Does an inhaled PDE4 blocker dampen allergic asthma attacks?
A week of an inhaled PDE4 inhibitor substantially reduced the drop in lung function that people with allergic asthma had after breathing in an allergen, while barely reaching the bloodstream.
Source
The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma
Study at a glance
- Design
- RCT — Double-blind, placebo-controlled crossover: 7 days of once-daily inhaled GSK256066 or placebo, 14-21 day washout, allergen challenge on day 7.
- N
- N=24 · 24 steroid-naive asthma patients randomised; 19 completed both treatment periods.
- Population
- Adults with mild, steroid-naive allergic asthma who showed both early and late responses to inhaled allergen at screening.
- Outcome
- Fall in FEV1 during the early (0-2 h) and late (4-10 h) asthmatic responses after allergen challenge; secondary: methacholine reactivity, exhaled nitric oxide, pharmacokinetics.
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What they did
Twenty-four adults with mild asthma not on inhaled steroids took either GSK256066 or a matching placebo inhaler once a day for 7 days, then switched to the other treatment after a washout. On the last day of each period they inhaled a dose of the allergen they were sensitive to, and researchers tracked how far their FEV1 (a measure of how much air they could blow out in one second) fell over the next 10 hours. They also measured airway reactivity to methacholine the next day, exhaled nitric oxide, and drug levels in the blood.
What they found
Compared with placebo, the drug reduced the early response (the minimum FEV1 fall) by 40.9% and the late response by 26.2%. It did not change methacholine reactivity after the challenge, exhaled nitric oxide, or baseline lung function. Blood levels of the drug were extremely low and mostly undetectable after 4 hours, and there were none of the nausea or stomach side effects typical of oral PDE4 inhibitors.
The limits
What it doesn't show
This was a small, short study (19 completers, one week of dosing) in mild steroid-naive asthma, so it cannot show whether the drug reduces real-world symptoms or exacerbations, or whether it adds benefit on top of inhaled corticosteroids. Allergen challenge is a laboratory model, and the authors did not measure airway inflammatory cells, so the proposed anti-inflammatory mechanism is inferred rather than shown. The secondary endpoints were not powered, so the null results for methacholine and nitric oxide are inconclusive, and several authors were employees of the drug's manufacturer.
Key terms
- Phosphodiesterase 4 (PDE4)
- An enzyme in inflammatory cells that breaks down cAMP; blocking it keeps cAMP high, which relaxes smooth muscle and damps immune cell activation.
- Early asthmatic response (EAR)
- The fall in lung function within minutes to about two hours of inhaling allergen, driven mainly by mast cell mediators causing bronchoconstriction.
- Late asthmatic response (LAR)
- A second fall in lung function several hours after allergen exposure, reflecting an influx of inflammatory cells such as eosinophils into the airways.
- FEV1
- Forced expiratory volume in one second: the amount of air a person can blow out in the first second of a forced breath, a standard measure of airway narrowing.
- Crossover design
- A trial in which each participant receives both the active drug and placebo in random order, so each person serves as their own control.
- Therapeutic index
- The margin between the dose that gives benefit and the dose that causes unacceptable side effects.
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Quiz yourself
What type of trial design was used to test GSK256066?
Common questions
Why deliver a PDE4 inhibitor by inhalation instead of as a pill?
Oral PDE4 inhibitors cause nausea and gut side effects because they reach the whole body. Inhaling the drug puts it straight into the lungs and, as the blood tests here showed, keeps levels in the rest of the body very low.
Why use an allergen challenge rather than just follow patients for months?
An allergen challenge produces a predictable, measurable asthma response in a controlled setting, so a small number of patients can show whether a new drug has biological activity before larger, longer trials are run.
Does this mean the drug works better than inhaled steroids?
No. The study did not compare against steroids. The authors note that steroids usually do little to the early response, whereas this drug reduced it, but only a head-to-head trial could establish which is better.
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