Is an antibody against IL-9 safe to give people with asthma?
Repeated injections of an experimental anti-IL-9 antibody were tolerated about as well as placebo in people with mild asthma, with early hints that it might blunt exercise-triggered airway narrowing.
Source
Safety profile and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti-interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma
Study at a glance
- Design
- RCT — Two randomized, double-blind, placebo-controlled phase 2a trials: study 1 escalated weight-based doses (3:1 drug:placebo); study 2 tested a fixed 50 mg dose (2:1) with exercise challenge and was halted early.
- N
- No single N: 36 adults randomized in study 1 (all included in safety analyses) and 11 in study 2 (9 evaluable for the exercise-challenge outcome).
- Population
- Adults with mild persistent asthma (study 1) or stable mild-to-moderate asthma with exercise-induced bronchoconstriction (study 2), recruited at US multicentre sites
- Outcome
- Primary: safety and tolerability (adverse events) of repeated subcutaneous MEDI-528; secondary/exploratory: pharmacokinetics, anti-drug antibodies, exercise-induced fall in FEV1, exacerbations, symptoms and quality of life
Structured fields used in claim comparison tables when every cited study has a complete layer.
What they did
Researchers ran two placebo-controlled, double-blind trials of MEDI-528, a humanized antibody that blocks the immune signal interleukin-9. In study 1, 36 adults with mild asthma were randomized 3:1 to the drug or placebo at doses of 0.3, 1 or 3 mg/kg, injected under the skin twice weekly for 4 weeks, then followed to day 150. In study 2, 11 adults with exercise-induced bronchoconstriction received 50 mg or placebo (2:1) and did treadmill exercise challenges before and after dosing; this trial was planned with three dose cohorts but stopped after the first.
What they found
Adverse events, including severe ones, occurred at similar rates on drug and placebo, and no participant developed antibodies against MEDI-528. Blood levels rose roughly in proportion to dose and the drug's half-life was about 35-38 days. Resting lung function, rescue-inhaler use and quality of life did not differ, and the lower exacerbation count on drug (1 of 27 vs 2 of 9) was not statistically significant. In study 2, the average maximum post-exercise drop in FEV1 at day 56 was -0.04 L on drug versus -0.60 L on placebo, and in a post hoc analysis 7 of 7 drug-treated participants met the responder definition at day 56.
The limits
What it doesn't show
With only 36 and 11 participants and no formal hypothesis testing for most outcomes, these trials were built to look for safety problems, not to prove the drug works; the exercise-challenge benefit comes from a handful of people at one time point, and the responder analysis was done after the fact. Study 2 was stopped early after a brain MRI abnormality that later proved to be an artifact, so its planned higher doses were never tested. Participants had mild disease, so the results say little about the severe, poorly controlled asthma the drug would ultimately target, and the studies were sponsored and largely analysed by the manufacturer.
Key terms
- Phase 2a trial
- An early trial in patients, usually small, that mainly checks safety and dosing and looks for first signs that a drug has any effect.
- Interleukin-9 (IL-9)
- A signalling protein made by immune cells that is thought to recruit and activate mast cells in the airways, which can drive asthma inflammation.
- Exercise-induced bronchoconstriction (EIB)
- Narrowing of the airways triggered by exercise, measured as a fall in FEV1 after a treadmill test; it depends on mast cells releasing mediators.
- FEV1
- Forced expiratory volume in one second: how much air a person can blow out in the first second of a forced breath, a standard measure of airway narrowing.
- Immunogenicity
- Whether the body mounts an antibody response against a therapeutic protein, which could neutralize it or cause reactions.
- Post hoc analysis
- An analysis decided on after seeing the data rather than planned in advance, which makes chance findings more likely to look meaningful.
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Quiz yourself
What kind of trial design did both MEDI-528 studies use?
Common questions
If the drug reduced the exercise-induced drop so much, why don't the authors say it works?
Because study 2 had only 11 participants, only one time point reached significance, the responder analysis was post hoc, and the trial was stopped early. Those features make the result a hypothesis to test in larger trials, not proof of efficacy.
Why were brain MRIs done at all in an asthma trial?
Toxicology studies in monkeys had shown cell infiltrates around brain blood vessels in both treated and control animals, so MRI was added as a precaution. Later animal work found nothing, and the one abnormal scan in study 2 was judged to be an imaging artifact.
Why might blocking IL-9 take weeks to show any effect?
IL-9 is thought to act by recruiting and maturing mast cells in the lung, so blocking it would work by gradually depleting those cells rather than by an immediate effect; the largest change was seen at day 56, consistent with that slow onset.
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