Personalized Healthcare in Autoimmune Diseases - Genomic Biomarkers for Pharmaceutical Development - page 52

3.3 A TYPE I INTERFERON SIGNATURE AS A PD MARKER
AND POTENTIAL PREDICTIVE MARKER FOR ANTI-TYPE I
INTERFERON THERAPY IN SYSTEMIC LUPUS ERYTHEMATOSUS
( SLE), MYOSITIS AND SYSTEMIC SCLEROSIS (SSc )
The type I interferon (IFN) family consists of multiple members, including types α (with
14 subtypes), β, ε, κ, ω, δ, and τ. Biological functions range from viral or bacterial infection
defense to immunomodulation and anti-proliferation activity. Because type I IFNs, specifi-
cally IFN-α / β, have such a range of functional influence on immune-mediated activity, they
have been investigated for decades for their roles in indications such as inflammation, auto-
immunity, and cancer [19-22] .
The type I IFN receptor (IFNAR), a heterodimer of IFNAR-1 and IFNAR-2, is activated by the
binding of type I IFN, resulting in the conformational changes of IFNAR and activation of the
Janus kinase (JAK) / signal transducers and activators of transcription (STAT) signaling pathway
[23-25] . This in turn initiates a cascade of alternative processes, eventually leading to transcrip-
tion activators binding the IFN response element (ISRE) and the production of IFN-inducible
genes. The activation of this type I IFN pathway has been quantified using the expression level
of these IFN-inducible genes with high sensitivity in multiple rheumatic diseases [26-30] .
Sifalimumab, an investigational human IgG1κ mAb that binds to most of the IFN-α subtype
with high affinities, has been evaluated in four separate clinical trials studying adult patients
with SLE or myositis (dermatomyositis [DM] or polymyositis [PM]) [13-17] (NCT00299819,
NCT00482989, NCT00657189, and NCT00533091). All four trials were randomized, double-
blinded, placebo-controlled and dose escalation studies, with three using intravenous dosing
and one, subcutaneous dosing of the drug. A type I IFN-inducible gene signature was devel-
oped and used to evaluate the PD of this molecule in both SLE and myositis patients. This gene
signature, consisting of 13 or 21 genes in myositis or SLE respectively, was shown to be neutral-
ized to different degrees in blood by sifalimumab in SLE and both blood and muscle tissue in
myositis patients in the aforementioned clinical trials [31-34] . The degree of neutralization of
this signature in patients of varying disease activities might be due to the type of type I IFNs
present in those patients. This hypothesis needs further confirmation from future trials. Figure
3.1 and Figure 3.2 illustrate the target neutralization of the type I IFN signature in the blood
in a Phase Ia clinical trial at dose levels of 1 (N = 6), 3 (N = 6), 10 (N = 7), and 30 (N = 8) mg /
kg (plus placebo; N = 17) in SLE and in both blood and muscle tissue in a Phase Ib clinical
trial at dose levels of 0.3 (N = 7), 1 (N = 8), 3 (N = 16), and 10 (N = 8) mg / kg (plus placebo
[N = 12]) in myositis patients, respectively.
Although this type I IFN signature has been used to evaluate the drug-target engagement
in the above mentioned clinical trials, there exists a subgroup of either SLE or myositis patients
that do not show substantial target neutralization by sifalimumab. Besides the possibility of
dose, it could be that other type I IFNs, besides IFN-α, were the major contributor to elevated
type I IFN signature observed in these patients. As noted previously, sifalimumab has specific-
ity for the majority of the IFN-α subtypes, but not IFN-β, which can signal through the same
IFNAR and activate the type I IFN pathway. The prevalence of IFN-β compared to IFN-α, and
its contribution to disease pathogenesis in myositis, is not clear. The IFN-β level in the blood
has been shown to both be unique to and correlate with an elevated IFN signature in DM
patients [35] . One group has shown that IFN-β and not IFN-α transcripts are over-expressed