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differences in target expression and pathway activation in different diseases, and facilitate
bridging between clinical trials in different indications. In this section, we present a case
where a 'universal' PD marker to measure anti-type I IFN PD effect in multiple autoimmune
diseases was developed select doses in two different but related disease indications.
Type I IFNs are a family of cytokines including 14 IFN-α subtypes, IFN-β, -ω, and -κ, and
there is strong evidence in the literature that suggests a potential role for type I IFNs in the
disease pathogenesis of multiple autoimmune diseases, such as systemic sclerosis (SSc), sys-
temic lupus erythematous (SLE), primary Sjögren's syndrome, and myositis
[41-49]
. Elevated
levels of IFN-α have been detected in the serum of some SLE patients
[50,51]
and numerous
microarray studies have strengthened the hypothesis of type I IFN involvement in the disease
pathogenesis of SLE
[42,44,52]
. Type I IFN-inducible genes can be conveniently measured by
techniques such as TaqMan quantitative polymerase chain reaction or microarray with bet-
ter sensitivity and specificity than traditional protein bioassays
[53-56]
. Several well defined
type I IFN gene signatures have been used to correlate the type I IFN activity with SLE or SSc
disease pathogenesis
[49,52,57,58]
and disease activity
[44,59,60]
, as well as assessing the PD
effect of an anti-IFN-α therapy in SLE and myositis
[52,61,62]
.
One large study that enrolled patients who suffered from SLE, dermatomyositis (DM),
polymyositis (PM), SSc, or rheumatoid arthritis (RA) showed that a consensus type I IFN sig-
nature could be identified in the whole blood (WB) of these patients [
49
;
Fig. 1.6
]. Among
these, a five-gene type I IFN-inducible gene panel was developed to identify subpopula-
tions with concordant activation of the type I IFN pathway between the peripheral blood and
disease-affected tissues in SLE, DM, PM and SSc [
49
;
Fig. 1.7
]. This development allowed the
potential utility for the same type I IFN gene panel as a PD marker for anti-type I IFN recep-
tor (IFNAR) therapy in both SLE and SSc.
Although multiple clinical trials evaluating anti-IFN-α monoclonal antibody in SLE have
been conducted and larger confirming trials are underway, it remains to be seen whether
targeting IFNAR, which suppresses all type I IFN subtypes, might show a favorable benefit
risk ratio in SLE. It also remains to be seen whether neutralizing the type I IFN signature,
a surrogate of suppressing the type I IFN pathway, shows positive correlation with clini-
cal benefit in SLE. MEDI-546, a fully human IgG1κ mAb, is one such drug that targets the
subunit 1 of the IFNAR1. It was evaluated in a FTIH study in subjects with SSc (MI-CP180)
where a complete neutralization of the type I IFN signature was observed (
Fig. 1.8
). The
pharmacokinetic (PK) profile and type I IFN signature were analyzed using a mechanistic
model incorporating the binding of MEDI-546 to IFNAR1, internalization kinetics of MEDI-
546
/
IFNAR1 complex as determined from confocal imaging studies, and the inhibition of
type I IFN signature by MEDI-546
[63]
.
To support the transition of MEDI-546 from a FTIH study in SSc patients to a large proof
of concept (PoC) study in SLE, we used translational simulations to bridge across the two
patient populations in lieu of an additional Phase I trial in SLE. Briefly, stochastic simula-
tions suggested that a 300mg monthly fixed dose could sustain suppression of the type I
IFN signature in a typical SLE subject; a higher dose (1000 mg) was also recommended for
the PoC trial to ensure adequate drug exposure and target neutralization in skin, especially
for SLE patients with substantially elevated type I IFN signature at baseline (
Fig. 1.9
). In
addition, the 1000 mg dose would ensure against potential divergence of the SLE simulation
assumptions (e.g., the potency and activity of MEDI-546 in SLE could be different from that
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