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Clinical Trials

Date: 2015-06-06

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of new data at the World Diabetes Congress

Company: Sanofi (France) Zealand Pharma (Denmark)

Product: Lyxumia® (lixisenatide)

Action mechanism:

GLP-1 agonist/peptide. Lixisenatide is a glucagon-like peptide-1 agonist (GLP-1). GLP-1 is a naturally-occurring peptide that is released within minutes of eating a meal. It is known to suppress glucagon secretion from pancreatic alpha cells and stimulate insulin secretion by pancreatic beta cells. GLP-1 receptor agonists are in development as an add-on treatment for type 2 diabetes.
Lyxumia® was invented by Zealand Pharma and licensed to Sanofi, which holds global commercial rights for the drug. 

Disease:

type 2 diabetes

Therapeutic area: Metabolic diseases

Country:

Trial details:

The GetGoal Phase III clinical program, which completed in February 2012, provided data for lixisenatide (Lyxumia®) in adults with Type 2 diabetes treated in monotherapy, with various oral anti-diabetic agents or in combination with basal insulin. The GetGoal program started in May 2008 and enrolled more than 5,000 patients.
GetGoal Duo 1 is a randomized, double-blind, multicenter Phase III study, having assessed the efficacy and safety of lixisenatide as a novel treatment for Type 2 diabetes, compared to placebo and in combination with insulin glargine (Lantus®) and OADs (mostly metformin). During a 12-week run-in phase to the study, 898 insulin-naïve patients were initiated on treatment with insulin glargine, which was titrated to reach a target level for fasting plasma glucose (FPG) of 80-100 mg/dL.
After the run-in phase, 446 patients whose HbA1c was >7% (despite well controlled FPG levels) were randomised to receive either once-daily lixisenatide 20 µg or placebo for 24 weeks while OAD treatment and insulin glargine titration were continued.
GetGoal-L is a 24-week randomized, double-blind multicenter, placebo-controlled study, having assessed the efficacy and safety of lixisenatide in 495 patients with Type 2 diabetes, insufficiently controlled on basal insulin with or without metformin.

Latest news:

* On June 6, 2015, Zealand Pharma announced that Sanofi reported results from a clinical Phase IIIb trial, GetGoal Duo-2, with Lyxumia® (lixisenatide). GetGoal Duo-2 has evaluated the efficacy and safety of once-daily lixisenatide as an add-on to basal insulin for the treatment of Type 2 diabetes patients poorly controlled on basal insulin, versus the addition of rapid acting insulin once daily at main meal (basal-plus) or three times daily at meal-times (basal-bolus). In the trial, lixisenatide was shown to be non-inferior to both comparator insulin regimens for reduction in blood sugar (HbA1c), and statistically superior to the basal-bolus regimen for body weight change, as co-primary endpoints. Further results from the study showed that in the lixisenatide group of patients, documented hypoglycemia was numerically lower than in the group receiving rapid insulin once daily and significantly lower than in the group receiving rapid insulin three times daily. The results from GetGoal Duo-2 have been presented at the 75th Scientific Sessions of the American Diabetes Association (ADA), taking place 5 – 9 June 2015 in Boston, MA, US under the following title: “Advancing Basal Insulin Glargine with Prandial Lixisenatide QD vs Insulin Glulisine QD or TID in T2DM: The GetGoal Duo-2 Evidence-Based Trial (NCT01768559). 

Analysis of results from GetGoal-Duo II: The 26-week, randomized, open-label study compared the addition of once-daily lixisenatide (20 µg) to optimally titrated insulin glargine with/without metformin versus the addition of one daily injection (basal-plus) or three daily injections (basal-bolus) of insulin glulisine with or without metformin. The study included 894 patients with Type 2 diabetes, who were predominantly obese and who had been poorly controlled on basal insulin ± oral anti-diabetics (OADs) for at least 6 months prior to the study. Lixisenatide was shown to be non-inferior to both comparator insulin regimens for reduction in blood sugar (HbA1c) (LS mean difference [95% CI]: -0.05% [-0.17 to 0.06] vs. basal-plus; 0.21% [0.10 to 0.33] vs. basal-bolus; mITT n=890), and superior to basal-bolus for body weight change (LS mean difference [95% CI]: -2.0kg [-2.6 to -1.4kg], p<0.0001 vs. basal-bolus). In addition, post-prandial glucose (PPG) was measured in patients treated before breakfast, and was significantly reduced with lixisenatide compared with both insulin glulisine regimens (LS mean difference [95% CI]: -37mg/dL [-59 to -15mg/dL] vs. basal-plus; -40md/dL [-61 to -19mg/dL] vs. basal-bolus).

