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Nov 11, 2013

New Diabetes Drugs Moving Through the Pipeline

Some feature more patient-friendly delivery methods.

New Diabetes Drugs Moving Through the Pipeline

Each entry includes the name of the drug candidate; the sponsor and any collaboration partners involved; method of action; indication; Phase III trials; and other information where applicable. [© Radu Razvan - Fotolia.com]

  • Lyxumia® (lixisenatide)

    Sponsor/Developer: Sanofi; licensed from Zealand Pharma

    Mechanism of action: GLP-1 agonist

    Indication: Once-daily for type 2 diabetes

    Regulatory review status:

    • U.S.—Application for marketing authorization withdrawn in September, after FDA requested an analysis of early interim results from the ongoing ELIXA cardiovascular outcomes study, expected to be completed in 15 months, at which point a new NDA will be submitted to the agency in 2015, Sanofi said. “Sanofi believes that potential public disclosure of early interim data, even with safeguards, could potentially compromise the integrity of the ongoing ELIXA study,” the company stated September 12. Application filed with FDA in December 2012.
    • EU—Approved for use with basal insulin and/or oral glucose-lowering medicinal product in February by the European Commission, following positive CHMP recommendation in November 2012. Marketing authorization application submitted November 2011.
    • Japan— Approved for use in combination with basal insulin in June by Ministry of Health, Labour and Welfare.

    Phase III trial(s): GetGoat clinical program consisting of 11 clinical studies with a total 5,000 patients. The studies showed significant HbA1c reductions, a pronounced post-prandial glucose-lowering effect and a beneficial effect on body weight in adults with type 2 diabetes.

    Other Phase III trials:

    • Comparing the Efficacy and Safety of lixisenatide to Insulin Glulisine Once Daily and Insulin Glulisine Three Times Daily in Patients with Type 2 Diabetes, Insufficiently Controlled with Insulin Glargine with or without Metformin (NCT01768559, last updated October 30);
    • Assessing effects of two single subcutaneous lixisenatide doses (5 and 10 µg) as compared to placebo in reducing postprandial glucose in type 2 diabetic pediatric population (10–17 years old) and adults as controls (NCT01572649, last updated October 30); and
    • Evaluating effect of lixisenatide vs. placebo over 24 weeks on glycemic control, as evaluated by HbA1c reduction, in older type 2 diabetes patients who are inadequately controlled with their current antidiabetic treatment regimen (NCT01798706, last updated October 29).
  • LY2605541 (basal insulin peglispro)

    Sponsor/Developer: Eli Lilly

    Mechanism of action: Basal insulin analog

    Indication: Types 1 and 2 diabetes

    Phase III trial(s): Recruiting patients for three trials:

    • Comparing LY2605541 to human insulin NPH over 26 weeks, based on change in participants' overall blood sugar control, number of nighttime low blood sugar episodes, number of participants that reach blood sugar targets without low nighttime blood sugar episodes, and total number of low blood sugar episodes reported (NCT01790438, last updated October 11);
    • Comparing safety and efficacy of different dosing schedules of once-daily LY2605541 and their effects on HbA1c on patients treated for 36 weeks during the 42-week IMAGINE 7 study (NCT01792284, last updated September 23); and
    • Comparing LY2605541to insulin glargine over 26 weeks in Asian insulin naïve participants who have been treated with oral anti hyperglycemia medications (NCT01894568, last updated September 13).

    Depending on outcome, Lilly said, it could begin sharing Phase III results and submitting marketing applications to regulators in 2014. Addressing investors October 3, Lilly said LY2605541 was one of three new medicines it expects to launch sometime beyond 2014.

    Phase II studies: At the 73rd American Diabetes Association Scientific Sessions® in Chicago, Lilly presented details of reductions in required prandial insulin in LY2605541-treated patients compared to those treated with insulin glargine, in a study of 137 patients. Initial clinical data showed that LY2605541-treated patients with type 1 diabetes had greater improvements in glycemic control along with reduced mealtime insulin doses compared to insulin glargine-treated patients. Additional analysis showed that among those who completed the Phase II study, which included eight weeks of treatment with LY2605541 and eight weeks of insulin glargine, LY2605541 led to significantly lower average blood glucose levels (143.1 mg/dL vs. 151.7 mg/dL) with statistically significantly less mealtime insulin per day compared to insulin glargine. Reduced mealtime insulin use was found per day and across all major meals—a 13.7% reduction at breakfast, 18.6% at lunch, 22.4% at dinner, and a 20.7% overall reduction.

