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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]

  • Last year, GEN presented 25 drugs in the pipeline for diabetes; now we bring you an updated list of drug candidates for which diabetes or complications from diabetes is at least one proposed or approved indication, and for which one indication has reached Phase III registration phases and/or approval or rejection of application. Entries are listed alphabetically.

    Transparency Market Research recently reported that the global market for diabetes management accounted for $41.9 billion in 2010 and is expected to attain a market size of $114.3 billion in 2016 following a growth rate of 18.2% CAGR. Accordingly, pharma and biotech firms are developing and clinically testing novel therapeutic formulations and experimenting with a range of delivery systems, some new and others old reliables. These include pens, syringes, smart sponges, oral, and tablets.

  • Afrezza® (insulin human [rDNA origin])

    Sponsor/Developer: MannKind

    Mechanism of action: Ultra rapid-acting mealtime insulin therapy administered using next-generation Dreamboat™ inhaler; inhalable powder

    Indication: Adults with type 1 or type 2 diabetes

    Regulatory review status: Awaiting decision from FDA on NDA submitted in October.

    Phase III trial(s):

    • Phase III, Study 175—Positive preliminary results in patients with type 2 diabetes announced August 14; primary efficacy endpoint of superiority to metformin was met, with or without a second or third oral medication, through a drop in mean A1c levels of 0.82% in patients using Afrezza, compared to a 0.42% decrease in patients taking metformin.
    • Phase III, Study 171—Positive preliminary results in patients with type 1 diabetes announced August 14; primary efficacy endpoint noninferiority to insulin aspart was met. Also, changes in pulmonary function observed in Afrezza patients using the Dreamboat inhaler were no different than those observed in Afrezza patients using MannKind’s first-generation MedTone inhaler.
  • Albiglutide (formerly Syncria)

    Sponsor/Developer: GlaxoSmithKline; developed by Human Genome Sciences, which licensed the drug for late-stage trials before Glaxo acquired the company for $3 billion last year

    Mechanism of action: Glucagon-like peptide (GLP) 1 agonist

    Indication: Once-weekly for adults with type 2 diabetes

    Regulatory review status:

    • U.S.—Awaiting decision by FDA following submission of BLA in January. FDA has set a Prescription Drug User Fee Act goal date of April 15, 2014, a date extended three months following agency requests for additional information.
    • EU—Awaiting decision by European Union on marketing authorization application submitted in March.

    Phase III trial(s): Clinical program assessed some 5,000 patients in eight Phase III studies (Harmony 1–8). Harmony 8, a 52-week trial comparing albiglutide to sitagliptin in type 2 diabetes patients with renal impairment, met its 26-week primary endpoints, showing clinically and statistically significant reductions in glycosylated hemoglobin levels (HbA1c) from baseline (8.08% for albiglutide and 8.22% for sitagliptin), as well as superiority versus sitagliptin (reduction of 0.83% vs. 0.52%) and significantly greater weight loss (-0.79 kg vs. -0.19 kg). An FDA-required meta-analysis ruled out excess cardiovascular risk according to an agency-set threshold.

  • Aleglitazar (RG1439)

    Sponsor/Developer: Roche

    Mechanism of action: Dual peroxisome proliferator-activated receptor (PPAR) α/γ activation

    Indication: Cardiovascular risk reduction in type 2 diabetes

    Phase III trial(s): All terminated in July due to what the company called “safety signals and lack of efficacy”, though several news reports quoted a company spokesman as saying the drug caused side effects in some patients that included fractures, kidney failure, and heart failure. On October 30, Roche told GEN it would “shortly” update a posting on ClinicalTrials.gov to reflect the termination. The posting, still on the website as of November 4, stated that the company was recruiting patients to assess the efficacy, safety, and tolerability of aleglitazar monotherapy compared with placebo in patients with type 2 diabetes who have not previously received antihyperglycemic therapy, based on change in Hb1Ac over 26 weeks, with estimated completion date of February 2014 (NCT01691755, last updated October 28).

