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Clinical Trials

Date: 2017-06-10

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the American Diabetes Association 77th Scientific Sessions in New Orleans

Company: Sanofi (France) Zealand Pharma (Denmark)

Product: Soliqua®/iGlarLixi® (single injection Lyxumia®(lixisenatide) /Lantus® (insuline glargine) combination product

Action mechanism: GLP-1 agonist/peptide/insulin analogue. LixiLan® is a fixed-ratio single-injection combination of Sanofi’s insulin glargine 100 units/mL (Lantus®) and lixisenatide. Lixisenatide is a prandial GLP-1 receptor agonist, invented by Zealand, and marketed globally outside the US by Sanofi as Lyxumia® for the treatment of Type 2 diabetes. 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.

Disease: diabetes

Therapeutic area: Metabolic diseases

Country: Australia, Belgium, Canada, Chile, Czech Republic, Denmark, Estonia, France, Germany, Hungary, Italy, Latvia, Lithuania, Mexico, Netherlands, Poland, Romania, Russian Federation, Slovakia, South Africa, Spain, Sweden, Ukraine, UK, USA

Trial details: The Phase III program comprises two studies; LixiLan-O (NCT02058147), evaluating the Fixed-Ratio combination of Lantus® and Lyxumia® in 1,125 patients insufficiently controlled on oral antidiabetics drugs (OADs), and LixiLan-L (NCT02058160), evaluating LixiLan in 700 patients not at target on basal insulin.

Latest news:

