Date: 2016-05-09
Type of information: Results
phase: 3
Announcement: results
Company: Intarcia Therapeutics (USA - MA)
Product: ITCA 650 (exenatide, delivered continuously once or twice yearly through a matchstick-sized, subcutaneous osmotic mini-pump)
Action
mechanism: peptide/glucagon-like peptide-1 (GLP-1) receptor agonist. ITCA 650 is an injection-free GLP-1 receptor agonist that continuously delivers exenatide with a once or twice-yearly dosing via a small matchstick-size subdermally placed osmotic mini-pump. ITCA 650 is being developed for the treatment of type 2 diabetes. The investigational therapy employs Intarcia's proprietary technology platform involving a matchstick-size, miniature osmotic pump that is placed sub-dermally to provide continuous and consistent drug therapy, and the company's proprietary formulation technology, which maintains stability of therapeutic proteins and peptides at human body temperatures for extended periods of time.
Disease: type 2 diabetes
Therapeutic area: Metabolic diseases
Country: USA
Trial
details: The FREEDOM-1 study was a placebo-controlled, double-blind study involving type 2 diabetes patients whose HbA1c was not controlled on diet and exercise alone, or in many cases, were taking up two or three oral anti-diabetes drugs. Subjects enrolled in the trial had HbA1c measures between 7.5% and 10.0%. 460 patients were randomized into three groups in a 1:1:1 ratio, evaluating ITCA 650 40 mcg/d and 60 mcg/d versus placebo. Subjects in the active arms were treated for the first 13 weeks with 3-month devices that delivered an initial dose of 20 mcg/d, and then treated with 6-month ITCA 650 at doses of 40 or 60 mcg/d. The Primary Endpoint was HbA1c reduction over 39 weeks. Secondary endpoints included changes in weight, and the percent of subjects reaching an HbA1c goal of <7%. Concurrent with FREEDOM-1, Intarcia also conducted an open-label study called FREEDOM-1 HBL (high baseline), for patients who met all eligibility criteria for FREEDOM-1, but whose baseline HbA1c was greater than 10% but less than 12%. All patients in this study were treated with ITCA 650 20 mcg/d for the first 3 months and with ITCA 650 60 mcg/d for the next 6 months. Pre-study oral anti-diabetic agents (OADs) were maintained unchanged for the 39 weeks of treatment. The Overall FREEDOM Phase 3 Clinical Trial Program is designed to evaluate the safety and efficacy of ITCA 650 (continuous subcutaneous delivery of exenatide) for the treatment of type 2 diabetes. Intarcia expects to enroll 5,000 patients at more than 500 clinical trial sites in more than 30 countries. The clinical studies will cover a broad range of patients whose diabetes is not controlled by oral anti-diabetes medications including metformin and metformin-based combinations. FREEDOM-1 is a U.S.-only, placebo-controlled, double-blind study comparing ITCA 650 doses of 40 mcg/d and 60 mcg/d to placebo. This study has been completed. FREEDOM-1 HBL (High Baseline) is an open-label study for patients meeting all the entrance criteria for FREEDOM-1, but with HbA1c levels greater than 10%. This study has been completed. FREEDOM-2 is a 500-patient, global, active-comparator controlled, double-blind, double-dummy study in patients on metformin only, comparing ITCA 650 20 mcg/d for 13 weeks plus ITCA 650 60 mcg/d for 39 weeks to patients taking sitagliptin (Januvia®, Merck). This study is ongoing and on track for completion in summer of 2015. The primary endpoint is change in HbA1c between Week 52 and Day 0. With superiority demonstrated, secondary endpoints included the proportion of patients with a decrease in HbA1c of >0.5% and >2 kg weight loss between Week 52 and Day 0, change in body weight between Week 52 and Day 0 and proportion of patients with HbA1c <7% measured at Week 52. FREEDOM-CVO Safety Study is a global, placebo-controlled cardiovascular outcomes study examining the safety of ITCA 650 at 60 mcg/d vs. placebo in approximately 4,000 patients on a variety of approved anti-diabetes therapies. The FREEDOM-CVO Safety Trial is the fourth and final Phase 3 clinical trial of the FREEDOM program. It is a global, placebo-controlled cardiovascular outcomes study designed to meet the pre-approval safety assessment requirements set out in the FDA’s Guidance for Industry to evaluate cardiovascular risk for new therapies to treat type 2 diabetes.
