Becky McCall

September 28, 2015

STOCKHOLM — Type 2 diabetes patients using a subdermally implanted minipump, ITCA 650 (Intarcia Therapeutics), which delivers exenatide for 6 months, achieved encouraging results in two phase 3 trials, and the company developing the device said it expects to file for US approval next year.

Results of the FREEDOM-1 and FREEDOM-1 HBL (higher baseline) studies were presented by Michelle Baron, MD, chief medical officer, Intarcia Therapeutics, Boston, Massachusetts, and Robert Henry, MD, University of California, San Diego, respectively, at the recent European Association for the Study of Diabetes (EASD) 2015 Meeting.

Dr Baron said that the company now plans to further study ITCA 20 µg/day followed by ITCA 60 µg/day, and this is the dose it will seek approval for. "We now have experience with almost 80,000 procedures and hope to file this [new drug application] with the [Food and Drug Administration] FDA around the middle of 2016," she noted.

Session moderator Yutaka Seino, MD, director general, Kansai Electric Power Medical Research Institute, Osaka, Japan, noted that ITCA 650 has the potential to become one of the preferred therapies to treat type 2 diabetes.

"It appears to relieve patients from daily or weekly drug injections of this [drug] class for up to 6 months or even 12 months and might improve healthcare-related quality of life, leading to medical cost reductions."

He added that particular patient groups might benefit from this device, such as "young patients in the prime of life, who are too busy for daily injections, and also in aged patients with cognitive decline who have problems taking regular daily medications."

Potential for Improved Adherence: 6- or 12-Month Duration

The FREEDOM program explores what is potentially the first once- or twice-yearly injection-free delivery of the glucagonlike peptide receptor-1 (GLP-1) agonist exenatide.

Exenatide (Bydureon, Lilly/Amylin Pharmaceuticals) is already available as a weekly or twice-daily injection.

"Patients are getting 100% adherence for as long as it is in place," said Dr Baron, referring to the matchstick-sized device that is placed subdermally in the abdomen and remains there for either 6 or 12 months delivering a continuous supply of exenatide.

She explained that by using a device inserted only once or twice a year, ITCA 650 aims to overcome some of the adherence problems associated with type 2 diabetes.

For example, only two-thirds of patients in the European Union are adherent to medication. "This results in poor glycemic control, increased morbidity and mortality, and greater costs. If ITCA 650 reaches the market, the device may help overcome at least some of these adherence issues.

"FREEDOM-1 and our current program include only the 3- and 6-month pumps, but we expect that our 12-month pumps will be in the clinic next year," she noted.

FREEDOM-1

FREEDOM-1 was a placebo-controlled, double-blind trial where patients were treated for 39 weeks with ITCA 650 examining two eventual doses of exenatide — 40 µg/day and 60 µg/day — against placebo delivered using pumps of 6 months' duration.

Baseline characteristics were similar in the three groups of patients: mean HbA1c level of 8.5%, mean body mass index (BMI) measurement of 33.5 kg/m2, and mean duration of diabetes of 9 years. Patients in the study were uncontrolled despite almost 90% being treated with up to three oral antidiabetic drugs.

After screening, patients were randomized to ITCA 650 at a dose of 20 µg/day for 13 weeks followed by 60 µg/day for 26 weeks (n=153); 20 µg/day for 13 weeks followed 40 µg/day for 26 weeks (n=153); or ITCA 650 placebo (device with placebo inside) for both the 13-week and the 26-week periods (n=154).

The pump was changed from a 3-month to a 6-month pump at the 13-week switchover point. All patients were followed up for a further 4 weeks.

The primary efficacy end point was change in HbA1c for each dose compared with placebo; secondary outcomes included body weight changes with the two doses compared with placebo, and attainment of target HbA1c below 7%. Around 80% of patients in each group completed treatment.

