Impending results in a large phase III uncontrolled asthma study have the potential to confirm Sanofi and Regeneron’s Dupixent as one of the most notable new drugs to reach the market this year.
Like other antibodies being used or tested in asthma, the drug is being targeted at people with severe disease; Dupixent is unique in that its efficacy does not appear to be restricted to a narrow subtype of these patients. But confirmation of this broader utility is needed to cement already lofty sales forecasts and put the drug on track for a second blockbuster indication.
|Total product NPV||$20.4bn||$4.4bn|
|% of sales assigned to asthma indication||~25%||~25%|
|Total product NPV as % of mkt cap||19%||9%|
|Event||Phase III results in asthma|
Hopes are high after the results of a large phase IIb study that first read out in 2014. In a finding that shifted thinking about the use of antibodies in this space, the data showed remarkable efficacy in patients regardless of their eosinophil levels.
Eosinophil status became relevant during the development of antibodies targeting IL-5, like Glaxosmithkline’s Nucala. It was only through clinical failure that researchers realised that patients with high levels responded much more strongly – the clinical trials that eventually won Nucala approval selected patients with blood eosinophils greater than or equal to 150 cells/mcL at screening or greater than or equal to 300 cells/mcL within 12 months of enrolment.
However, it seems with Dupixent this threshold is much less relevant. Although the primary endpoint of its 776-patient phase IIb trial tested only a high-eosinophil subgroup, secondary endpoints incorporating patients with low eosinophil levels and the whole study group were also hit. Significant improvements in lung function and impressive reductions in annual exacerbation rates were seen across the trial.
Sanofi and Regeneron hope to replicate this finding in the phase III Liberty Quest study. The trial has recruited around 1,600 patients with persistent asthma, regardless of eosinophil levels, and has two primary endpoints: annual severe exacerbation events and change in lung function, as measured by FEV1, over 12 weeks.
|Setting the bar – Dupixent phase IIb results|
|High eosinophil||Low eosinophil||Overall pop|
|Change in FEV1 at 12 weeks vs placebo||>15%||>8%||~>12%|
|Adjusted annual severe exacerbation rate||-64% to -75%||-68% to -62%||-67% to -68%|
|Note: Data are from the two doses progressed to phase III|
In a bold move, the primary endpoint is being tested in the all-comers group. In the phase IIb study the effect size was stronger in the high-eosinophil group, albeit marginally, so there are reasons for caution in the broader population.
Sanofi and Regeneron have said topline results would emerge in the coming weeks, with a filing planned for the fourth quarter, based on the phase IIb and III data.
The Dupixent data were not only notable for their efficacy in a broader, severe population: the effect size was considerably stronger than with IL-5 antibodies.
Nucala, for example, has only managed to prove that it can reduce exacerbations – its pivotal programme failed to show a consistent improvement in lung function. Teva’s IL-5 Cinquair, which also hit on exacerbations, did manage to show a stronger effect on lung function, but is hampered by a black box warning of anaphylaxis.
This apparent difference in efficacy could be down to different cytokine targets, which play distinct if overlapping roles in the coordination of eosinophils. IL-5, IL-4 and IL-13 are all expressed on type 2 helper T cells; about half of asthma patients are thought to have atopic disease, which is driven by these cytokines.
The mass of clinical data on Dupixent suggests that this antibody blocks a particularly relevant receptor in atopic disease, in both asthma and dermatitis; it is directed against the α-subunit of the IL-4 receptor, through which both IL-4 and IL-13 signal.
EvaluatePharma’s consensus already has sales of $1.2bn in asthma by 2022, although many analysts reckon peak sales in the indication could reach double this. Liberty Quest will need to generate strong efficacy in a broad section of severe asthma patients to achieve such numbers.
The use of antibodies to treat asthma is unlikely ever to move beyond small subsets of patients. While Dupixent will not change this, the data could prompt thinking to get a little bit more optimistic.