Novo Nordisk is offering reassurance that its GLP-1 analog Victoza (liraglutide) will pass muster with FDA, even though the supporting program fails to meet a key requirement of new guidance on cardiovascular safety of type 2 diabetes drugs.

They're same rules that have slowed Takeda's progress with alogliptin - but Takeda isn't saying exactly how, which makes handicapping the chances for Novo's drug far from simple.

Liraglutide is among NDAs pending review in type 2 diabetes, along with Bristol-Myers Squibb and Astra Zeneca's Onglyza (saxagliptin) and Takeda's alogliptin (¹ Also see "FDA’s Diabetes Guidance On CV Risk Will Get First Test With Pending NDAs" - Pink Sheet, 22 December, 2008. p. 25).

Takeda announced March 6 that FDA is going to apply new CV safety guidance to the application of alogliptin, a DPP-4 inhibitor, and that its data are not sufficient to satisfy new statistical requirements.

The guidance, unveiled in December, requires an in-depth safety review for type 2 diabetes medications, including studies of cardiovascular mortality, myocardial infarction and stroke (² Also see "FDA Diabetes Guidance Encourages Enrollment Of Sicker Patients" - Pink Sheet, 17 December, 2008.).

To rule out risk, programs need to treat more people longer and include enough patients with advanced disease to register a minimum number of CV events.

Even though officials made it clear in December that the new rules would apply to all drugs, there has been a degree of uncertainty about real-world implementation because the guidance document itself does not clarify that drugs already pending review must comply, said Novo Nordisk Chief Scientific Officer Mads Krogsgaard Thomsen.

Industry observers have been looking forward to an early April advisory meeting on Victoza to shed light on implementation and the Takeda news is proving instructive ahead of that - maybe not in a good way, for Novo.

Takeda's trouble gives "absolute clarity that FDA will now apply its new guidelines to all new diabetes drug applications," wrote J.P. Morgan analyst Richard Vosser in a March 6 note.

FDA taking "path of least resistance"

Takeda is discussing the protocol of a new CV safety study with FDA and development delays are expected, though the PDUFA data of June 26, 2009 has not changed. San Francisco, Calif.-based Close Concerns, a consultancy specializing in diabetes, notes that development could be stalled for at least one to two years at a cost of $100 million to $200 million.

"This is an aggressive path taken by the FDA and the one of least resistance for the agency, in our view," wrote Lazard Capital Markets analyst Matthew Osborne in a March 6 note.

However, Thomsen says the agency has been "prudent" in its communications about the regulatory path for liraglutide, in contrast with the "radical points of view" aired by cardiologists at last year's summertime advisory meeting that laid the foundation for the guidance (³ [A#00700280003], p. 6).

Obviously, liraglutide trials were planned long before the guidance was released, and thus did not include the preferred patient populations or register the required minimum number of cardiovascular events, Thomsen said in an interview.

Communications with FDA suggest the drug still has a very favorable regulatory outlook, he said.

The Phase III program supporting the drug was very large. With 4,615 patients and a total of more than 2,600 years of exposure to the compound, the liraglutide clinical trial program is more than double the size of aloglitptin's. Takeda, on the other hand, enrolled only 2,000 patients in Phase III trials and, considering that the vast majority of trials lasted only 26 weeks, the company probably only had about 1,000 years of exposure, Vosser noted.

"Unlike alogliptin, we believe liraglutide has sufficient data to meet the FDA guidance from existing trials, and will not be delayed," he wrote.

FDA guidance stipulates that Phase III trial data must be available for at least 2,500 subjects exposed to the investigational product with at least 1,300 to 1,500 of these subjects exposed for one year or more and at least 300 to 500 subjects exposed to the investigational product for 18 months or more.

Takeda declined to say where exactly its program fell short statistically. But it's possible that the new CV safety study now being developed with FDA could be done post-approval, Takeda said.

GLP-1 analogs may have a better shot

Thomsen also points out that unlike alogliptin, liraglutide is a GLP-1 analog, part of a class that offers benefits for weight loss and blood pressure.

Novo Nordisk has performed several major adverse CV event analyses, with very good results and has already mapped out a dedicated cardiovascular outcomes study. Similarly, Amylin recently pledged to perform a meta-analysis of Byetta (exenatide) safety data plus perform a large cardiovascular outcomes trial.

That could help. "Novo Nordisk and Amylin already plan to begin CV outcome trials this year, prior to approval, and proactive steps usually resonate well with the agency," Osborne noted. "Takeda may not have been so proactive."

Like Novo Nordisk, BMS is projecting optimism to investors, recently indicating that its DPP-4 inhibitor Onglyza should be approvable (⁴ Also see "Bristol Readies Saxagliptin Launch In Anticipation Of FDA Approval" - Pink Sheet, 9 February, 2009. p. 9).

But DPP-4 inhibitors as a class may face a tougher time meeting the CV safety requirements than other types of type 2 diabetes drugs, since they are increasingly being used to treat disease in earlier stages, which presents challenges for recording enough CV events to satisfy FDA (⁵ Also see "VCs Think Twice About Type 2 Diabetes Investments" - Pink Sheet, 2 March, 2009. p. 14).

Merck's no-frills, highly efficient program for Januvia (sitagliptin phosphate), the first DPP-4 inhibitor on the market, was supported by research in just over 2,700 patients (⁶ Also see "DPP IV Inhibitor Januvia First Out Of The Gate" - Pink Sheet, 17 October, 2006.). After approval, the firm followed up with additional studies to enhance the label, most recently embarking on a massive cardiovascular event study of 14,000 patients. Thanks to the new rules, Merck's future DPP-4 rivals will have to get those added trials out of the way earlier.

- Emily Hayes (e.hayes@elsevier.com)

Novo Nordisk Makes Case For Alogliptin-Shadowed Victoza

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