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This issue is further complicated by the imprecision of using severe exacerbations as an out-
come measure. While a severe exacerbation is an objectively definable event, exacerbations are
rare in individual patients ('frequent exacerbators' may have 2 per year; many patients in each
arm of the DREAM trial had no exacerbations during the study). Thus to provide adequate
statistical power to determine an optimal biomarker cutoff to predict benefit in terms of asthma
exacerbations, a study may become prohibitively large, depending on what is meant by an
'optimal' cutoff, as any cutoff will necessarily reflect a compromise between the magnitude of
treatment benefit and the size of the treatment-eligible population. Finally, given the temporal
intrapatient variability of each of these biomarkers, a given patient is likely to oscillate between
'diagnostic-positive' and 'diagnostic-negative' states over time. These issues are not unique to
IL5 blocking agents, as we shall describe in the next section.
4.3.2 Agents Targeting IL13
Four biologic agents targeting IL13 (±IL4) have been investigated in Phase II proof-of-con-
cept clinical studies in moderate-severe asthmatics whose asthma is inadequately controlled
despite ICS treatment: pitrakinra [69] , AMG 317 [70] , tralokinumab [71] , and lebrikizumab
[72] . Pitrakinra is an inhaled IL4 mutein that binds to, but does not signal through, IL4Rα,
the shared receptor component for IL4 and IL13 signaling, thereby blocking access of IL4
and IL13 to the IL4Rα/γc and IL4Rα/IL13Rα1 receptor complexes. AMG 317 is a human-
ized monoclonal antibody that binds to IL4Rα, thereby blocking IL4 and IL13 signaling.
Tralokinumab and lebrikizumab are humanized monoclonal antibodies that bind to and
block signaling downstream of IL13. Pitrakinra was administered twice daily by inhalation
while AMG 317 (weekly), tralokinumab (q2 weeks), and lebrikizumab (q4 weeks) were all
administered by subcutaneous injection. The pitrakinra, AMG 317, and tralokinumab studies
were dose ranging, with approximately equal distributions of patients across each dose and
placebo arm while the lebrikizumab study tested a single dose level with a 1:1 distribution
vs. placebo.
While each study differed in specific design features, all four studies assessed lung func-
tion via FEV1, symptom control via ACQ, and exacerbation rates over at least 12 weeks of
treatment. Pitrakinra, AMG 317, and tralokinumab failed to show significant clinical ben-
efit relative to placebo in terms of their primary endpoints (exacerbation rate for pitrakinra
and ACQ for AMG 317 and tralokinumab) in all comers [69-71] , while lebrikizumab dem-
onstrated a statistically significant, albeit modest benefit in terms of its primary endpoint
(FEV1) in all comers [72] . Evaluating each agent across common outcome measures, none
of the four demonstrated significant benefits in terms of ACQ, which may reflect regression
to the mean, as all four studies pre-specified poor asthma control (ACQ ≥ 1.5) at study entry
and patients in the placebo arms exhibited substantial ACQ improvement in each study. In a
post hoc analysis of the AMG 317 study, patients in the highest tertile of baseline ACQ scores
in the highest dose arm trended toward FEV1 improvement [70] . FEV1 was a secondary end-
point in the tralokinumab study, and while there was a greater mean magnitude of FEV1
improvement at 13 weeks in the combined tralokinumab-treated arms vs. placebo, this effect
failed to reach statistical significance (p = 0.072) although the effect was nominally significant
(p = 0.041) in the highest dose arm. In a substudy of patients that provided induced sputum
samples at baseline, there was greater FEV1 improvement in tralokinumab-treated patients
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