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Insight & Intelligence™ : Nov 11, 2013

New Diabetes Drugs Moving Through the Pipeline

Some feature more patient-friendly delivery methods.

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.

Fasiglifam (TAK-875)

Sponsor/Developer: Takeda

Mechanism of action: G-protein-coupled receptor (GPCR) 40 agonist

Indication: Type 2 diabetes

Phase III trial(s): Phase III, CCT-003 trial—Positive results presented at the 56th Annual Meeting of the Japan Diabetes Society in May; 24-week study assessing the efficacy and safety of once-daily fasiglifam 25 mg and 50 mg in 192 Japanese patients with type 2 diabetes. Statistically significant reduction in HbA1c was found in patients treated with fasiglifam 25 mg (-0.75) and fasiglifam 50 mg (-1.01) compared to placebo.

FIAsp (NN1218)

Sponsor/Developer: Novo Nordisk

Mechanism of action: Faster-acting formulation of insulin aspart (marketed as NovoLog® in the U.S., and NovoRapid® in the rest of the world).

Indication: Type 1 and 2 diabetes

Phase III “onset” trials: Three trials launched in August, the company disclosed October 31 in its third-quarter results:

  • Assessing efficacy and safety of faster-acting insulin aspart compared to insulin aspart in combination with basal insulin in 1,100 people with type 1 diabetes for 52 weeks;
  • Assessing efficacy and safety of faster-acting insulin aspart compared to insulin aspart in combination with basal insulin in 670 people with type 2 diabetes for 26 weeks; and
  • Comparing faster-acting insulin aspart used as part of a basal-bolus regimen with basal insulin treatment for 18 weeks in 220 people with type 2 diabetes.

Forxiga™ (dapagliflozin)

Sponsor/Developer: Bristol-Myers Squibb and AstraZeneca

Mechanism of action: SGLT2 inhibitor

Indication: Once-daily tablets for adults with type 2 diabetes

Regulatory review status:

  • Awaiting decision by FDA on its NDA resubmission, accepted for review by the agency in July. The Prescription Drug User Fee Act action date is January 11, 2014. FDA requested submission of additional clinical trial data in October 2012 when it postponed a decision on the original NDA, filed March 2011; FDA Endocrinologic and Metabolic Drugs Advisory Committee recommended against approval, July 2011. The complete response letter was issued January 2012.
  • Marketed in the EU, where it was approved last year as a once-daily oral medication for adults with type 2 diabetes—the first SGLT2 drug to gain such approval.
  • Awaiting decisions by China’s State Food and Drug Administration and Japan’s Ministry of Health, Labour and Welfare on regulatory submissions.

Phase III trial(s): In September, at the EASD annual meeting, the company and its partner, AstraZeneca, announced positive results from a Phase III study evaluating dapagliflozin in adults with type 2 diabetes who were inadequately controlled on combination treatment with metformin plus sulfonylurea. Patients treated with dapagliflozin 10 mg as an add-on therapy to metformin plus sulfonylurea showed significant improvements in HbA1c and significant reductions in fasting plasma glucose and in body weight compared to placebo at 24 weeks. Significant improvements were also observed in seated systolic blood pressure at eight weeks in patients treated with dapagliflozin compared to placebo.

Line extensions—As of August 1, AstraZeneca listed in Phase III several line extensions of Forxiga: a Forxiga/metformin fixed-dose combination; Forxiga as an add on to DPP-4; Forxiga as an add-on to insulin and add-on to metformin, long-term data; Forxiga in patients with high CV risk, studies 18 and 19, long-term data; Forxiga as triple therapy with metformin and a sulfonylurea; and Forxiga-DECLARE outcomes study, with an estimated filing date of 2020.

IDegLira (NN9068)

Sponsor/Developer: Novo Nordisk

Mechanism of action: Combination of Tresiba® (insulin degludec), a once-daily new-generation basal insulin analog; and Victoza® (liraglutide), a once-daily human GLP-1 analogue

Indication: Type 2 diabetes

Regulatory review status: Awaiting decision on marketing authorization application submitted in June to European Union.

Phase III trial(s):

  • Phase IIIa, DUal Action of Liraglutide and Insulin Degludec in Type 2 Diabetes (DUAL) I trial—Positive results detailed September 27 at 49th Annual European Association for the Study of Diabetes (EASD) Congress from 26-week trial comparing the efficacy and safety of IDegLira, in people with type 2 diabetes inadequately controlled with metformin with or without pioglitazone. Patients treated once daily with IDegLira showed an HbA1c reduction of 1.9% (from baseline of 8.3%), achieving primary endpoints of superiority versus liraglutide and noninferiority versus insulin degludec, with no weight gain and a low rate of hypoglycemia compared to insulin degludec in adults with type 2 diabetes.
  • Phase IIIa; DUAL II trial—Positive results announced December 19, 2012, of 26-week trial comparing IDegLira and Tresiba®, in addition to metformin, in people with type 2 diabetes who were previously inadequately controlled on basal insulin in combination with 1–2 oral antidiabetic agents. Patients treated once daily with IDegLira showed an HbA1c reduction of 1.9% (from baseline of 8.7%), meeting the primary endpoint of superiority compared to stand-alone therapy with Tresiba. IDegLira patients also experienced a weight loss of approximately 2.5 kg (5.5 pounds).

