Four years after FDA promulgated its guidance on assessment of cardiovascular risk in type 2 diabetes therapy trials, cardiovascular safety remains a major hurdle in reviews of new anti-diabetic agents.

FDA reviewers will address new agents in four major categories of recent diabetes advances – glucagon-like peptide 1 agonists, dipeptidyl peptidase IV inhibitors, long-acting basal insulin and the yet-to-be-approved sodium glucose co-transporter 2 inhibitors – but the overarching theme is not so much innovation as continued balancing of safety concerns.

The agency’s first NME approval of 2013 was for Takeda Pharmaceutical Co. Ltd.’s alogliptin, alone as Nesina, in combination with metformin as Kazano and in combination with pioglitazone as Oseni. Both as a single agent and in combination with the thiazolidinedione pioglitazone, alogliptin has received two “complete response” letters in the five years since the original NDA submissions, due to safety issues ([A#28120802003]). The Jan. 25 approval means Takeda will finally make it to market with the fourth dipeptidyl peptidase IV inhibitor.

Two new entrants in the GLP-1 agonist segment, one of the fastest growing categories in pharma, were submitted at the end of 2012: GlaxoSmithKline PLC’s once-weekly albiglutide and Sanofi/Zealand Pharma AS’ once-daily Lyxumia (lixisenatide). The once-daily product appears to have greater efficacy, while the once-weekly has advantages in convenience and tolerability. Eli Lilly & Co. aims to join the race later in 2013 with a projected NDA submission for its once-weekly GLP-1 analog dulaglutide.

The upcoming year could see the approval of the first sodium glucose co-transporter 2 inhibitor. The class has shown solid efficacy in managing glucose, but has been dogged by safety concerns, especially regarding urinary infections. Additionally, FDA’s decision to approve (or not) the pending SGLT-2 inhibitors will be an important signal of how the agency feels about using interim data from ongoing cardiovascular outcomes trials to support initial approval in the space Also see "Use Of Pre-Approval CV Data From Ongoing Trial Gets Once-Over At Canagliflozin Panel" - Pink Sheet, 21 January, 2013..

After an advisory committee endorsement Jan. 10, Johnson & Johnson’s Invokana (canagliflozin) is in the lead in the SGLT-2 race, but Bristol-Myers Squibb Co. and AstraZeneca PLC are getting ready to resubmit Forxiga (dapagliflozin) in response to a January 2012 “complete response” letter Also see "Bristol Signals Dapaglifozin’s Back On Track, Plans FDA Resubmission" - Pink Sheet, 24 October, 2012.. Lilly is also predicting a 2013 submission for its SGLT-2 candidate with Boehringer Ingelheim GMBH, empagliflozin Also see "Lilly/BI Report Success For Oral Diabetes Drug, Adjust Alliance" - Pink Sheet, 7 January, 2013..

Will The Type 2 Diabetes CV Risk Guidance Have An Impact On New Insulins?

In long-acting basal insulins, Novo Nordisk AS hopes to take on Sanofi’s venerable Lantus (insulin glargine) with its insulin degludec (Tresiba, also submitted in combination with Novo’s market-leading GLP-1 agent liraglutide as Ryzodeg). As the first new insulin to come before FDA since the 2008 cardiovascular safety guidance for type 2 diabetes, degludec is something of a test case for how CV safety should be weighed in type 1 diabetes NDAs – a conundrum that is likely behind FDA’s now-unusual continuation of the review past the user fee goal.

One of FDA’s concerns about degludec is based on two of three meta-analyses of CV event data from the Novo clinical trials that failed to meet the guidance’s risk threshold for type 2 drugs ([A#00121112022]). While an advisory committee suggested the insulin class should be held to a more forgiving standard that would allow approval with a post-marketing CV outcomes trial, FDA has not communicated a timeframe for a decision to Novo, the company told investors in December, suggesting that the issue is still being debated within the agency.

So far, the degludec experience suggests that other novel insulin sponsors should expect close scrutiny of CV safety and may want to consider incorporating a CV outcomes trial into development plans from the outset. The guidance currently suggests that insulin sponsors prospectively collect CV data and include pre-specified CV analysis in NDAs.

While the degludec review drags on, Sanofi is not standing still with Lantus. The company’s new insulin glargine formulation “gives us a flat PK-PD profile,” R&D chief Elias Zerhouni told J.P. Morgan; the product forms a depot after subcutaneous injection. Sanofi is conducting six Phase III trials for the U-300 formulation, and “we hope that we’ll have results this year in the second quarter,” Zerhouni said.

The EDITION I and EDITION II trials, which enrolled 1,600 high-dose insulin-using type 2 diabetics, will provide headline results. A second set of Phase III studies in insulin-naïve type 2 diabetes patients (EDITION III) and type 1 diabetics taking basal insulin (EDITION IV) started in the second half of 2012.

Sanofi is testing a combination of Lantus with the GLP-1 agonist Lyxumia in Phase III. “We have 8 million patients today on basal insulin. Only half of them are reaching goal of 7% A1c levels. … And this is where our next step is to develop a combination of Lantus and Lyxumia,” Zerhouni said.

The Lilly/BI partnership also predicts submitting its long-acting insulin glargine candidate in 2013. Presentations at the American Diabetes Association conference in June 2012 suggest better glycemic control than Lantus and a small boost in weight loss Also see "New Long-Acting Insulin Offerings Could Derail Lantus Franchise" - Pink Sheet, 18 June, 2012..

2013 Diabetes NMEs Span Classes, But Safety Is A Review Issue For All

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