A Survey of Promising Late-Stage Diabetes Drugs

 

THIS IS DEC2012 COMPILATION. READER MAY ENCOUNTER AN APPROVED OR DROPPED ENTRY

A variety of new drugs are in development for the treatment of type 1 or type 2 diabetes. In addition to new dipeptidyl peptidase-4 (DPP-IV) inhibitors, glucagon-like peptide (GLP) 1 analogs, basal insulin analogs, and new insulin formulations, there are also unique dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist, G-protein-coupled receptor (GPR) 40 agonist, sodium dependent glucose transporter 2 (SGLT2) inhibitor, and several other unique agents now in development.

A list of 25 drug candidates has been compiled for which diabetes is at least one proposed or approved indication, and for which one indication has reached Phase III or Registration phases. Each entry includes the name of the drug candidate, the sponsor, and, where applicable, chemical structures, collaboration partners; method of action; indication (by market, where applicable); and phase of trial. Some products are still in clinical trial phases for new indications or formulations after winning marketing approval for initial indications; these approvals, where applicable, are listed on the bottom of each entry.

Albiglutide (formerly Syncria)

Sponsor/Developer: GlaxoSmithKline; developed by Human Genome Sciences, which licensed the drug for late-stage trials before Glaxo acquired HGS in a $3 billion deal completed Aug. 3

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

Indication (Phase): Once-weekly for type 2 diabetes (Phase III completed; NDA expected to be filed early 2013)

https://newdrugapprovals.wordpress.com/2013/03/09/maa-eu-gsk-submits-diabetes-drug-eperzan-albiglutide-in-eu/

Alogliptin (Nesina®)

Sponsor/Developer: Takeda Pharmaceuticals and Furiex Pharmaceuticals

Mechanism of action: DPP-4 inhibitor

Indication (Phase): U.S.—Oral treatment of type 2 diabetes, individually and as a fixed-dose combination (FDC) with the thiazolidinedione pioglitazone (Registration; NDA re-submitted July 2012 after initial NDA rejected via complete response letter April 2012)

EU—Oral treatment of type 2 diabetes (Registration; MAA submission accepted May 2012)

Japan—Marketed as Nesina®; Approved 2011 for oral treatment of type 2 diabetes as FDC with pioglitazone; Approved 2010 for oral treatment of type 2 diabetes

Update: On January 25, 2013, U.S. Food and Drug Administration approved Takeda Pharmaceutical Co’s alogliptin to treat type 2 diabetes as a standalone drug and in two other formulations in combination pills with older diabetes medicines. Alogliptin by itself will be sold under the brand name Nesina. The drug in combination with metformin will be sold as Kazano, and alogliptin along with pioglitazone – the chemical name for Takeda’s Actos – will be sold as Oseni.

Chemical Structure of Alogliptin (Nesina®)

Chemical Name: 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile

CAS number: 850649-62-6

https://newdrugapprovals.wordpress.com/2013/04/29/china-market-takeda-and-sanofi-sign-co-promotion-agreement-to-expand-reach-of-diabetes-treatment-alogliptin-in-china/

ASP1941 (ipragliflozin)

Sponsor/Developer: Astellas; co-developed with Kotobuki

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

Indication (Phase): Japan—Type 2 diabetes with inadequate glycemic control while on a sulfonylurea or pioglitazone alone (Phase III)

U.S. and EU—Development discontinued “after comprehensive consideration of intensified competition for this product, and the prioritization in our pipeline”

Canagliflozin

Sponsor/Developer: Johnson & Johnson (Janssen Research & Development); licensed from Mitsubishi Tanabe Pharma

Mechanism of action: SGLT2 inhibitor

Indication (Phase): U.S.—Once-daily oral treatment for adults with type 2 diabetes (registration; NDA filed May 2012)

EU—Once-daily oral treatment for adults with type 2 diabetes (registration; MAA filed June 2012)

Canagliflozin is the most advanced diabetes therapy in the pipeline at J&J.

Chemical Structure of Canagliflozin

Chemical Name for Canagliflozin:  (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

CAS number: 842133-18-0

https://newdrugapprovals.wordpress.com/2013/05/28/mitsubishi-tanabe-seeks-manufacturing-marketing-approval-for-ta-7284-canagliflozin-in-japan/

Darapladib (SB-480848)

Sponsor/Developer: GlaxoSmithKline; developed by Human Genome Sciences, which licensed the drug for late-stage trials before Glaxo acquired HGS in a $3 billion deal completed Aug. 3.

