FIGURE 1
Proportion of patients achieving PASI 75 at weeks 12* and 16
■ Week 16 ■ Week 12
Placebo
Tildrakizumab 200mg
Tildrakizumab 100mg
Tildrakizumab 25mg
Tildrakizumab 5mg
0 10 20 30 40 50 60 70 80
% responders
*NICE guidance for biologic agents recommends that if patients have not achieved a PASI 75 by week 12 then they are defined as a non-responder
convert into the major effector T cells, T 17 helper
cells (Th 17), which themselves secrete further
inflammatory cytokines (for example, IL-17A and
IL-17F). The activity of the Th 17 cells can be either
protective, in particular, against candida infections
of the skin, nails, oral and genital mucosae, or
promote inflammatory changes as in psoriasis and
various autoimmune disorders. In psoriasis, IL-17
cytokines stimulate activation and proliferation of
keratinocytes.
IL-23 is composed of two subunits; IL-12/23p40
and IL-23p19. The former subunit is shared
with IL-12 and is the target for the biologic antipsoriatic
drug ustekinumab. However, it has
been demonstrated that intra-dermal injection of
IL-23 but not IL-12, can provoke clinical signs of
psoriasis, suggesting that it is the action of IL-23 on
the IL-23p19 subunit that is more relevant in the
pathogenesis of psoriasis. Moreover, an unfortunate
consequence of IL-12/23p40 blockage is a reduction
in the production of Th 1 cells (initiated by IL-12)
which lowers the hosts’ immune response to various
pathogens. Indeed, ustekinumab has the potential to
increase the risk of infections and should be avoided
in those with active infections. Consequently,
specifically targeting the p19 subunit of IL-23, as
with tildrakizumab, is theoretically a more effective
treatment option, sparing the hosts’ immune
system.
Clinical efficacy
Tildrakizumab is a high-affinity, humanised
monoclonal antibody that was approved by the
US Food and Drug Administration in March
2018. In July 2018, the Committee for Medicinal
Products for Human Use adopted a positive opinion
recommending marketing authorisation for
tildrakizumab in Europe.
The first Phase IIb randomised, double-blind,
placebo-controlled trial to evaluate the safety and
efficacy of tildrakizumab was published in 2015. 2
The study enrolled patients over the age of 18
with plaque psoriasis for ≥6 months and who were
The first Phase
IIb, randomised,
double-blind,
placebocontrolled
trial
to evaluate the
safety and efficacy
of tildrakizumab
was published
in 2015
candidates for phototherapy or systemic therapy
with a psoriasis area and severity index score
(PASI) ≥12; psoriasis body surface area involvement
≥10% and a Physicians’ Global Assessment (PGA) of
moderate, marked or severe at baseline. The PGA is
a 6-point scale that assesses erythema, induration
(thickness) and scale over the entire body. The 6
points on the scale are: 0 = none; 1 = minimal; 2 =
mild; 3 = moderate; 4 = severe; and 5 = very severe.
Thus patients had a score of at least 3 upon entry
into the trial. The study continued for 52 weeks
and was divided into two parts: part 1 represented
the first 16 weeks and part 2, weeks 16 to 52. In
addition, participants could also enter a 20-week,
non-treatment follow-up period after week 52. All
patients received active treatment in part 2 and
non-responders at week 16 taking the lower doses
of the drug or placebo, received an increase in dose
to 100mg tildrakizumab and 100mg non-responders
were increased to the 200mg dose. Treatment was
given every 12 weeks.
In total, 355 patients were randomised to
receive one of five treatments in a 1:2:2:2:1 ratio
(tildrakizumab 5, 25, 100, 200mg or placebo
respectively) via subcutaneous injection at weeks
0 and 4.
The primary clinical endpoint was the
proportion of patients who achieved a ≥ PASI 75
at week 16. Secondary outcomes included the
proportion of those with a PGA of ‘cleared’ or
‘minimal’ (that is, scores of 0 or 1) at week 16 and
a PASI 90 at week 16.
In total, 339 patients completed parts 1 and 2 and
289 entered part III. The PASI 75 scores for each of
the doses at week 12 and 16 are shown in Figure 1.
In part 3 of the study, 96 % and 93% of patients
who were receiving 100 and 200mg of tildrakizumab
maintained a PASI 75 at week 72 (end of the nondrug
extension period).
Phase III studies
Two Phase III randomised, double-blind trials have
been undertaken with tildrakizumab – reSURFACE 1
30 | Issue 91 | 2019 | hospitalpharmacyeurope.com