by Manasi Vaidya in New York.

AstraZeneca/Amgen’s endeavor with tezepelumab in severe asthma could encompass the hitherto unaddressed noneosinophilic patient subgroup, providing an edge over other biologics. While there are mostly high expectations for the Phase III due to a differentiated mechanistic rationale and positive Phase II data, some caution remained since efficacy in the that group is yet to be established in any late-stage study.

Noneosinophilic asthma, which is symptomatic asthma in the absence of eosinophilic airway inflammation, is not the best known and most prevalent asthma phenotype.

In terms of eosinophilic patients, it is challenging to predict the asthma phenotypes most likely to respond to a monoclonal antibody specific to a certain cytokine. So if tezepelumab shows better efficacy than existing biologics among these patients, it could also be the preferred choice. The bar is much lower in noneosinophilic patients, who have no comparable options. While there is caution in extrapolating data to a larger trial, tezepelumab’s relatively unique thymic stromal lymphopoietin (TSLP) focus suggests it could address a broader range of asthma patients than other biologics. Its competitors target downstream cytokines like IL5, IL4 and IL13 or IgE.

Tezepelumab’s overall efficacy profile was impressive in a Phase II study, which set high expectations for a Phase III trial that is looking at the same broad severe asthma population regardless of eosinophil counts and a primary endpoint focused on exacerbations. However, given the lack of precedence of biologic efficacy in the noneosinophilic population, there is some caution pending Phase III results.

One analyst estimates peak sales of $2.8bn for the antibody, while GlobalData consensus forecasts estimate the drug to earn $1.8bn by 2026. A second analyst noted tezepelumab’s potential to benefit asthma broadly, and that Phase III (NCT03347279) data is expected in 4Q.

AstraZeneca and Amgen did not respond to a request for comment.

Opportunity to stand out in competitive landscape

Tezepelumab’s potential use will depend on the magnitude of reduction in exacerbations in both eosinophilic and noneosinophilic subgroups, said Dr Michael Wechsler, director, Cohen Family Asthma Institute, National Jewish Health, Denver, Colorado. The expectation is that tezepelumab could be effective in the noneosinophilic severe asthmatics based on the Phase II data, he added. In the Phase II tezepelumab study, exacerbations were lower with tezepelumab regardless of eosinophil counts at three doses compared to the placebo by 62% (p<0.001), 71% (p<0.001) and 66% (p<0.001) (Corren et al., N Engl J Med, 2017; 377:936-946).

In the eosinophilic subgroup, Sanofi /Regeneron’s Dupixent (dupilumab) also has a clinically valuable asthma exacerbation rate reduction of 60–70%, which is greater than anti-IL-5 antibodies, said Dr Peter Barnes, professor of medicine, National Heart and Lung Institute, London, on potential benchmarks for Phase III efficacy. Approved mAbs directed to IL5 or its receptor include AstraZeneca’s Fasenra (benralizumab), GlaxoSmithKline’s Nucala (mepolizumab) and Teva Pharmaceuticals’ Cinqair (reslizumab).

However, in noneosinophilic patients even a 30% reduction in exacerbation rate may be significant, said Dr Dean Befus, director, Alberta Asthma Centre, Edmonton, Canada, while Barnes said since there are no good treatment alternatives so any reduction would be valuable. Nonetheless, it is necessary to wait for the data on noneosinophilic patients with tezepelumab, said Dr Steven Weinstein, allergist-immunologist, Allergy and Asthma Specialists Medical Group, Huntington, California, before assuming efficacy in that subgroup.

If the exacerbation reduction with tezepelumab is greater than seen with other antibodies targeting IL-5, tezepelumab will be the first choice of biologic, and if not, it will be the second choice, said Wechsler. But Befus said tezepelumab is more attractive than available anti-IL5 antibodies because its target is upstream and can address other impacts on the airways regardless of eosinophil involvement.

Tezepelumab’s potency is not restricted to atopic responses or Th2-type responses, which make its activity exciting because it could be effective against different phenotypes of asthma, said Befus. Antibodies that target IL5, IL13 and IL4 are classic Th2 blockers, he added. Tezepelumab’s target is upstream of the aforementioned cytokines, and serves as a critical point of entry for multiple effects on downstream pathways, said Befus, adding clinical data supports this hypothesis.

Hence, there is good reason to believe tezepelumab may have a broader spectrum of efficacy because tezepelumab regulates not just Th2 cytokines, which other biologics do, but also Th17 cytokines, which could contribute to controlling neutrophilic inflammation, said Barnes. But additional data is needed to fully establish that, he added.

Considering the landscape, an inhaled anti-TSLP antibody, unlike mAbs delivered through infusions or a subcutaneous injections like tezepelumab, would be significant enough to gain an advantage over other biologics, said Weinstein. Novartis’ CSJ117 is an inhaled anti-TSLP antibody that will be studied in a 652-patient Phase II study (NCT04410523) that has yet to start recruiting.

Phase II efficacy bodes well for Phase III

Tezepelumab is not just reducing exacerbations, but also improving FEV1 and patient quality of life, said Barnes. The impact on FEV1 has been seen with Dupixent also, but less so with anti-IL5 antibodies, with tezepelumab having a greater effect on such outcomes, said Barnes. The change from baseline in the prebronchodilator FEV1 with tezepelumab was greater than placebo in the three dose groups by 0.12 liters (p=0.015), 0.13 liters (p=0.009), and 0.15 liters (p=0.002). In a Phase III trial (NCT02414854), Dupixent at two doses resulted in significant improvements in prebronchodilator FEV1 versus placebo of 0.20 liters and 0.13 liters (Castro et al., ERJ Open Res.; 2020 Jan; 6(1): 00204-2019).

Still, for the eosinophilic group, head-to-head trials with other biologics are unlikely so it will be hard to extrapolate data across studies, said Weinstein. It is difficult to identify specific asthma phenotypes and the mAbs they may respond to best, said Befus. Having said that, efficacy in other comorbidities like nasal polyposis may differentiate the mAbs, said Weinstein. In addition to severe asthma, Dupixent is also FDA-approved to treat nasal polyps accompanied by chronic rhinosinusitis, as per a 26 June press release.

Befus referred to early Phase I data where tezepelumab improved early- and late-phase bronchoconstriction significantly, as further evidence of its efficacy. In the Phase I study (NCT01405963) of 31 patients with mild allergic asthma, tezepelumab reduced allergen-induced bronchoconstriction and indexes of airway inflammation before and after allergen challenge (Gauvreau et al., N Engl J Med.; 2014 May 29;370(22):2102-10).

In the Phase II study, the asthma exacerbation rate versus placebo in those with blood eosinophil counts less than 400 cells/microliter and more than or equal to 400 cells/microliter was 63% and 57%, respectively, on 70mg Q4W, 69% and 73% on 210 mg Q4W, and 54% and 83% on 280mg Q4W.

Biologics’ trials have used different eosinophil cutoffs, and the general consensus is that the higher the blood eosinophil count is, the greater the effect seen, said Barnes. That said, blood eosinophils are not the only potential biomarker to predict responses, said Barnes, referring to exhaled nitric oxide-related data with Dupixent. Dupixent’s EMA approval encompasses patients with severe asthma with type 2 inflammation characterised by raised blood eosinophils and/or raised fractional exhaled nitric oxide, as per a 7 May press release, but the same is not specified on its FDA label. However, currently there are few biomarker tests to evaluate eosinophilia, and even sputum eosinophil counts are difficult to do on a large scale, said Barnes.

Manasi Vaidya is a Senior Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.