Mechanism of action: Lp-PLA2 inhibitor

Indication (Phase): U.S.—Diabetic macular edema (DME; Phase II as of July 2012; expected to be completed December 2012); Atherosclerosis (Phase III; AIM III study recruiting patients as of November 2012); Atherosclerosis (Phase III; ongoing but not recruiting patients); Chronic coronary heart disease (Phase III; STABILITY trial, ongoing but not recruiting patients as of November); Cardiovascular event (heart attack or stroke) within 30 days after an acute coronary syndrome (Phase III; ongoing but not recruiting as of November 2012); Severe renal impairment (Phase I; recruiting as of November 2012)

EU—DME (Phase II)

Chemical Structure of  Darapladib (SB-480848)

Chemical Name for Darapladib (SB-480848): N-(2-diethylaminoethyl)-2-[2-[(4-fluorophenyl)methylsulfanyl]-4-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-1-yl]-N-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]acetamide

CAS number: 356057-34-6

Dulaglutide (LY2189265)

Sponsor/Developer: Eli Lilly

Mechanism of action: GLP-1 analog

Indication (Phase): Once-weekly, for type 2 diabetes (Phase III; results from three of five AWARD trials released Oct. 22; AWARD 2 and 4 results to be released “in the next few months”; major cardiovascular events and other serious outcomes in persons with type 2 diabetes (Phase III; REWIND trial, recruiting as of November 2012); Type 2 diabetes compared with glimepiride, liraglutide, insulin glargine (Phase III; recruiting as of November 2012); Japanese participants with type 2 diabetes, with monotherapy of oral antihyperglycemic medications (Phase III; recruiting as of November 2012); Chinese participants with type 2 diabetes (Phase III; recruiting as of November 2012)

NDA to be submitted in 2013

https://newdrugapprovals.wordpress.com/2013/06/25/dulaglutide-shows-superiority-in-phase-3-trials/

Empagliflozin (BI10773)

Sponsor/Developer: Eli Lilly and Boehringer Ingelheim

Mechanism of action: SGLT 2 inhibitor

Indication (Phase): Oral treatment of adults with type 2 diabetes (Phase III, expected to conclude by year’s end); Oral treatment of adults with type 2 diabetes plus high blood pressure (Phase IIb; trial results released Oct. 2)

NDA, MAA filings planned for 2013

Chemical Structure of Empagliflozin (BI10773)

Chemical name of Empagliflozin (BI10773): (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol

CAS number：864070-44-0

Forxiga™ (dapagliflozin)

Sponsor/Developer: Bristol-Myers Squibb and AstraZeneca

Mechanism of action: SGLT2 inhibitor

Indication (Phase): EU—Approved Nov. 14 as once-daily oral medication for adults with type 2 diabetes; first SGLT2 drug to gain such approval

U.S.—Once-daily oral medication for adults with type 2 diabetes (Registration; FDA in October 2012 postpones decision three months pending submission of additional clinical trial data; complete response letter issued January 2012; FDA Endocrinologic and Metabolic Drugs Advisory Committee recommends against approval, July 2011; NDA filed March 2011)

Japan—Diabetes (Registration; NDA expected to be filed in first half of 2013)

Forxiga is the first medicine in the new SGLT2 class to gain regulatory approval for the treatment of type 2 diabetes. Dapagliflozin is awaiting approval in the USA, where the Food and Drug Administration earlier this year issued a complete response letter requesting additional data.

In addition to dapagliflozin, AstraZeneca and Bristol-Myers Squibb’s diabetes alliance included the approved DPP-4 inhibitor Onglyza (saxagliptin) and a form of the drug combined with metformin called Kombiglyze.

Chemical Structure of Dapagliflozin (Forxiga)

Chemical Name of Dapagliflozin (Forxiga): (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

CAS number: 461432-26-8

IDegLira (NN9068)

Sponsor/Developer: Novo Nordisk

Mechanism of action: Combination of Tresiba® (insulin degludec) and Victoza® (liraglutide)

Indication (Phase): Type 2 diabetes (Phase IIIa; DUAL II study, expected to be completed by year’s end); Type 2 diabetes in patients previously inadequately controlled on one or two oral anti-diabetic drugs (Phase IIIa; DUAL I study, results released August 2012)

Lantus® (insulin glargine)

Sponsor/Developer: San

Lantus® (insulin glargine)

ofi

Mechanism of action: Human insulin analog

Indication (Phase): U.S.—Prediabetes or early type 2 diabetes with high cardiovascular risk (Phase III; ORIGIN study; results announced Oct. 5); Approved for adults and children with type 1 diabetes, and adults with type 2 diabetes