    At the 72nd American Diabetes Association (ADA) Scientific Sessions® in Philadelphia, Lilly and then-partner Boehringer Ingelheim said LY2605541 was associated with greater improvements of glycemic control (lowering blood sugar levels) than insulin glargine in type 1 diabetes patients, while LY2605541 and insulin glargine showed similar glycemic control improvements in type 2 diabetes patients. Later last year at the 48th European Association for the Study of Diabetes (EASD) Annual Meeting in Berlin, clinical results were presented showing a statistically significant 48% baseline-adjusted reduction in nocturnal hypoglycemia compared with insulin glargine (0.25 vs. 0.39 events/ 30 days/patient, after adjusting for baseline hypoglycemia events), while patients treated with LY2605541 reported a statistically significant reduction in the anxiety and fear associated with experiencing a hypoglycemic event based upon the Adult Low Blood Sugar Survey (ALBSS).

    Lilly reassumed sole worldwide development and commercialization rights to LY2605541 in January, after Boehringer Ingelheim elected to terminate a collaboration with Lilly for that compound, but not other compounds co-developed through an alliance launched in 2011.

  • LY2963016 (new insulin glargine product)

    Sponsor/Developer: Eli Lilly and Boehringer Ingelheim

    Mechanism of action: Basal insulin

    Indication: Types 1 and 2 diabetes

    Regulatory review status: Awaiting decision from on marketing authorization applications submitted to FDA and European Medicines Agency (EMA). In July, the EMA accepted for review the companies’ application, filed through the agency’s biosimilar pathway. Addressing investors October 3, Lilly said LY2963016 was one of three new medicines it expects to launch sometime beyond 2014.

    Phase III trial(s): Phase III ELEMENT trials—Lilly has concluded a pair:

    • Comparing the effectiveness and safety of LY2963016 vs. Lantus when taken once daily by adults with type 1 diabetes with insulin lispro before meals three times a day (ELEMENT I, NCT01421147, last updated April 23); and
    • Comparing the effectiveness and safety of LY2963016 vs. Lantus in controlling blood sugar levels in adults with type 2 diabetes, in combination with two or more oral diabetes medications (ELEMENT II, NCT01421459, last updated January 11).

    One of three compounds slated for development through a diabetes alliance of the companies.

  • Omarigliptin (MK-3102)

    Sponsor/Developer: Merck & Co.

    Mechanism of action: DPP-4 inhibitor

    Indication: Once-weekly for adults with type 2 diabetes

    Phase III trial(s): Recruiting patients for 24-week trials:

    • Evaluating drug efficacy and safety of MK-3102 in participants with type 2 diabetes and moderate or severe chronic renal insufficiency or end stage renal disease on dialysis with inadequate glycemic control (NCT01698775, last update October 24);
    • Evaluating safety and efficacy of once-weekly MK-3102 in participants 18 to <45 years of age with type 2 diabetes and inadequate glycemic control (NCT01814748, last updated October 22);
    • Evaluating safety and efficacy of MK-3102 dosed once-weekly in participants with type 2 diabetes who have inadequate glycemic control on diet and exercise (NCT01717313, last updated October 9);
    • Evaluating the safety and efficacy of MK-3102 compared with glimepiride in type 2 diabetes participants with inadequate glycemic control on metformin monotherapy (NCT01682759, last updated October 9);
    • Evaluating safety and efficacy of adding MK-3012 in participants with type 2 diabetes with inadequate glycemic control on metformin and sulfonylurea, compared with placebo (NCT01704261, last updated October 9);
    • A noninferiority study comparing MK-3102 with sitagliptin in participants with type 2 diabetes with inadequate glycemic control on metformin therapy (NCT01841697, last updated October 4);
    • Assessing safety and efficacy of MK-3102 compared with glimepiride in type 2 diabetes participants who are metformin intolerant or who have a contraindication to the use of metformin (NCT01863667, last updated October 24);
    • Evaluating the cardiovascular safety profile of MK-3102 in participants with type 2 diabetes compared with placebo (NCT01703208, last updated October 30); and
    • Assessing safety and efficacy of MK-3102 compared to placebo in participants with inadequate glycemic control on metformin monotherapy (NCT01755156, last updated October 9).

