The US approval of Astrazeneca’s anti-interleukin-5 antibody benralizumab, one of its big pipeline hopes, will be a relief to the company. But the product, now trademarked Fasenra, is entering a crowded segment of the asthma market and Astra might have its work cut out convincing doctors it is better than existing options (see table below).
And this is before considering Sanofi and Regeneron’s Dupixent, which should be filed in asthma before the end of the year. If Dupixent gets the go-ahead in a broader population than Fasenra and its IL-5 rivals, they could all feel the squeeze.
Third to market
Fasenra, like the other approved anti-IL5s – Glaxosmithkline’s Nucala and Teva’s Cinqair – is limited to asthma patients with an eosinophilic phenotype. However, no definition of this population, by eosinophil count for example, is given in the products’ labels.
Cinqair has a black-box warning on anaphylaxis, so Fasenra’s main rival is likely to be Nucala. A look at the pivotal trial data suggests that Astra’s agent has similar efficacy at best, the caveats of cross-trial comparisons notwithstanding.
|Cross-trial comparison of asthma agents|
|Product||Company||Mechanism||Status in asthma||Study/ies||% reduction in annual exacerbations vs placebo|
|Nucala||Glaxosmithkline||Anti-IL-5 MAb||Marketed||Trial 1 & 2||47-53%|
|Cinqair||Teva||Anti-IL-5 MAb||Marketed||Study I & II||50-59%|
|Dupixent||Regeneron/Sanofi||Anti-IL-4 & IL-13 MAb||Phase III||Liberty Asthma Quest||46%*|
|Liberty Asthma Venture||59%|
|*Only results with 300mg dose disclosed; Source: Product labels, company presentations.|
Wildly differing data across Fasenra’s pivotal trials do not help any attempt at a comparison. Astra blamed the lacklustre result from the Calima study on a strong placebo response (Astra could be fashionably late with benralizumab, September 5, 2016).
Meanwhile, the Zonda trial found a reduction in exacerbations of up to 70%, although this was only a secondary endpoint – the trial had been designed to primarily assess a reduction in oral steroid use.
Nuances between these trials further complicate matters – for example, different definitions of what constitutes a high eosinophil patient. The pivotal Fasenra trials, Calima and Sirocco, analysed patients with eosinophil counts of 300 cells/µl or greater, while Nucala’s Trial 2 enrolled patients with counts of 150 cells/µl or more. Eosinophil levels are considered highly predictive of a patient's response to anti-IL-5, so these different inclusion criteria would presumably impact the apparent effectiveness of a drug.
Still, all this could become academic if Dupixent is approved in asthma, especially if Sanofi and Regeneron's project can get the thumbs up in all patients regardless of eosinophil status.
Although this is clearly the goal, it is not a certainty – the first phase III trial to read out, Liberty Asthma Quest, hit its co-primary endpoints of exacerbation rate and lung function improvement, but much of the all-comers benefit looked to have been driven by results in high eosinophil patients (Regeneron and Sanofi breathe easier on Dupixent, September 11, 2017).
Even so, the 60-67% reduction in exacerbations in patients with eosinophils of above 150 cells/µl was impressive, and looks to have given Dupixent the edge over the IL-5s in this population – although again caveats about cross-trial comparisons apply.
|High and low: how Dupixent fares in different patient populations|
|Endpoint||Overall population||Patients with ≥150 eosinophilic cells/µl||Patients with ≥300 eosinophilic cells/µl|
|Liberty Asthma Quest study results with 300mg dose of Dupixent|
|Reduction in exacerbations at 52 weeks||46%*||60%*||67%*|
|Liberty Asthma Venture study results|
|Reduction in exacerbations at 24 weeks||59%**||-||71%|
|*p<0.001, **p<0.0001; Source: Company website.|
Meanwhile, the Liberty Asthma Venture study of Dupixent reported comparable results on exacerbations, although the primary endpoint of that study was reduction in steroid dose.
Dupixent's result in the overall population in the Quest study dented very high hopes for this project in asthma, though many analysts believe that it will still win a broad label. According to Leerink, around 70% of patients have eosinophil counts of over 150 cells/µl, while 30% have levels of under 150 cells.
Fasenra has one ace up its sleeve: less frequent dosing, at once every eight weeks versus once every two weeks for Dupixent and once every four weeks for Nucala. However, without an edge on efficacy this might not be enough to set it apart, particularly with Dupixent looming.