Asthma

New mAb halves exacerbation rates and cuts steroid reliance in severe asthma


Dupilumab, a monoclonal antibody against the interleukin-4 receptor, has been shown to reduce exacerbations and improve lung function in moderate-severe uncontrolled asthma and also reduce reliance on steroids.

The phase 3 trials, presented at ATS 2018 and published in the New England Journal of Medicine, found the benefits were seen regardless of baseline blood eosinophil count, though more pronounced in patients with eosinophils ≥ 300 cells/mm3.

The LIBERATE ASTHMA QUEST study of 1,902 patients over 12 years of age with moderate-severe uncontrolled asthma added either 200mg or 300mg of subcutaneous dupilumab or volume-matched placebo fortnightly to their current medications over 52 weeks.

It found adjusted annualised exacerbation rates of 0.46 with 200mg dupilumab and 0.52 with 300 mg dupilumab compared to rates of 0.87 and 0.97 respectively with placebo.

Sub-group analyses showed the highest benefit in patients with eosinophils ≥ 300 cells/mm3 and in patients with higher baseline FeNO.

 The study also found improvements in FEV1 and Asthma Control Questionnaire (ACQ-5) scores were evident as early as two weeks into treatment and maintained for the study period.

In the LIBERATE ASTHMA VENTURE study, a smaller group of 210 patients with oral glucocorticoid–treated asthma were given 300mg dupilumab or placebo fortnightly for 24 weeks and their steroid dose tapered off.

It found an impressive 70.1% reduction in glucocorticoid dose in the treated group compared to 41.9% in the control group.

Chief investigator Professor Klaus Rabe, from the LungenClinic Grosshansdorf in Germany, told the limbic steroid withdrawal trials were notoriously difficult to do because the starting doses were not always based on clinical logic.

“And that would mean that once you put people in the trial you can reduce steroids in most of them. But the difference was people in the dupilumab arm could reduce steroids quite significantly, that is 70% of the dose was gone and more people could be reduced under 5mg.”

“And despite the dose reduction, these people still had much fewer exacerbations than the placebo arm and their lung function went up quite significantly so it works in this population.”

“The data would suggest that the patients who have severe asthma, need steroids and have exacerbations would in principle benefit from this,” said Professor Rabe.

“It shows that people who have more eosinophils would fare a little better but this study shows people with low eosinophils also have a benefit from this drug. If you had high phenol levels you would also benefit more. It is a very good modifier for bad outcomes in severe asthma.”

He said about 1 in 7 patients develop a transitory eosinophilia which was reported as an adverse event but was more likely to be related to the mechanism of the drug and the trafficking of cells around the body.

More MABs to choose from

Professor Rabe said the antibody was already registered for atopic dermatitis in the US where a license for asthma was expected this year, with Europe following next year.

“It will very likely be a clinical reality. And from both studies and from the experience in skin, this drug appears to be very safe.

“Doctors now have a choice. We need to ensure that we as taxpayers can afford this. Everybody who needs it should have it but nobody should get it who doesn’t benefit.”

An editorial in the NEJM called on clinical researchers to mount head to head trials between mepolizumab, reslizumab, benralizumab and dupilumab.

“Without more data, these decisions are likely to be driven by the marketing arms of the various entities that produce these drugs,” the editorial said.

“Drug companies may be reluctant to risk their franchise on such trials, but with costs for a year of treatment substantially more than a year’s labor at minimum wage in the United States, we deserve to know whether there are clinically important differences among these treatments.”

Both trials were supported by Sanofi and Regeneron Pharmaceuticals.

 

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