Personalized Healthcare in Autoimmune Diseases - Genomic Biomarkers for Pharmaceutical Development - page 50

provide the right dose and right medications to patients with different molecular pheno-
types of diseases.
3.2 INTERFERON GAMMA (IFN- γ ) AS A PHARMACODYNAMIC (PD)
MARK ER FOR USTEKINUMAB (CNTO 1275) IN PSOR IASIS
Skin-infiltrating lymphocytes expressing T helper type 1 cytokines, such as interferon
gamma (IFN-γ), have been linked to the pathophysiology of psoriasis. Cytokines that elicit
these immune responses include interleukin12 (IL12) and interleukin23 (IL23) produced by
antigen presenting cells, both of which may represent potential therapeutic targets [1] . IL12,
which has a substantial role in Th1 cell development from naïve T cells and IL23, known
to activate Th17 cells, share a p40 subunit, which is activated in lesional skin of psoriatic
plaques [2,3] . Both IL12 and IL23 were thought to be potentially involved in the pathogenesis
of the disease in preclinical studies [4,5] .
Briakinumab (ABT-874, Abbott) is a human IgG1 monoclonal antibody directed against
the p40 subunit of IL12 / IL23. Treatment with this molecule demonstrated improvement in
Psoriasis Area and Severity Index (PASI-75) scores for all five treatment arms at week 12 in a
Phase II dose-finding study [6] . Four Phase III studies evaluating briakinumab have shown
superior response rates compared to patients treated with placebo, etanercept, or methotrex-
ate, although one study showed an increase in major adverse cardiac events and malignan-
cies in briakinumab-treated patients [7-11] . To date, briakinumab has not been approved by
the Food and Drug Administration (FDA) for treatment of patients with psoriasis.
Ustekinumab (CNTO 1275, Centocor) is another human monoclonal antibody (IgG1κ)
directed against the IL12 / IL23 p40 subunit. In two Phase III trials (PHOENIX I and II) for
moderate to severe psoriasis, at >76 weeks, ustekinumab was found to be both safe and
effective [12,13] . A third Phase III trial (ACCEPT), compared the efficacy and safety of usteki-
numab with etanercept in the treatment of moderate to severe plaque psoriasis [14] . This trial
showed a significantly higher clinical response with ustekinumab over the 12-week study
period compared to high-dose of etanercept [14] . Results also demonstrated the clinical
benefit of ustekinumab among patients who failed to respond to etanercept [14] . Currently,
ustekinumab is approved in Canada, Europe, and the United States for the treatment of mod-
erate to severe plaque psoriasis.
In the case of development of ustekinumab, the investigators developed an effective PD
marker to aid in the confirmation of mechanism of action (MoA). For example, in a Phase
I study evaluating short-term safety, pharmacokinetics, pharmacodynamics, and clinical
response of single subcutaneous (SC) administration of IL12 / 23 mAb in patients with mod-
erate to severe plaque psoriasis, 20 patients were enrolled into dose cohorts of 0.27, 0.675,
1.35, and 2.7 mg / kg, or placebo and mRNA expression of type-1 cytokines or chemokines was
measured from lesional skin biopsies both 24 hours before and 1 week following administra-
tion of IL12 / 23 mAb [15] .
The transcripts included: TNF-α, IFN-γ, IL8, IL18, IL12 / 23 p40 subunit, IL23, p19 subu-
nit, IL12 p35 subunit, IL10, interferon-inducible protein 10 (IP-10), regulated upon activa-
tion, normal T-cell expressed and secreted (RANTES), and CC chemokine ligand 2 (CCL2)
[15] . It was observed that none of the mRNAs was significantly altered from baseline 1 week