    Phase IIb results: In a 12-week study of 685 patients, successfully met primary endpoint of reduced HbA1c from baseline compared to placebo across doses in patients with type 2 diabetes. In the full study population at 12 weeks, the placebo-adjusted reduction from baseline in HbA1c was 0.71% with MK-3102 at 25 mg; 0.67% with 10 mg; 0.49% with 3 mg; 0.50% with 1 mg; and 0.28% with 0.25 mg.

  • Ryzodeg® (insulin degludec + insulin aspart)

    Sponsor/Developer: Novo Nordisk

    Mechanism of action: Soluble fixed combination of basal insulin with bolus insulin aspart (NovoRapid®)

    Indication: Once-daily for types 1 and 2 diabetes

    Regulatory review status:

    • U.S.—Marketing application rejected in February by FDA, which in a Complete Response Letter requested additional safety data from a new cardiovascular outcomes trial, as well as correction of violations alleged by the agency to have occurred following inspection last year of the company’s manufacturing plant in Novo Alle, Bagsvaerd Denmark. Novo Nordisk said the additional data was unlikely to be gathered during 2013, later adding it could take two to three years. Rejection came despite favorable recommendation in November 2012 by FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, albeit in an 8–4 vote and with commitment to a post-approval cardiovascular outcomes trial. Original NDA submitted September 2011.
    • EU—Approved in January by European Commission, which granted marketing authorization simultaneously to Tresiba (insulin degludec). Decision followed positive opinion by CHMP in October 2012, 13 months after submission of the drug’s marketing authorization application. Commercial launches in Europe are planned through 2014.
    • Japan—Approved in February by Ministry of Health, Labor and Welfare.

    Phase III trial(s): Novo Nordisk is recruiting patients for a new Phase III clinical trial aimed at investigating the efficacy and safety of insulin degludec/insulin aspart once daily, plus insulin aspart for the remaining meals, compared with insulin detemir once or twice daily plus meal time insulin aspart in children and adolescents with type 1 diabetes (NCT01835431, last updated October 23).

  • Semaglutide (NN9535)

    Sponsor/Developer: Novo Nordisk

    Mechanism of action: GLP-1 analog

    Indication: Once-weekly for type 2 diabetes

    Phase III trial(s): SUSTAIN™ study—Part of a global clinical development program expected to include more than 8,000 patients. Recruiting patients for SUSTAIN 6, a trial to evaluate cardiovascular and other long-term outcomes with semaglutide in subjects with type 2 diabetes. The maximum trial duration (up to a maximum 148 weeks) will depend on the accrual of major adverse cardiovascular events (MACE) in this trial and the remaining research program (NCT01720446, last updated October 11).

    Also recruiting patients for Phase I study in Europe investigating the safety, tolerability, and pharmacokinetics of single and multiple doses of oral semaglutide in healthy male subjects (NCT01866748, last updated October 17).

    Novo Nordisk disclosed plans for two additional Phase III trials and an additional Phase II study, none of which are recruiting patients.

    Manufacturing plans—On May 6, Novo Nordisk said it will spend DKK 380 million (about $69 million) toward converting manufacturing capacity in its existing Kalundborg, Denmark, plant to allow for future production of semaglutide. The project will create 50 new production and engineering jobs to a facility that now employs more than 2,400 people. The converted plant is expected to be operational in the first quarter of 2014.

  • SYR-472 (trelagliptin succinate)

    Sponsor/Developer: Takeda Pharmaceuticals and Furiex Pharmaceuticals

    Mechanism of action: DPP-4 inhibitor

    Indication: Once-weekly oral treatment for type 2 diabetes

    Phase III trial(s): Earlier this year, began recruiting patients for three Phase III trials:

    • Evaluating safety and efficacy of treatment with SYR-472 compared with alogliptin 25 mg and placebo based on HbA1c change after 24 weeks (NCT01632007, last updated June 17);
    • Evaluating the safety and efficacy, based on HbA1c change, of 52-week treatment with SYR-472 in patients with type 2 diabetes with inadequate glycemic control despite diet and/or exercise therapies or treatment with an existing oral antidiabetic drug added to diet and/or exercise therapies (NCT01431807, last updated January 17); and
    • Assessing efficacy and safety of 100 mg of SYR-472 based on HbA1c change after seven days (NCT01751360, last updated January 8).
  • Tresiba® (Insulin degludec)

    Sponsor/Developer: Novo Nordisk

    Mechanism of action: Once-daily basal insulin

    Indication: Types 1 and 2 diabetes

    Regulatory review status:

