An FDA advisory committee's views on Sanofi's long-delayed GLP-1 agonist lixisenatide could portend the market challenges the company will face with a new agent in a well-established drug class and crowded therapeutic category.

At its May 25 meeting, the agency's Endocrinologic and Metabolic Drugs Advisory Committee said there were no efficacy or safety issues that would preclude approval of single-agent lixisenatide as the sixth member of the injectable GLP-1 agonist class.

They further affirmed the drug's risk/benefit profile when used in conjunction with basal insulin, voting 12-2 for approval of iGlarLixi, a fixed-ratio combination of Lantus (insulin glargine) and lixisenatide, although they generally disagreed with Sanofi's view that the combination was appropriate for patients naïve to both types of drugs (see related story, [A#00160530013]).

However, the panelists echoed FDA concerns about risks for serious allergic reactions and development of antidrug antibodies. They also questioned lixisenatide's efficacy relative to other agents and whether it was better suited for twice-daily dosing. The proposed maintenance dose is 20 mcg once daily, which would be a more frequent dosing schedule than three other members of the class (see box).

GLP-1 Agonists: The Current Class Of Five
Approval Date	Drug Product	Dosing	Sponsor
2005	Byetta (exenatide)	Twice daily	AstraZeneca
2010	Victoza (liraglutide)	Once daily	Novo Nordisk
2012	Bydureon (exenatide extended-release)	Once weekly	AstraZeneca
2014	Tanzeum (albiglutide)	Once weekly	GlaxoSmithKline
2014	Trulicity (dulaglutide)	Once weekly	Eli Lilly

One committee member questioned what lixisenatide offered that the other GLP-1 agonists do not. Sanofi's response focused on lixisenatide's impact on postprandial glucose levels, suggesting an avenue by which the company will attempt to differentiate its product once it enters the crowded US market.

Nevertheless, it's clear that the three-year regulatory delay resulting from the need to complete a cardiovascular outcomes trial has put Sanofi at a disadvantage when it comes to the single-agent product, making the fixed-ratio combination with insulin glargine all the more important to the company's battered diabetes franchise ([A#14151109004]).

Lixisenatide's struggles to even reach the US market reinforce the maxims that firms often rely on when developing products – be first in class, be unquestionably better, or be prepared for pitched marketing and formulary placement battles.

ELIXA Puts To Rest CV Safety Questions …

Lixisenatide received European Union marketing authorization in 2013 and is currently approved in more than 60 countries. Its entry in the US market was delayed, however, after Sanofi decided to withdraw the original NDA in September 2013 to complete the then-ongoing ELIXA cardiovascular outcomes trial. Sanofi said it withdrew the NDA ahead of a scheduled advisory committee meeting due to concerns that any public disclosure of the interim ELIXA data could compromise the trial's completion Also see "FDA CV Requirements Sideline Sanofi’s Lixisenatide" - Pink Sheet, 12 September, 2013..

In the original NDA, an interim analysis of ELIXA excluded an excess CV risk of 80% or more, as required by FDA's December 2008 guidance on CV safety evaluations of type 2 diabetes drugs. However, the hazard ratio point estimate for the primary endpoint was above 1.0, FDA's briefing documents state.

The NDA was resubmitted in 2015, and the user fee date is July 27. The application now includes the final ELIXA data, which showed lixisenatide neither increased nor decreased the risk of major CV events in adults with type 2 diabetes and at high CV Also see "Sanofi's Lixisenatide Gets Clean Bill Of Health On CV Safety, Heart Failure" - Pink Sheet, 9 June, 2015..

Although ELIXA was the first outcomes trial for a GLP-1 agonist to complete, it seems unlikely the results will give lixisenatide much of a commercial edge. In March, Novo Nordisk AS announced that its LEADER trial demonstrated a CV outcomes benefit with Victoza (liraglutide), although the full data have not yet been publicly released ([A#14160304003]).

FDA agreed that ELIXA demonstrated no increased CV risk with lixisenatide, Furthermore, the drug's safety profile was generally similar to that of other GLP-1 agonists, with gastrointestinal symptoms the most common adverse reaction, the agency said.