  • • On June 10, 2017, Zealand Pharma's partner Sanofi announced that Soliqua® 100/33 (insulin glargine and lixisenatide injection) 100 units/ml and 33 mcg/ml lowered mean blood sugar levels (HbA1c) by 1.09-2.41% after 30 weeks in adults with type 2 diabetes previously treated with 15-40 units of basal insulin daily. The abstract is entitled "iGlarLixi® Reduces A1c to a Greater Extent Than Basal Insulin Therapy Regardless of A1c Levels at Screening" (Niemoeller E et al. Poster presentation 1079-P, American Diabetes Association (ADA) 77th Scientific Sessions, San Diego, CA, U.S., June 10). This new post-hoc analysis of data from the LixiLan-L Phase 3 study, which grouped participants according to HbA1c level at screening, also showed that all subgroups achieved a mean HbA1c of less than 7% during the study period.
  • • On June 12, 2016, Sanofi announced the presentation of the results of the pivotal Phase 3 LixiLan-O and LixiLan-L clinical trials with the investigational titratable fixed-ratio combination of basal insulin glargine 100 Units/mL and GLP-1 receptor agonist lixisenatide in adults with type 2 diabetes. Both studies met their primary endpoints, demonstrating statistically superior reduction of HbA1c (average blood glucose over the previous three months) with the titratable fixed-ratio combination versus comparators (lixisenatide and insulin glargine 100 Units/mL, respectively). The most frequent adverse events were nausea, vomiting and diarrhea. Full results were presented on June 12 at the American Diabetes Association 76th Scientific Sessions in New Orleans, LA, U.S. Top-line results were previously reported in Q3 of 2015. The results of the LixiLan-O and LixiLan-L studies have been included in regulatory submissions to the FDA and European Medicines Agency (EMA), with regulatory decisions anticipated in August 2016 (FDA) and Q1 2017 (EMA). The presentation abstracts are titled: "Clinical Impact of Titratable Fixed-Ratio Combination of Insulin Glargine/Lixisenatide vs. Each Component Alone in Type 2 Diabetes Inadequately Controlled on Oral Agents: LixiLan-O Trial (NCT02058147)" (Rosenstock, J et al. Oral presentation 186-O) and "Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed-Ratio Combination vs. Insulin Glargine in Patients with T2DM: the LixiLan-L Trial (NCT02058160)" (Aroda, V et al. Oral presentation 238-O). The proprietary name for the titratable fixed-ratio combination is under consideration. Its safety and efficacy have not been evaluated by any regulatory authority. Results of Analyses:  LixiLan-O investigated the efficacy and safety of a once-daily single injection of the titratable fixed-ratio combination of insulin glargine 100 Units/mL and lixisenatide versus treatment with either lixisenatide or insulin glargine 100 Units/mL alone over a 30 week period in 1,170 patients whose type 2 diabetes was not adequately controlled on metformin alone or on metformin combined with a second oral anti-diabetic agent. Treatment with metformin was continued for all participants throughout the study while other oral agents were discontinued. After 30 weeks, the titratable fixed-ratio combination showed significantly greater reductions in HbA1c from baseline (8.1%) versus insulin glargine 100 Units/mL and lixisenatide (-1.6%, -1.3%, -0.9%, respectively; p<0.0001), reaching mean HbA1c levels of 6.5%, 6.8%, 7.3%, respectively. More subjects reached target HbA1c <7% with the titratable fixed-ratio combination (74%) versus insulin glargine 100 Units/mL (59%) or lixisenatide (33%). Mean body weight increased with insulin glargine 100 Units/mL (+1.1kg), and decreased with the titratable fixed-ratio combination (-0.3kg; difference 1.4kg, p<0.0001) and lixisenatide (-2.3kg). Documented (?70 mg/dL) symptomatic hypoglycemia was similar with the titratable fixed-ratio combination (25.6% of patients; 1.44 events/year; E/Y) and insulin glargine 100 Units/mL (23.6% of patients; 1.22 E/Y), but lower with lixisenatide (6.4% of patients; 0.34 E/Y). With the titratable fixed-ratio combination, 9.6% of participants experienced nausea and 3.2% experienced vomiting; with insulin glargine 100 Units/mL, 3.6% of participants experienced nausea and 1.5% experienced vomiting; and with lixisenatide 24.0% of participants experienced nausea and 6.4% experienced vomiting. LixiLan-L investigated the efficacy and safety of the titratable fixed-ratio combination of insulin glargine 100 Units/mL and lixisenatide versus treatment with insulin glargine 100 Units/mL over a 30 week period in 736 patients whose type 2 diabetes was not adequately controlled at screening on basal insulin, alone or combined with one to two oral anti-diabetic agents. Treatment with metformin, if previously taken, was continued throughout the study while other oral agents were discontinued. After 30 weeks, the titratable fixed-ratio combination showed significantly greater reductions in HbA1c from baseline (8.1%) versus insulin glargine 100 Units/mL (-1.1% versus -0.6%; p<0.0001), reaching mean HbA1c levels of 6.9% and 7.5%, respectively. More subjects reached target HbA1c <7% with the titratable fixed-ratio combination (55%) versus insulin glargine 100 Units/mL (30%; p<0.0001). Mean body weight increased with insulin glargine 100 Units/mL (+0.7 kg), and decreased with the titratable fixed-ratio combination (-0.7 kg; difference 1.4 kg, p<0.0001). Documented (?70 mg/dL) symptomatic hypoglycemia was similar with the titratable fixed-ratio combination (40% of patients; 3.0 events/year; E/Y) and insulin glargine 100 Units/mL (42.5% of patients; 4.2 E/Y). With the titratable fixed-ratio combination, 10.4% of participants experienced nausea, and 3.6% experienced vomiting; while with insulin glargine 100 Units/mL 0.5% of participants experienced nausea and 0.5% experienced vomiting.
