 to 93.5 kg), body mass index (31.8 to 33.5 kg/m2), and sex (approximately half male). However, for the 3 initial groups -- exenatide injections, ITCA 650 20 μg/day, and ITCA 650 40 μg/day groups -- the duration of diabetes was 5.2, 6.2, and 8.4 years, respectively.

The aims of the trial were to investigate the effectiveness, safety, and tolerability of ITCA 650, and the feasibility of switching patients from injected exenatide to ITCA 650.

Overall, 93% of the patients started on ITCA 650 completed the first 12-week period, as did 89% of the group started on exenatide injections.

Exenatide use has been associated with nausea, and 3.9% of patients started on ITCA 650 and 5.7% of patients started on exenatide injections dropped out because of this adverse effect.

All patients were re-randomized to ITCA 650 at 12 weeks, and 95% completed the second 12-week phase; less than 1% dropped out because of nausea.

Dr. Henry reported that all doses of ITCA 650 resulted in substantial reductions in HbA1c and body weight. A starting dose of 20 μg/day showed the best tolerability, and switching to 60 μg/day for weeks 13 to 24 provided further reductions in HbA1c and weight at week 24. He stated that a phase 3 trial of ITCA 650 will use this dosing regimen.

Summary of Week 24 Results

Results	20 μg/day (n = 20)	40 μg/day (n = 42)	60 μg/day (n = 41)	80 μg/day (n = 19)
Mean baselineHbA_1c (%)	7.96	7.79	8.05	8.03
Week 24
- Mean HbA_1c (%)	7.07	6.93	6.67	6.67
- Mean HbA_1c change from baseline (%)	–0.89*	–0.86*	–1.38*	–1.36*
- % of subjects with HbA_1c ≤7%	60	71	73	79
- Mean weight change from baseline (kg)	–0.8	–3.6*	–3.1*	–3.5†

*P < .0001 vs baseline †P < .01 vs baseline

Tolerability was better with ITCA 650 20 μg/day than with exenatide injections during weeks 1 to 12, and the mean duration of nausea was shorter (17 vs. 47.7 days). Dose escalation to ITCA 650 60 μg/day was well tolerated. Interestingly, exenatide injections at weeks 1 to 12 did not protect against nausea when patients were switched to ITCA 650 60 μg/day at 12 weeks.

In summary, Dr. Henry said an initial dosing of ITCA 650 at 20 μg/day escalating to 60 μg/day resulted in the best tolerability and activity profile and provided significant reductions in HbA1c and weight at 24 weeks.

He noted that this drug-delivery method has a "unique potential for long-term optimal treatment of Type 2 diabetes," adding that this is the first GLP-1 therapy that does not require injections and ensures compliance. He speculated that the method might allow exenatide to be moved up from third-line to second- or even first-line use.

He noted that insertion of the device is a reimbursed 10-minute office procedure that can be performed by a physician, physician's assistant, or nurse practitioner. Removal requires only skin preparation and a small nick with a scalpel. Once removed, the drug effect is gone within 24 hours, he said.

"The significance of the study is that, this novel therapy allows for 100% compliance. So this device, although it wasn't used this way in the trial, could potentially deliver exenatide for a year, and the benefit of that is that we don't have to rely on the patients to do the injections on a regular basis," Dr. Henry concluded. However, he also noted that a potential risk is that the physician might not see and monitor a patient as frequently.

Source: http://www.diabetesincontrol.com/index.php?option=com_content&view=article&id=9908&catid=53&Itemid=8, European Association for the Study of Diabetes (EASD) 46th Annual Meeting: Abstract 78. Presented September 22, 2010