"Innovative Method…With Interesting Clinical Results"

After 39 weeks, on an intention-to-treat basis, HbA1c levels dropped by 1.4% overall. Patients in the ITCA 650 40-µg/day group showed a change of -1.1% (8.4% to 7.4%; P < .001 vs placebo), and patients in the 60-µg/day group showed a change of -1.2% (8.5% to 7.2%; P < .001 vs placebo). In patients on placebo, HbA1c dropped by only about 0.1%.

Of patients on ITCA 60 µg/day, 44% obtained an HbA1c of less than 7%, compared with 37% on ITCA 40 µg/day and 9% on placebo (both ITCA doses P < .001 vs placebo).

An HbA1c of less than 6.5% was reached by 33% of those on ITCA 60 µg/day (p<0.001 vs placebo), 22% for those on ITCA 40 µg/day (p=0.062), and 6% on placebo.

Greater reductions in HbA1c occurred in subjects not taking sulfonylureas (-1.7% for patients on ITCA 60 µg/day vs -1.2% in those on sulfonylureas).

"Clearly the drug worked in both populations — with and without sulfonylureas — but if you want to get the most out of the drug then you need to use it at the right time in the patient's course of treatment. Early is probably better," Dr Baron noted.

There was a significant, dose-dependent weight loss over the 39 weeks. Patients lost a mean of 3 kg in the ITCA 650 60-µg/day group (P < .001 vs placebo) vs 2.3 kg in the ITCA 40-µg/day group (P < 0.015 vs placebo), and 1 kg in the placebo group.

With regard to adverse events, the safety was consistent with reported data for exenatide and the GLP-1 receptor agonist class as a whole, with a low rate of discontinuation for nausea and vomiting (2%–3.3%), which was similar between ITCA 650 groups.

Comoderator of the session, Tina Vilsbøll, MD,director of the Center for Diabetes Research at the University of Copenhagen, Denmark, said that she considered the device to be an innovative method of administration with interesting clinical results.

"Potentially it could be of significant advantage for patients with type 2 diabetes. The ITCA 650 would be the first GLP-1 receptor agonist to offer an interesting alternative to regular subcutaneous injections," she commented.

FREEDOM-1 HBL in Patients with HbA1c >10%

The second study presented at the meeting, FREEDOM-1 HBL, included patients who had had a diagnosis of type 2 diabetes for at least 3 months and an HbA1c between 10% and 12%. They were stable on a treatment regimen of diet and exercise alone or in combination with metformin, sulfonylurea, or thiazolidinedione monotherapy, or any combination of the three.

Treatment with ITCA 650 20/60 µg/day for 39 weeks resulted in clinically and statistically significant reductions in HbA1c from baseline and a mean weight loss of 1.23 kg, likely attenuated due to the correction of glycosuria with improved glucose control.

A total of 25% of these poorly controlled patients reached an HbA1c goal of less than 7%.

FREEDOM-2: Comparison to Sitagliptin

Intarcia Therapeutics has also recently reported top-line results from FREEDOM-2, a head-to-head study comparing ITCA 650 with the oral dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin (Januvia, Merck) for 1 year.

ITCA 650 met all primary and secondary end points, demonstrating superiority over sitagliptin at every measured time point through and including week 52 end points for reduction in HbA1c and reduction in body weight, the company reported last month. Full results will be presented at an upcoming conference.

Dr Baron works for Intarcia Therapeutics. Dr Seino declares the following disclosures: consulting and/or speaker fees from Eli Lilly, Sanofi, Novo Nordisk, Intarcia Therapeutics, Taisho Pharmaceutical, Astellas Pharma, Boehringer Ingelheim, Arkray, and Takeda and clinical commissioned/joint research grants from MSD, Nippon Boehringer Ingelheim, and Eli Lilly. Dr Vilsbøll reports being an advisory board member for Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, MSD, Novo Nordisk, and Sanofi and consulting or being a speaker for or receiving research support from AstraZeneca/Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Janssen Cilag, MSD, Novo Nordisk, Sanofi, and Zealand Pharma.

European Association for the Study of Diabetes 2015 Meeting; Stockholm, Sweden. Abstract 112, Abstract 786, presented September 16, 2015.

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