  • • On September 14, 2015, Zealand announces that Sanofi reported a positive study outcome of LixiLan-L, a pivotal Phase III clinical trial with LixiLan for the treatment of Type 2 diabetes. In the LixiLan-L trial, LixiLan® successfully met the primary study endpoint of demonstrating a statistically superior reduction in HbA1c (average blood glucose over the previous three months) compared with insulin glargine 100 units/mL. Overall, LixiLan® had a safety profile reflecting those of insulin glargine 100 units/mL and lixisenatide. The planned regulatory submissions of LixiLan® by Sanofi are planned before year-end in the US and next year in Europe. LixiLan-L investigated the efficacy and safety of LixiLan® versus treatment with insulin glargine 100 units/mL over a 30 week period in 736 patients whose Type 2 diabetes was not adequately controlled at screening on basal insulin, alone or combined with one to two oral anti-diabetic agents. Treatment with metformin, if previously taken, was continued throughout the study. In July 2015, Sanofi announced the positive outcome of the first pivotal Phase III trial, LixiLan-O (see below). In the LixiLan-O trial, LixiLan showed a significant reduction in HbA1c over a 30 week period in 1,170 patients whose Type 2 diabetes was not adequately controlled on metformin alone or on metformin combined with a second oral anti-diabetic agent. Sanofi plans to communicate the full results of both LixiLan-O and LixiLan-L at a future scientific forum.
  • • On July 29, 2015, Zealand announces that Sanofi has reported the successful completion of LixiLan-O, one of two trials comprising the pivotal Phase III development program for LixiLan® as a novel treatment for patients with Type 2 diabetes. In the LixiLan-O trial, LixiLan® (fixed-ratio combination of lixisenatide and insulin glargine 100 units/mL) met the primary study objective of showing a statistically superior reduction in HbA1c (three months average blood glucose) compared with lixisenatide and compared with insulin glargine 100 units/mL. Overall, LixiLan had a safety profile similar to those of lixisenatide and insulin glargine 100 units/mL. LixiLan-O enrolled 1,170 patients with Type 2 diabetes, insufficiently controlled on metformin alone or on metformin plus a second oral anti-diabetic agent. The patients were randomized to 30 weeks of treatment with either LixiLan®, lixisenatide or insulin glargine, while treatment with metformin was continued for all participants throughout the study. Sanofi will communicate full results from the LixiLan-O trial at an appropriate scientific forum. Commenting on the results of LixiLan-O, Britt Meelby Jensen, President and CEO at Zealand, said: “These first Phase III conclusions confirm the therapeutic relevance of LixiLan and support the product’s potential as a new single-injection combination treatment for patients with Type 2 diabetes. This is an important event indicating that LixiLan remains on track towards planned regulatory submissions by Sanofi in the US in Q4 2015 and in the EU in Q1 2016 – and that Zealand remains on track towards potential milestone payments and royalty revenues, envisaged under our license agreement with Sanofi. I now look forward to the completion of the full Phase III program with results from the LixiLan-L trial later in Q3 and to Sanofi’s next regulatory steps.”
  • • On November 21, 2014, Zealand Pharma informed that Sanofi has confirmed that the Phase III development of LixiLan® remains on track with expected completion by Q3 2015. Sanofi also stated that the company plans for an FDA submission of LixiLan® as early as at the end of 2015.
  • • On February 6, 2014, Zealand Pharmab and Sanofi have announced that the clinical Phase III development program for LixiLan® has been started. LixiLan® is the Fixed-Ratio combination of Sanofi’s Lantus® (insulin glargine)  and Lyxumia® (lixisenatide), administered as single daily injection via a disposable pen. The Phase III program comprises two studies; LixiLan-O, evaluating the Fixed-Ratio combination of Lantus® and Lyxumia® in 1,125 patients insufficiently controlled on oral antidiabetics drugs (OADs), and LixiLan-L, evaluating LixiLan in 700 patients not at target on basal insulin. The Fixed-Ratio combination of Lantus® and Lyxumia® has been evaluated by Sanofi in a Phase IIb study versus Lantus® alone for its effect on glycemic control, as measured by HbA1c (glycosylated hemoglobin) reduction over 24 weeks, in Type 2 diabetic patients treated with metformin. The study was completed in 2013 and publication of the results is expected in connection with a medical congress later in 2014. The first study protocol for the LixiLan Phase III program was approved in January 2014, which triggered a previously announced milestone payment of USD 15 million to Zealand from Sanofi. The confirmed start of the Phase III studies is fully in line with announced expectations of a start in Q1 2014.
  • • On January 15, 2014, Zealand Pharma has announced that under its license agreement with Sanofi covering Lyxumia® (lixisenatide) and any combination product including lixisenatide, a milestone has been achieved in the advance of LixiLan, the once-daily single injection Lantus® (basal insulin) / Lyxumia® (lixisenatide) combination product, towards start of Phase III development in the 1st quarter of 2014. The milestone relates to the approval of the first Phase III study protocol for LixiLan by a Health Authority, triggering a $ 15 million payment to Zealand. The announced first LixiLan Phase III study protocol approval follows an update provided by Sanofi yesterday at the Annual J.P. Morgan Healthcare Conference, held in San Francisco, on the status of Lyxumia® and LixiLan. As part of the update, Sanofi confirmed plans to start Phase III development of LixiLan in the 1st quarter of 2014, narrowing its earlier guidance of an expected start in H1 2014. Further to this, in their presentation, Sanofi also confirmed that Lyxumia® is being introduced progressively in a larger number of countries as a new once-daily prandial GLP-1 agonist therapy for patients with Type 2 diabetes. In addition to its pronounced effect on lowering meal related glucose (post-prandial glucose, PPG), Lyxumia® has a beneficial effect on body weight and is associated with a limited risk of hypoglycemia. This profile makes Lyxumia® particularly well suited for use as add-on therapy to basal insulin, including Lantus®.
  • Under the license agreement with Sanofi, covering lixisenatide (Lyxumia®) and any combination products including lixisenatide, Zealand is eligible to up to $ 160 million in remaining milestones. Further, Zealand will receive tiered low double-digit percentage royalties on Sanofi's global sales of Lyxumia® and fixed low double-digit percentage royalties on global full net sales of the Lyxumia®/Lantus® combination product.

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