Documented hypoglycemia was numerically and statistically lower with lixisenatide than with basal-plus and basal-bolus, respectively (estimated rate ratio [95% CI]: 0.8 [0.5 to 1.1], p=0.123 vs. basal-plus; 0.5 [0.3 to 0.7], p<0.0001 vs. basal-bolus; safety n=894). Nausea events were higher with lixisenatide (25% of patients receiving lixisenatide experienced one or more nausea event, 2% of patients on basal-plus regimen, and 1% of patients on basal-bolus). Patients receiving lixisenatide also reported vomiting (9%) and diarrhea (7%). Sanofi has informed that following the presentation of results at ADA, data from GetGoal Duo-2 will be shared with health authorities worldwide and be included also in the regulatory application for lixisenatide in the US, which is on track for re-submission in the third quarter of 2015.

* On December 5, 2013, Sanofi has provided results of a 24-week Phase IIIb clinical study showing that Lyxumia® (lixisenatide) met the primary endpoint of non-inferiority in blood sugar lowering (HbA1c) when administered either before breakfast or before the main meal of the day. These results support that lixisenatide can effectively lower blood sugar at either time of administration. The results also showed that a mean change in body weight of -2.6 to -2.8kg, was achieved regardless of the meal before which lixisenatide was administered. In addition, gastro-intestinal tolerability was comparable regardless of time of administration, with no cases of severe hypoglycemia.The 24-week Phase IIIb study examined 451 patients with Type 2 diabetes, uncontrolled on metformin alone and randomized to lixisenatide either prior to prior to breakfast or the main meal. Lunch (as defined by questioning patients) was the main meal of the day for 53% of patients. The primary endpoint of the study was to demonstrate non-inferiority in HbA1c decrease at 24 weeks from baseline, when lixisenatide was injected prior to the main meal of the day vs. breakfast. The endpoint was successfully achieved with mean HbA1c reductions of 0.65% and 0.74% respectively. In addition, 43.6% of patients in the main meal group and 42.8% in the breakfast group achieved HbA1c below 7% at week 24. The mean change in body weight was -2.6kg in the main meal group and -2.8kg in the breakfast group. Gastrointestinal tolerability was comparable between the two groups (nausea 14.7% and 15.5% and vomiting 2.7% and 3.5%, respectively) and the incidence of symptomatic hypoglycemia was low in both groups, with no severe cases. (‘Flexibility in timing of lixisenatide administration prior to either the main meal of the day or the breakfast in T2DM patients’ (Ahren B, et al.)  World Diabetes Congress, oral presentation, December 5, 2013, 10:45?12:45 [ABS OP-0454]).

* On September 24, 2013, Sanofi has announced new GetGoal-L sub-analysis results showing that reductions in HbA1c with Lyxumia® (lixisenatide), when added to basal insulin, were greatest in patients with type 2 diabetes who had well-controlled baseline fasting plasma glucose (FPG). These findings are consistent with the efficacy profile of Lyxumia®, which shows a clinical and statistically significant reduction in HbA1c across different patient populations. The results also showed that reductions in body weight with Lyxumia®, when added to basal insulin, were greatest in this group. The GetGoal-L sub-analysis was shared during an oral presentation at the 49th Annual Meeting of the European Association for the Study of Diabetes in Barcelona.

This sub-analysis examined 496 patients with type 2 diabetes and inadequate glucose control. Results showed that the addition of lixisenatide to basal insulin treatment, with or without metformin (oral anti-diabetic therapy), reduced overall HbA1c, body weight and post-breakfast self-monitored post-prandial glucose in all groups. These effects were greater in patients with relatively wellcontrolled baseline FPG levels (below or equal to 6.7 mmol/L; FPG in people without diabetes is ~5.5 mmol/L1) compared to those with higher baseline FPG levels (between 6.7 and 8.9 mmol/L, and over 8.9 mmol/L, respectively).The GetGoal-L sub-analysis abstract is entitled: ‘Therapeutic efficacy of lixisenatide added to basal insulin is greater when FPG is well-controlled’ (Vidal J, et al. [Abstract no. oral presentation 6]).

