Novo’s obesity strategy will turn on safety

Long-awaited data from the biggest trial of liraglutide in obesity, released yesterday, kickstarted Novo Nordisk’s plan to expand use of the once-daily injectable GLP-1 agonist beyond its approved indication in type 2 diabetes.

While on pure efficacy grounds liraglutide looks easily approvable, it is safety that will determine its real potential. True, the study saw a relatively low rate of patient withdrawals, but the GLP-1 class’s side effects are hard for patients to spot, and the FDA might be further troubled by Novo’s proposed use of almost twice the dose approved in diabetes.

Novo’s Scale-Diabetes trial, in 3,731 obese patients, showed 56 weeks’ treatment with liraglutide to cause placebo-adjusted weight loss of 5.4%. So far so good: this is broadly in line with two previous liraglutide studies, and with Vivus’s Qsymia and Arena Pharmaceuticals’ Belviq – oral drugs approved on the strength of efficacies of around 8.5% and 3.4% respectively.

However, Novo has disclosed little about the important issue of safety, saying only that the completion rate in Scale-Diabetes was 72%, versus 64% for placebo recipients, and that withdrawals due to adverse events were under 10% in both groups. Pancreatitis is a risk with all GLP-1 agonists, and is the reason behind an FDA review of the safety of incretin mimetics, which comprise GLP-1 agonists and DPP-IV inhibitors (Event – Novo looks to prove obesity doubters wrong with liraglutide, February 1, 2013).

Pros and cons

Analysts are divided. Bryan, Garnier & Co cautions that none of the previously reported events for liraglutide, including thyroid cancer, heart rate changes and pancreatitis, are easily self-detectable by patients, and thus withdrawal rates are of limited use; the analysts do not factor obesity sales in their liraglutide revenue forecasts.

On the other hand UBS expects 21% of liraglutide’s 2017 sales of $4.3bn to come from non-diabetic populations. Consensus is lighter, with total 2018 revenue of $3.9bn in both diabetes and obesity, according to EvaluatePharma.

In its defence UBS analysts cite liraglutide’s action on the balance of blood sugar levels, in contrast to Qsymia and Belviq’s effects on the central nervous system, which arguably cause worse side effects. They might also add that an injectable drug, while being less convenient than an oral one, carries a lower potential for abuse.

Moreover, GLP-1 agonists might have additional cardiovascular benefits – something that the 6,000-patient Elixa study of Sanofi’s lixisenatide aims to prove. This is due to read out next year, and a positive result should benefit the whole drug class. Onglyza’s Savor study could bring DPP-IV inhibitors a similar benefit (Event – DPP-IVs could Savor the moment, courtesy of Onglyza, May 22, 2013).

Extensive scrutiny

Still, Novo should expect extensive scrutiny from the US FDA when it submits the obesity filing around the end of 2013, especially as 3mg looks like being the dose for obesity. This is much higher than the 0.9mg, 1.2mg and 1.8mg approved for diabetes.

The Danish company will undoubtedly point to liraglutide’s effects beyond pure weight loss. Some 2,276 patients in the trial just reported had pre-diabetes at enrolment, but after 56 weeks’ treatment 69% on liraglutide no longer had these symptoms, versus 33% of placebo recipients – a statistically significant effect.

In the earlier Scale-Diabetes trial in 846 overweight type 2 diabetics more than twice as high a percentage of those on 3mg of liraglutide reached target 7% HbA1c level than placebo recipients.

These pros and cons will give the FDA plenty of food for thought, and that is before Novo begins to make the delicate pharmacoeconomic case for using liraglutide in non-diabetics.

Liraglutide's phase III obesity trials
Study Detail Status Trial ID
Scale-Maintenance  422 patients Reported 2010 NCT00781937
Scale-Diabetes  846 patients Reported March 2013 NCT01272232
Scale-Obesity and Pre-diabetes 3,731 patients Reported May 2013 NCT01272219
Scale-Sleep apnoea 308 patients Completion Q3 2013 NCT01557166

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobEPVantage on Twitter

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