New data on tezepelumab, an experimental drug for people with severe uncontrolled asthma developed by Amgen Inc. in collaboration with Astrazeneca plc's Medimmune unit, showed that adding it to standard therapies for the condition significantly reduced annual asthma exacerbation rates vs. placebo. Analysts said the candidate's performance in the phase IIb trial, called Pathway, appeared similar to Dupixent (dupilumab, Regeneron Pharmaceuticals Inc./Sanofi SA), but they differed on how substantial a competitor it might become.

Asthma affects an estimated 315 million individuals worldwide. Up to 10 percent of people with the condition have severe asthma.

The results provided new evidence that binding thymic stromal lymphopoietin (TSLP), a cytokine discovered to be an important mediator of inflammation in severe asthma, affects multiple downstream inflammatory pathways associated with asthma.

René van der Merwe, senior director of respiratory and inflammation at Medimmune, likened the triggers of asthma to storm clouds at the top of a mountain, raining down inflammatory chemicals like interleukin-4 (IL-4), IL-5, and IL-13. Current therapies seek to block streams feeding the cascade of those chemicals and their contributions to inflammation. "Where tezepelumab works," she told BioWorld, "is right upstream, where the river starts, blocking the inflammatory cascade high up in the hills. This enables us to treat a much broader population."

Due to its activity early in the inflammatory cascade, tezepelumab may also be suitable for patients with both type 2 (T2) inflammation and non-T2 driven asthma, including those ineligible for current biologic therapies which only target the T2 pathway, according to principal Pathway investigator Jonathan Corren of the David Geffen School of Medicine. That's important because it suggests tezepelumab may have applications in helping patients with non-T2 inflammation who aren't served by asthma drugs like the anti-interleukin-5 Nucala (mepolizumab, Glaxosmithkline plc) and Medimmune's own benralizumab. (See BioWorld Today, Nov. 6, 2015.)

Amgen shares (NASDAQ:AMGN) rose 1.3 percent on the news to close at $180.71, while Astrazeneca shares (NYSE:AZN) followed suit, rising $1.55, or about 5.1 percent to close at $31.89. Highlighting fears about the potential impact of new competition, shares of Regeneron (NASDAQ:REGN) fell about 5.7 percent, or $28.30, on the news, closing at $471.92. Sanofi's shares (NYSE:SNY) ticked down by just 10 cents, to $49.32.

Will the FDA ask for additional dose-ranging studies?

Pathway investigators randomized patients whose asthma was uncontrolled with inhaled glucocorticoids plus long-acting beta-agonist (LABA) therapy to receive one of three different doses of subcutaneous tezepelumab or placebo. Each patient was assigned to receive subcutaneous injections of tezepelumab – teze, for short – at a low dose of 70 mg every four weeks, a medium dose of 210 mg every four weeks, a high dose of 280 mg every two weeks or of placebo every two weeks for the duration of the trial.

The study achieved its primary efficacy endpoint, showing annual asthma exacerbation rate reductions relative to placebo of 61 percent for the low dose, 71 percent for the medium dose and 66 percent for the high dose in the teze arms (p<0.001 for all comparisons to placebo).

Teze also demonstrated improvements in lung function at all doses and in asthma control at the two higher doses (p<0.05 for all comparisons to placebo).

The incidence of adverse events (AEs) was similar between the tezepelumab and placebo groups. The most common AEs (≥5 percent) in teze-treated patients were asthma, nasopharyngitis, headaches and bronchitis.

The results of Pathway, published in the New England Journal of Medicine concurrent with reporting by the companies, will be followed by an oral presentation of the data on Sept. 12 at the ERS International Congress International Congress in Milan.

In an editorial accompanying the NEJM article, Elisabeth Bel, a professor of pulmonary diseases at the University of Amsterdam, wrote that while multiple therapies are effective in subgroups of people with various forms of asthma, "they are not a panacea for uncontrolled asthma, probably because these biologics are directed against targets downstream in the inflammatory cascade."

While noting that the Pathway trial holds "important implications for our understanding of the pathobiologic basis of asthma and for the management of persistent uncontrolled asthma," Bel also expressed concern that "targeting upstream cytokines may have downsides as well." In particular, she noted three serious drug-related AEs reported in the study: pneumonia and stroke in one patient and the Guillain-Barré syndrome in another. While characterizing the overall safety profile of tezepelumab as "reassuring," she added that confirming its safety should be "a priority in future trials."

After gaining FDA approval earlier this year for the treatment of certain cases of moderate to severe atopic dermatitis, Dupixent is in phase III testing in uncontrolled asthma, with results expected to be reported before year-end. If positive, Regeneron and Sanofi will prepare a supplemental biologics license application for asthma. (See BioWorld Today, March 29, 2017.)

Based on the strength of Pathway's data, Leerink Partners LLC analyst Seamus Fernandez wrote that his team believes the trial may qualify as a registrational study, with the need for a confirmatory phase III trial for approval, similar to the approach that Sanofi and Regeneron are taking with Dupixent.

"However, this may be dependent on whether the FDA will want to see additional dose-ranging studies to address questions regarding safety and the lack of a clear efficacy dose response," he wrote.