… But Allergic Reactions Are A Concern

However, FDA raised other safety issues. These included the risk of immunogenicity due to a high incidence of antidrug antibodies and the potential to adversely impact efficacy of lixisenatide or other drugs in the class. The agency also pointed to a possible increased risk for serious hypersensitivity reactions, including anaphylaxis, compared with other GLP-1 agonists.

While the overall incidence of anaphylaxis in the lixisenatide clinical development program was low, "it is notable that the reported findings suggest an increased risk for anaphylaxis with lixisenatide," FDA's briefing document states. "While the approved GLP-1 receptor agonists are labeled with a Warning and Precaution for hypersensitivity reactions, a signal for anaphylaxis is not described in the clinical trial data and references to anaphylaxis are based on post-marketing data."

The agency noted, however, that differences in the GLP-1 agonist development programs, "as well as the rigor of identification, could have contributed to these differences and makes across-program comparisons difficult."

HbA1c reduction with lixisenatide was statistically inferior to that of exenatide twice daily in an active-controlled trial.

With regard to efficacy, FDA said lixisenatide demonstrated a greater reduction in HbA1c compared to placebo across a range of clinical use scenarios. In active-controlled studies, the difference in HbA1c reduction between lixisenatide and comparators excluded the pre-specified non-inferiority margin of 0.4% against exenatide twice daily (AstraZeneca PLC's Byetta), insulin glulisine once daily and insulin glulisine three times daily. However, HbA1c reduction with lixisenatide was statistically inferior to that of exenatide twice daily and insulin glulisine three times daily.

Furthermore, twice-daily dosing with 10 mcg lixisenatide demonstrated slightly greater efficacy in HbA1c reduction and better tolerability in terms of gastrointestinal adverse events compared to the proposed 20 mcg once-daily dose, FDA said.

Committee member Ellen Seely, an endocrinologist at Brigham and Women's Hospital, questioned "what does lixisenatide give us that the other GLP agonists don't give us that should make us approve it?"

"The most important distinguishing factor about lixisenatide compared to other GLP agents is its strong effect on postprandial glucose," responded Paul Chew, Sanofi's senior VP-R&D. "Postprandial glucose is at least 50%, sometimes 70%, of the hyperglycemic burden, and in fact the closer you get to goal the more of a problem it is."

Seely asked whether postprandial glucose control is similarly achievable with other GLP-1 agonists. "While we haven't done comparative studies on that point, that is one aspect that distinguishes this product from the literature that we've seen," Chew said.

Hypersensitivity Risk Warrants Monitoring

Although FDA did not request a vote on the approvability of lixisenatide, it sought panel discussion on whether any safety or efficacy issues precluded approval.

"In the efficacy data that we've seen, my interpretation is that it has efficacy and that it is in general comparable to other drugs within its class," said panel chairman Robert Smith, an endocrinologist at Brown University. "I have not seen concerning safety data for the most part. The cardiovascular data are quite reassuring from the rather large ELIXA study."

However, Smith said it was worth noting the concern about severe allergic reactions "and (a) the possibility that they may occur in patients and (b) the perhaps not fully resolved possibility that there may be a greater occurrence with this drug than from some other members of the class, and I don't think we conclusively know that."

Smith suggested "serious consideration" should be given to including a labeling statement about the need for ongoing monitoring for severe allergic reactions, and he was among several panelists who urged FDA to require post-marketing studies or surveillance of this risk ([A#14160525004]).

Seely questioned whether the allergic reaction signal was real or merely an artifact of heightened scrutiny in the clinical development program. "The company had in place a very, very sensitive detection system for picking up allergic reactions that may not have been as extensive for the previous drugs in this class, some of which we found out had a lot of the allergic side effects in post-marketing studies," Seely said. "I think the statement should be that [for] all drugs of this class we need to be vigilant for allergic reactions."

Steven Meisel, system director of patient safety at Fairview Health Services in Minneapolis, said that in addition to lingering concerns about allergic reactions he questioned whether Sanofi's proposed dose was the most appropriate.

"My concern is whether or not a once-daily dose is the right dose," he said. "That brings another concern … if it's only once a day and the clinicians recognize the problem, will they end up prescribing it twice a day anyway?"

Sanofi's Lixisenatide Shows Challenges Of Being Late Entrant In Class

More from United States

More from North America