Personalized Healthcare in Autoimmune Diseases - Genomic Biomarkers for Pharmaceutical Development - page 51

following treatment with either the IL12 / 23 mAb or placebo. However, when patients receiv-
ing IL12 / 23 mAb were stratified into groups of those who had a sustained PASI improvement
(i.e., 70% average PASI improvement at weeks 8, 12, and 16; N = 4), and those who did not
(N = 9), the sustained PASI improvers show significant decreases in mRNAs for the cytokines
IFN-γ IL8, IL18 at week 1 post treatment, although the sample size was modest [15] .
An additional non-randomized, open label, single dose, dose escalation Phase I trial
confirmed the MoA of the intravenously administered human anti-IL12 / IL23 p40 subunit
mAb and demonstrated promising therapeutic efficacy in psoriasis [16,17] . Eighteen sub-
jects with at least 3% body surface area involvement were enrolled in four dose groups
that ranged from 0.1 to 5.0mg / kg (0.1, 0.3, 1.0 and 5.0mg / kg, respectively). Researchers
used immunohistochemistry (IHC) and Real-Time Quantitative Reverse Transcription
Polymerase Chain Reaction (qRT-PCR) to evaluate the histological and molecular changes
of both cellular infiltrates and the same relevant type-1 cytokines and chemokines thought
to play a role in the pathogenesis of psoriasis that were evaluated in the SC study, follow-
ing a single administration of an anti-p40 mAb in psoriatic patients. At baseline, skin biop-
sies showed high infiltration of CD3+ T cells and CD11c+ dendritic cells into the lesion.
At two weeks after administration of anti-IL12p40mAb, the high responding patients
(N = 9) showed a significant decrease from baseline (p = 0.025) in total CD3+ cells, unlike
the low responding patients, indicating early signs of improvement at the cellular level in
the high responders [16] . For mRNAs assayed in these patients, 17 / 18 patients treated with
anti-IL12p40 mAb showed a significant reduction in IFN-γ at two weeks compared to base-
line (p = 0.00001) [16] . Additional mRNAs that were significantly reduced at two weeks
following administration of anti-IL12p40mAb compared to baseline include IL8 (17 / 18
patients), IL10 (17 / 18 patients), IL12p40, IL23p19 (17 / 18 patients), TNF-α, IP-10, and MCP-
1. When patients were stratified into high and low responders, the only major difference in
mRNA patterns between baseline and two weeks post anti-IL12p40 mAb was with TNF-α,
which failed to show a significant decrease in the low responder group [16] . The reduction
of expression levels of these signaling molecules preceded clinical response and histo-
logical improvement [16] . IFN-γ is downstream of IL12 and the substantial decrease in its
mRNA expression level two weeks following the administration of anti-IL12p40 mAb indi-
cates that it could be used as a PD marker to evaluate inhibition of this molecule on IL12 / IL
23-driven cellular activation, and could potentially be used for PK / PD modeling to deter-
mine the optimal dosing schedule to be used in the pivotal trial.
The baseline TNF-α mRNA expression showed a unique correlation to IFN-γ and RANTES
and had a significantly higher expression level in high responders compared to low respond-
ers [16] . Additionally, a positive correlation was observed between baseline TNF-α mRNA
level and clinical improvement at week 16 post drug treatment, as measured by the per-
cent improvement of PASI [16] . This observation suggests the potential utility of baseline
TNF-α mRNA level as a predictive marker to identify which plaque psoriatic patients might
respond to anti-IL12p40 mAb therapy.
Taken together, the correlative studies in a Phase I trial confirmed that the anti-IL
12p40mAb successfully inhibited the desired target, and provided positive, although early
demonstration of therapeutic efficacy of the drug. This paved the way for the subsequent suc-
cess of Phase II [18] and Phase III [7] clinical trials that followed that confirmed the therapeu-
tic efficacy of the human anti-p40 subunit mAb in larger plaque psoriatic patient population.