Novo Nordisk announces positive topline results from LEADER CVOT for Victoza (liraglutide) – March 4, 2016

Novo Nordisk just announced early this morning (PST) that LEADER results are out and GLP-1 Victoza demonstrated significant risk reduction for the primary MACE endpoint, with all three components (CV death, non-fatal MI, non-fatal stroke) contributing. This trial enrolled 9,340 patients with type 2 diabetes at high risk of cardiovascular disease (established CVD or multiple risk factors) and was both time and event-driven (up to five years; over 633 events). There has been much speculation about the potential for superiority in this trial, and Novo Nordisk had expressed cautious optimism on the subject in several recent earnings calls, citing GLP-1 agonists’ potential effects on the underlying mechanisms of atherosclerosis and LEADER’s greater individual patient exposure compared to trials of other agents in the class. However, the company had also repeatedly emphasized that LEADER was only designed to show non-inferiority, so these results come as a major, very positive surprise to us!

This news is big and should have very positive implications for Victoza as well as for Novo Nordisk’s pipeline (once-weekly GLP-1 semaglutide, oral GLP-1) and the GLP-1 agonist class. We are hopeful that the label could be enhanced fairly dramatically, though the magnitude of risk reduction will be an important question. Victoza is now the second type 2 diabetes drug to demonstrate cardioprotection after Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) in EMPA-REG OUTCOME. We expect Novo Nordisk to continue to emphasize Victoza’s beneficial effect on all components of the primary endpoint, as the benefit with Jardiance was driven only by CV death. Two more GLP-1 agonist CVOTs, for Novo Nordisk’s injectable semaglutide and Intarcia’s ITCA 650 (implantable exenatide mini-pump), are scheduled to report in the first half of this year. If both are positive, this would likely have enormous implications for the GLP-1 agonist class, which we have long felt is underutilized.

In a conversation with Novo Nordisk’s Chief Scientific Officer Mads Thomsen, he said that the results were driven partly by better glucose control as well as partly by weight and partly by blood pressure. We are surprised to hear glucose control cited as a contributing factor, as we had assumed this trial (like other CVOTs) would aim for “glycemic equipoise” between the groups to reveal any non-glycemic effects – we will be very curious to see how large the A1c difference was. We are also very curious whether there was any beneficial effect on heart failure or other secondary endpoints.  From a safety perspective, results seem similar to what has been seen with Victoza to date – manageable nausea is the primary side effect. We will be looking closely during the full results presentation to see if there were any imbalances in pancreatic adverse events.

There will be a full symposium at ADA, likely on Monday afternoon, to discuss the results, and Novo Nordisk will submit the data to regulatory authorities in the second half of 2016. While too early to fully discuss in any detail, we believe the clinical implications will be enormously positive for patients, providers, families, and payors – Victoza significantly reduces cardiovascular risk in this very sick, very high risk population that was studied. Although we look forward to Victoza being tested in other populations, this population is the one that needs the most help and is the most costly.

We understand that Novo Nordisk itself got the news less than 24 hours ago; we salute the company for getting this important news out so quickly on this landmark trial that shows conclusively in this type 2 diabetes population how to reduce cardiovascular risk, the be-all, end-all for patients with diabetes. See below for some of our burning questions on this exciting news.

Close Concerns Questions

Q: What was the hazard ratio and confidence interval for the composite three-point MACE endpoint?

Q: What were the hazard ratios and confidence intervals for cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke separately?

Q: Was the risk reduction significant for each individual component of the endpoint?

Q: Did Victoza have a greater effect on risk reduction for one component of the composite endpoint than the others?

Q: How does the participant profile of LEADER compare to that of EMPA-REG OUTCOME? To ELIXA? To the DPP-4 inhibitor CVOTs?

Q: Does the benefit extend to individuals at lower risk for cardiovascular events?

Q: Will semaglutide also demonstrate a cardioprotective benefit when SUSTAIN 6 reports in the near future? Will ITCA 650? Other GLP-1 agonists?

Q: What is the likelihood that the oral formulation of semaglutide will also demonstrate a cardioprotective benefit?

Q: Will these results lead patients, providers, and payers to view Novo Nordisk’s GLP-1 agonist/basal insulin fixed-ratio combination Xultophy (insulin degludec/liraglutide) more favorably than Sanofi’s combination LixiLan (lixisenatide/insulin glargine)?

Q: How will payers view the LEADER data when determining formulary positioning for Xultophy?

Q: What kind of label update could the data support?

Q: Victoza is the market leader in the GLP-1 agonist class but has been losing some market share in past quarters, largely to patient-friendly alternatives such as Trulicity (dulaglutide). Will we see an uptick in Victoza sales following this announcement?

Q: Are the superior vs. neutral results seen with LEADER compared to ELIXA related to the distinction between long-acting and short-acting GLP-1 agonists or more to differences in trial design?

Q: Will Novo Nordisk try to position Victoza earlier in the treatment algorithm?

Q: How will the diabetes community view these results relative to those for Jardiance? Will GLP-1 agonist/SGLT-2 inhibitor combination therapy become standard of care?

Q: What are the implications for Saxenda?

Q: It would be terrific to hear more about the mechanism – partly glucose, partly weight, partly blood pressure – what about the anti-inflammatory effects?

-- by Helen Gao, Emily Regier, and Kelly Close