During the last decades, inside and deep knowledge of the pathogenesis of psoriasis, has led to new therapeutic agents for
the treatment of the disease, resulting in a revolutionary and holistic therapeutic approach. For many years the anti-TNF
agents as well as the agents that target the IL12/23 pathway, have changed the armamentarium of drugs in the treatment
of psoriatic disease with excellent results. In the present article we will present all available data about new agents that
are under development for the treatment of psoriasis, like anti-IL17 and anti-IL23 biologics, as well as the small molecules,
like JAK inhibitors and inhibitors of phosphodiesterase-4 (PDE4).
During the last decades, new targeted therapeutic agents
for the treatment of psoriasis are available, the biologic
agents. Three anti-TNF-a agents are available (adalimumab,
etanercept, infliximab) and one antiIL-12/23 drug
(ustekinumab). All these drugs have long-term high efficacy
for the treatment of psoriasis, increased safety profile and
low toxicity. The advantage of biologics is the concurrent very
good control, not only of psoriasis, but also of all the other
comorbidities that are related with psoriasis, like psoriatic
arthritis (all four agents mentioned above are indicated also
for psoriatic arthritis). Another important advantage is the
luck of organ toxicity with biologics, compared with the wellknown
toxicity of either cyclosporine or methotrexate after
long-term use. There are many reports in the literature about
the protective role of anti-TNF agents against cardiovascular
events and especially myocardial infarction.New drugs are under development or have recently been
approved for the treatment of psoriasis, like IL-17, IL-23,
phosphodiesterase-4 (PDE4) and JAK inhibitors.It is a fully human antibody against IL-17A. Secukinumab
has recently been approved and is indicated for the treatment
of moderate to severe plaque psoriasis in adult patients who
are candidates for systemic treatment.
The approved dosageis 300 mgr subcutaneously in weeks 0-4 and once monthly
thereafter. ERASURE και FIXTURE are the two studies on
which the approval has been based on.
In the ERASURE study, double-blind phase, two different
doses of Secukinumab where compared (150 and 300 mgr,
once weekly for 5 doses and once monthly thereafter), with
placebo. At week 12, the percentage of patients who achieved
PASI (Psoriasis Area Severity Index) 75 was 81. 6% (with 300
mgr Secukinumab), 71. 6% (with 150 mgr Secukinumab) και
4.5% (with placebo).
Moreover, PASI 90 was achieved in 59.2% and 39.1% of
patients under 300 and 150 mgr Secukinumab, respectively,
compared with 1.2% of patients under placebo. With regards
to IGA (Investigator’s Global Assessment) 0/1 index (almost
or total clearance of psoriasis) at week 12, the percentages
were 65.3%, 51.2% και 2.4% for 300, 150 mgr Secukinumab
and placebo, respectively.
In the FIXTURE study, Secukinumab (150 and 300 mgr,
once weekly for 5 doses and once monthly thereafter) was
compared with Etanercept (50 mgr twice weekly for 12 weeks
and 50 mgr once weekly thereafter), with placebo.
With regards to PASI 75 at week 12, the percentage of patients
who achieved PASI 75 was 77.1% (300 mgr Secukinumab),
67% (150 mgr Secukinumab), 44% (etanercept) and 4.9%
(placebo). In 4.7% and 2.3% of patients under Secukinumab(300 and 150 mgr respectively), mild Candida infections were
reported and the percentage for Etanercept patients was
1.2%. 3rd grade neutropenia was reported in 1% of patients
under Secukinumab, with 0 cases in the etanercept group.
IL-17A is implicated in the innate immunity against Candida
albicans and in some haemopoiesis pathways.3 Up to now
there is no safety concern about these two parameters and
Secukinumab. All Candida infections were mild and only
topical or in a few cases systematic antifungal treatment was
needed, without being necessary to discontinue Secukinumab
in any case. Neutropenia was also not important in all cases
as well.
It is a humanized IgG4 monoclonal antibody against IL-17A. A
phase 2, double-blind, compared with placebo study, reports
at week 12 achievement of PASI 75 in 82.1% of patients under
Ixekizumab 150 mgr, 82.8% under 75 mgr, 76.7% under 25
mgr against 7.7% under placebo (the administration of drug
was performed at weeks 0, 2, 4, 8, 12 and 16, subcutaneously).
Ixekizumab was compared with Etanercept (in studies phase
ΙΙΙ UNCOVER 2, 3). At week 12 (UNCOVER 2), patients
under Ixekizumab achieved PASI 75 in a percentage of 90%
(administration every 2 weeks), 78% (administered every 4
weeks), compared with 42% under etanercept and 2% under
placebo. In UNCOVER 3 these percentages were 87%, 84%,
53% and 7%, respectively.It is a fully human antibody against the receptor of IL-17 (IL-
17A και IL-17F). Brodalumab was compared with placebo
in a phase III study (AMAGINE-1) and the results of efficacy
with regards to PASI 75 at week 12 were 83.3%, 60.3% and
2.7% for doses of Brodalumab 210mgr and 140 mgr every
two weeks subcutaneously and placebo, respectively. In
studies AMAGINE 2 and 3, Brodalumab was compared to
Ustekinumab and to placebo. At week 12 the percentage
of patients who achieved a PASI 75 improvement was 86%
and 67% for Brodalumab dose of 210 mgr and 140 mgr
respectively, in comparison with 70% for Ustekinumab and
8% for placebo (AMAGINE 2). In AMAGINE 3 study, the
results were 85.1%, 69.2%, 69.3% and 6%, respectively.
In May 2015, all studies of Brodalumab for psoriasis were
paused, worldwide, because of some cases of suicidal
ideation and changIt is a humanized IgG1 monoclonal antibody that blocks the
p19 subunit of IL-23. The drug was compared with placebo in
a phase 2b study with primary endpoint PASI 75 at week 16. Patients were randomized in 5 groups with doses of 200,
100, 25, 5 mgr Tildrakizumab or placebo.
The results for PASI
75 were 74%, 66%, 64% and 33% for Tildrakizumab and 4.9%
for placebo, respectively. The most common adverse event
was rhinofaringitis. At the time that this paper is written,
phase ΙΙΙ clinical trials are under development.
2.2 Guselkumab
It is a human monoclonal IgG1 antibody against the p19
subunit of IL-23. In a double-blind phase I study, the drug was
compared to placebo. One dose of 10 mgr was administered
to 5 patients, one dose of 30 mgr to 5 patients, one dose of
100 mgr to 5 more and 300 mgr to 5 patients also. Placebo
was administered to 4 patients. At week 12, the percentage
of patients that achieved PASI 75 was 50%, 60%, 60%, 100%,
respectively, for the four doses of guselkumab and 0% for
placebo.
The drug was also compared with adalimumab in a phase II
study with a 52-week duration. 293 patients were randomized
to receive either Guselkumab 5 mgr at weeks 0, 4 and every
12 weeks thereafter, 15 mgr every 8 weeks, 50 mgr at weeks
0, 4 and every 12 weeks thereafter, 100 mgr every 8 weeks
or 200 mgr at weeks 0, 4 and every 12 weeks thereafter, until
week 40, or placebo, or adalimumab (with the administration
program that is indicated for psoriasis). At week 16, the
placebo group patients were initiated guselkumab 100 mgr
every 8 weeks. The primary endpoint was the evaluation of
PGA 0 or 1 at week 16. The results regarding this index were
34% for 5-mg guselkumab group, 61% for 15-mg group, 79%
for 50-mg group, 86% for 100-mg group and 83% for 200-
mg group, compared with 7% for the placebo group. The
percentage for adalimumab was 58%.
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