  • Alogliptin (Nesina®, Vipidia™), Alogliptin and pioglitazone (Incresync™), Alogliptin and metformin (Vipdomet™)

    Sponsor/Developer: Takeda Pharmaceuticals and Furiex Pharmaceuticals

    Mechanism of action: DPP-4 inhibitor

    Indication: Oral treatment of type 2 diabetes, individually and in two fixed-dose combinations

    Regulatory review status:

    • EU—On September 24, the European Commission granted marketing authorization for Vipidia for adults with Type 2 diabetes patients who are uncontrolled on existing therapies; as well as for fixed-dose combinations with the thiazolidinedione pioglitazone (Incresync) and a combination with metformin (Vipdomet).
    • U.S.—In January, FDA approves alogliptin both alone (as Nesina) and in the fixed-dose combinations with metformin (under the name Kazano) and with pioglitazone (under the name Oseni), as adjuncts to diet and exercise.
    • China—China FDA issued an import drug license for Nesina for type 2 diabetes.

    Phase III trial(s): Two key studies were completed in 2013: ENDURE (Efficacy and Safety of Alogliptin Plus Metformin Compared to Glipizide Plus Metformin in Subjects With Type 2 Diabetes Mellitus), performed to support EU registrations, showed that 25 mg alogliptin in addition to metformin, offers superior durability of glycemic control, more favorable effects on glycohemoglobin, and no negative impact on weights compared to a sulphonylurea plus metformin. EXAMINE (EXamination of CArdiovascular OutcoMes: AlogliptIN vs. Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome), which compared alogliptin to standard of care, met its primary objective of demonstrating noninferiority of CV risk based on a primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Rates of hypoglycemia, malignancy, pancreatitis, serum aminotransferase elevations, and of serious adverse events were similar for the alogliptin and placebo groups. A total 13,000 patients were assessed in placebo- and active-controlled clinical trials worldwide.

  • Atrasentan

    Sponsor/Developer: AbbVie

    Mechanism of action: Selective endothelin-A receptor antagonist

    Indication: Oral once-daily treatment for diabetic nephropathy

    Phase III trial(s): Study Of Diabetic Nephropathy with Atrasentan (SONAR) trial now recruiting patients for a study designed to assess the effects of atrasentan (0.75 mg administered orally once daily) when added to standard of care on progression of kidney disease in patients with stage 2 to 4 chronic kidney disease (CKD) and type 2 diabetes. The study is expected to evaluate atrasentan's impact on renal outcomes, such as the onset of end-stage renal disease (ESRD), as defined by need for chronic dialysis, transplant or death due to renal failure progression. (NCT01858532, last updated October 7). SONAR trial announced in May, following positive results from Phase IIb studies presented at the 2013 European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Congress in Istanbul, Turkey. Findings from 12-week studies of two doses of atrasentan (0.75 mg and 1.25 mg) vs. placebo showed sustained reductions in urine albumin-to-creatinine ratio (UACR; the study’s primary endpoint) of 36% in the 0.75 mg, 44% in 1.25 mg group vs. increase of 2% in placebo group.

  • Dulaglutide (LY2189265)

    Sponsor/Developer: Eli Lilly

    Mechanism of action: GLP-1 analog

    Indication: Once-weekly for type 2 diabetes

    Regulatory review status: Awaiting decisions from FDA and EU on marketing approval submissions. Addressing investors October 3, Lilly said dulaglutide was one of three new medicines it expects to launch in 2014.

    Phase III trial(s):

    • Assessment of Weekly AdministRation of LY2189265 in Diabetes (AWARD) trials 1, 3, and 5—Positive top-line results announced October 22, 2012. Primary efficacy endpoints, as measured by reduction in HbA1c at the 1.5 mg dose, were met in all three studies. In September at the 49th European Association for the Study of Diabetes (EASD) Annual Meeting in Barcelona, Lilly released positive patient-reported health outcomes from the 52-week 978-patient AWARD-1, including reductions in HbA1c and weight at 26 and 52 weeks with dulaglutide 1.5 mg, and significant, positive improvements compared to baseline across several patient-reported indicators of diabetes management, measured using validated questionnaires.
    • AWARD trials 2 and 4—Positive top-line results announced April 16. Primary efficacy endpoints of noninferiority to insulin glargine, as measured by reduction of HbA1c at the 1.5 mg dose, were met in both studies. In AWARD 2, dulaglutide 1.5 mg dose demonstrated statistically superior reduction in HbA1c from baseline compared to insulin glargine at 52 weeks in patients with type 2 diabetes on metformin and glimeperide. In AWARD 4, dulaglutide 1.5 mg dose in combination with insulin lispro demonstrated statistically superior reduction in HbA1c from baseline compared to insulin glargine in combination with insulin lispro at 26 weeks.
    • Researching Cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial (NCT01394952)—Major cardiovascular events and other serious outcomes in persons with type 2 diabetes, compared with placebo (study is ongoing but not recruiting participants as of last update on ClinicalTrials.gov, September 3).
  • Empagliflozin (BI10773)