Latest
news: * On May 6, 2016, Intarcia Therapeutics announced top-line results from its more than 4,000 patient Cardiovascular Safety Study (FREEDOM-CVO trial), clearing the last major clinical hurdle in the global FREEDOM Phase 3 Clinical Trial Program that started in early 2013. Regulatory filing in the U.S. is targeted for end of 3Q, 2016. The FREEDOM-CVO trial was designed to test CV safety in a pre-approval setting. The study evaluated the safety of ITCA 650 at 60 micrograms per day vs. placebo in just over 4,000 patients on a variety of approved standard of care anti-diabetes therapies. The duration of study was dependent on event-based outcomes, and lasted just under 3 years, reaching the target number of cardiovascular events in the fourth quarter of 2015. The average treatment duration in FREEDOM-CVO was 1.2 years. Age eligibility for the study was 40 years and older. Inclusion criteria stipulated patients must have HbA1c > 6.5%, a history of coronary, cerebrovascular or peripheral artery disease, or multiple CV risk factors. The primary objective was to conduct a meta-analysis across FREEDOM-CVO and other phase 3 studies to demonstrate that the upper limit of the 95% confidence interval of the hazard ratio of major adverse cardiac events (MACE) in adult patients on Standard of Care for type 2 diabetes receiving either ITCA 650 or placebo, does not exceed 1.8. There were a total of 160 strict MACE events observed in the FREEDOM-CVO trial. The overall safety and tolerability data for ITCA 650 was consistent with the three phase 3 trials that have already been presented and what is documented in the published literature for exenatide and other GLP-1 receptor agonist therapies. The Company also announced a $75 million round of debt financing timed to facilitate ongoing scale-up of manufacturing and the production of inventory for the anticipated global launch of ITCA 650 in type 2 diabetes. The new credit facility is with MidCap Financial and Silicon Valley Bank. * On September 16, 2015, Intarcia Therapeutics announced the presentation of results from its first two Phase 3 clinical trials (FREEDOM-1 and FREEDOM-1 HBL) of ITCA 650 (exenatide delivered continuously via a matchstick-size subcutaneous osmotic mini-pump) at the 51st European Association for the Study of Diabetes (EASD) Meeting in Stockholm, Sweden. * On August 18, 2015, Intarcia Therapeutics announced results from its 52-week Phase 3 FREEDOM-2 clinical trial to determine the comparative efficacy of the company’s late-stage investigational candidate ITCA 650 to Merck’s Januvia® in reducing HbA1c in patients with type 2 diabetes following a year of treatment. All patients were on background metformin monotherapy. In the FREEDOM-2 trial, ITCA 650 met all primary and secondary endpoints, demonstrating superiority over Januvia® at every measured time point through and including week 52 endpoints for reduction in HbA1c and reduction in body weight (BW). Full details of the trial results will be submitted for publication and presentation at major medical meetings including data on the following: Oral Presentation of FREEDOM-1: "Clinical Impact of ITCA 650 in Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled 39 Week Trial," led by Julio Rosenstock, M.D., Director of the Dallas Diabetes and Endocrine Center at Medical City and a Clinical Professor of Medicine at the University of Texas Southwestern Medical Center at Dallas. FREEDOM-1, a placebo-controlled study, demonstrated positive results for ITCA 650 when added to diet and exercise with or without standard oral diabetes medications, for those patients who were not at goal. All key endpoints were met, including significant reductions in HbA1c and weight, and the percentage of patients treated to goal. ITCA 650 produced significant and sustained mean reductions in HbA1c of 1.4% at 39 weeks of treatment (mITT population). Two pre-specified patient populations were assessed to determine how HbA1c reductions may vary based on whether or not patients were on a background regimen including a sulfonylurea (SU)-based regimen, or a metformin or diet & exercise regimen without any SUs. Non SU-containing Regimens: Patients primarily on background metformin (~40% of patients), or diet and exercise (~11% of patients), showed a mean HbA1c reduction of 1.7%. SU-containing