* On October 2, 2012, Sanofi has announced Phase III trial results that support the clinical rationale for lixisenatide as a potential once-daily GLP-1 receptor agonist (RA) incombination with basal insulin.These data were presented at the 48th Annual Meeting of the European Association for the Study of Diabetes (EASD) in Berlin. “Once-daily lixisenatide added on to consistently titrated insulin glargine plus oral agents in type 2 diabetes: The GetGoal Duo 1 study” [Abs 807-EASD] and “Efficacy and safety of once-daily lixisenatide in type 2 diabetes insufficiently controlled with basal insulin ± metformin: GetGoal-L study” [Abs 3-EASD]: GetGoal Duo 1 and GetGoal-L both achieved the primary efficacy endpoint of HbA1c improvement with an associated significant reduction in PPG. Results showed that lixisenatide caused mild and transient nausea and vomiting, the most common adverse events, and a limited additional or comparable risk of hypoglycemia. These studies are part of the GetGoal Phase III clinical program for lixisenatide, which includes a broad range of patients with type 2 diabetes, including a large number of patients treated with basal insulin (706 patients in three trials). “Effects of lixisenatide once daily on gastric emptying and its relationship to postprandial glycaemia in type 2 diabetes mellitus” [Abs 808-EASD] Sanofi has also announced results from a study showing that the mechanism of action of once-daily Lyxumia® (lixisenatide) significantly delayed gastric emptying, a process accompanied by significant post-prandial glucose (PPG) lowering. Treatment after a standardized breakfast with a final dose of once-daily 20?g lixisenatide and up to two OADs contributed significantly to slowing the rate of gastric emptying, compared with placebo (p=0.0031) in this 28-day, randomized, double-blind, placebo-controlled, parallel-group study in patients with type 2 diabetes (lixisenatide n=19; placebo n=22; final dose reached after titrating from 5–20 microg with 2.5 microg increments every 4 days). This had a pharmacodynamic effect on blood glucose levels throughout the day. Delayed gastric emptying is associated with lower PPG levels. At day 28, PPG was significantly reduced after a standardized breakfast (p<0.0001), after lunch (p=0.0004) and after dinner (p=0.0082). No such relationship was found for placebo. The European Medicines Agency (EMA) acknowledged receipt of the Marketing Authorization Application filing for Lyxumia® (lixisenatide) in November 2011. Submission for regulatory approval of lixisenatide in the U.S. is expected in December 2012.

* On June 9, 2012, Sanofi has presented further data from phase III studies with lixisenatide at the ADA’s 72th Annual Scientific sessions, taking place on 9 – 12 June 2012 in Philadelphia, Pennsylvania, USA. Results from the GetGoal Duo 12 and GetGoal-L3 Phase III studies demonstrate that as add-on to basal insulin plus anti-diabetic agents (OADs), lixisenatide significantly reduced blood glucose levels (HbA1c) in patients with Type 2 diabetes; including patients, who were new to insulin therapy, i.e. who had been treated with insulin for only 12 weeks (GetGoal Duo 1), and patients who had already been treated with insulin for an average of 3.1 years (GetGoal-L).

GetGoal Duo 1: Results show that in the study run-in period, HbA1c decreased on average from 8.60% to 7.60% with insulin glargine. The addition of lixisenatide led to a further significant decrease in the patients’ HbA1c to a mean value of 6.96% after 24 weeks, compared to 7.3% for placebo (p<0.0001). A significantly higher percentage of patients treated with lixisenatide achieved target HbA1c <7.0% compared to placebo (56.3% vs. 38.5%, respectively, p=0.0001). Associated with the reduction in HbA1c, lixisenatide also significantly improved 2-hour PPG, after a standardized breakfast, with a mean difference of -3.16 mmol/L compared to placebo (p<0.0001). The mean difference in change in body weight between the lixisenatide and placebo groups was -0.89 kg (p=0.0012). Incidence of symptomatic hypoglycemia was 22.4% among patients receiving lixisenatide vs. 13.5% in the placebo group. Other common adverse events in the lixisenatide group were nausea and vomiting, which occurred in 27.4% and 4.9%, respectively, compared to placebo (9.4% and 1.3%, respectively). 88% of patients in the lixisenatide arm reached and remained on the 20 microg maintenance dose.  GetGoal-L: In the lixisenatide arm, patients’ mean HbA1c was significantly reduced from baseline compared to placebo (-0.74% vs. -0.38%, p=0.0002) along with a significant decrease in mean 2-hour PPG (-5.54 mmol/L vs. -1.72 mmol/L, p<0.0001) after a standardized breakfast. Patients treated with lixisenatide also experienced a significant mean reduction in body weight compared to placebo (-1.8 kg vs. -0.52 kg, p<0.0001). The incidence of per protocol symptomatic hypoglycemia was 27.7% for lixisenatide vs. 21.6% for placebo. Severe hypoglycemia occurred in 1.2% of patients treated with lixisenatide compared to none with placebo. Other common adverse events were nausea (26.2%), vomiting (8.2%), and diarrhea (7.3%).