EU—On May 25, European Commission approved changing the indication to “Treatment of diabetes mellitus in adults, adolescents and children aged 2 years and above,” from “treatment of adults, adolescents and children of 6 years or above with diabetes mellitus, where treatment with insulin is required”

https://newdrugapprovals.wordpress.com/?s=Lantus%C2%AE+%28insulin+glargine%29&submit=

Lyxumia® (lixisenatide; AVE0010)

Sponsor/Developer: Sanofi; in-licensed from Zealand Pharma

Mechanism of action: GLP-1 agonist

Indication (Phase): U.S.—Once-daily, for adults with type 2 diabetes with oral glucose-lowering medicinal products and/or basal insulin (Phase III results announced June 2012; NDA expected by year’s end)

EU—Once-daily, for adults with type 2 diabetes with oral glucose-lowering medicinal products and/or basal insulin (Registration; MAA submitted November 2011; recommended for approval by Committee for Medicinal Products for Human Use (CHMP) on Nov. 15)

https://newdrugapprovals.wordpress.com/2013/02/05/eu-approves-lyxumia-lixisenatide-sanofi-for-the-treatment-of-type-2-diabetes/

LY2605541

Sponsor/Developer: Eli Lilly and Boehringer Ingelheim

Mechanism of action: Basal insulin analog

Indication (Phase): Adults with type 1 diabetes, compared with insulin glargine and insulin lispro (Phase III; IMAGINE 1 study; ongoing but not recruiting as of November 2012); Adults with type 1 diabetes, compared with insulin glargine and insulin lispro (Phase III; IMAGINE 3 study; recruiting as of November 2012); Adults with type 2 diabetes, compared with insulin glargine and insulin lispro (Phase III; IMAGINE 4 study; recruiting as of November 2012); Adults with type 2 diabetes, compared with insulin glargine (Phase III; IMAGINE 2 and IMAGINE 5 studies; recruiting as of November 2012); Adults with type 1 diabetes, compared with insulin glargine (Phase I); Patient reported results from Phase II announced Oct. 2

LY2963016

Sponsor/Developer: Eli Lilly and Boehringer Ingelheim

Mechanism of action: Basal insulin analog

Indication (Phase): Type 1diabetes, compared with Lantus and Insulin Lispro (Phase III; ELEMENT I study ongoing but not recruiting as of August 2012); Type 2 diabetes, compared with Lantus and oral antihyperglycemic medications (Phase III; ELEMENT II study completed as of September 2012); Comparison to Lantus, healthy participants (Phase I, completed September 2012); Comparison to Lantus after single dose for healthy subjects (Phase I, recruiting as of September 2012); Type 1 diabetes, comparison to Lantus (Phase I, completed July 2012); Comparison to Lantus, pharmacokinetics and pharmacodynamics (Phase I, completed July 2012); Comparison to Lantus after single dose for healthy subjects (Phase I, completed 2011)

Metreleptin

Sponsor/Developer: Bristol-Myers Squibb; Developed by Amilyn Pharmaceuticals, acquired by BMS in a $7 billion deal completed Aug. 8

Mechanism of action: Leptin analog

Indication (Phase): Diabetes and/or hypertriglyceridemia in patients with rare forms of lipodystrophy (Registration; BLA submitted April 2012; Fast Track designation)

MK-3102

Sponsor/Developer: Merck & Co.

Mechanism of action: DPP-4 inhibitor

Indication (Phase): Once-weekly for adults with type 2 diabetes: Comparison with Sitagliptin in Japanese participants with type 2 diabetes (Phase III; recruiting as of November 2012); Comparison with chronic kidney disease or kidney failure on dialysis (Phase III; recruiting as of November 2012); Add-on to oral antihyperglycemic agent study in Japanese participants with type 2 diabetes (Phase III; recruiting as of November 2012); Compared with glimepiride in participants with type 2 diabetes who have inadequate glycemic control on metformin (Phase III; recruiting as of November 2012); Adults with type 2 diabetes and inadequate glycemic control following combination therapy of glimepiride and metformin (Phase III; recruiting as of November 2012); Phase IIb results announced in October 2012

Merck is the dominant player in the market for diabetes drugs known as DPP-4 inhibitors, with the blockbuster success of its first-in-class therapy Januvia (Sitagliptin). And the Whitehouse Station, NJ-based pharma giant has built a pipeline of novel and combo therapies that could build on this position.In September, Merck published phase 2b results for MK-3102 that showed efficacy and safety nearly even with Januvia. Janumet is more effective for some patients, since it’s a combination of Januvia and metformin, but MK-3102 is convenient with a once-weekly dosage.