    Sponsor/Developer: Boehringer Ingelheim and Eli Lilly

    Mechanism of action: Sodium dependent glucose transporter 2 (SGLT2) inhibitor

    Indication: Oral treatment for adults with type 2 diabetes

    Regulatory review status: Awaiting decisions from regulators on marketing authorization applications submitted in March to FDA in March, and to European Medicines Agency. Addressing investors October 3, Lilly said empagliflozin was one of three new medicines it expects to launch in 2014.

    Phase III trial(s): Clinical trial program has enrolled more than 14,500 patients, and comprises more than 10 multinational clinical trials. In September at 49th European Association for the Study of Diabetes (EASD) Annual Meeting, BI and Lilly presented results based on efficacy data from 2,477 patients treated with empagliflozin (10 mg or 25 mg) for 24 weeks—either as monotherapy or as add-on to metformin, metformin with sulphonylurea, or pioglitazone with or without metformin. At week 24, patients treated with empagliflozin 10 mg and 25 mg showed significant reductions from baseline in HbA1c of 0.70% and 0.76% respectively (compared to a change of -0.08% for placebo), as well as a loss of 2.05 kg (4.5 lbs.) and 2.25 kg (about 5 lbs.) of body weight respectively from baseline, compared to a reduction of 0.24 kg for placebo.

    In June at the American Diabetes Association 73rd Scientific Sessions®, Lilly and BI cited additional pooled Phase III results of more than 14,500 patients enrolled in 12 multinational trials, including a large cardiovascular outcome trial showing that people with type 2 diabetes treated with empagliflozin vs. placebo achieved significant reductions after 24 weeks in HbA1c (of 0.62% for 10 mg and 0.68% for 25 mg), fasting plasma glucose (FPG; of 27.9 mg/dL for 10 mg, and 30.6 mg/dL for 25 mg), weight (of 3.99 lbs. for 10 mg and 4.43 lbs. for 25 mg), and blood pressure.

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

  • Ertugliflozin (MK-8835; PF-04971729)

    Sponsor/Developer: Merck & Co., licensed from Pfizer

    Mechanism of action: SGLT2 inhibitor

    Indication: Type 2 diabetes

    Phase III trial(s): Phase III trial listed online on ClinicalTrials.gov, but not yet recruiting patients as of November 4—A study evaluating the efficacy and safety of ertugliflozin monotherapy in the treatment of subjects with type 2 diabetes and inadequate glycemic control on diet and exercise, based on change in HbA1c after 26 weeks and numbers of participants experiencing adverse events, and discontinuing treatment due to adverse events (NCT 01958671, first received October 7).

    Listed as Phase II by both companies in their official pipelines, though the only trial open to patient recruitment as of November 4 was a Phase I study evaluating the effect of renal impairment on the pharmacokinetics, pharmacodynamics, safety, and tolerability of ertugliflozin in participants with type 2 diabetes and in healthy participants with normal renal function (NCT01948986, last updated October 29). Pfizer lists the compound as one of four diabetes compounds it has in Phase II; the others are PF-04937319 for type 2 diabetes, and two diabetic nephropathy compounds, PF-00489791 and PF-04634817.

    When they signed their $60 million-plus worldwide (except Japan) collaboration agreement for development and commercialization of ertugliflozin, the companies agreed to jointly commercialize ertugliflozin and ertugliflozin-containing fixed-dose combinations with metformin and Januvia® (sitagliptin) tablets. Merck and Pfizer also said they expected trials to begin late this year.



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