Personalized Healthcare in Autoimmune Diseases - Genomic Biomarkers for Pharmaceutical Development - page 53

2.5

Placebo
1 mg/kg
3 mg/kg
10 mg/kg
30 mg/kg 2.0

1.5

1.0

0.5

0.0

0 7 14

Time (days)

21 28

FIGURE 3.1 Effects of sifalimumab on type I IFN signature in subjects with SLE. Level of expression of 21 type
I IFN-inducible genes for each subject relative to baseline expression. For this plot, SLE subjects must have had an
overexpression of the gene signature of at least threefold, normalized to 1 at baseline. The change from baseline
mean±SE level of signature gene expression in whole blood after sifalimumab treatment is shown. Maximum neu-
tralization of the gene signature occurred within 24 hrs after treatment. Hotelling's T2 test with pairwise compari-
sons up to 14 days after dosing was used for this analysis. Courtesy of Ann Rheum Dis [32] .

in polymyositis (PM) patients as well as dermatomyosistis (DM) and juvenile DM muscle speci-
mens from patients, which suggests that there is a local source of IFN-β that might contribute
to the lack of stronger target neutralization by sifalimumab in muscle compared to blood [36] .
Type III IFN (IFN-λ) can also bypass the PD effect of sifalimumab and induce activation of IRF-9
and transcription of IFN-inducible genes [37] , although IFN-λ induces a much smaller effect on
type I IFN-inducible genes in blood. One interesting question that stemmed from these observa-
tions is whether the neutralization of the type I IFN signature in SLE and myositis ultimately
showed positive correlation with clinical response. MEDI-546, an investigational human IgG1κ
mAb directed against subunit 1 of the IFNAR, has been evaluated in an open label single- and
multiple-dose Phase Ia clinical trial in patients with systemic sclerosis (SSc) (NCT00930683) and
is currently under investigation in a Phase IIb trial in patients with SLE (NCT01438489). A five
gene, type I IFN signature was used to assess the PD of MEDI-546 in SSc patients, similar to
that conducted with sifalimumab in both SLE and myositis patients [38] . The results from the
trial (N = 34) indicated that the type I IFN signature was neutralized in a dose-dependent man-
ner in SSc patients following both single- and multiple-dose regimens of MEDI-546 [38] . In the
high-dose 20.0 mg / kg single-dose cohort and the 1.0 mg / kg and 5.0 mg / kg multiple-dose cohorts,
median-fold change scores generally remained fully neutralized through day 84 ( Fig. 3.3 ).
The potential clinical utility of the type I IFN signature as a potential predictive marker
for anti-type I IFN therapy, especially for those that target the IFNAR where complete target