TYPE 2 DIABETES

Among the many classes of effective treatments for type 2 diabetes, a new class called incretin mimetics represents some very important advantages. Incretin mimetics have the effect of lowering blood glucose and decreasing weight through multiple biological activities. The development of incretin mimetics offering these beneficial effects has been an important focus of research in the fields of type 2 diabetes and obesity. The first incretin mimetic was approved by the US FDA in 2005 and others are currently in clinical and preclinical development.

ITCA 650

Intarcia's clinical stage type 2 diabetes candidate known as ITCA 650 involves the delivery of exenatide, an approved incretin mimetic, with our subcutaneous delivery device. Intarcia is developing ITCA 650 to provide type 2 diabetes patients with long-term steady state dosing of a incretin mimetic therapy. Exenatide and other incretin mimetics have demonstrated effective glycemic control and weight loss, as single agents and in combination with oral antidiabetic drugs. Like other incretin mimetics, exenatide is limited by pharmacokinetics that require twice-daily self injection and cause side effects such as nausea that often lead to poor compliance or premature discontinuation of treatment. ITCA 650 is designed to deliver a continuous and constant dose of exenatide over an extended period of time, thereby providing round-the-clock therapeutic benefits to the patient but minimizing peak drug level related side effects such as nausea. Due to the inherently short half-life of incretin mimetics, extended duration delivery options are an important consideration to facilitate patient compliance and convenience. However, some extended delivery options have compromised a healthcare provider's ability to quickly withdraw therapy should an unscheduled cessation of treatment be required. Our proprietary delivery system provides the longest duration of continuous treatment with the flexibility of near immediate reversibility.

ITCA 650 Program Status

Final 48 week results of the ITCA 650 phase 2 study were presented at the 47th Annual Meeting of the European Association for the Study of Diabetes in September 2011. The phase 2 study enrolled 155 type 2 diabetes patients (51-53 patients/arm) across 50 centers in the United States. Prior to study entry, patients were on a stable treatment regimen of metformin monotherapy that was continued throughout the study. The study compared six different regimens of ITCA 650 to optimize dose and regimen for further evaluation in phase 3 studies.

After an initial 12-week treatment period comparing ITCA 650 20 mcg/day and 40 mcg/day with twice-daily injections of exenatide, patients continued treatment with one of 4 doses of ITCA 650: 20, 40, 60 or 80 mcg/day in the following manner through the planned 24-week endpoint:

Treatment Weeks 1 – 12   Treatment Weeks 13 – 24
ITCA 650 20 mcg/day ITCA 650 20 μg/day
ITCA 650 20 mcg/day ITCA 650 60 μg/day
     
ITCA 650 40 mcg/day ITCA 650 40 μg/day
ITCA 650 40 mcg/day ITCA 650 80 μg/day
     
Exenatide BID injection ITCA 650 40 μg/day
Exenatide BID injection ITCA 650 60 μg/day

Clinical sites were authorized to offer patients an extension of up to an additional 24 weeks of ITCA 650 treatment to evaluate longer term safety and durability of response. Among the sites participating in the extension phase, a total of 86 patients (85% of patients at these sites) elected to continue ITCA 650 therapy.

Sustained reductions in HbA1c, FPG and weight were observed across all treatment arms from week 24 through week 48. Reductions in HbA1c were greatest in the 60 mcg/day and 80 mcg/day dose arms but not statistically different between these two dose arms.

ITCA 650 dose weeks 13–48 20 mcg/day 40 mcg/day 60 mcg/day 80 mcg/day
Mean baseline HbA1c (%) 7.8 7.8 8.1 7.9
Mean week 48 HbA1c (%) 6.8 6.8 6.6 6.5
Mean HbA1c change at week 48 -1.0 -1.0 -1.5 -1.4
Mean weight change at week 48 (lbs) -6 -10.8 -7.7 -7.9

Throughout the extended treatment duration of the study, there were no treatment discontinuations due to nausea. Numeric improvements were observed in measures of blood pressure and lipids at weeks 24 and 48 compared to baseline.

Patient Satisfaction with ITCA 650 Therapy

A survey utilizing the Diabetes Medication Satisfaction Tool (DM-SAT), a validated and published self-assessment tool was administered to patients in the ITCA 650 phase 2 study before treatment began, at treatment week 8 and at treatment week 20. Study results indicated that patients receiving ITCA 650 at doses of either 20 mcg/day or 40 mcg/day experienced a statistically significant improvement in their quality of life after 8 weeks of ITCA 650 therapy compared with their level of satisfaction at study entry on oral metformin therapy. Patients on either dose of ITCA 650 also experienced a greater increase in their level of satisfaction with treatment compared with patients on twice-daily self-injections of exenatide. Results of the week 20 assessment showed a statistically significant improvement in treatment satisfaction among patients switching to ITCA 650 from exenatide injection. The substantial improvement observed among patients initially randomized to ITCA 650 was maintained after transition to higher doses of ITCA 650.

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Type 2 Diabetes

Type 2 diabetes is the most common form of diabetes, accounting for more than 90% of all cases, affecting approximately 347 million adults worldwide and more than 23.6 million in the US alone. According to the American Diabetes Association, 1.6 million new cases of diabetes were diagnosed in people aged 20 years or older in the US in 2007. The treatment for type 2 diabetes can be divided into insulin and non-insulin segments. Patients can manage their type 2 diabetes for a time with careful adherence to a prescribed diet along with regular exercise. When diet and exercise alone can no longer provide adequate control of glucose levels, patients are usually treated with one or more oral antidiabetic drugs. Ultimately however, even combinations of these drugs fail to adequately control type 2 diabetes for most patients, at which point an insulin-based treatment regimen is prescribed. The Consensus Statement of the American Diabetes Association and the European Association for the Study of Diabetes recommends use of incretin mimetic therapy in combination with or to replace oral therapies in order to improve glycemic control or to avoid side effects common to other therapies.