Regimens: Those on an SU-based background regimen (47% of patients) had a mean HbA1c reduction of 1.2%. Significant and progressive weight loss that was dose dependent was observed over 39 weeks (mITT population). Patients on the primary phase 3 dosing regimen lost a mean of 4 kg in the 60 mcg/d ITCA 650 dose group vs. 2 kg in the placebo group at Week 39, which was statistically significant. The overall tolerability profiles, including G.I. events, were very similar between the 40 mcg/d and the higher 60 mcg/d dose groups. There was a low single-digit discontinuation rate for nausea. No new safety findings were identified compared to what is known for the GLP-1 receptor agonist class. Other adverse events associated with the administration site and the procedures to place and remove the ITCA 650 were generally mild and transient. Discontinuations due to procedures and administration site adverse events were also a very low single digit rate across each arm of the 39-week study. Efficacy endpoints were statistically significant for both doses versus placebo in the pre-specified analysis presented at the ADA meeting. Efficacy was assessed with an LOCF analysis at week 39 vs. placebo and a separate mITT population analysis by visit was conducted over the 39 weeks in all patients with a post-baseline HbA1c measurement. Additionally, pre-specified subset analyses of the mITT population treated with different background therapies were carried out to see if results varied across different background therapies. Baseline characteristics were similar in the three groups: mean HbA1c level of 8.5% (uncontrolled), mean body mass index (BMI) measurement of 33.5 kg/m2 (clinically obese), and mean duration since diabetes diagnosis of 9 years. Ninety percent of the patients in the study were uncontrolled despite being treated with up to three oral anti-diabetes medicines. Subjects in the active arms were treated for the first 13 weeks with 3-month devices that delivered an initial exenatide starting dose of 20 mcg/d, and then treated with 6-month ITCA 650 devices at doses of 40 or 60 mcg/d. The primary endpoint was HbA1c reduction over 39 weeks; secondary endpoints included weight loss and percent of patients reaching goal HbA1c levels of <7%. Poster Presentation of FREEDOM-1 HBL: On Saturday June 6th, poster session (1107-P) titled: "Efficacy and Tolerability of 39 Wks of ITCA 650 (Continuous Subcutaneous Exenatide) in Poorly Controlled T2DM with High Baseline A1c (>10%)," led by Robert R. Henry, M.D., Chief, VA Endocrinology & Metabolism, and Professor of Medicine in Residence at UCSD. The FREEDOM-1 HBL study was an open-label trial that ran concurrently with Intarcia's FREEDOM-1 phase 3 trial and enrolled type 2 diabetes patients who met all eligibility criteria for FREEDOM-1, but whose baseline HbA1c was greater than 10% but less than or equal to 12%. All patients in this study were treated with ITCA 650 20 mcg/d for the first 3 months and with ITCA 650 60 mcg/d for the next 6 months. Pre-study oral anti-diabetic agents were maintained and remained unchanged for the 39 weeks of treatment. The primary endpoint was change in HbA1c. Secondary endpoints included change in weight from baseline and percentage of patients achieving HbA1c levels <7% at week 39. At baseline, the 60 patients who entered the study had extremely poor glycemic control as indicated by a mean HbA1c level of 10.8%, a mean body mass index measurement of 32.0 kg/m2 (clinically obese) and mean duration since diabetes diagnosis of 9 years. Notably, significant reductions in HbA1c levels were achieved by week 6, a period during which patients were receiving only the initial 20 mcg/d ITCA 650 dose. The change from baseline was sustained over time, with patients achieving a mean reduction in HbA1c of 3.4% at week 39. 