Invokana (canagliflozin)

Sponsor/Developer: Johnson & Johnson (Janssen Research & Development); licensed from Mitsubishi Tanabe Pharma for North America, South America, Europe, the Middle East, Africa, Australia, New Zealand, and parts of Asia

Mechanism of action: SGLT2 inhibitor

Indication: Once-daily tablets for adults with type 2 diabetes

Regulatory review status:

  • U.S.—Approved by FDA in March, two months after the agency’s Endocrinologic and Metabolic Drugs Advisory Committee voted 10–5 to recommend approval of the drug. That approval came with a requirement of five post-marketing studies: a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for malignancies, serious cases of pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities, and adverse pregnancy outcomes; a bone safety study; and two pediatric studies under the Pediatric Research Equity Act, including a pharmacokinetic and pharmacodynamic study, and a safety and efficacy study.
  • EU—Invokana won a positive opinion in September from the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP), removing a key hurdle to marketing approval for the drug by the European Commission.

Phase III trial(s): Clinical program enrolled 10,285 patients in nine studies assessing Invokana at 100 mg and 300 mg once-daily doses in placebo- and active comparator-controlled studies, as well as three large studies in special populations: older patients, patients with moderate renal impairment, and patients who had or were at risk for cardiovascular disease. Results showed that in addition to improvements in glycemic control, both doses of canagliflozin were associated with weight loss and reductions in blood pressure across clinical studies.

Ipragliflozin L-proline (ASP1941)

Sponsor/Developer: Astellas, MSD, and Kotobuki Pharmaceutical

Mechanism of action: SGLT2 inhibitor

Indication: Type 2 diabetes

Regulatory review status:

  • Japan—Awaiting decision from Ministry of Health, Labour and Welfare on market authorization application filed in March. Astellas agreed to manufacture and sell ipragliflozin, and co-promote the drug in Japan with MSD and Kotobuki Pharmaceutical, with which Astellas discovered the compound in a research collaboration.
  • U.S. and EU—Development has been discontinued “after comprehensive consideration of intensified competition for this product, and the prioritization in our pipeline,” Astellas said in its annual report for the year that ended March 31.

Phase III trial(s): Astellas said it conducted six Phase III studies to investigate the safety and efficacy of ipragliflozin, both as a monotherapy and in combination with six other hypoglycemic agents for a long-term period. According to Astellas, these studies confirmed the drug’s effectiveness and favorable safety, in combination with other hypoglycemic agents.

Luseogliflozin hydrate (TS-071)

Sponsor/Developer: Taisho Pharmaceutical

Mechanism of action: SGLT2 inhibitor

Indication: Once-daily for type 2 diabetes

Phase III trial(s): Five Phase III clinical trials in Japan, targeting 1,310 type 2 diabetes patient. Positive results of two trials were presented at the 49th Annual Meeting of the European Association for the Study of Diabetes (EASD) in Barcelona:

  • In a study of 158 Japanese patients with type 2 diabetes who received either 2.5 mg of luseogliflozin or a placebo orally once daily for 24 weeks, luseogliflozin significantly reduced hemoglobin A1c (HbA1c), the study’s primary endpoint. At the time of completing drug administration, the difference between the HbA1c reduction from the baseline and the placebo was -0.75%.
  • In a study of 299 Japanese patients with type 2 diabetes receiving 2.5 mg of luseogliflozin orally once-daily for 52 weeks (a dosage was increased to 5 mg when glycemic control was insufficient), luseogliflozin significantly reduced the level of HbA1c, the study’s primary endpoint. HbA1c reduction from the baseline was -0.50%. Among both studies’ secondary endpoints, according to Taisho, luseogliflozin significantly improved postprandial blood glucose levels two hours after meals and fasting blood glucose levels, while also significantly lowering body weight and abdominal circumference.

LixiLan (lixisenatide+ insulin glargine)

Sponsor/Developer: Sanofi; lixisenatide licensed from Zealand Pharma

Mechanism of action: Combination of GLP-1 agonist (Lyxumia or lixisenatide) and basal insulin analog (Lantus® or insulin glargine)

Indication: Type 2 diabetes

Phase III trial(s): Set to launch in the first half of 2014. Sanofi is evaluating both a Fix-Flex device allowing for flexible Lantus dosing combined with a fixed lixisenatide dose, as well as a Fixed-Ratio device in Phase IIb. Positive results were announced from clinical studies of “free combination” lixisenatide and Lantus in about 1,250 patients, according to Zealand Pharma. Sanofi lists the drug in its Phase II pipeline, according to Sanofi’s Early Stage Pipeline Pharma & Vaccines, as of August 2013.

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%).