Mounjaro bests Wegovy yet again

But supply problems are getting worse.

Short of a head-to-head trial against Wegovy – and that is in the works – it is hard to see what more Lilly could do to prove Mounjaro’s greater efficacy in obesity over Novo Nordisk’s drug. 

The latest clutch of topline Mounjaro data, released today, come from the Surmount-3 and -4 trials, and a comparison with the roughly equivalent Wegovy trials shows Mounjaro ahead once again. Approval in obesity could come this year, but the company is still grappling with supply problems that could mean any launch is a damper squib than investors might like. 

In Surmount-3, patients first underwent a 12-week programme of intensive caloric restriction, exercise and weekly counselling sessions. Those who had at least 5% body weight reduction by the end of the lead-in period were then randomised to placebo or Mounjaro, the latter at a maximum tolerated dose of 10 or 15mg, for 72 weeks.

At the end of the three-month lifestyle management period, participants achieved 6.9% mean weight loss. For the efficacy estimand, one of two co-primary endpoints, those taking Mounjaro lost an average of 21.1% of their body weight in the subsequent 72 weeks, whereas placebo recipients saw weight regain of 3.3%.

The other co-primary was the number of patients showing weight loss from randomisation of at least 5%. 94.4% of those taking Mounjaro hit this benchmark, versus 10.7% in the placebo group.

In Novo Nordisk’s lifestyle intervention study, Step-3, patients saw lower mean weight loss – but the design was different, meaning comparing the two is not strictly fair and should be regarded as merely illustrative. 

In Step-3 subjects underwent lifestyle management simultaneously with drug therapy, rather than experiencing the two interventions sequentially. In Step-3 patients took Wegovy for 68 weeks, eating a low-calorie diet for the first eight weeks of that period and having 30 counselling visits throughout the entire period. 

Novo's Wegovy vs Lilly's Mounjaro - lifestyle trials
Project and dose Wegovy 2.4mg Mounjaro 10 or 15mg
Trial Step-3 (NCT03611582) Surmount-3 (NCT04657016)
Population 611 overweight and obese pts who underwent a simultaneous lifestyle modification programme 806 overweight and obese pts who had completed a lifestyle modification programme
Pbo-adj weight loss 10.3% at wk68 24.5% from wk12 to wk84
Pbo-adj proportion achieving weight loss of at least 5% 39% at wk68 83.7% from wk12 to wk84
Mounjaro data are efficacy estimands. Source: company communications, JAMA.

If Surmount-3 was an attempt to show how much of a difference drug therapy can make compared with the diet and exercise that overweight people have been encouraged towards for decades, Surmount-4 is, from a commercial perspective, even more important. 

It is already clear that patients who stop taking incretins begin regaining the weight they have lost almost immediately, so chronic therapy appears to be the only solution. Maintenance trials are therefore crucial. 

This study began with a 36-week open-label Mounjaro lead-in period, during which patients achieved 21.1% mean weight loss. After that, they were randomised to either continue on Lilly’s agent or switch to placebo for the following 52 weeks. In this maintenance phase, the Mounjaro group lost an additional 6.7% of their body weight, compared with weight regain of 14.8% among placebo patients.

In Novo’s comparable Step-4 trial, patients took Wegovy for 20 weeks before being randomly assigned to continue or switch to placebo. After a further 48 weeks, those taking the drug had lost 7.9% of their weight, vs a regain of 6.9% in the placebo group. 

With both a longer lead-in and a longer maintenance phase, Lilly’s Surmount-4 was arguably likely to yield better results than Novo’s Step-4. But the difference between the two still makes Mounjaro look pretty impressive.

Novo's Wegovy vs Lilly's Mounjaro - maintenance trials
Project and dose Wegovy 2.4mg Mounjaro 10 or 15mg
Trial Step-4 (NCT03548987) Surmount-4 (NCT04660643)
Population 902 overweight and obese pts 783 overweight and obese pts
Pbo-adj weight loss 14.8% from wk20 to wk68 21.4% from wk36 to wk88
Mounjaro data are efficacy estimands. Source: company communications, JAMA.

With Lilly disclosing no nasty surprises on the safety front – the most commonly reported adverse events in both trials were gastrointestinal and generally mild to moderate – all is looking good for Mounjaro’s approval in obesity. Lilly has started a rolling filing, and while no Pdufa date has been given yet approval is expected by the end of the year.

At that point Lilly will run straight into a problem. The FDA recently added a fourth dose of Mounjaro, which is already sold in the US for diabetes, to its drug shortage database, and also said it expected the supply issues for the other three doses to last longer than its previous reckoning. Having a drug so popular demand cannot be met might be a nice problem to have, but it is still a problem.

The head-to-head Wegovy vs Mounjaro trial, Surmount-5, will read out in 2025. 

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