22% of patients achieved HbA1c reductions of 4% or greater and 25% of patients achieved an HbA1c level <7% at the LOCF endpoint. Weight reduction was observed but the results were not statistically significant. Investigators believe this is most likely due to the correction of glycosuria as the blood glucose decreased. ITCA 650 treatment was well tolerated in these poorly controlled patients with type 2 diabetes. The most common adverse events were consistent with the known effects of exenatide and the GLP-1 receptor agonist class (mainly gastrointestinal). Most were observed early in the course of treatment and improved over time. Poster Session Treatment, Adherence and Change in A1C in Type 2 Diabetes with HBL:This poster included a comparison of real-world outcomes to results from the FREEDOM-1 HBL study. The retrospective study used the Optum/Humedica SmartFile™ database and a sensitivity analysis was conducted to select a group of type 2 diabetes patients comparable to the FREEDOM-1 HBL study population. At baseline, the 1,248 patients who met study criteria had a mean HbA1c level of 10.8% and a mean body mass index measurement of 35.1 kg/m2. Mean HbA1c declined 1.8% points from index to outcome HbA1c (mean 364 days) in the base real-world sample. A similar reduction (2.0%) was observed in the sensitivity analysis of patients who likely would have met trial inclusion and exclusion criteria for the FREEDOM-1 HBL study. 16.2% of patients had HbA1c <7% at the end of the observation period. A similar reduction (17.5%) was observed in the sensitivity analysis of patients who likely would have met trial inclusion and exclusion criteria * On October 1, 2014, Intarcia Therapeutics announced successful top-line results from two of its four phase 3 clinical trials for ITCA 650 (exenatide, delivered continuously once or twice yearly through a matchstick-sized, subcutaneous osmotic mini-pump). The first trial, FREEDOM-1, was a placebo-controlled, double-blind phase 3 clinical trial that tested the efficacy and safety of ITCA 650 in patients with type 2 diabetes against placebo. This study demonstrated ITCA 650 to be significantly superior to placebo for both 40 mcg and 60 mcg doses, and met all its clinical endpoints. Also, pre-specified sub-group analyses showed substantial improvement in hyperglycemia across a wide spectrum of patients and background medications. The second trial, FREEDOM-1 HBL (High Baseline), was an open-label phase 3 clinical trial in type 2 diabetes patients with very high baseline HbA1c levels between 10-12%. The 39-week (9-month) results showed a sustained reduction of 3.4% in HbA1c among these poorly controlled patients. The HBL study also showed the ability of a 39-week therapy with ITCA 650 to bring 25% of these patients, many uncontrolled on multi-drug therapy, to their HbA1c goal of <7%. The full findings for both phase 3 trials will be submitted for presentation at the American Diabetes Association (ADA) annual meeting in June of 2015 in Boston. If approved, ITCA 650 would be the first and only injection-free GLP-1 therapy to deliver up to a full year of treatment in a single subcutaneous mini-pump. Both 6-month and 12-month mini-pumps are in full development for ongoing and additional phase 3B studies planned for next year. * On September 19, 2014, Intarcia Therapeutics announced the presentation of positive interim clinical data for its lead candidate ITCA 650 (continuous subcutaneous delivery of exenatide) in type 2 diabetes patients with high baseline HbA1c levels at the 50th Annual Meeting of the European Association for the Study of Diabetes (EASD). Data from the open-label, phase 3 FREEDOM-HBL (high baseline) trial showed markedly reduced levels of blood sugar in patients with poorly controlled type 2 diabetes. The results were presented by Dr.Robert R. Henry, Chief, VA Endocrinology & Metabolism and Professor of Medicine at UCSD. The overall results from the full 9-month HBL study and the FREEDOM-1 trial are expected to be announced in the fourth quarter of 2014. In an oral presentation today, Dr. Henry reviewed the 6-month interim data from the FREEDOM-HBL trial, which enrolled T2D patients whose HbA1c levels exceeded the entrance criteria for the FREEDOM-1 phase 3 trial. The presentation, entitled"Efficacy and Tolerability of ITCA 650 (continuous subcutaneous exenatide) in Poorly Controlled Type 2 Diabetes with Baseline A1C >10%," included the following comments, results and conclusions: • FREEDOM-1 is a double-blind, randomized, placebo-controlled, multicenter study to evaluate the efficacy and safety of ITCA 650 in type 2 diabetes patients with an HbA1c between 7.5% and 10.0%. • Patients who met all inclusion criteria for FREEDOM-1 but had HbA1c greater than or equal to 10% but less than or equal to 12% were enrolled in FREEDOM-HBL. • On average, patients