Intarcia releases positive topline results from first two phase 3 trials for ITCA 650 exenatide mini-pump – October 3, 2014

Intarcia released topline results on Wednesday from two phase 3 trials of ITCA 650, its subcutaneously placed osmotic mini-pump for long-term (up to one year) delivery of exenatide. Results from the FREEDOM-1 study demonstrated significantly greater A1c reductions with two doses (40 mcg/day and 60 mcg/day) of ITCA 650 compared to placebo in 460 patients with type 2 diabetes on up to three oral medications. Mean A1c reductions with ITCA 650 after 39 weeks ranged from 1.4% to 1.7% from a mean baseline of 8.4%, with the largest reductions seen in patients on background metformin; patients with a higher baseline A1c (>8.5%) also experienced greater mean reductions (up to 2.1%). Continuing the theme of greater efficacy from a higher baseline, Intarcia also reported topline results from the full 39-week FREEDOM-1 High Baseline (HBL) study, which investigated the higher (60 mcg/day) dose of ITCA 650 in 60 type 2 diabetes patients with a baseline A1c of 10%-12%. Results showed sustained mean A1c reductions of 3.4% (mean baseline = 10.8%) after 39 weeks; strikingly, 25% of patients achieved a target A1c <7%. The drug was well tolerated in both trials, with overall nausea rates in the low single digits over time and only a 2-3% discontinuation rate due to nausea. Patients in FREEDOM 1 also experienced weight loss on the order of three to four kilograms with ITCA 650. Full results from both trials are expected at ADA in June 2015.

We are very optimistic about the potential for ITCA 650 to be a real game-changer in type 2 diabetes pharmacotherapy thanks to its ability to bring patients from a wide range of baseline A1cs to goal, ensure adherence, and do away with regular injections. A key company goal during the past year two years has been refining the engineering aspects of placing and removing the matchstick sized osmotic mini-pump so that any provider (endocrinologists, primary care physicians, or qualified non-physician HCPs) can either place or remove the mini pumps in less than two minutes. Intarcia created a senior management position titled Head of Customer Experience and Outcomes to further this goal. The company has previously indicated that it plans to pursue a partnership for ex-US development and commercialization of ITCA 650; in our conversation, management indicated that the key selection criteria include shared commitment to Intarcia’s vision, a well-established presence in diabetes, an absence of conflicts of interest, in addition to financial considerations.

Looking to the future, Intarcia is interested in the up-and-coming SGLT-2 inhibitor class as both a competing alternative and a potential partner to ITCA 650. Initiating a head-to-head trial against an SGLT-2 inhibitor is high on the company’s priority list for the coming year, and management has indicated that Intarcia sees the combination of ITCA 650 and an SGLT-2 inhibitor (first as an oral regimen alongside the mini-pump, and later a co-formulated combo within the 12 month mini-pumps) as an area of great potential. Excitingly, given the enthusiasm we have heard about “twincretins” and other approaches involving synergistic combinations of hormones, Intarcia is looking to begin a handful of proof-of-concept studies sometime next year in diabetes and obesity with co-formulations of peptides and potentially even peptides (including exenatide) combined with novel antibody fragments it has found.

