Sanofi and Regeneron face a high-risk test for Dupixent

Dupixent is already forecast to become an $18bn drug by 2028, according to Evaluate Pharma sellside consensus, but its makers Sanofi and Regeneron clearly want more. The next potential avenue for expansion is chronic obstructive pulmonary disease, where the partners have a high-risk/high-reward readout coming.

There are plenty of reasons to be cautious: other antibodies have failed in this heterogeneous disease, and there are concerns about the fact that the late-stage trials of Dupixent have excluded asthma patients, which might reduce their chances of getting a result.

On the other side of the coin, Sanofi and Regeneron will hope that homing in on a high-eosinophil population could boost the probability of success.

All should become clear soon, with results from the Boreas trial expected as early as March. Bullish sellside analysts have pointed to the fact that the study sailed through an interim analysis that included an early look at efficacy.

To continue, the study had to meet a prespecified target for exacerbation rate reduction, the primary endpoint. The companies have not said what this bar was, however.

If Dupixent succeeds it will be the first biological to take aim at COPD, a multi-billion-dollar market. The anti-IL-3 and IL-4 antibody is already approved in asthma, specifically in patients with high eosinophils, a marker of type 2 inflammation. In this respect it is similar to Astrazeneca and GSK’s anti-IL-5 MAbs Fasenra and Nucala respectively.

But asthma and COPD are different diseases, and Fasenra and Nucala previously disappointed in the latter. Still, findings in eosinophilic patients spurred the drugs’ developers to press on, and pivotal COPD studies are under way in patients with eosinophil levels of 300 cells/ml or above.

Dupixent’s COPD trials have the same eosinophil threshold. At least one pulmonologist, cited by SVB analysts, believes that the hurdle should have been higher – his view is that any efficacy will be driven by patients with levels “dramatically higher” than 300.

Another reason for caution is the exclusion of asthma patients, apparently in response to FDA guidance. The agency criticised Nucala’s COPD trials for including asthma patients, raising concerns that the drug’s effects on concomitant asthma might have been driving efficacy.  

Smoking status

Also of interest will be how Dupixent performs in current versus former smokers. Boreas and Notus include both, but the drug is expected to do worse in smokers, as active smoking triggers a non-type 2-mediated immune response, according to SVB. Lastly, the pandemic has decreased overall COPD exacerbation rates; however, the companies have said that Boreas should still be well powered enough to show a benefit.

So what bar will Boreas need to clear to be judged a hit? The primary endpoint is the annual rate of acute COPD exacerbations, and SVB reckons a reduction of 30% or greater versus placebo would be “clinically compelling”, while over 35% would be a “slam dunk”. The analysts describe themselves as “hopeful”, but Jefferies is more cautious, pencilling in €700m ($750m) COPD sales in 2030 based on just a 20% probability of success.

If Boreas does fail it could be bad news for the anti-IL5s, whose new COPD trials are set to start reading out from next year. Another late-stage target is IL-33. Sanofi and Regeneron have a shot here with itepekimab, although with this project they are targeting former smokers, and are not exclusively looking at high eosinophil patients.

Astrazeneca also has an IL-33 project in tozorakimab, one of the first tests of its increasingly personalised approach to autoimmune disease.