enrolled to FREEDOM-HBL had been diagnosed with T2D for 9 years and a majority was being treated with multiple background oral anti-diabetes therapies. • Enrolling patients with high baseline HbA1c provides a robust opportunity to evaluate treatment response in a poorly controlled patient population. • In this interim analysis, the addition of ITCA 650 resulted in mean HbA1c reductions greater than 3% in patients who reached 6 months of treatment. • 30% of patients who reached 13 weeks of treatment (n=50) achieved the target HbA1c of less than 7%. • ITCA 650 treatment was also accompanied by weight loss, which is not commonly observed in the treatment of patients with high baseline HbA1c. ITCA 650 may offer potential benefits over existing oral and injectable therapies for type 2 diabetes via sustained glycemic control, favorable weight profile, improved tolerability, ensured adherence with once- or twice-yearly dosing, and no injections. "More than 50% of people with type 2 diabetes remain inadequately controlled, often despite one or more treatments," said Dr. Henry. "These interim results may represent a very promising advance toward addressing that unmet need. There are a variety of reasons why there is this large segment of treatment-experienced type 2 diabetes patients who remain poorly controlled, including the progressive nature of the disease, poor adherence to therapy, and lack of aggressive treatment. These results appear to indicate that ITCA 650 can deliver potent effects both in terms of glycemic control and weight loss to a group of patients with very poorly controlled type 2 diabetes and for whom other therapies have failed. While ITCA 650 holds promise for the broad diabetes population, the unique delivery technology has the potential to address the contribution that sub-optimal efficacy and non-adherence play in poor glycemic control. With such promising interim results, I look forward with great anticipation to seeing the full data from the FREEDOM-HBL and FREEDOM-1 studies very soon."
Intarcia is preparing to conduct additional head-to-head superiority studies against market-leading oral and injectable medicines. Some of the comparative trials will start this year, while other trials are planned to start with payers after approval to evaluate the relative performance of ITCA 650 vs. other type 2 diabetes therapies in ‘real-world’ settings where poor adherence and poor control with pills and self-injections are best assessed.
FREEDOM-1 Results – Oral Presentation: “A randomized, double-blind, placebo-controlled, 39 week trial of ITCA 650 as add-on therapy in type 2 diabetes.” FREEDOM-1 was a placebo-controlled, double-blind, Phase 3 clinical trial that tested the efficacy and safety of ITCA 650 in patients whose HbA1c was not controlled on different oral antidiabetic drugs or diet and exercise alone. The 460 patients enrolled had baseline HbA1c levels between 7.5% and 10.0% and were randomized into three groups in a 1:1:1 ratio, evaluating ITCA 650 40 mcg/d and 60 mcg/d versus placebo. Baseline characteristics were similar in the three groups: mean HbA1c level of 8.5% (uncontrolled), mean body mass index (BMI) measurement of 33.5 kg/m2 (clinically obese), and mean duration since diabetes diagnosis of 9 years. Patients in the study were uncontrolled despite almost ninety percent being treated with up to three oral antidiabetic drugs. Subjects in the active arms were treated for the first 13 weeks with 3-month devices that delivered an initial exenatide starting dose of 20 mcg/d, and then treated with 6-month ITCA 650 devices at doses of 40 or 60 mcg/d. The primary endpoint was HbA1c reduction over 39 weeks; secondary endpoints included weight loss and percent of patients reaching goal HbA1c levels of <7%.
ITCA 650 produced significant and sustained mean reductions in HbA1c of 1.4% at 39 weeks of treatment (mITT population). Two pre-specified patient populations were assessed to determine how HbA1c reductions might vary based on whether or not patients were on a background regimen including a sulfonylurea (SU) therapy.
Patients primarily on background metformin (~40% of patients), or diet and exercise (~11% of patients), showed a mean HbA1c reduction of 1.7%. Those on an SU-based background regimen (47% of patients) had a mean HbA1c reduction of 1.2%.