Chemical Structure of Januvia(Sitagliptin Phosphate):

Nucynta® ER (tapentadol)

Sponsor/Developer: Johnson & Johnson and Grunenthal

Mechanism of action: Centrally-acting synthetic analgesic; agonist of the μ-opioid receptor and as a norepinephrine reuptake inhibitor

Indication (Phase): Approved August 2012 for diabetic peripheral neuropathy (extended release formulation)

Ranolazine

Sponsor/Developer: Gilead

Mechanism of action: Late sodium current inhibitor

Indication (Phase): Type 2 diabetes (Phase III)

A Phase 3 Study of Ranolazine in Subjects With Type 2 Diabetes Who Are Not Well Controlled on Metformin Alone (currently recruiting participants as of August 2012, ClinicalTrials.gov Identifier: NCT01555164, see the link here)

Chemical Structure of Ranolazine

Chemical Name of Ranolazine: (RS)-N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]piperazin-1-yl]acetamide

CAS number: 142387-99-3

Ranolazine, developed by CV Therapeutics whom Gilead Sciences bought in 2009, is also sold under the trade name Ranexa for the treatment of  chronic angina (chest pain).

RG1439 (aleglitazar)

Sponsor/Developer: Roche

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

Indication (Phase): Cardiovascular risk reduction in type 2 diabetes (Phase III; NDA filing expected 2015)

Chemical Structure of  RG1439 (aleglitazar) 

Chemical Name of  RG1439 (aleglitazar) : (2S)-2-methoxy-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]- 7-benzothiophenyl]propanoic acid

CAS number : 475479-34-6

Ryzodeg® (insulin degludec + insulin aspart)

Sponsor/Developer: Novo Nordisk

Mechanism of action: Soluble fixed combination of basal insulin with bolus insulin aspart

Indication (Phase): U.S.—Once daily for type 1 and type 2 diabetes (Registration; NDA submitted September 2011; recommended for approval Nov. 9 by FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, with commitment to a post-approval cardiovascular outcomes trial)

EU—Type 1 and type 2 diabetes (Registration; MAA submitted September 2011; recommended for approval Oct. 18 by CHMP)

Semaglutide (NN9535)

Sponsor/Developer: Novo Nordisk

Mechanism of action: GLP-1 analog

Indication (Phase): Once-weekly for type 2 diabetes (Phase III; SUSTAIN™ study, set to start first half of 2013)

Starsis (nateglinide)

Sponsor/Developer: Ajinomoto and Astellas

Mechanism of action: Insulin secretion enhancer

Indication (Phase): Japan—Type 2 diabetes, with DPP-4 inhibitors (Phase III; new indication)

TAK-875

Sponsor/Developer: Takeda

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

Indication (Phase): Asia-Pacific adults with type 2 diabetes (Phase III; GRAND-307 study, recruiting as of November 2012); Diabetic patients, compared with Glimepiride (Phase III; recruiting as of November 2012); Adults with type 2 diabetes, with metformin, compared with Glimepiride (Phase III; GRAND-305 study, recruiting as of August 2012); Adults with type 2 diabetes (Phase III; recruiting as of August 2012); Adults with type 2 diabetes, compared to placebo and sitagliptin with metformin (Phase III; recruiting as of August 2012); Adults with type 2 diabetes and cardiovascular disease (Phase III; recruiting as of August 2012)

Tofogliflozin hydrate (CSG452)

Sponsor/Developer: Roche and Chugai Pharmaceutical

Mechanism of action: SGLT2 inhibitor

Indication (Phase): Oral treatment for type 2 diabetes (Phase III)

Trelagliptin succinate (SYR-472)

Sponsor/Developer: Takeda Pharmaceuticals and Furiex Pharmaceuticals

Mechanism of action: DPP-4 inhibitor

Indication (Phase): Japan—Once-weekly oral treatment for type 2 diabetes (Phase III; study expected to be completed in second half of 2013)

Tresiba® (Insulin degludec, NN1250)

Sponsor/Developer: Novo Nordisk

Mechanism of action: Once-daily basal insulin

Indication (Phase): U.S.—Type 1 and type 2 diabetes (Registration; NDA submitted September 2011; recommended for approval Nov. 9 by FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, with commitment to a post-approval cardiovascular outcomes trial)

EU—Type 1 and type 2 diabetes (Registration; MAA submitted September 2011; recommended for approval Oct. 18 by CHMP in 100 units/mL and 200 units/mL formulations, the latter would be the first insulin in Europe to be marketed at a higher strength than 100 units/mL)

Japan—Approved September 2012 for type 1 and type 2 diabetes