• Two additional phase 3 trials for ITCA 650 are ongoing: FREEDOM-2, which will compare ITCA 650 60 mcg/day (after a 13-week titration period with a 20-mcg dose) to sitagliptin (Merck’s Januvia) over 12 months in 500 type 2 patients on background metformin (baseline A1c: 7.5%-10%), and FREEDOM-CVO, a cardiovascular outcomes trial primarily designed to assess safety in 2,000 patients with type 2 diabetes and a history of cardiovascular disease. Primary completion is expected in June 2015 for FREEDOM-2 and in July 2018 for the CVOT. 
• ITCA 650 is a small (matchstick-size) osmotic mini-pump that is placed under the skin and releases a steady stream of exenatide for up to one year. Once the mini-pump is implanted, a small stream of body fluid diffuses into the device, pushing the exenatide suspension out in a controlled fashion, leading to continuous delivery without the peaks commonly seen with injectable drugs. Intarcia’s formulation of exenatide is also notable, enabling stability at human body temperature for up to three years. Intarcia plans to market both 40 mcg/day and 60 mcg/day doses of ITCA 650, and both six-month and one-year mini-pumps (in addition to a three-month mini-pump with a 20 mcg/day “starter” dose that will be used to begin treatment regardless of the final dose).
• The FREEDOM-1 trial (ClinicalTrials.gov Identifier: NCT01455857) was a US-only, double-blind study that evaluated both the 40 mcg/day and 60 mcg/day doses of ITCA 650 compared to placebo in 460 type 2 patients over 39 weeks. Participants had a baseline A1c between 7.5% and 10% and were previously treated with lifestyle or various combinations of metformin, sulfonylureas, and/or TZDs. Patients were randomized 1:1:1 to placebo or ITCA 650 40 or 60 mcg per day for 26 weeks (following a 13-week period with the 20 mcg/day starter mini-pump). The primary endpoint was change in A1c after 39 weeks; secondary endpoints included change in body weight and percent of patients reaching an A1c goal of <7%.
• The FREEDOM-HBL trial (ClinicalTrials.gov Identifier: NCT01785771) was an open-label study evaluating the higher (60 mcg/day) dose of ITCA 650 in 100 patients excluded from the FREEDOM-1 trial on the basis of high baseline A1c (10%-12%). Patients received a 20 mcg/day dose of ITCA 650 for 13 weeks, followed by the full 60 mcg/day dose for the remaining 26 weeks. There was no control group in this trial. The primary endpoint was change in A1c at 39 weeks.
• The ongoing FREEDOM-2 study (ClinicalTrials.gov Identifier: NCT01455870) is a global, double-blind 52-week trial comparing ITCA 650 60 mcg/day to sitagliptin in 500 patients with type 2 diabetes. All patients in this trial were previously treated with metformin alone, and baseline A1c ranged from 7.5%-10%. Intarcia management has previously indicated that this trial is important for the company’s strategy to position ITCA 650 as the optimal second-line therapy after metformin. The study has a primary endpoint of change in A1c at 52 weeks, and an estimated primary completion date of June 2015.
• The FREEDOM-CVO cardiovascular outcomes trial for ITCA 650 (ClinicalTrials.gov Identifier: NCT01455896) is currently recruiting participants and has an estimated primary completion date of July 2018. Notably, FREEDOM-CVO is designed primarily as a safety study, and the company has not ruled out the possibility of a longer-term study powered to investigate superiority at a later point in time. The study aims to enroll 2,000 patients with type 2 diabetes and a history of cardiovascular disease who will be randomized to either ITCA 650 60 mcg/day or placebo; the primary endpoint is time to first MACE event (CV death, non-fatal MI, non-fatal stroke, or hospitalization for unstable angina). Interim results from the CVOT will likely be submitted as part of the NDA package for the product.
• Intarcia should be able to get to the point of a US regulatory filing solo, but plans to seek a partner for ex-US commercialization. As we understand it, Intarcia’s ideal partner is one that shares its ambitious vision for the product and its potential to serve as the preferred second-line therapy after metformin. Other essential criteria include a respected reputation in the diabetes community and a lack of conflict of interest with Intarcia over the short or long term. While it is of course difficult to speculate on which companies might best fit this profile, we imagine that those with expertise in both drugs and devices (e.g., J&J or Sanofi) might hold particular appeal given that ITCA 650 uniquely combines drug and device factors. Companies with a GLP-1 agonist already on the market might be slightly less interested, though the data package so far is compelling enough that we do not see that being a deal-breaker or anything close. We also suspect that a company with an SGLT-2 inhibitor on the market or in development could be an appealing partner given Intarcia’s future vision for ITCA 650, though this will not be a top factor in the decision.

--by Emily Regier, Manu Venkat, and Kelly Close