Significant and progressive dose-dependent weight loss was observed over 39 weeks (mITT population). Patients lost a mean of 4 kg in the 60 mcg/d ITCA 650 dose group vs. 2 kg in the placebo group at Week 39, a difference that was statistically significant.
The overall tolerability profiles, including G.I. events, were very similar between the 40 mcg/d and the higher 60 mcg/d dose groups. There was a low single-digit discontinuation rate for nausea. No new safety findings were identified compared to what is known for the GLP-1 receptor agonist class. Other adverse events associated with the administration site and the procedures to place and remove the ITCA 650 were generally mild and transient. Discontinuations due to procedures and administration site adverse events were also a very low single digit rate across each arm of the 39-week study.
FREEDOM-1 HBL (High Baseline) Results:“Efficacy and tolerability of ITCA 650 (continuous subcutaneous exenatide) for 39 weeks in patients with poorly controlled T2DM and high baseline HbA1c (>10%).”
The FREEDOM-1 HBL study was an open-label trial that ran concurrently with Intarcia’s FREEDOM-1 Phase 3 trial and enrolled type 2 diabetes patients who met all eligibility criteria for FREEDOM-1, but whose baseline HbA1c was greater than 10% but less than or equal to 12%. All patients in this study were treated with ITCA 650 20 mcg/d for the first 3 months and with ITCA 650 60 mcg/d for the next 6 months. Pre-study oral anti-diabetic agents were maintained and remained unchanged for the 39 weeks of treatment. The primary endpoint was change in HbA1c. Secondary endpoints included change in weight from baseline and percentage of patients achieving HbA1c levels <7% at week 39. At baseline, the 60 patients who entered the study had extremely poor glycemic control as indicated by a mean HbA1c level of 10.8%, a mean body mass index measurement of 32.0 kg/m2 (clinically obese) and mean duration since diabetes diagnosis of 9 years. Notably, significant reductions in HbA1c levels were achieved by week 6, a period during which patients were receiving only the initial 20 mcg/d ITCA 650 dose. The change from baseline was sustained over time, with patients achieving a mean reduction in HbA1c of 3.4% at week 39.
22% of patients achieved HbA1c reductions of 4% or greater and 25% of patients achieved an HbA1c level <7% at the LOCF endpoint.
Weight reduction was observed in the trial, but the results were not statistically significant. Investigators and experts believe, based on published literature from multiple trials in this distinct population, this is most likely due to the correction of glycosuria, which stopped the loss of calories in the urine that is common among such uncontrolled patients. The most common adverse events were consistent with the known effects of exenatide and the GLP-1 receptor agonist class (mainly gastrointestinal). Most were observed early in the course of treatment and improved over time.
Significantly more patients on ITCA 650 60mcg versus Januvia® 100mg achieved the secondary composite endpoint combining glucose reductions of >0.5% and weight reductions of 2 kg or greater; ITCA 650 results were superior vs. Januvia 100mg
Significantly more patients on ITCA 650 60mcg achieved the ADA-recommended HbA1c target of <7.0% versus Januvia 100mg; ITCA 650 results were superior vs. Januvia 100mg
In the FREEDOM-2 trial, ITCA 650 60 mcg/d also demonstrated an overall and G.I. tolerability profile similar to prior Phase 3 results recently presented at ADA in the FREEDOM-1 placebo-controlled trial. Discontinuations for nausea were in the low single digits over the full 12 months of treatment. There were no cases of major hypoglycemia in either study arm and minor events of hypoglycemia were reported in the low single digits for both study arms. The placements and removals of ITCA 650 were very well tolerated and the rate of minor infections at the application site was less than 1% of all procedures in the trial.
* On June 8, 2015, Intarcia announced the presentation of results from its first two phase 3 clinical trials (FREEDOM-1 and FREEDOM-1 HBL) of its late-stage investigational candidate ITCA 650 at the 75th Scientific Sessions of the American Diabetes Association. Results showing positive data on key endpoints from the trials were highlighted in an oral presentation and a poster session at the conference in Boston.