* On February 8, 2012, Zealand Pharma has announced that Sanofi in its Full Year 2011 results announcement reported positive top line results from the GetGoal-P Phase III study. In the study, lixisenatide achieved its primary efficacy endpoint of significantly reducing blood glucose levels (HbA1c) compared to placebo (p<0.0001) with HbA1c decreasing from a mean baseline value of 8.08% to a mean value of 7.06% after 24 week in the patient group receiving lixisenatide and from 8.05% to 7.59% in the placebo group.  Safety and tolerability results were consistent with other studies within the GetGoal program. Results from GetGoal-P also showed that symptomatic hypoglycemia rates were low in both groups. Patients randomized to the lixisenatide group had an incidence of symptomatic hypoglycemia at 24 weeks of 3.4% compared to 1.2% in the placebo group. As expected for a GLP-1 agonist, the most frequent adverse event was nausea, with 1.9% of patients discontinuing due to nausea in the lixisenatide arm vs. none in the placebo group. The full study results from the GetGoal-P study are planned for presentation at a future medical congress.

* On June 24, 2011, Sanofi has announced data from two phase III studies of its once-daily GLP-1 receptor agonist Lyxumia® (lixisenatide), including data that demonstrates positive results in type 2 diabetes patients not at goal on oral therapies or with basal insulin. These data are being presented or published at the American Diabetes Association’s 71st Scientific Sessions in San Diego, California. In the GetGoal-X trial, a randomized, open-label, active-controlled, two-arm parallel-group, multicenter study with a 24-week main treatment period, lixisenatide once daily achieved its primary endpoint of non-inferiority in A1C reduction from baseline with less symptomatic hypoglycemia (low blood sugar) and better gastrointestinal tolerability versus exenatide twice daily, as an add-on to metformin in patients with type 2 diabetes. A total of 634 people were randomized to receive either lixisenatide or exenatide. Both groups received a stepwise increase in dose, up to a maximum daily dose of 20 microg. At baseline, the mean age in the trial was 57.4 years, mean diabetes duration 6.8 years, mean body mass index (BMI) 33.6 kg/m2 and mean A1C 8.0 percent. Lixisenatide once daily achieved its primary endpoint of non-inferiority in A1C reduction versus exenatide twice daily (LS mean ± SE change from baseline: -0.79 ± 0.05 vs. -0.96 ± 0.05). Improvements in mean fasting plasma glucose – measurement of blood glucose levels when a patient is fasting – (LS mean ± SE change from baseline: -22.0 ± 2.1 vs. -26.1 ± 2.1) and the percentage of patients achieving the study target A1C < 7.0 percent (48.5% vs. 49.8%) were comparable between groups. Compared to baseline, mean body weight significantly decreased in the lixisenatide group and in the exenatide group (94.5 to 91.7 kg with lixisenatide and 96.7 to 92.9 kg with exenatide). The proportion of patients with serious adverse events was generally comparable between groups. More lixisenatide patients tolerated the target dose of 20 microg per day and completed the trial versus the exenatide 10 mcg target dose (93% vs. 83%). Data from the GetGoal-L Asia trial, showed in Asian patients with type 2 diabetes insufficiently controlled by basal insulin ± sulfonylurea, that lixisenatide once daily significantly improved glycemic control (as measured by the number of patients reaching a target A1C < 6.5 percent or < 7.0 percent) versus placebo at week 24 with a pronounced post-prandial glucose and fasting plasma glucose effect, and was well tolerated. Lixisenatide once daily significantly improved A1C versus placebo (LS mean difference -0.9%). Significantly more lixisenatide patients achieved A1C 6.5 percent (17.8%)

* On May 31, 2011, Sanofi announced new results from a Phase III study showed that the investigational product Lyxumia® (lixisenatide), when used as an add-on therapy to basal insulin (in association with or without metformin), achieved its primary efficacy endpoint of significantly reducing HbA1c versus placebo for patients with type 2 diabetes without significantly increasing their risk of hypoglycemia. The GetGoal-L study showed a significant reduction in HbA1c levels (p=0.0002) with lixisenatide, without a significant increase in the incidence of symptomatic hypoglycemia (p=0.14) versus placebo. In addition, patients treated with lixisenatide had significantly improved postprandial plasma glucose after a test meal (p<0.0001). Patients in the lixisenatide arm of the study also reported a significant reduction in body weight (p<0.0001). These results confirm those previously reported on GetGoal-L Asia, this time in a broader population including both Caucasian and Asian patients. As expected with a GLP-1, the most commonly reported adverse event with lixisenatide was nausea with a low rate of discontinuation. The full study results from GetGoal-L are planned to be presented at a medical congress. The GetGoal Phase III clinical program will provide data for the efficacy and safety of lixisenatide in adults with type 2 diabetes treated with various oral anti-diabetic agents or insulin. With nine trials in  the program, GetGoal started in May 2008 and has enrolled more than 4300 patients. To date GetGoal-X, GetGoal-Mono, GetGoal-L Asia and GetGoal-S have reported positive top-line results supporting efficacy and safety for lixisenatide. Further results are expected during 2011.

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