    • U.S.—Marketing application rejected in February by FDA, which in a Complete Response Letter requested additional safety data from a new cardiovascular outcomes trial, as well as correction of violations alleged by the agency to have occurred following inspection last year of the company’s manufacturing plant in Novo Alle, Bagsvaerd Denmark. Novo Nordisk said the additional data was unlikely to be gathered during 2013, later adding it could take two to three years. In August, the company said it expected to launch “before the end of the year” a Phase III study comparing Tresiba to Lantus in some 7,500 patients with diabetes. Rejection came despite favorable recommendation in November 2012 by FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, albeit in an 8–4 vote and with commitment to a post-approval cardiovascular outcomes trial. Original NDA submitted September 2011.
    • EU—Approved in January by European Commission, which also granted marketing authorization simultaneously to Ryzodeg (insulin degludec + insulin aspart). Decision followed positive opinion by CHMP; available in two concentrations enabling maximum doses of 80 and 160 units per injection. Commercial launches in Europe are planned through 2014.
    • Japan—Approved September 2012 for type 1 and type 2 diabetes.

    In June, the company released the first data from BEGIN™ONCE LONG, a one-year extension trial on Tresiba, showing that type 2 diabetes patients receiving Tresiba had statistically significant better health-related quality of life compared to patients receiving insulin glargine. BEGIN ONCE LONG was within one of two clinical programs consisting of 17 trials in more than 40 countries, with more than 11,000 people assessed.

    In September, Novo Nordisk presented data at the Annual Meeting of the European Association for the Study of Diabetes (EASD) showing that most type 2 diabetes patients receiving Tresiba plus metformin were able to maintain good glycemic control for 2.5 years. Specifically, 80.5% of patients in good glycemic control after two years with Tresiba plus metformin maintained HbA1c below 7% when continuing treatment with Tresiba and metformin only, in a further 26-week add-on study that recruited patients already receiving Tresiba once-daily plus metformin for two years, through BEGIN ONCE LONG trial plus an additional year-long extension.

    Novo Nordisk is also recruiting patients to two Phase III trials:

    • A study of efficacy and safety of the combination of insulin degludec and insulin aspart once daily, plus insulin aspart for the remaining meals in children and adolescents with type 1 diabetes, based on change from baseline in HbA1c after 16 weeks (NCT01835431, last updated October 23); and
    • A study in Asia, Europe, and North and South America comparing efficacy and safety of a combination of Tresiba and Victorza (liraglutide) to insulin glargine, based on change from baseline in HbA1c over 26 weeks (NCT01952145, last updated October 21).
  • U300

    Sponsor/Developer: Sanofi

    Mechanism of action: Insulin glargine

    Indication: Type 1 and 2 diabetes

    Regulatory review status: Marketing authorization applications to be filed for U.S. and EU during the first half of 2014, Sanofi said June 22 at the 73rd Scientific Sessions of the American Diabetes Association.

    Phase III trial(s): Positive preliminary results in patients with type 2 diabetes announced June 22 at the 73rd Scientific Sessions of the American Diabetes Association. Sanofi released details of EDITION I, evaluating efficacy and safety of U300 vs. Lantus in people with type 2 diabetes using basal plus mealtime insulin. Population of 807 was randomized to once-daily evening new insulin or Lantus (n=403) while continuing mealtime insulin. Primary endpoint was change in HbA1c from baseline to month 6. Results showed similar reductions in HbA1c from baseline between new insulin U300 and Lantus at six months in patients with challenging treatment needs. About 40% of study participants with uncontrolled blood sugar levels despite receiving a combined therapy of oral antidiabetic agents plus basal and prandial insulins reached glycemic control at month 6 both using U300 (39.6%) and Lantus (40.9%).

    Sanofi also released topline results of the EDITION II trial, assessing efficacy and safety of U300 in a type 2 diabetes population of 811 patients treated with basal insulin plus oral antidiabetic therapy. Top-line results showed U300 achieved similar blood sugar reduction while fewer patients experienced nighttime low blood sugar events compared with Lantus. Full EDITION II results showed a 21% reduction in severe or confirmed nocturnal low blood sugar from month 3 to month 6. Significantly fewer patients had nocturnal (severe and/or confirmed, i.e., less than or equal to 70 mg/mL) hypoglycemia during months 3 to 6 (prespecified main secondary endpoint: 36.1% vs. 46.0%).



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